Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques [2 ed.] 1119448859, 9781119448853

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Practical Synthetic Organic Chemistry

Practical Synthetic Organic Chemistry Reactions, Principles, and Techniques

Edited by Stéphane Caron Pfizer Worldwide R&D Groton, CT, USA

Second Edition

This edition first published 2020 © 2020 John Wiley & sons Inc. Edition History John Wiley & Sons Inc. (1e, 2011) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Stéphane Caron to be identified as the author of the editorial material in this work has been asserted in accordance with law. Registered Office John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA Editorial Office 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data Names: Caron, Stéphane, editor. Title: Practical synthetic organic chemistry : reactions, principles, and techniques / edited by Stéphane Caron. Description: Second edition. | Hoboken, NJ : Wiley, [2020] | Includes bibliographical references and index. Identifiers: LCCN 2019024991 (print) | LCCN 2019024992 (ebook) | ISBN 9781119448853 (paperback) | ISBN 9781119448884 (adobe pdf ) | ISBN 9781119448907 (epub) Subjects: LCSH: Organic compounds–Synthesis. Classification: LCC QD262 .P688 2020 (print) | LCC QD262 (ebook) | DDC 547/.2–dc23 LC record available at https://lccn.loc.gov/2019024991 LC ebook record available at https://lccn.loc.gov/2019024992 Cover Design: Wiley Cover Image: © Sebastian Kaulitzki/Shutterstock Set in 10/12pt WarnockPro by SPi Global, Chennai, India Printed in United States of America

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Dedicated to the memory of Frank R. Busch and Mark E. Webster Two outstanding scientists and friends who left us too soon and to Jean-Yves Caron an exceptional father and role model

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Contents List of Contributors xxxi Preface xxxiii

1

1

Aliphatic Nucleophilic Substitution Jade D. Nelson

1.1 1.2 1.2.1 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5 1.2.1.6 1.2.1.7 1.2.1.8 1.2.1.9 1.2.2 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.8 1.2.2.9 1.2.2.10 1.2.2.11 1.2.2.12 1.2.3 1.2.3.1 1.2.3.2 1.2.3.3 1.2.3.4 1.2.3.5 1.2.3.6 1.2.4 1.2.4.1 1.2.4.2 1.2.4.3 1.2.4.4 1.2.4.5

Introduction 1 Oxygen Nucleophiles 1 Reactions with Water 1 Hydrolysis of Alkyl Halides 1 Hydrolysis of gem-Dihalides 2 Hydrolysis of 1,1,1-Trihalides 2 Hydrolysis of Alkyl Esters of Inorganic Acids 3 Hydrolysis of Diazo Ketones 3 Hydrolysis of Acetals, Enol Ethers, and Related Compounds 3 Hydrolysis of Silyl Enol Ethers 5 Hydrolysis of Silyl Ethers 5 Hydrolysis of Epoxides 6 Reactions with Alcohols 6 Preparation of Ethers from Alkyl Halides 6 Preparation of Methyl Ethers 7 Preparation of Ethers from Alkyl Sulfonates 9 Iodoetherification 9 Preparation of Silyl Ethers 9 Cleavage of Silyl Ethers with Alcohols 10 Transetherification 10 Preparation of Epoxides 11 Reaction of Alcohols with Epoxides 12 The Reaction of Alcohols with Diazo Compounds 12 Preparation of Ethers via Dehydration of Alcohols 13 Addition of Alcohols to Boron, Phosphorous, and Titanium 13 Reactions with Carboxylates 14 Alkylation of Carboxylic Acid Salts 14 Iodolactonization 14 Preparation of Silyl Esters 15 Preparation of Mixed Organic–Inorganic Anhydrides 15 Cleavage of Ethers with Acetic Anhydride 16 Alkylation of Carboxylic Acids and Enols with Diazo Compounds Reactions with Other Oxygen Nucleophiles 17 Formation of Silyl Enol Ethers and Silyl Ketene Acetals 17 Formation of Enol Triflates 18 Formation of Oxonium Salts 19 Reactions of Carbonyl Compounds with Oxonium Salts 19 Preparation of Hydroperoxides and Peroxyethers 19

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1.2.4.6 1.3 1.3.1 1.4 1.4.1 1.4.1.1 1.4.1.2 1.4.2 1.4.3 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.5 1.5.1 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4 1.5.1.5 1.5.1.6 1.5.1.7 1.5.1.8 1.5.1.9 1.5.1.10 1.5.1.11 1.5.2 1.5.2.1 1.5.2.2 1.5.3 1.5.3.1 1.5.3.2 1.5.3.3 1.6 1.6.1 1.6.1.1 1.6.1.2 1.6.1.3 1.6.1.4 1.6.1.5 1.6.1.6 1.6.1.7 1.6.1.8 1.6.1.9 1.6.1.10 1.7 1.7.1 1.7.1.1 1.7.1.2 1.7.1.3 1.7.1.4 1.7.1.5 1.7.1.6

Alkylation of Oximes 20 Phosphorus Nucleophiles 21 Preparation of Reagents for Wittig Reactions 21 Sulfur Nucleophiles 21 Reactions with Thiols 21 Preparation of Thioethers 21 Cleavage of Arylmethyl Ethers 22 Alkylation of Sulfides 22 Reactions with Other Sulfur Nucleophiles 22 Preparation of Thiols 22 Formation of Bunte Salts 24 Alkylation of Sulfinic Acid Salts 24 Attack by Sulfite Ion 25 Preparation of Alkyl Thiocyanates 25 Nitrogen Nucleophiles 26 Amine Alkylation 26 Amine Alkylation with Alkyl Halides and Onium Salts 26 Amine Alkylation with Inorganic Esters 27 Amine Alkylation with Alcohols 29 Amine Alkylation with Diazo Compounds 30 Transamination 30 Amine Alkylation with Epoxides 30 Amine Alkylation with Cyclic Carbonates 31 Preparation of 1∘ Amines via Hexamethyldisilazane 32 Preparation of Isocyanides (“Isonitriles”) 32 Methylation of Amines, the Eschweiler–Clarke reaction 33 Preparation Sulfenamides 33 N-Alkylation of Amides, Lactams, Imides, and Carbamates 34 Alkylation with Alkyl Halides 34 Alkylation with Alkyl Sulfonates and Derivatives 35 Other Nitrogen Nucleophiles 36 Nitrite Nucleophiles: Preparation of Nitro Compounds 36 Azide Nucleophiles 36 Isocyanates and Isothiocyanates as Nucleophiles 37 Halogen Nucleophiles 38 Attack by Halides at Alkyl Carbon or Silicon 38 Halide Exchange 38 Preparation of Halides from Sulfonic Acid Esters 38 Preparation of Alkyl Halides from Alcohols 39 Preparation of Alkyl Halides from Ethers 40 Preparation of Alkyl Halides from Epoxides 41 Cleavage of Alkyl Ethers with Halide Ion 42 Cleavage of Silyl Ethers and Silyl Enol Ethers with Halide Ion 44 Cleavage of Carboxylic Acid and Sulfonic Acid Esters with Halide Ion 45 Preparation of Halides from α-Diazo Carbonyl Compounds 46 Preparation of Cyanamides 46 Carbon Nucleophiles 47 Attack by Carbon at Alkyl Carbon 47 Direct Coupling of Alkyl Halides 47 Reactions of Organometallic Reagents with Alkyl Halides 47 Couplings of Allylic and Propargylic Halides 48 Couplings of Organometallic Reagents with Sulfonate Esters 49 Couplings Involving Alcohols 49 Reactions of Organometallic Reagents with Allylic Esters and Carbonates 50

Contents

1.7.1.7 1.7.1.8 1.7.1.9 1.7.1.10 1.7.1.11 1.7.1.12 1.7.1.13 1.7.1.14 1.8 1.8.1 1.8.1.1 1.8.1.2 1.8.2 1.8.2.1 1.8.3 1.8.3.1 1.8.4 1.8.4.1

Reactions of Organometallic Reagents with Epoxides 50 Alkylation of Malonate and Acetoacetate Derivatives 51 Alkylation of Aldehydes, Ketones, Nitriles, and Carboxylic Esters Alkylation of Carboxylic Acid Salts 54 Alkylation α to a Heteroatom 54 Alkylation α to a Masked Carboxylic Acid 56 Alkylation at Alkynyl Carbon 57 Alkylation of Cyanide Ion – Preparation of Nitriles 58 Nucleophilic Substitution at a Sulfonyl Sulfur Atom 60 Attack by Oxygen 60 Hydrolysis of Sulfonic Acid Derivatives 60 Formation of Sulfonate Esters 61 Attack by Nitrogen 61 Formation of Sulfonamides 61 Attack by Halogen 61 Formation of Sulfonyl Halides 61 Attack by Carbon 63 Preparation of Sulfones 63

2

Addition to Carbon-Heteroatom Multiple Bonds 65 Prantik Maity and Rajappa Vaidyanathan

2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.7.1 2.7.2 2.8 2.9 2.10 2.11 2.11.1 2.11.2 2.11.3 2.12 2.12.1 2.12.2 2.12.3 2.13 2.14 2.15 2.15.1 2.15.2 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23

Introduction 66 Addition of Water to Aldehydes and Ketones: Formation of Hydrates 66 Addition of Bisulfite to Aldehydes and Ketones 67 The Addition of Alcohols to Aldehydes and Ketones: Acetal Formation 69 The Addition of Thiols to Aldehydes and Ketones: S,S-Acetal Formation 71 Reductive Etherification 72 Addition of NH3 , RNH2 , and R2 NH 74 The Addition of Amines to Aldehydes and Ketones: Imine and Oxime Formation 74 Redox Neutral Amination 77 Formation of Hydrazones 79 Formation of Oximes 80 The Formation of gem-Dihalides from Aldehydes and Ketones 80 The Aldol Reaction 82 Ketene and Silyl Enol Ether Addition to Aldehydes 87 Silyl Enol Ether Addition to Aldehydes: The Mukaiyama Aldol 87 Ketene Silyl Acetal and Thioacetal Addition to Aldehydes 90 Allylorganometallics: Stannane, Borane, and Silane 92 Allylsilane Additions 92 Allylborane Additions 94 Allylstannane Additions 96 The Nozaki–Hiyama–Kishi Reaction 97 Addition of Transition Metal Alkynylides to Carbonyl Compounds 99 Addition of Organometallic Reagents to Carbonyls 100 Using Organolithium Reagents 100 Using Organomagnesium Reagents 102 Addition of Conjugated Alkenes to Aldehydes: the Baylis–Hillman Reaction 103 The Reformatsky Reaction 104 The Wittig Reaction 106 Horner–Wadsworth–Emmons Reaction 108 Peterson Olefination 109 Julia–Lythgoe Olefination 110 Tebbe Methylenation 112 The Mannich Reaction 113

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2.24 2.25 2.26 2.26.1 2.26.2 2.26.3 2.26.4 2.27 2.28 2.28.1 2.28.2 2.28.3 2.28.4 2.28.5 2.29 2.30 2.31 2.31.1 2.31.2 2.31.3 2.31.4 2.31.5 2.31.6 2.31.7 2.32 2.32.1 2.32.2 2.32.3 2.32.4 2.33 2.34 2.35 2.35.1 2.35.2 2.35.3 2.36 2.37 2.38 2.39 2.40 2.40.1 2.40.2 2.40.3 2.41 2.42 2.43 2.44 2.44.1 2.44.2 2.44.3 2.44.4 2.44.5 2.45 2.45.1

The Strecker Reaction 115 Hydrolysis of Carbon–Nitrogen Double Bonds 117 Conversion of Carboxylic Acids to Acyl Chlorides 118 Procedures Using Oxalyl Chloride in the Absence of DMF 119 Procedures Using Thionyl Chloride in the Absence of DMF 119 Procedures Using a Halogenating Agent and DMF 120 Procedures Using Vilsmeier Reagent 122 Synthesis of Acyl Fluorides from Carboxylic Acids 122 Formation of Amides from Carboxylic Acids 123 Direct Coupling of Carboxylic Acids and Amines 123 Via Acid Chlorides 126 Via Acyl Imidazoles (Imidazolides) 126 Via Acyl Imidazolium Ions 127 Via Anhydrides 128 Formation of Amides from Esters 130 Hydrolysis of Acyl Halides 132 Conversion of Carboxylic Acids to Esters 132 Fisher Esterification 132 Widmer’s Method for the Synthesis of t-Butyl Esters 133 Via Acid Chlorides 133 Via Acyl Imidazoles (Imidazolides) 133 Using Carbodiimides 134 Via Anhydrides 134 Miscellaneous Methods 136 Hydrolysis of Amides 136 Under Acidic Conditions 136 Under Basic Conditions 137 Under Oxidative Conditions 137 Miscellaneous Methods 138 Conversion of N-Acyloxazolidinones to Other Carboxyl Derivatives 139 Alcoholysis of Amides 140 Hydrolysis of Esters 141 Under Basic Conditions 141 Under Acidic Conditions 142 Miscellaneous Methods 143 Transesterification 143 Alkyl Thiol Addition to Esters 144 Addition of Organometallic Reagents to Carboxylic Acid Derivatives 145 The Kulinkovich Cyclopropanation 149 Synthesis of Acyl Cyanides 150 Using Trimethylsilyl Cyanide 150 Using Copper (I) Cyanide 150 Miscellaneous Methods 151 The Ritter Reaction 151 Thorpe Reaction 154 Addition of Organometallic Reagents to Nitriles 155 Conversion of Nitriles to Amides, Esters, and Carboxylic Acids 155 Hydrolysis of Nitriles Under Acidic Conditions 155 Hydrolysis of Nitriles Under Basic Conditions 157 Hydrolysis of Nitriles Under Oxidative Conditions 157 Enzymatic Hydrolysis of Nitriles 157 Miscellaneous 158 Conversion of Nitriles to Thioamides 158 Conversion of Nitriles to Aldehydes 159

Contents

2.46 2.47 2.48 2.49 2.50 2.51 2.52 2.53 2.54 2.55

The Addition of Ammonia or Amines to Nitriles 160 The Addition of Alcohol to Nitriles 161 Alkyl Thiol Addition to Nitriles 162 The Blaise Reaction 162 The Addition of Alcohols to Isocyanates 163 The Addition of Amines and Amides to Isocyanates 164 The Formation of Xanthates 165 The Addition of Amines to Carbon Dioxide 166 The Addition of Amines to Carbon Disulfide 167 Addition of Organometallic Reagents to Carbon Dioxide 167

3

Addition to Carbon–Carbon Multiple Bonds 169 John A. Ragan

3.1 3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.2 3.3.2.1 3.3.2.2 3.4 3.4.1 3.4.2 3.5 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.5.6 3.5.7 3.5.8 3.6 3.7 3.8 3.9 3.9.1 3.9.2 3.10 3.10.1 3.10.2 3.10.3 3.10.4 3.10.5 3.11 3.12 3.12.1 3.12.2 3.12.3 3.12.4

Introduction 169 Hydrogen–Halogen Addition (Hydrohalogenation) 169 Hydrohalogenation of Olefins 169 Hydrohalogenation of Alkynes 172 Hydrogen–Oxygen Addition 173 Addition of H–OH (Hydration) 173 Hydration of Olefins 173 Hydration of Acetylenes 175 Addition of H–OR (Hydroalkoxylation) 176 Addition of H–OR to Olefins 176 Addition of H–OR to Acetylenes 177 Hydrogen–Nitrogen Addition (Hydroamination) 178 Hydroamination of Olefins 178 Hydroamination of Acetylenes and Allenes 179 Hydrogen–Carbon Addition (Hydroalkylation) 180 Direct Hydrogen-Alkyl Addition 180 Hydrogen–Allyl Addition (Alder Ene Reaction) 181 Hydrogen–Malonate/Enolate Addition (Michael Reaction) 182 Hydrogen–Alkyl Addition, Stork Enamine Reaction 184 Hydrogen–Alkyl Addition, Metal-Catalyzed 185 Hydroformylation/Hydroacylation 188 Nazarov Cyclization 190 Radical-Mediated C—H Addition 191 Halogen–Halogen Addition 191 Hydroxy–Halogen Addition 192 Amino–Halogen Addition 194 Carbon–Halogen Addition 194 Alkyl–Halogen Addition 194 Acyl–Halogen Addition 195 Oxygen–Oxygen Addition 196 Dihydroxylation of Olefins 196 Keto-Hydroxylation of Olefins 197 Dihydroxylation of Acetylenes 198 Epoxidation 198 Singlet Oxygen Addition to Dienes 202 Oxygen–Nitrogen Addition 202 Nitrogen–Nitrogen Addition 204 Aziridination 204 N—N Addition to Olefins 204 Triazines from Azide–Olefin Cycloaddition 205 N—N Addition to Dienes (1,4) 205

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3.13 3.13.1 3.13.1.1 3.13.1.2 3.13.1.3 3.13.2 3.13.2.1 3.14 3.14.1 3.14.2 3.14.3 3.15 3.15.1 3.15.1.1 3.15.1.2 3.15.1.3 3.15.1.4 3.15.1.5 3.15.1.6 3.15.1.7 3.15.1.8 3.15.1.9 3.15.1.10 3.15.2 3.15.3 3.15.4 3.15.5 3.15.6 3.15.7 3.15.8

Carbon–Oxygen Addition 206 Carbon–Oxygen Addition to Olefins (1,2) 206 [2+2] Cycloadditions of Olefins and Carbonyl Compounds 206 Nitrone–Olefin [3+2] Cycloadditions 207 Noncycloaddition Carbon–Oxygen Additions 209 Carbon–Oxygen Addition to Dienes (1,4) 210 Hetero Diels–Alder Cycloaddition 210 Carbon–Nitrogen Addition 211 Carbon–Nitrogen Addition to Olefins 211 Carbon–Nitrogen Addition to Alkynes 212 Carbon–Nitrogen Addition to Dienes 212 Carbon–Carbon Addition 212 [4+2] Cycloaddition: Diels–Alder Reaction 212 Intermolecular, Nonsubstituted 212 Intermolecular, Heteroatom-substituted Dienophile 213 Intermolecular, Heteroatomsubstituted Diene 213 Intermolecular, Aqueous Media 214 Intermolecular, Aromatic Product 214 Intermolecular, Lewis Acid–Catalyzed 215 Intermolecular, Inverse-electron Demand 216 Intermolecular, Benzyne as Dienophile 217 Intramolecular Examples 217 Asymmetric Examples 218 [2+2] Cycloaddition 219 [3+2] Cycloaddition 221 Carbene Addition (Cyclopropanation) 225 [4+3] Cycloadditions 227 Conjugate Addition-Alkylation 228 Bis-Alkoxycarbonylation 229 Cascade Cyclizations 229

4

Nucleophilic Aromatic Substitution Stéphane Caron and Emma McInturff

4.1 4.2 4.2.1 4.2.2 4.2.3 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.4.2 4.4.3 4.4.4 4.5 4.5.1 4.5.2 4.6 4.6.1 4.6.2 4.6.3 4.7

Introduction 231 Oxygen Nucleophiles 232 Preparation of Phenols 232 Preparation of Aryl Ethers 232 Preparation of Diaryl Ethers 234 Sulfur Nucleophiles 234 Preparation of Aryl Thioethers 234 Preparation of Diaryl Thioethers 235 Other Sulfur Nucleophiles 236 Nitrogen Nucleophiles 236 Preparation of Anilines 236 Preparation of Aryl Amines 237 Preparation of Diaryl Amines 238 Other Nitrogen Nucleophiles 240 Halogen Nucleophiles 241 Reaction of Diazonium Salts 241 Preparation of 2-Halopyridines and Derivatives 242 Carbon Nucleophiles 243 Cyanide as a Nucleophile 243 Malonates as Nucleophiles 243 Other Carbon Nucleophiles 244 ortho-Arynes 245

231

Contents

247

5

Electrophilic Aromatic Substitution Stéphane Caron and Emma McInturff

5.1 5.2 5.2.1 5.2.2 5.2.3 5.3 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.3.6 5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.5.7 5.5.8 5.5.9 5.5.10 5.5.11 5.5.12 5.5.13 5.5.14

Introduction 247 Nitrogen Electrophiles 247 Nitration 247 Nitrosation 249 Diazonium Coupling 250 Sulfur Electrophiles 250 Sulfonation 250 Halosulfonation 251 Sulfurization 251 Sulfinylation 252 Sulfonylation 252 Thiocyanation 252 Halogenation 253 Fluorination 253 Chlorination 253 Bromination 254 Iodination 255 Carbon Electrophiles 257 Friedel–Crafts Alkylation 257 Friedel–Crafts Arylation 259 Claisen Rearrangement 259 Formylation 260 Hydroxyalkylation 261 Haloalkylation 262 Aminoalkylation 262 Thioalkylation 263 Friedel–Crafts Acylation 263 Fries Rearrangement 265 Carboxylation 265 Amidation 266 Thioamidation and Thioesterification 266 Cyanation 267

6

Selected Catalytic Reactions 269 Sebastien Monfette, Adam R. Brown, Pascal Dubé, Nathan D. Ide, Chad A. Lewis, Jared L. Piper, Shashank Shekhar, and Shu Yu

6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5 6.2.6 6.2.7 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.4 6.4.1 6.4.2

Introduction 269 Organoboron Reagents: The Suzuki–Miyaura Coupling 270 Preparation of Biaryls 271 Preparation of Alkynyl-Substituted Arenes 278 Preparation of Vinyl-Substituted Arenes 279 Preparation of Dienes 280 Preparation of Alkyl-Substituted Arenes 280 Preparation of Alkyl-Substituted Alkenes 281 Preparation of Alkanes 282 Organomagnesium Reagents: Kumada–Corriu Coupling 282 Preparation of Biaryls 283 Preparation of Vinyl-Substituted Arenes 283 Preparation of Aryl—Alkyl Bonds 285 Preparation of Vinyl—Alkyl Bonds 286 Organozinc Reagents: Negishi Coupling 287 Preparation of Biaryls 287 Preparation of Aryl—Alkyl Bonds 289

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6.4.3 6.4.4 6.4.5 6.5 6.6 6.6.1 6.6.2 6.6.3 6.6.4 6.7 6.8 6.8.1 6.8.2 6.9 6.9.1 6.9.2 6.9.3 6.9.4 6.10 6.10.1 6.10.2 6.10.3 6.10.4 6.11 6.11.1 6.11.2 6.11.3 6.11.4 6.11.5 6.11.6 6.12 6.13 6.14 6.14.1 6.14.2 6.14.3 6.15 6.16 6.16.1 6.16.2 6.16.3 6.17 6.17.1 6.17.2 6.17.3 6.17.4 6.17.5 6.17.6 6.17.7 6.18 6.18.1 6.18.2 6.18.2.1 6.18.2.2

Preparation of Alkanes 290 Preparation of 1,3-Dienes 290 Preparation of Ketones 291 Cross-Electrophile Coupling 291 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction) 292 Preparation of Biaryls 292 Preparation of Vinyl-Substituted Arenes 293 Preparation of 1,3-Dienes 294 Preparation of Alkyl-Substituted Alkenes 295 Cross-Coupling Reactions with Organosilicon Compounds 295 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling) 296 Reaction with Aryl Halides 296 Preparation of Enynes 298 Metal-Catalyzed Coupling of Alkenes (Heck Coupling) 298 Formation of Aryl Alkenes 299 Formation of Dienes 301 Reductive Heck 302 Oxidative Heck 303 Enolate Arylations 303 α-Arylation of Ketones 304 α-Arylation of Esters 304 α-Arylation of Amides 305 α-Arylation of Nitrile 305 Pd- and Cu-Catalyzed Aryl C—N Bond Formation 306 Alkyl Amine as Nucleophile 307 Aryl Amine as Nucleophile 311 Amides as Nucleophile 312 Other Amine as Nucleophile 314 Coupling with Ammonia Surrogate 316 Oxidative Coupling 318 Pd- and Cu-Catalyzed Aryl C—O Bond Formation 320 Pd- and Cu-Catalyzed Aryl C—S Bond Formation 322 Aryl C—B Bond Formation 324 Aryl Bromides and Iodides 324 Vinyl Bromide 326 Aryl Chlorides and Triflates 327 Pd-Catalyzed Aryl C—CN Bond Formation 327 Metal-Catalyzed Allylic Substitution 329 Carbon Nucleophiles 331 Nitrogen Nucleophiles 334 Oxygen Nucleophiles 335 Catalytic Metal-Mediated Methods for Fluorination 337 Aryl Fluorination 337 Vinyl Fluorides 339 α-Fluorination of Carbonyl Compounds 340 Difluoromethylation (—CF2 R) 342 Trifluoromethylation (—CF3 ) 344 Emerging Methods for Metal-Catalyzed Fluorination 346 Summary and Outlook for Metal-Catalyzed Fluorination 347 Selected Metal-Mediated C—H Functionalization 347 Introduction 347 Metal-Catalyzed, Directed C—H Functionalization 348 Ru-Catalyzed Methods 348 Palladium-Catalyzed Methods 351

Contents

6.18.2.3 6.18.3 6.18.3.1 6.18.3.2 6.18.3.3 6.19 6.19.1 6.19.2 6.19.2.1 6.19.2.2 6.19.3 6.19.4 6.19.5 6.19.5.1 6.19.5.2 6.19.5.3 6.20 6.20.1 6.20.2 6.20.2.1 6.20.2.2 6.20.2.3 6.20.2.4 6.20.3 6.20.3.1 6.20.3.2 6.20.3.3 6.20.4 6.21 6.21.1 6.21.2 6.21.2.1 6.21.2.2 6.21.2.3 6.21.2.4 6.21.3 6.21.3.1 6.21.3.2 6.21.3.3 6.21.4 6.21.4.1 6.21.4.2 6.21.4.3

Rhodium-Catalyzed Methods 353 Metal-Catalyzed Undirected C—H Functionalization 353 Formation of C—B Bonds 353 Formation of C—Si Bonds 354 Formation of C—C Bonds 355 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies 357 Introduction 357 C—C Bond formation 357 Allylation/Crotylation 357 Alkylation of Aromatics 358 Redox Neutral Homologation of Alcohols 359 Ketone Functionalization 359 C—N Bond Formation 360 Primary Amines 360 Secondary Amines 360 Tertiary Amines 361 Alkene and Alkyne Metathesis Reactions 362 Introduction 362 Ring-closing Metathesis 363 Alkene Ring-Closing Metathesis 363 Alkyne Ring-Closing Metathesis 364 Enyne Ring-closing Metathesis 366 Z-Selective Olefin Metathesis 366 Cross-Metathesis 367 Alkene Cross-Metathesis 367 Alkane Cross-Metathesis 368 Alkyne Cross-Metathesis 368 Metathesis Polymerization 369 Organocatalysis 369 Introduction 369 Phase Transfer Catalysis 369 Carbon Alkylation 369 Heteroatom Alkylation 370 Conjugate Additions of Carbon Nucleophiles 371 Addition of Heteroatom Nucleophiles 372 Amino Organocatalysis via Iminium and Enamine Intermediates 372 Iminium Catalysis: Conjugate Addition 372 Iminium Catalysis: Cycloadditions 373 Enamine Catalysis: Aldol/Mannich 373 Nucleophilic Catalysis 373 Acyl Transfer Reactions 374 Reactions Proceeding via Acyl Anion Equivalents 374 Morita–Baylis–Hillman Reactions 375

7

Rearrangements 377 David H. Brown Ripin and Chad A. Lewis

7.1 7.2 7.2.1 7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.1.5

Introduction 377 [1,2]-Rearrangements 377 Carbon-to-Carbon Migrations of Carbon and Hydrogen 377 Wagner–Meerwein and Related Reactions 377 Pinacol Rearrangement: Vicinal Diols to Ketones or Aldehydes 378 Expansion and Contraction of Rings 380 Rearrangements of Ketones and Aldehydes 381 Dienone to Phenol Rearrangement 381

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7.2.1.6 7.2.1.7 7.2.1.8 7.2.1.9 7.2.1.10 7.2.1.11 7.2.1.12 7.2.2 7.2.2.1 7.2.2.2 7.2.2.3 7.2.3 7.2.3.1 7.2.3.2 7.2.3.3 7.2.3.4 7.2.3.5 7.2.3.6 7.2.4 7.2.4.1 7.2.5 7.2.5.1 7.2.5.2 7.2.5.3 7.2.6 7.2.6.1 7.3 7.3.1 7.3.1.1 7.3.1.2 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.3.2.6 7.3.2.7 7.3.2.8 7.3.2.9 7.3.2.10 7.3.2.11 7.3.2.12 7.3.2.13 7.3.3 7.3.3.1 7.3.4 7.3.4.1 7.3.4.2 7.3.4.3 7.3.4.4 7.3.4.5

Benzil to Benzilic Acid Rearrangement 382 Favorskii Rearrangement: Anionic Rearrangement of α-Haloketones 382 Arndt–Eistert Synthesis: Homologation of Carboxylic Acids via Wolff Rearrangement of α-Diazoketones 384 Homologation of Aldehydes and Ketones 384 Fritsch–Buttenberg–Wiechell Rearrangement: Acetylenes from 1,1-Disubstituted Olefins 385 Other Carbon-to-Carbon Migrations of Carbon 386 Other Carbon-to-Carbon Migrations of Hydrogen 387 Carbon-to-Carbon Migrations of Other Groups 387 Migration of Halogen, Hydroxy, Amino, and Other Groups 387 Neber Rearrangement: Carbon-to-Carbon Migration of Nitrogen of Activated Oximes 388 Payne Rearrangement: Rearrangement of α-Hydroxyepoxides 389 Carbon-to-Nitrogen Migrations of Carbon 390 Hofmann Rearrangement: Primary Amides to Amines or Carbamates 390 Curtius Rearrangement: Acyl Azides to Amines or Carbamates 391 Lossen Rearrangement: Hydroxamic Imides to Amines or Carbamates 392 Schmidt Rearrangement: Ketones to Amides 395 Beckmann Rearrangement: Oximes to Amides 395 Stieglitz Rearrangements and Related Reactions: Cationic C to N Migration of Carbon 396 Carbon to Oxygen Migrations of Carbon 397 Baeyer–Villiger Oxidation: Ketones or Aldehydes to Esters 397 Heteroatom to Carbon Migrations 398 Stevens Rearrangement – [1,2]-Rearrangement of N, O, or S Ylides with Migration of Carbon 398 [1,2]-Meisenheimer Rearrangement – Rearrangement of R3 NO to R2 NOR 400 Other Heteroatom to Carbon Rearrangements 400 Carbon to Heteroatom Rearrangements 402 Brook Rearrangement, Carbon-to-Oxygen Migration of Silicon 402 Other Rearrangements 402 Electrocyclic Rearrangements 402 Rearrangements of Cyclobutenes and 1,3-Cyclohexadienes 402 Stilbenes to Phenanthrenes 403 Sigmatropic Rearrangements 403 Cyclopropylimine Rearrangement 403 Cyclopropanes to Allenes: The Skattebøl and Related Rearrangements 404 Cope Rearrangement 405 Claisen Rearrangement 406 Fischer Indole Synthesis 411 Boekelheide Rearrangement: 2-Alkylpyridine N-Oxide Rearrangements 412 [2,3]-Wittig Rearrangement: O-to-C Shift of Carbon 412 [2,3]-Meisenheimer Rearrangement: N-to-O Migration of Carbon in Tertiary N-Oxides 413 [2,3]-Sulfoxide, Selenoxide, and Sulfilimine Rearrangements 414 Sommelet–Hauser Rearrangement and Related Reactions – [2,3]-Sigmatropic Rearrangements of Ylides 415 Benzidine Rearrangement 415 Overman Rearrangement 416 Propargyl O-to-N Migration 416 Other Cyclic Rearrangements 417 Di-π-Methane and Related Rearrangements 417 Acyclic Rearrangements 417 Migration of Double Bonds 417 Hydride Shifts 418 Newman–Kwart Rearrangement – O-phenylthiocarbanate to S-phenylcarbamate 419 Nitrosamide Decomposition 419 The Achmatowitz Reaction: Oxidative Furan Rearrangement 420

Contents

7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5

Miscellaneous Migrations 420 Hunsdiecker 420 Jocic 420 Smiles/Truce–Smiles 421 Dakin–West–Dimroth 422 Meinwald 423

8

Eliminations 425 Sally Gut Ruggeri

8.1 8.2 8.2.1 8.2.2 8.2.3 8.2.4 8.2.5 8.2.6 8.2.7 8.2.8 8.2.9 8.2.10 8.2.11 8.2.12 8.2.13 8.2.14 8.2.15 8.2.16 8.2.17 8.2.18 8.2.19 8.2.20 8.2.21 8.2.22 8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5 8.3.6 8.3.7 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.5 8.5.1 8.6 8.6.1 8.6.2 8.6.3 8.7

Introduction 425 Formation of Alkenes 425 Elimination of Alcohols 426 Elimination of Ethers 426 Elimination of Esters 427 Elimination of Xanthates 428 Elimination of Ammonium or Sulfonium Salts 428 Elimination of N-Oxides 429 Elimination of Diazonium Salts 429 Elimination of Hydrazones 429 Elimination of Sulfoxides and Selenoxides 430 Elimination of Halides 431 Elimination of Nitriles 431 Elimination β to an Electron-withdrawing Group 432 Elimination of Diol Derivatives 432 Elimination of Epoxides and Episulfides 434 Elimination of α-Halo Sulfones 435 Elimination of Aziridines 435 Elimination of Dihalides 436 Elimination of Haloethers 436 Elimination of Hydroxy- or Haloacids 437 Elimination of Hydroxysulfones 437 Elimination of β-Silyl Alcohols 438 Elimination of β-Silyl Esters, Sulfides, and Sulfones 438 Formation of Dienes 438 From Allylic Systems 439 From 1,4-Dihalo-2-butenes 440 From Diols 440 From δ-Elimination 440 From Sulfolenes 441 Via Retro Diels–Alder Reactions 441 From Extrusion of CO 442 Formation of Alkynes 442 From Ketones 442 From Bis(hydrazones) 443 From Dihalides 443 From Vinyl Halides 443 From Elimination of Sulfones 444 Formation of C=N bonds 444 Carbodiimides from Ureas 445 Formation of Nitriles 445 Nitriles from Amides 445 Nitriles from Cleavage of N—O Bonds 446 Isonitriles from Formamides 447 Formation of Ketenes and Related Compounds 447

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8.7.1 8.7.2 8.7.3 8.8 8.8.1 8.8.2 8.8.3 8.8.4 8.8.5 8.8.6 8.9

Ketenes 447 Isocyanates and Isothiocyanates 448 Ketimines 448 Fragmentations 449 Grob Fragmentations 449 Eschenmoser Fragmentations 450 Formation of Arenes 450 Extrusion of N2 450 Extrusion of S 451 Multicomponent Extrusions 451 Dehydrating Reagents 451

9

Reductions 455 Sally Gut Ruggeri, Stéphane Caron, Pascal Dubé, Nathan D. Ide, Kristin E. Price Wiglesworth, John A. Ragan, and Shu Yu

9.1 9.2 9.2.1 9.2.1.1 9.2.1.2 9.2.2 9.2.2.1 9.2.2.2 9.2.3 9.2.3.1 9.2.3.2 9.2.3.3 9.2.3.4 9.2.4 9.2.4.1 9.2.4.2 9.2.4.3 9.3 9.3.1 9.3.2 9.3.3 9.3.3.1 9.3.3.2 9.3.3.3 9.3.4 9.3.5 9.3.5.1 9.3.5.2 9.3.5.3 9.4 9.4.1 9.4.1.1 9.4.1.2 9.4.1.3 9.4.1.4 9.4.1.5 9.4.1.6 9.4.1.7 9.4.1.8 9.4.2

Introduction 455 Reduction of C—C Bonds 455 Reduction of Alkynes 455 Reduction of Alkynes to Alkenes 455 Reduction of Alkynes to Alkanes 456 Reduction of Alkenes 457 Reduction of Alkenes to Alkanes Without Facial Selectivity 457 Reduction of Alkenes to Alkanes with Facial Selectivity 458 Reduction of Aromatic Rings and Heterocycles 461 Reduction of Benzene and Naphthalene Rings 461 Reduction of Pyridines and Quinolines 462 Reduction of Pyrroles and Indoles 464 Reduction of Furans 464 Conjugate Reductions 465 Reduction of Conjugated Alkynes 465 Reduction of α,β-Unsaturated Acids and Derivatives 466 Reduction of Enones 469 Reduction of C—N Bonds 471 Reduction of Nitriles to Imines or Aldehydes 471 Reduction of Nitriles to Primary Amines 471 Reduction of Imines or Imine Derivatives 472 Achiral Reductions 472 Substrate Control in Stereoselective Reductions 473 Enantioselective Reductions 474 Reduction of Hydrazones to Alkanes 477 Reduction of Carbon–Nitrogen Single Bonds 477 Reduction of Benzylic Amines 477 Reduction of Aromatic Carbon–Nitrogen Single Bonds 478 Reduction of Aliphatic Nitro Groups 479 Reduction of C—O Bonds 479 Reduction of Carboxylic Acid Derivatives 479 Reduction of Esters to Aldehydes 479 Reduction of Esters to Primary Alcohols 480 Reduction of Carboxylic Acids to Primary Alcohols 481 Reduction of Anhydrides and Mixed Anhydrides to Aldehydes 481 Reduction of Anhydrides and Mixed Anhydrides to Primary Alcohols Reduction of Amides and Imides to Aldehydes 482 Reduction of Amides to Alkylamines 484 Reduction of Carbamates to N-Methylamines 484 Reduction of Aldehydes and Ketones to Alcohols 485

481

Contents

9.4.2.1 9.4.2.2 9.4.2.3 9.4.2.4 9.4.2.5 9.4.2.6 9.4.3 9.4.3.1 9.4.3.2 9.4.3.3 9.4.4 9.4.4.1 9.4.4.2 9.4.4.3 9.5 9.5.1 9.5.2 9.5.3 9.5.4 9.5.5 9.5.6 9.6 9.6.1 9.6.2 9.6.3 9.6.4 9.7 9.7.1 9.7.1.1 9.7.2 9.7.2.1 9.7.2.2 9.7.2.3 9.7.3 9.7.3.1 9.7.3.2 9.7.4 9.7.4.1 9.7.4.2 9.7.5 9.7.6

Reduction with Hydride Donors 485 Meerwein–Ponndorf–Verley Reaction 488 Reduction via Catalytic Hydrogenation 489 Biocatalytic Routes to Reduction of Aldehydes and Ketones 490 Aldol–Tishchenko Reaction 490 Reduction of Acetals and Ketals 491 Reduction of Ketones to Alkanes 492 Wolff–Kishner Reduction 492 Clemmensen Reduction 492 Silane-Mediated Reduction 492 Reduction of Alcohols to Alkanes 492 Reduction of Aliphatic Alcohols 492 Reduction of Benzylic Alcohols 493 Reduction of Benzylic Ethers 493 Reduction of C—S Bonds 494 Reduction of Alkyl Sulfides, Sulfoxides, and Sulfones 494 Reduction of Vinyl Sulfides, Sulfoxides, and Sulfones 496 Reduction of Aryl Sulfides, Sulfoxides, and Sulfones 497 Reduction of Thioketones 498 Reduction of Thioesters and Thioamides 498 Reduction of Miscellaneous Thiocarbonyls 499 Reduction of C—X Bonds 500 Alkyl Halide Reductions 500 Acid Halides to Aldehydes 502 Vinyl Halide Reductions 503 Aryl Halide Reductions 503 Reduction of Heteroatom–Heteroatom Bonds 504 Reduction of Nitrogen–Nitrogen Bonds 504 Reduction of Azides 505 Reduction of Nitrogen–Oxygen Bonds 505 Reduction of Nitro Groups to Amines 506 Partial Reduction of Aromatic Nitro Compounds 507 Partial Reduction of Aliphatic Nitro Compounds 507 Reduction of Oxygen–Oxygen Bonds 508 Reduction of Peroxides 508 Reduction of Ozonides 508 Reduction of Oxygen–Sulfur Bonds 509 Reduction of Sulfones to Sulfides 509 Reduction of Sulfoxides to Sulfides 510 Reduction of Disulfides to Thiols 510 Reduction of Phosphine Oxides to Phosphines 511

10

Oxidations 513 Eric C. Hansen, Robert Perkins, and David H. Brown Ripin

10.1 10.2 10.2.1

Introduction 513 Oxidation of C—C Single and Double Bonds 514 Oxidative Cleavage of Glycols β-Aminoalcohols, α-Hydroxyaldehydes and Ketones, and Related Compounds 514 Ozonolysis 515 Ozonolysis Followed by Reduction to the Alcohol 515 Ozonolysis to the Ketone or Aldehyde Oxidation State 515 Ozonolysis Resulting in Carboxylic Acids or Esters 516 Ozonolysis Followed by Criegee Rearrangement 517 Oxidative Cleavage of Double Bonds and Aromatic Rings 517

10.2.2 10.2.2.1 10.2.2.2 10.2.2.3 10.2.2.4 10.2.3

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10.2.4 10.2.5 10.2.6 10.2.7 10.3 10.3.1 10.3.2 10.3.3 10.3.3.1 10.3.3.2 10.3.3.3 10.3.3.4 10.3.3.5 10.3.3.6 10.3.4 10.3.5 10.3.5.1 10.3.5.2 10.3.5.3 10.3.5.4 10.3.6 10.3.7 10.3.8 10.3.8.1 10.3.8.2 10.3.9 10.4 10.4.1 10.4.1.1 10.4.1.2 10.4.1.3 10.4.1.4 10.4.1.5 10.4.1.6 10.4.2 10.4.2.1 10.4.2.2 10.5 10.5.1 10.5.1.1 10.5.1.2 10.5.1.3 10.5.2 10.5.3 10.5.4 10.6 10.6.1 10.6.1.1 10.6.1.2 10.7 10.7.1 10.7.2 10.7.3 10.7.4

Oxidative Cleavage of Alkyl Groups from Rings 518 Oxidative Decarboxylation 518 Oxidative Decyanation 519 Oxidation of Olefins to Aldehydes and Ketones 520 Oxidation of C—H Bonds 520 Aromatization of Six-Membered Rings 520 Dehydrogenations Yielding Carbon–Carbon Bonds 521 Halogenation α to a Ketone or Aldehyde, or Carboxylic Acid 522 Chlorination 522 Bromination 523 Iodination 525 Fluorination 525 Haloform Reaction 526 Cleavage of Ketones with MNH2 527 Oxygenation α to a Ketone, Aldehyde, or Carboxylic Acid 527 Introduction of Nitrogen α to a Ketone, Aldehyde, or Carboxylic Acid 528 Aliphatic Diazonium Coupling 528 Nitrosation of Activated Carbon–Hydrogen Bonds 529 Formation of Diazo Compounds 529 Amination α to a Carbonyl 530 Sulfenation and Selenylation of Ketones, Aldehydes, and Esters 531 Sulfonylation of Aldehydes, Ketones, and Acids 531 Allylic and Benzylic Halogenation 532 Oxygenations 533 Allylic Amination 534 Nitrene Insertion into Carbon–Hydrogen Bonds 535 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent 536 Oxidation of Alcohols to Aldehydes and Ketones 536 TEMPO-Mediated Processes 537 Moffatt and Modified-Moffatt Processes 537 Metal-Mediated Processes 539 Alternative Methods 541 Oxidation of Benzylic and Allylic Alcohols 541 Oxidation of Diols to Lactones, Selective Oxidation of Primary or Secondary Alcohols 542 Oxidation of Primary Alcohols to Carboxylic Acids 542 TEMPO/Sodium Chlorite Oxidation of Alcohols to Carboxylic Acids and Derivatives 542 Metal-Mediated Oxidation of Alcohols to Carboxylic Acids and Derivatives 543 Oxidation of Aldehydes to Carboxylic Acids and Derivatives 543 Sodium Chlorite Oxidation of Aldehydes to Carboxylic Acids and Derivatives 543 Hydrogen Peroxide Oxidation of Aldehydes to Carboxylic Acids and Derivatives 543 Metal-Mediated Oxidations of Aldehydes to Carboxylic Acids and Derivatives 543 Oxidation of Bisulfite Adducts 544 Oxidation of Carboxylic Acids to Peroxyacids 544 Oxidation of Phenols and Anilines to Quinones 544 Oxidation α to Oxygen and Nitrogen 545 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent 546 Dehydrogenation of Amines to Imines and Nitriles 546 Oxidation α to Nitrogen 546 Oxidation of Aldoximes and Hydrazones of Aldehydes 548 Oxidation of Nitrogen Functionalities 548 Diazotization of Amines 548 Oxidations of Hydrazines and Hydrazones 549 Amination of Nitrogen 550 Oxidation of Amines to Azo or Azoxy Compounds 551

Contents

10.7.5 10.7.6 10.7.6.1 10.7.6.2 10.7.7 10.7.8 10.7.9 10.7.10 10.7.11 10.8 10.8.1 10.8.2 10.8.3 10.8.4 10.8.4.1 10.8.4.2 10.8.5 10.8.5.1 10.8.5.2 10.8.5.3 10.8.6 10.9 10.9.1 10.9.2

Oxidation of Primary Amines to Hydroxylamines 551 Oxidation of Nitrogen to Nitroso Compounds 551 Nitrone Formation 552 Oxidation of Hydroxylamine to Nitroso Compounds 552 Nitrosation of Secondary Amines and Amides 553 Oxidation of Primary Amines, Oximes, or Nitroso Compounds to Nitro Compounds 553 Oxidation of Tertiary Amines to Amine Oxides and Elimination to Form Imines 553 Oxidation of Pyridines to Pyridine N-Oxides 554 Halogenation or Sulfination of Amines and Amides 554 Oxidation of Sulfur and at Carbon Adjacent to Sulfur 555 Pummerer Rerrangement 555 Formation of α-Halosulfides 556 Halogenation of Sulfoxides, Sulfones, and Phosphine Oxides 556 Oxidation of Mercaptans and Other Sulfur Compounds to Sulfonic Acids or Sulfonyl Chlorides 557 Peroxide-Based Oxidations 557 Chlorine Oxidations 557 Oxidation of Sulfides to Sulfoxides and Sulfones 557 Oxidation of a Sulfide to a Sulfoxide 557 Oxidation of a Sulfide to a Sulfone 559 Oxidation of Selenides 560 Oxidation of Mercaptans to Disulfides 561 Oxidation of Other Functionality 561 Oxidation of Primary Halides 561 Oxidation of C—Si Bonds: The Tamao Oxidation 562

11

Selected Free Radical Reactions 563 Christophe Allais, Eric C. Hansen, Nathan D. Ide, Robert J. Perkins, and Elizabeth C. Swift

11.1 11.1.1 11.2 11.2.1 11.2.2 11.2.3 11.2.3.1 11.2.3.2 11.2.4 11.2.5 11.2.5.1 11.2.6 11.2.7 11.2.7.1 11.2.7.2 11.2.7.3 11.2.7.4 11.2.8 11.2.9 11.2.9.1 11.2.9.2 11.2.10 11.2.11 11.3 11.3.1 11.3.2 11.3.3

Introduction 563 Radical Reactions Discussed in Other Chapters 563 Radical Reactions via Chemical Initiation 563 Radical Cyclizations 563 Atom Transfer Radical Cyclizations 564 Radical Allylation 564 Keck Radical Allylation 564 Tin-Free Radical Allylations 565 Remote Functionalization Reactions 566 Barton Nitrite Ester Reaction 566 Hofmann–Löffler–Freytag Reaction 567 Hypohalite Reaction 568 The Hunsdiecker Reaction 568 Barton Modification of the Hunsdiecker Reaction 569 Suárez Modification of the Hunsdiecker Reaction 569 Catalytic Hunsdiecker Reaction with α,β-Unsaturated Carboxylic Acids 570 Nitro-Hunsdiecker Reaction 571 The Minisci Reaction 571 Radical Conjugate Additions 572 Intramolecular Radical Conjugate Additions 573 Intermolecular Radical Conjugate Additions 573 β-Scission Reactions 574 Free Radical Polymerization 575 Photoredox Catalysis 575 Dual Catalytic Cross-coupling Reactions 576 Photoredox Minisci Reactions 578 Photoredox Conjugate Addition 580

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11.3.4 11.3.5 11.3.6 11.3.6.1 11.3.6.2 11.4 11.4.1 11.4.2 11.4.3 11.4.4 11.4.5

Photoredox Rearrangements 580 Photoredox Cycloadditions 581 Photoredox Net Oxidations and Reductions 582 Oxidations 582 Reductions 583 Electrochemical Methods 583 Anodic Decarboxylations: Kolbe and Non-Kolbe Reactions 583 The Shono Oxidation 585 Electrochemical Reduction of Alkyl Halides 585 Indirect Electrolysis Reactions 586 Oxidation and Reduction at Sulfur 588

12

Synthesis of “Nucleophilic” Organometallic Reagents 591 David H. Brown Ripin and Adam R. Brown

12.1 12.2 12.2.1 12.2.1.1 12.2.1.2 12.2.1.3 12.2.2 12.2.2.1 12.2.2.2 12.2.2.3 12.2.2.4 12.2.2.5 12.2.3 12.2.3.1 12.2.3.2 12.2.3.3 12.2.3.4 12.2.4 12.2.4.1 12.2.4.2 12.2.4.3 12.2.4.4 12.2.5 12.2.5.1 12.2.5.2 12.2.5.3 12.2.5.4 12.2.5.5 12.2.6 12.2.6.1 12.2.6.2 12.2.7 12.2.7.1 12.2.8 12.2.8.1 12.2.9 12.2.9.1 12.2.10 12.2.10.1 12.2.11

Introduction 591 Synthesis of “Nucleophilic” Organometallic Reagents 592 Lithium 592 Deprotonation 592 Metal–Halogen Exchange 593 Metal–Metal Exchange 594 Boron 594 Hydroboration 594 Metal–Metal Exchange 595 Cross-coupling with R2 B–BR2 596 C–H Borylation 597 Other 597 Magnesium 598 Metal–Halogen Exchange 598 Metal–Metal Exchange 599 Hydromagnesiation 600 Carbomagnesiation 600 Aluminum 600 Metal–Halogen Exchange 600 Carboalumination 601 Hydroalumination 601 Metal–Metal Exchange 602 Silicon 602 Metal–Metal Exchange 602 Hydrosilylation 603 Metal–Halogen Exchange 603 C–H Silylation 603 Use of Nucleophilic Silicon Reagents 604 Titanium 604 Metal–Metal Exchange 604 Other 605 Chromium 605 Metal–Halogen and Metal–Metal Exchange 605 Manganese 606 Metal–Metal Exchange 606 Iron 606 Metal–Halogen Exchange 606 Copper 607 Metal–Metal Exchange 607 Zinc 608

Contents

12.2.11.1 12.2.11.2 12.2.11.3 12.2.12 12.2.12.1 12.2.13 12.2.14 12.2.14.1 12.2.14.2 12.2.14.3 12.2.14.4 12.2.14.5 12.2.15 12.2.16 12.3 12.3.1 12.3.2 12.4 12.4.1 12.4.2 12.4.3 12.4.4

Metal–Halogen Exchange 609 Metal–Metal Exchange 609 Other 610 Zirconium 610 Hydrozirconation 610 Indium 611 Tin 612 Metal–Metal Exchange 612 Nucleophilic Sn 612 Cross-coupling with R3 Sn–SnR3 613 Hydrostannation 613 Electrophilic Tin 614 Cerium 614 Bismuth 615 Strategies for Metalating Heterocycles 615 Strategies for Metalating Five-Membered Heterocycles 615 Strategies for Metalating Six-Membered Heterocycles 617 Reactions of “Nucleophilic” Organometallic Reagents 618 Uncatalyzed C–M to C–O 618 Uncatalyzed C–M to C–S or C–Se 619 Uncatalyzed C–M to C–X 619 Uncatalyzed C–M to C–N 620

13

Synthesis of Common Aromatic Heterocycles 621 Stéphane Caron

13.1 13.2 13.2.1 13.2.2 13.2.3 13.3 13.3.1 13.3.2 13.3.3 13.3.4 13.3.5 13.3.6 13.4 13.4.1 13.4.2 13.4.3 13.5 13.5.1 13.5.2 13.6 13.6.1 13.6.2 13.7 13.7.1 13.7.2 13.8 13.8.1 13.8.2 13.8.3

Introduction 621 Pyrroles 623 Condensation of 1,4-Dicarbonyls with a Primary Amine 623 Condensation of 1,3-Dicarbonyls with an α-Aminocarbonyl Compound 624 Dipolar Cycloaddition 624 Indoles 624 Fisher Indole Synthesis 625 Intramolecular Condensation of Anilines with Phenacyl Derivatives 625 Cycloelimination of Enamines 625 Aldol and Michael Additions 625 Alkylation of an Aniline 626 Addition of Vinyl Grignard Reagents to Nitrobenzene Derivatives 626 2-Indolinones (Oxindoles) 626 Lactamization 627 Friedel–Crafts Alkylation 627 C–H Insertion 627 Isatins (2,3-Indolindiones) 628 Cyclization of Isonitrosoacetanilides 628 Friedel–Crafts Acylation 628 Carbazoles 628 Oxidation of an Indole 628 Reductive Cyclization of a Nitro-Biphenyl Derivative 628 Pyrazoles 629 Condensation of a Hydrazine with a 1,3-Dicarbonyl Derivative 629 Condensation of a Hydrazine with a Michael Acceptor 630 Indazoles 630 Nucleophilic Aromatic Substitution of Arylhydrazones 630 Diazotization of a Toluidine 631 Metal-Mediated Cyclization 631

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13.9 13.9.1 13.9.2 13.9.3 13.9.4 13.10 13.10.1 13.10.2 13.10.3 13.11 13.11.1 13.12 13.12.1 13.12.2 13.13 13.13.1 13.13.2 13.14 13.14.1 13.14.2 13.14.3 13.15 13.15.1 13.15.2 13.15.3 13.15.4 13.16 13.16.1 13.16.2 13.16.3 13.16.4 13.17 13.17.1 13.17.2 13.17.3 13.18 13.18.1 13.18.2 13.19 13.19.1 13.19.2 13.19.3 13.20 13.20.1 13.20.2 13.20.3 13.21 13.21.1 13.21.2 13.21.3 13.21.4 13.22 13.22.1 13.22.2

Imidazoles and Benzimidazoles 631 Condensation of a 1,2-Diamine with a Carboxylic Acid 632 Condensation of an Amidine with a Halocarbonyl Derivative 632 Condensation of 1,4-Dicarbonyls with an Amine 633 Condensation of 1,2-Dicarbonyls with an Aldehyde and Ammonia 633 1,2,3-Triazoles and Benzotriazole 633 Dipolar Cycloaddition of Azides with an Alkynes 634 Dipolar Cycloaddition of Azides with Enolates 634 Diazaotization of o-Dianilines 634 1,2,4-Triazoles 635 Cyclodehydration 635 Tetrazoles 635 Cycloaddition of an Azide and a Nitrile 636 Activation of an Amide and Addition of an Azide 636 Dihydropyridines 637 Reaction of Ketoesters and Aldehydes in the Presence of Ammonia 637 Reaction of Aminocrotonates with Aldehydes and ß-Ketoesters 637 Pyridines 637 Condensation of a 1,3-Dicarbonyl Derivative with a Cyanoacetamide 637 Condensation of Enolates with Enaminoesters 638 Condensation of a 1,5-Dicarbonyl Compound with Ammonia 638 Quinolines 639 Friedländer Quinoline Synthesis 639 Addition to Isatins 640 Electrophilic Aromatic Substitution 640 Intramolecular Cyclization of an Iminium Ion 640 Quinolinones and 2-Hydroxyquinolines 641 Electrophilic Cyclization 641 Intramolecular Aldol Ring Closure 641 Intramolecular Condensation 641 Oxidation of a Quinoline 642 Isoquinolines 642 Intramolecular Cyclization of Imidoyl Chlorides 642 Intramolecular Cyclization of an Oxonium Ion 643 Condensation of Phenacyl Derivatives with Ammonia 643 Isoquinolinones 643 Benzamide Imine Condensation 643 Amide Cyclization 643 Quinolones (4-Hydroxyquinolines) 644 Electrophilic Cyclization 644 Nucleophilic Aromatic Substitution 644 Intramolecular Claisen Ring Closure 645 Pyrimidines and Pyrimidones 645 Condensation of Amidines with 1,3-Dicarbonyl Derivatives 645 Condensation of Amidines with Michael Acceptors 646 Cyclization of Cyano Amides 646 Quinazolines and Quinazolinones 647 Derivatization of Anthranilic Acids 647 Reaction of Benzonitriles 647 Intramolecular Condensations 648 Electrophilic Aromatic Substitution 648 Pyrazines and Quinoxalines 648 Condensation of Dianilines 649 Condensation of Dicarbonyl Derivatives with Ammonia 649

Contents

13.23 13.23.1 13.23.2 13.23.3 13.24 13.24.1 13.24.2 13.24.3 13.25 13.25.1 13.25.2 13.25.3 13.25.4 13.26 13.26.1 13.26.2 13.26.3 13.26.4 13.27 13.27.1 13.27.2 13.28 13.28.1 13.28.2 13.28.3 13.28.4 13.29 13.29.1 13.29.2 13.29.3 13.29.4 13.30 13.30.1 13.30.2 13.31 13.31.1 13.31.2 13.32 13.32.1 13.32.2 13.32.3 13.33 13.33.1 13.33.2 13.34 13.34.1 13.34.2

Pyridazines, Phtalazines, and Cinnolines 650 Addition of Hydrazine to Dicarbonyl Derivatives 650 Addition to a Diazo Derivative 650 Electrophilic Aromatic Substitution 651 1,2,4-Triazines 651 Reaction of Amidrazones with Glyoxal Derivatives 651 Reaction of Nitroanilines with Cyanamide 651 Reaction of Aminopyrroles 651 Furans and Benzofurans 652 Condensation of 1,3-Dicarbonyls with an α-Halocarbonyl 652 Cyclodehydration of a 1,4-Dicarbonyl Compound 653 Dehydration 653 Metal-Mediated Cyclization 653 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone 653 Condensation of ortho-Phenoxy-1,3-dicarbonyl Derivatives 654 Condensation of ortho-Acylcarbonyl Derivatives 654 Electrophilic Cyclization 654 Nucleophilic Aromatic Substitution 654 Coumarins 655 Condensation of ortho-Acylcarbonyl Derivatives 655 Arylation of Bromobenzoic Acid Derivatives 655 Thiophenes and Benzothiophenes 656 Aldol Condensation 656 Knoevenagel Condensation 656 Cyclodehydration of 1,4-Dicarbonyl Derivatives 657 Nucleophilic Addition to Sulfur Followed by Cyclocondensation 657 Isoxazoles and Benzisoxazoles 657 Hydroxylamine Addition to 1,3-Dicarbonyl Derivatives/Enaminoketones 658 Alkylation of Dihalides 658 Dipolar Cycloaddition 658 Nucleophilic Aromatic Substitution 659 Oxazoles and Benzoxazoles 659 Cyclization on an Activated Carbonyl Derivative 659 Dipolar Cycloaddition 660 Isothiazoles and Benzisothiazoles 660 Intramolecular Cyclization 660 Addition to ortho-Thiobenzonitriles 661 Thiazoles and Benzothiazoles 661 Condensation of Thioamides with Haloketones 661 Condensation of Carboxylic Acid Derivatives with 2-Aminothiols 662 Nucleophilic Aromatic Substitution 662 1,2,4-Oxadiazoles 662 Condensation of Hydroxyurea with Carboxylic Acids 662 Condensation of Hydroxyurea with Carboxylic Acid Derivatives 663 1,3,4-Oxadiazoles 663 Cyclodehydration of Hydrazide 663 Nitrogen Extrusion 664

14

Access to Chirality 665 Angela L. A. Puchlopek-Dermenci and Robert W. Dugger

14.1 14.2 14.3 14.3.1

Introduction 665 Using the Chiral Pool 665 Classical Resolutions 668 The Family Approach (the Dutch Resolution) 670

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14.3.2 14.3.3 14.3.3.1 14.3.3.2 14.3.3.3 14.4 14.4.1 14.4.2 14.5 14.6

Separation of Covalent Diastereomers 670 Kinetic Resolutions 670 Resolution of Alcohols 671 Resolution of Amines 672 Resolution of Epoxides 672 Dynamic Kinetic Resolutions 673 Dynamic Kinetic Resolutions via Chemical Reactions 673 Dynamic Kinetic Resolutions via Crystallization 674 Desymmetrization of Meso Compounds 675 Chiral Chromatography 676

15

Biocatalysis 679 Carlos A. Martinez, Rajesh Kumar, and John Wong

15.1 15.2 15.2.1 15.2.2 15.2.2.1 15.2.2.2 15.2.2.3 15.3 15.3.1 15.3.2 15.3.3 15.3.3.1 15.4 15.4.1 15.4.2 15.4.3 15.4.4 15.4.4.1 15.4.4.2 15.4.5 15.5 15.5.1 15.5.1.1 15.5.1.2 15.5.1.3 15.5.1.4 15.5.2 15.5.3 15.6

Introduction 679 Group Transfer Reactions 682 Amine Synthesis Catalyzed by Transaminases 682 Reactions Catalyzed by Hydrolases 685 Chiral Carboxylic Acids and Amides from Esters 685 Acylation of Racemic and Prochiral Alcohols and Amines in Organic Solvents 686 Miscellaneous Hydrolases 687 Reductions 688 Reduction of C=C Bonds 689 Reductive Amination of α-Ketoacids to α-Amino Acids 690 Reduction of C=O Bonds 691 Reduction of Ketones and Aldehydes 691 Oxidations 693 Baeyer–Villiger Monoxygenase (BVMO) Oxidations 693 C—H Oxidations 694 C=C Oxidations 695 Alcohol Oxidations 696 Cofactor-Dependent Alcohol Oxidations 696 Cofactor-Independent Alcohol Oxidations 698 C—N Oxidations 698 C—C Bond Forming Reactions 699 Aldol Reaction 700 Acetaldehyde Aldolases 700 Pyruvate-Dependent Aldolases 701 DHAP Aldolases 701 Threonine Aldolase 702 Cyanohydrin Formation 702 Acyloin Condensation 702 Future Developments 703

16

Green Chemistry 705 Juan Colberg, Jared L. Piper, and John Wong

16.1 16.2 16.2.1 16.2.2 16.2.3 16.2.4 16.2.5 16.2.6 16.3

Introduction 705 Green Chemistry Metrics 706 Atom Economy (AE) 707 Reaction Mass Efficiency (RME) 707 E Factor 707 Process Mass Intensity (PMI) 708 Life Cycle Assessment (LCA) 708 Innovation Green Aspiration Level (iGAL) Methodology 708 Solvent and Reagent Selection 710

Contents

16.3.1 16.3.2 16.3.3 16.4 16.5 16.5.1 16.5.2 16.5.3 16.5.4 16.6 16.7 16.7.1 16.7.2

Organic Solvent Selection 710 Aqueous Systems 711 Classic Reactions in Aqueous Systems 711 Green Reactions/Reagents 716 Examples of Green Methods and Reagents for Common Reaction Types 716 Formation of Aryl Amines and Aryl Amides 716 Carbon–Carbon Bond Formation 718 Oxidation 719 Nonprecious Metals Catalysis 721 Predictive Tools to Design for Green Chemistry 724 Green Chemistry Improvements in Process Development 725 Pregabalin 725 Sitagliptin 726

17

Continuous Chemistry 729 David D. Ford, Robert J. Maguire, J. Christopher McWilliams, Bryan Li, and Jared L. Piper

17.1 17.2 17.2.1 17.2.2 17.2.3 17.3 17.3.1 17.4 17.4.1 17.4.2 17.4.3 17.5 17.6 17.6.1 17.7 17.8 17.8.1 17.8.2 17.8.3 17.8.4 17.9 17.9.1 17.9.2 17.10 17.10.1 17.10.2 17.10.3 17.11 17.11.1 17.11.2 17.11.3 17.12 17.12.1 17.12.2 17.13 17.13.1 17.13.2 17.13.3

Introduction 729 Aliphatic Nucleophilic Substitutions 731 Aliphatic Nucleophilic Substitutions at sp3 Carbons 731 Amidations 732 Esterification with Diazomethane 734 Additions to C—Het Multiple Bonds 735 Reductive Aminations 735 Addition to C—C Multiple Bonds 735 Cyclopropanation 735 Hydroformylation 737 Hydroboration/Oxidation of Olefins 738 Nucleophilic Aromatic Substitutions 739 Electrophilic Aromatic Substitution 739 Nitration 739 Catalysis 741 Rearrangements 743 Curtius Rearrangement 743 Claisen Rearrangement 745 Newman–Kwart Rearrangement 746 Overman Rearrangement 746 Eliminations 746 Thermal Deprotection of tert-Butyloxycarbonyl (Boc) Amines 746 Deprotection of t-Butyl Esters 747 Reductions 748 Hydrogenation of Olefins 748 Hydrogenation of Nitroarenes 748 Hydrogenolysis 750 Oxidations 751 Aerobic Oxidations 751 Nonaerobic Oxidation 754 Dehydrogenation 757 Free Radical Reactions 757 Chemical Initiated Free Radical Reactions 757 Photochemical Reactions 758 Syntheses of Organometallic Reagents 760 Organolithium 761 Organomagnesium 763 Organozinc 765

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17.14 17.14.1 17.14.2 17.15 17.15.1 17.16

Synthesis of Aromatic Heterocycles 766 Synthesis of Aromatic Hyterocycles under Superheated Conditions 766 Heterocycles from Azido or Hydrazine Compounds 769 Access to Chirality 770 Access to Chirality via Asymmetric Hydrogenations 770 Biotransformations 771

18

General Solvent Properties Stéphane Caron

18.1 18.2 18.3 18.4 18.5 18.6 18.7

Introduction 773 Definitions and Acronyms 774 Solvent Properties 775 Mutual Solubility of Water and Organic Solvents 778 Other Useful Information on Solvents 779 Solvent Safety 780 Risk Phrases Used in the Countries of EU 781

19

Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School 785 Sally Gut Ruggeri

19.1 19.2 19.2.1 19.2.2 19.2.3 19.2.4 19.2.5 19.2.6 19.2.7 19.3 19.3.1 19.3.2 19.3.3 19.3.4 19.3.4.1 19.3.4.2 19.3.4.3 19.3.4.4 19.3.4.5 19.3.4.6 19.3.4.7 19.3.4.8 19.3.4.9 19.4 19.4.1 19.4.1.1 19.4.1.2 19.4.1.3 19.4.1.4 19.4.1.5 19.4.1.6 19.4.1.7 19.4.2 19.4.2.1

Introduction 785 Reaction Execution 785 Heat Transfer 785 Heat Profiles 786 Stirring 786 Homogeneous vs. Heterogeneous Reactions 786 Electrophilic vs. Nucleophilic Substitution Reactions 786 Gas Generation 787 Execution of Energetic Reactions 787 Solvents and Reagents 788 Solvent Selection 788 Removal of Water from Solvents or Reactions 790 Solvent Contamination 791 Reagent Selection and Compatibility 791 Replacements for NaH 791 Use of Hydrides 791 Metal Catalysts 792 Generation of HCl 792 HF 792 NBS 793 Use of POCl3 793 KOH Contamination 793 Material Compatibility 793 Isolation 793 Reaction Workups 793 Extractions 794 Emulsions 794 Workup of Hydrides 794 Workup of POCl3 795 Reduction of Iodine 795 Removal of Ph3 PO 795 Removal of Triethylamine 795 Purification 795 Crystallization 795

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Contents

19.4.2.2 19.4.2.3 19.4.2.4 19.4.2.5 19.5 19.5.1 19.5.2 19.5.3 19.5.4 19.5.5

Reslurries or Repulping 796 Formation of Salts or Adducts 796 Purging Heavy Metals 797 Silica Gel Purification 797 Analysis 797 Thin Layer Chromatography 798 High or Ultra High Performance Liquid Chromatography 798 Supercritical Fluid Chromatography 798 Gas Chromatography 798 Nuclear Magnetic Resonance Spectroscopy 799 Subject Index 801 Combo Index 811

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List of Contributors Adam R. Brown

Emma McInturff

PfizerWorldwide R&D Groton, CT USA

PfizerWorldwide R&D Groton, CT USA

Angela L. A. Puchlopek-Dermenci

Elizabeth C. Swift

PfizerWorldwide R&D Groton, CT USA

Abbvie Inc. North Chicago, IL USA

Bryan Li

Eric C. Hansen

PfizerWorldwide R&D Groton, CT USA

PfizerWorldwide R&D Groton, CT USA

Carlos A. Martinez

Jade D. Nelson

PfizerWorldwide R&D Groton, CT USA

PfizerWorldwide R&D Groton, CT USA

Chad A. Lewis

Jared L. Piper

PfizerWorldwide R&D Groton, CT USA

PfizerWorldwide R&D Groton, CT USA

J. Christopher McWilliams

John A. Ragan

PfizerWorldwide R&D Groton, CT USA

PfizerWorldwide R&D Groton, CT USA

Christophe Allais

John Wong

PfizerWorldwide R&D Groton, CT USA

Pfizer Chemical R&D Worldwide Research & Development Groton, CT USA

David H. Brown Ripin

Clinton Health Access Initiative Boston, MA USA David D. Ford

Snapdragon Chemistry Inc. Waltham, MA USA

Juan Colberg

Pfizer Chemical R&D Worldwide Research & Development Groton, CT USA

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List of Contributors

Kristin E. Price Wiglesworth

Robert J. Maguire

Keller and Heckman LLP Washington, DC USA

Cybrexa Therapeutics New Haven, CT USA

Nathan D. Ide

Robert J. Perkins

Abbvie Inc. North Chicago, IL USA

St. Louis University St. Louis, MO USA

Pascal Dubé

Sally Gut Ruggeri

MATSYS, Inc. Sterling, VA USA

PfizerWorldwide R&D Groton, CT USA

Prantik Maity

Sebastien Monfette

Biocon Bristol-Myers Squibb R&D Center Bangalore India

PfizerWorldwide R&D Groton, CT USA

Rajappa Vaidyanathan

Shashank Shekhar

Biocon Bristol-Myers Squibb R&D Center Bangalore India Rajesh Kumar

PfizerWorldwide R&D Groton, CT USA Robert W. Dugger

PfizerWorldwide R&D Groton, CT USA

Abbvie Inc. North Chicago, IL USA Shu Yu

PfizerWorldwide R&D Groton, CT USA Stéphane Caron

PfizerWorldwide R&D Groton, CT USA

xxxiii

Preface When I was approached to prepare a second edition of Practical Synthetic Organic Chemistry, my first inclination was to decline the opportunity remembering the years it took to put together the first edition of the manuscript thanks to the excellent contributions made by my industry collaborators. However, as I reflected on the advancements in the field of synthetic organic chemistry since the publication of our book in 2011, I realized the magnitude of the changes in terms of novel synthetic methodologies, manufacturing technologies, analytical techniques, and multidisciplinary contributions from fields such as engineering, molecular biology, computational assistance, robotics, and automation. The science of synthetic organic chemistry is ever expanding and continues to blossom, impacting multiple industries in a fast-paced and technologically driven global economy. After discussions with many of my contributors, we committed to the preparation of this edition. The Second Edition of the book retains its original intent: to guide scientists toward proven synthetic methods that have the highest probability of success having been demonstrated on a practical scale. The content differs from several other textbooks which might focus on first principles and reaction mechanisms. In a digital world, where it is becoming increasingly easier to identify potential solutions to a given transformation, Practical Synthetic Organic Chemistry provides a more concise, focused list of likely reaction conditions that could rapidly lead to a desired outcome, especially when an experimentalist may be limited by the amount of starting materials available or not be able to screen a vast array of experimental possibilities. While an explanation is not always provided for the selection of the specific examples shown, the general rule in our methodology was that the conditions described were found to work on a variety of substrates from the primary literature, and that a representative example with an experimental procedure on multigram scale be available. Building from the First Edition, we sought novel examples that may be superior to what was originally available in 2011. We also included several new reactions from synthetic methods that have emerged or increased in predictability and robustness in the last eight years. When possible, we have used primary references from Organic Process Research and Development (OPR&D), the Journal of Organic Chemistry (JOC), and Organic Syntheses (Org. Syn.), as the experimental procedures from these publications are experimentally robust and would guide scientists conducting a specific reaction for the first time. There are several key changes from the original edition. The first part of the book (Chapters 1–11) remains focused on reactions based on the type of synthetic transformations. The second part (Chapters 12–19) discusses techniques and additional information that may influence scientists on selecting how to conduct a reaction and preferred conditions including solvent selection, how to safely quench a reaction, and when to use continuous chemistry. The original chapters (Aliphatic Nucleophilic Substitution, Addition to Carbon–Heteroatom Multiple Bonds, Addition to Carbon–Carbon Multiple Bonds, Nucleophilic Substitution and Electrophilic Substitution) have kept a similar structure to the First Edition, providing contemporary examples and new content. Chapter 6 has been changed from Selected Metal-Mediated Cross-Coupling Reactions to Selected Catalytic Reactions. As the field of catalysis, most notably homogenous catalysis, and the level of understanding and predictability of these reactions has grown significantly in the last decade, we felt this chapter needed to be expanded accordingly. It not only covers the previous substrate in much more detail, it also includes a section on catalytic halogenations and preparation of fluorinated compounds, organocatalysis, and metal-mediated C–H functionalization all of which has been area of extensive research in recent years. Similar updates have been made to Chapters 7–10 covering rearrangements, elimination, reductions, and oxidations. Chapter 11, Selected Free Radical Reactions, has been extensively updated with focus on Photoredox Catalysis and Electrochemistry, as these topics have received much more attention and provided useful synthetic methods in recent years. Chapter 12 on the Synthesis of Organometallic Reagents has kept the similar organizational structure

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and content. Chapter 13 on The Synthesis of Common Aromatic Heterocycles has been expanded to include additional ring systems and providing clarity on the heterocycles selected and order of presentation in the chapter. Chapter 14 on Access to Chirality continues to exemplify strategies that differ from chiral synthesis that are covered in the previous chapters. The First Edition chapter on the development of contemporary pharmaceutical drugs was omitted as this area is constantly evolving and many other sources are now publishing this content. Chapter 15 is now a totally new chapter on Biocatalysis. While enzyme-catalyzed reactions were known and used when the First Edition was published, this field of research has exploded in the last decade with many advancements in molecular biology. The scope and practicality for synthetic organic chemistry based on these findings has been truly remarkable. This new chapter covers four key classes of reactions and offers insights on future developments in this discipline. Chapter 16 on Green Chemistry was expanded as new metrics have been developed, and several new examples are provided. However, the chapters on Naming Carbocycles and Heterocycles and pK a have been eliminated as computational tools are now routinely used to obtain this information (something the majority of us are grateful for). A completely new Chapter 17 discusses Continuous Chemistry describing the principles for evaluating reactions or developing a chemical process using continuous processing. Numerous examples based on reaction type are included. Chapter 18 on General Solvent Properties and Chapter 19 on Practical Chemistry Concepts have been updated to include additional data and new examples. Like the previous edition, we created two indexes. The first index is based on functional groups manipulation (i.e. how to obtain one functional group by reaction of a starting material containing another functional group). The second is based on reaction, reagent, or structural names. I am incredibly grateful to all the contributors of this Second Edition. Based on feedback received, several authors for companies outside of Pfizer made significant contributions to this revised manuscript, and their insights provided additional perspectives. While these changes led to some additional logistical challenges, the dedication and professionalism from each of these already very busy scientists is greatly appreciated. November 2019

Stéphane Caron Pfizer Worldwide R&D Groton, CT, USA

1

1 Aliphatic Nucleophilic Substitution Jade D. Nelson Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 1 Oxygen Nucleophiles, 1 Phosphorus Nucleophiles, 21 Sulfur Nucleophiles, 21 Nitrogen Nucleophiles, 26 Halogen Nucleophiles, 38 Carbon Nucleophiles, 47 Nucleophilic Substitution at a Sulfonyl Sulfur Atom, 60

1.1 Introduction Nucleophilic substitution reactions at an aliphatic center are among the most fundamental transformations in classical synthetic organic chemistry and provide the practicing chemist with proven tools for simple functional group interconversion as well as complex target-oriented synthesis. Conventional SN 2 displacement reactions involving simple nucleophiles and electrophiles are well-studied transformations, are among the first concepts learned by chemistry students, and provide a launching pad for more complex subject matter such as stereochemistry and physical organic chemistry. A high-level survey of the chemical literature provides an overwhelming mass of information regarding aliphatic nucleophilic substitution reactions. This chapter attempts to highlight those methods that stand out from the others in terms of scope, practicality, and scalability.

1.2 Oxygen Nucleophiles 1.2.1 1.2.1.1

Reactions with Water Hydrolysis of Alkyl Halides

The reaction of water with an alkyl halide to form the corresponding alcohol is rarely utilized in target-oriented organic synthesis. Instead, conversion of alcohols to their corresponding halides is more common since methods for the synthesis of halides are less abundant. Nonetheless, alkyl halide hydrolysis can provide simple, efficient access to primary alcohols under certain circumstances. Namely, the hydrolysis of activated benzylic or allylic halides is a facile reaction, and following benzylic or allylic halogenation provides a simple approach to the synthesis of this subset of alcohols. Typical conditions involve treatment of the alkyl halide with a mild base in an acetone-water or acetonitrile-water mixed solvent system. Moderate heating will accelerate the reaction and is commonly employed.1

1 Lee, B. T.; Schrader, T. O.; Martin-Matute, B.; Kauffman, C. R.; Zhang, P.; Snapper, M. L. Tetrahedron 2004, 60, 7391–7396. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

2

1 Aliphatic Nucleophilic Substitution

1.2.1.2

Hydrolysis of gem-Dihalides

Geminal dihalides can be converted to aldehydes or ketones via direct hydrolysis. The desired conversion can be markedly accelerated by heating in the presence of an acid or a base, or by including a nucleophilic amine promoter such as dimethylamine.2

In the following example from Snapper and coworkers, a trichloro intermediate was prepared from p-methoxystyrene via the Kharasch addition of 1,1,1-trichloroethane. Contact with silica gel effected elimination of the benzylic chloride as well as hydrolysis of the geminal dichloride moiety to yield the α,β-unsaturated methyl ketone in good overall yield.3

Difluoromethyl substituents have become more prevalent in pharmaceutical applications. These functional groups can be quite sensitive to acid-catalyzed hydrolysis, providing aldehyde products. For example, while attempting to cleave a phthalimido protecting group with aqueous HCl, Grygorenko and coworkers reported the preferential hydrolysis of the difluoromethyl substituent.4

Reflux

1.2.1.3

Hydrolysis of 1,1,1-Trihalides

1,1,1-Trihalides are at the appropriate oxidation state to serve as carboxylic acid precursors. Select compounds react readily with water at acidic pH, providing the corresponding acids in high yield, and often at ambient temperature.5 Trichloromethyl groups, rather than tribromo-, trifluoro- or triiodo- analogs, are most often utilized due to superior access via nucleophilic displacements reactions by trichloromethyl anions.

2 Bankston, D. Synthesis 2004, 283–289. 3 See Note 1. 4 Ivonin, S. P.; Kurpil, B. B.; Bezdudny, A. V.; Volochnyuk, D. M.; Grygorenko, O. O. Journal of Fluorine Chemistry 2015, 176, 78–81. 5 Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.; Moura, S.; Sinhorin, A. P.; Cunico, W.; Zanatta, N.; Bonacorso, H. G.; Flores, A. C. F. Synthesis 2003, 2353–2357.

1.2 Oxygen Nucleophiles

The trifluoromethyl group has seen increased application in the pharmaceutical industry in recent years due to its relative metabolic stability. Although trifluoromethyl groups are susceptible to vigorous hydrolytic conditions,6 they are infrequently utilized as carboxylic acid precursors due to the relative expense of incorporating fluorine into building blocks. 1.2.1.4

Hydrolysis of Alkyl Esters of Inorganic Acids

Alkaline hydrolysis of inorganic esters may proceed through competing mechanisms, as illustrated by the mesylate and boric acid monoester in the following scheme. Sulfonate hydrolysis favors the product of stereochemical inversion, via direct SN 2 attack at the carbon bearing the sulfonate. In contrast, the corresponding boron derivative is hydrolyzed under identical reaction conditions with retention of configuration, which is the result of formal attack by hydroxide at boron.7

Enders et al. demonstrated that γ-sultone hydrolysis occurs exclusively via attack at carbon to provide γ-hydroxy sulfonates with a high degree of stereochemical control.8 In order to verify stereochemistry, the crude sulfonic acid was converted into the corresponding methyl sulfonate by treatment with diazomethane (see Section 1.2.3.6).

Re

1.2.1.5

Hydrolysis of Diazo Ketones

Treatment of simple α-diazo ketones with hydrochloric acid in aqueous acetone provides direct access to the corresponding alcohols.9 In their 1968 paper, Tillett and Aziz describe an investigation into the kinetics of this transformation that utilized a number of diazoketones and mineral acids.10 Although the reaction can be run under mild conditions, and is often high-yielding, the preparation and handling of diazo compounds is a safety concern that may preclude their use on large scale.

1.2.1.6

Hydrolysis of Acetals, Enol Ethers, and Related Compounds

Acetals are highly susceptible to acid-catalyzed hydrolysis, typically providing the corresponding aldehydes under very mild conditions. Almost any acid catalyst can be employed, so the choice is usually dependent upon substrate 6 Butler, D. E.; Poschel, B. P. H.; Marriott, J. G. Journal of Medicinal Chemistry 1981, 24, 346–350. 7 Danda, H.; Maehara, A.; Umemura, T. Tetrahedron Letters 1991, 32, 5119–5122. 8 Enders, D.; Harnying, W.; Raabe, G. Synthesis 2004, 590–594. 9 Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. The Journal of Organic Chemistry 1993, 58, 5683–5689. 10 Aziz, S.; Tillett, J. G. Journal of the Chemical Society [Section] B: Physical Organic 1968, 1302–1307.

3

4

1 Aliphatic Nucleophilic Substitution

compatibility. Solid-supported sulfonic acid catalysts such as Amberlyst-1511 are an especially attractive option due to the relative ease of catalyst removal by simple filtration.12

Enol ethers of simple ketones may be similarly hydrolyzed by treatment with aqueous acid. A water-miscible organic cosolvent such as acetone or acetonitrile is often included to improve substrate solubility.13 Moderate heating increases the rate of hydrolysis, but high temperatures are seldom required.

Dithioketene acetals may be hydrolyzed to thioesters under very mild conditions. Note that the strongly acidic reaction conditions employed in the following example resulted in concomitant β-dehydration and loss of the acid labile N-trityl protecting group.14

Ac

Orthoesters may also be hydrolyzed through treatment with aqueous acid, as exemplified in the following scheme.15 Methanol is often included as a nucleophilic cosolvent that participates in the hydrolysis.

Under mildly acidic conditions, a terminal orthoester will provide the carboxylic acid ester.16 However, prolonged exposure to aqueous acid will yield the carboxylic acid.

11 Kunin, R.; Meitzner, E.; Bortnick, N. Journal of the American Chemical Society 1962, 84, 305–306. 12 Coppola, G. M. Synthesis 1984, 1021–1023. 13 Fuenfschilling, P. C.; Zaugg, W.; Beutler, U.; Kaufmann, D.; Lohse, O.; Mutz, J.-P.; Onken, U.; Reber, J.-L.; Shenton, D. Organic Process Research & Development 2005, 9, 272–277. 14 See Note 9. 15 Kato, K.; Nouchi, H.; Ishikura, K.; Takaishi, S.; Motodate, S.; Tanaka, H.; Okudaira, K.; Mochida, T.; Nishigaki, R.; Shigenobu, K.; Akita, H. Tetrahedron 2006, 62, 2545–2554. 16 Martynow, J. G.; Jozwik, J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.; Wisniewski, K.; Winiarski, J.; Zegrocka-Stendel, O.; Golebiewski, P. European Journal of Organic Chemistry 2007, 689–703.

1.2 Oxygen Nucleophiles

1.2.1.7

Hydrolysis of Silyl Enol Ethers

Silyl enol ethers are prone to hydrolysis at a rate generally consistent with their relative steric bulk. Trimethylsilyl (TMS) enol ethers are particularly labile and may by hydrolyzed in the absence of an acid catalyst in some instances.17 In contrast, bulky triisopropylsilyl (TIPS) enol ethers are generally stable enough to withstand an acidic aqueous workup and may even be purified via silica gel chromatography. In the following scheme, the TMS, tert-butyl dimethylsilyl (TBS), and TIPS enol ethers of cyclohexanone are desilylated by treatment with aqueous hydrochloric acid in tetrahydrofuran (THF). The variation in reaction rate under these conditions is noteworthy.18

1.2.1.8

Hydrolysis of Silyl Ethers

Silyl ethers are generally less susceptible to acid-catalyzed hydrolysis than their enol ether counterparts. However, increasing the reaction time, reaction temperature, or acid concentration can provide a simple, high-yielding method for the removal of silicon-based hydroxyl protecting groups, provided that the rest of the molecule is stable to such treatment.19

In the following example, the removal of two silyl ethers and one silyl enol ether was accomplished with aqueous acetic acid in THF at room temperature.20 These milder conditions necessitated a longer reaction time but conserved the acid sensitive methyl ester and tertiary alcohol functional groups.

For acid sensitive substrates, the use of fluoride ion (e.g. tetra-n-butylammonium fluoride, TBAF) provides an attractive alternative (see Section 1.6.1.7) and is increasingly employed as a first choice reagent. Silyl ethers may be cleaved under aqueous alkaline conditions when the silicon center is less electron-rich. For example, tert-butyl diphenylsilyl (TBDPS or TPS) ethers are susceptible to base promoted cleavage, despite their relative stability to acid. This reactivity is complementary to that of TBS ethers, allowing for selective silyl protection of similar functional groups.21

17 Keana, J. F. W.; Eckler, P. E. The Journal of Organic Chemistry 1976, 41, 2850–2854. 18 Manis, P. A.; Rathke, M. W. The Journal of Organic Chemistry 1981, 46, 5348–5351. 19 Sun, H.; Abboud, K. A.; Horenstein, N. A. Tetrahedron 2005, 61, 10462–10469. 20 Collins, P. W.; Gasiecki, A. F.; Jones, P. H.; Bauer, R. F.; Gullikson, G. W.; Woods, E. M.; Bianchi, R. G. Journal of Medicinal Chemistry 1986, 29, 1195–1201. 21 Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.; Yamada, H.; Nishizawa, M. Tetrahedron 1994, 50, 13369–13376.

5

6

1 Aliphatic Nucleophilic Substitution

Re

Silyl ethers may also be cleaved by nucleophilic alcohols in the presence of strong acid catalysts (see Section 1.2.2.6). 1.2.1.9

Hydrolysis of Epoxides

Epoxides can be efficiently ring-opened under acid catalysis in an aqueous environment to afford 1,2-diol products. In cases where the regiochemistry of attack by water is inconsequential, or is directed by steric and/or electronic bias within the substrate, simple Brønsted acid catalysts are utilized. In the following example, hydrolysis is promoted by the sulfonated tetrafluoroethylene copolymer Nafion-H to provide the racemic 1,2-anti-diol product via backside attack on the epoxide.22

1.2.2 1.2.2.1

Reactions with Alcohols Preparation of Ethers from Alkyl Halides

The preparation of ethers from alcohols may be accomplished via treatment with an alkyl halide in the presence of a suitable base (the Williamson ether synthesis). For relatively acidic alcohols such as phenol derivatives, the use of potassium carbonate in acetone is a simple, low cost option.23

Ac

The rate of ether formation can be accelerated by increasing the reaction temperature, or more commonly by employing a more reactive alkyl halide. This is accomplished in the following example via conversion of benzyl chloride to benzyl iodide in situ by including potassium iodide in the reaction mixture (Finkelstein reaction; see Section 1.5.1.1).24 Since the iodide ions are regenerated over the course of the reaction, a substoichiometric quantity can often be used. However, a stoichiometric excess of iodide increases the concentration of the more reactive alkylating agent and thus improves the kinetics of the alkylation reaction. Note that under the conditions utilized, the carboxylic acid is also converted to the corresponding benzyl ester. For more on the preparation of esters from carboxylic acids, see Sections 1.2.3 and 2.31.

Ac

Henegar et al. reported the use of potassium isopropoxide in dimethyl carbonate for the large-scale preparation of an ether intermediate in the synthesis of the commercial antidepressant (±)-reboxetine mesylate.25

22 Olah, G. A.; Fung, A. P.; Meidar, D. Synthesis 1981, 280–282. 23 Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C. C.; Correia, C. R. D. The Journal of Organic Chemistry 2005, 70, 1050–1053. 24 Bourke, D. G.; Collins, D. J. Tetrahedron 1997, 53, 3863–3878. 25 Henegar, K. E.; Ball, C. T.; Horvath, C. M.; Maisto, K. D.; Mancini, S. E. Organic Process Research & Development 2007, 11, 346–353.

1.2 Oxygen Nucleophiles

Similarly, Piotrowski et al. utilized potassium tert-butoxide in tert-butanol for intramolecular O-alkylation to form a ring.26 In this case, dynamic epimerization of the methyl-bearing stereocenter prior to C—O bond formation provides the kinetic product as the dominant diastereomer. t t

In the following example, careful selection of solvent and reagent, while optimizing reaction parameters allowed for successful O-alkylation of the isoxazole, minimized competitive formation of the N-benzyl by-product.27

Fluorinated compounds have become increasingly prevalent in target oriented synthesis owing to their unique attributes in pharmaceutically active drug substances. In the following example, Sperry and Sutherland describe a high-yielding, scale-friendly process for difluoromethylation of methyl 4-hydroxy-3-iodobenzoate.28,29 The authors note the importance of a slow addition of reactants to the base, in order to minimize oligomeric by-products.

1.2.2.2

Preparation of Methyl Ethers

Dimethyl carbonate is an ambident electrophile that typically reacts with soft nucleophiles at a methyl carbon and with hard nucleophiles at the central carbonyl. Via the former mechanism, dimethyl carbonate has been used for the methylation of phenols, leading to the formation of arylmethyl ethers. This is an especially attractive reagent for large-scale applications, owing to the low cost, low toxicity, and negligible environmental impact of dimethyl carbonate30 ; however, scope is limited due to the modest reactivity of the reagent. In the following example, Thiébaud and coworkers illustrate the selective methylation of a bis-phenol compound with dimethyl carbonate and potassium carbonate in the absence of solvent.31 26 Piotrowski, D. W.; Futatsugi, K.; Casimiro-Garcia, A.; Wei, L.; Sammons, M. F.; Herr, M.; Jiao, W.; Lavergne, S. Y.; Coffey, S. B.; Wright, S. W.; Song, K.; Loria, P. M.; Banker, M. E.; Petersen, D. N.; Bauman, J. Journal of Medicinal Chemistry 2018, 61, 1086–1097. 27 Zhang, W.-Y.; Hogan, P. C.; Chen, C.-L.; Niu, J.; Wang, Z.; Lafrance, D.; Gilicky, O.; Dunwoody, N.; Ronn, M. Organic Process Research & Development 2015, 19, 1784–1795. 28 Sperry, J. B.; Sutherland, K. Organic Process Research & Development 2011, 15, 721–725. 29 Sperry, J. B.; Farr, R. M.; Levent, M.; Ghosh, M.; Hoagland, S. M.; Varsolona, R. J.; Sutherland, K. Organic Process Research & Development 2012, 16, 1854–1860. 30 Tundo, P.; Rossi, L.; Loris, A. The Journal of Organic Chemistry 2005, 70, 2219–2224. 31 Ouk, S.; Thiebaud, S.; Borredon, E.; Le Gars, P. Green Chemistry 2002, 4, 431–435.

7

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1 Aliphatic Nucleophilic Substitution

Shen et al. discussed the “greenness” of their protocol for the preparation of arylmethyl ethers from their phenol precursors.32 Thus, treatment of various phenols with dimethyl carbonate at 120 ∘ C in the recyclable ionic liquid 1-n-butyl-3-methylimidazolium-chloride ((BMIm)Cl) provides quantitative yields of aryl methyl ethers. The use of ionic liquids has been heavily debated in recent years, as these materials are relatively expensive, and current methods for their manufacture pose a significant environmental impact. Nevertheless, opportunities for reuse and recycle make continued development in this area a worthwhile venture.

The preferred method for the preparation of methyl ethers via alkylation of alcohol precursors generally utilizes dimethyl sulfate (MeO)2 SO2 , rather than methyl iodide, due to the decreased worker exposure risk that accompanies its lower volatility. Typically, the alcohol is treated with dimethyl sulfate and a suitable base in a polar aprotic solvent. Yields are generally high, and product isolation is relatively straightforward. The following examples are illustrative, and both were carried out on large scale.33,34 It should be noted that most alkylating agents–dimethylsulfate included–pose serious toxicological hazards and thus require cautious handling and environmental controls.

Re

In certain cases, dimethyl sulfate (or methyl iodide) may be replaced by the less toxic methyl tosylate, as illustrated in the following example. With more reactive nitrogen nucleophiles, this reagent should be considered as the first choice at any scale (see Section 1.5.1.2).35

32 Shen, Z. L.; Jiang, X. Z.; Mo, W. M.; Hu, B. X.; Sun, N. Green Chemistry 2005, 7, 97–99. 33 Liu, Z.; Xiang, J. Organic Process Research & Development 2006, 10, 285–288. 34 Prabhakar, C.; Reddy, G. B.; Reddy, C. M.; Nageshwar, D.; Devi, A. S.; Babu, J. M.; Vyas, K.; Sarma, M. R.; Reddy, G. O. Organic Process Research & Development 1999, 3, 121–125. 35 Littler, B. J.; Aizenberg, M.; Ambhaikar, N. B.; Blythe, T. A.; Curran, T. T.; Dvornikovs, V.; Jung, Y. C.; Jurkauskas, V.; Lee, E. C.; Looker, A. R.; Luong, H.; Martinot, T. A.; Miller, D. B.; Neubert-Langille, B. J.; Otten, P. A.; Rose, P. J.; Ruggiero, P. L. Organic Process Research & Development 2015, 19, 270–283.

1.2 Oxygen Nucleophiles

1.2.2.3

Preparation of Ethers from Alkyl Sulfonates

A widespread and practical strategy for the synthesis of ethers, especially on large scale, is through the intermediacy of alkyl sulfonates. Broad access to alcohol precursors, coupled with the low cost and high efficiency in converting these alcohols to electrophilic sulfonates has contributed to the popularity of this method. Mesylates or tosylates are used most often, as MsCl and TsCl are considerably less expensive than other sulfonyl halides. However, for demanding nucleophilic substitution reactions, the 4-bromobenzenesulfonate (brosylate) or 4-nitrobenzenesulfonate (nosylate, ONs) offer increased reactivity. In the following example, a substituted phenol was alkylated with a primary mesylate in good yield under representative conditions.36 (i) (ii)

In a second example, alkylation was shown to proceed through an epoxide intermediate formed via intramolecular displacement of the tosylate by the adjacent hydroxyl. The zinc alkoxide was superior to the lithium derivative in terms of yield and reaction rate.37

1.2.2.4

Iodoetherification

Treatment of olefins with iodine provides an electrophilic iodonium species that can be trapped with oxygen nucleophiles to provide ethers. A base is included to quench the HI that gets generated during the reaction. The intramolecular nucleophilic displacement occurs at a much higher rate than intermolecular trapping, so cyclic ethers are formed in high yield. In the following example, two additional stereocenters are created with high selectivity through treatment of an unsaturated cis-1,3-diol with iodine and sodium bicarbonate in aqueous ether at 0 ∘ C.38

1.2.2.5

Preparation of Silyl Ethers

Despite the relatively high molar expense of substituted silicon compounds such as tert-butyl dimethylsilyl chloride (TBSCl), silyl ethers are often utilized as alcohol protecting groups in synthesis because of their excellent compatibility with a broad range of common processing conditions, coupled with their relative ease of removal. Vanderplas et al. prepared the following TBS ether in high yield as part of a multikilogram synthesis of a β-3 adrenergic receptor agonist.39 36 Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R. K.; Shen, L.; Youells, S.; Zhang, Y. Organic Process Research & Development 2007, 11, 1010–1014. 37 Wu, G. G. Organic Process Research & Development 2000, 4, 298–300. 38 Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yoshida, Z. The Journal of Organic Chemistry 1987, 52, 4062–4072. 39 Vanderplas, B. C.; DeVries, K. M.; Fox, D. E.; Raggon, J. W.; Snyder, M. W.; Urban, F. J. Organic Process Research & Development 2004, 8, 583–586.

9

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1 Aliphatic Nucleophilic Substitution

The preferred conditions for TBS protection of this secondary alcohol included imidazole base in dimethylformamide (DMF).

The following example highlights the strong steric bias of TBSCl toward reaction with the unhindered secondary alcohol over the more hindered secondary and tertiary alcohols.40

1.2.2.6

Cleavage of Silyl Ethers with Alcohols

Although most common methods utilize fluoride ion (see Section 1.5.1.7), silyl ethers can be cleaved with alcohols promoted by strong acids. Watson et al. reported a high-yielding example of the use of ethanolic hydrogen chloride in their large-scale synthesis of the tumor necrosis factor-α inhibitor candidate MDL 201449A.41

Selective cleavage of a TMS ether in the presence of the more sterically encumbered TBS derivative has been accomplished via treatment with a methanolic solution of oxalic acid dihydrate.42

1.2.2.7

Transetherification

The direct interconversion of ethers is not typically a practical transformation and is thus rarely employed. The reaction can be accomplished, however, by treating the starting ether with an alcohol under the promotion of a strong mineral acid. The interconversion is an equilibrium process, so the alcohol is typically used as a cosolvent or in significant molar excess. A thorough study of the thermodynamics of interconversion of electronically diverse 1-phenylethyl ethers with aliphatic alcohols was reported by Jencks and coworkers.43 The following example from Pittman and coworkers highlights the efficiency of acetal exchange under Brønsted acid catalysis.44 This reaction is formally a double transetherification, although it has the advantage of proceeding via an 40 Van Arnum, S. D.; Carpenter, B. K.; Moffet, H.; Parrish, D. R.; MacIntrye, A.; Cleary, T. P.; Fritch, P. Organic Process Research & Development 2005, 9, 306–310. 41 Watson, T. J. N.; Curran, T. T.; Hay, D. A.; Shah, R. S.; Wenstrup, D. L.; Webster, M. E. Organic Process Research & Development 1998, 2, 357–365. 42 Maehr, H.; Uskokovic, M. R.; Adorini, L.; Reddy, G. S. Journal of Medicinal Chemistry 2004, 47, 6476–6484. 43 Rothenberg, M. E.; Richard, J. P.; Jencks, W. P. Journal of the American Chemical Society 1985, 107, 1340–1346. 44 Zhu, P. C.; Lin, J.; Pittman, C. U., Jr. The Journal of Organic Chemistry 1995, 60, 5729–5731.

1.2 Oxygen Nucleophiles

intermediate oxonium ion. In this instance, the reaction is rendered irreversible by running at a temperature where the liberated methanol is removed by distillation.

A wide variety of vinyl ethers can be prepared with ethylvinyl ether via Pd catalyzed transetherification, as exemplified in the following.45 Additional substitution on the olefin, however, severely diminishes the efficiency of the transformation and limits the scope. This reaction is not a nucleophilic aliphatic substitution but is included here to illustrate this complementary, albeit limited methodology. Me

Et

1.2.2.8

Preparation of Epoxides

Epoxides can be prepared in high yield through intramolecular nucleophilic displacement of halides by vicinal hydroxyls. In the following example, concentrated aqueous sodium hydroxide is used as the base in dichloromethane.46 This solvent choice, when used in combination with highly concentrated NaOH solution, minimizes water content within the organic phase to prevent competitive epoxide hydrolysis to the corresponding 1,2-diol. The addition of a phase transfer catalyst, as well as aggressive agitation, facilitates movement of hydroxide ions into the dichloromethane. (i)

(ii) Piper

Epoxides are often prepared from olefin precursors by sequential reaction with N-bromosuccinimide (NBS) and hydroxide in an aqueous environment. The NBS initially forms an electrophilic bromonium species, which is quickly converted to a bromohydrin via nucleophilic attack by water. As described in the following example, the bromohydrin can be converted to an epoxide in the same reaction vessel by addition of sodium hydroxide.47 In this instance, the epoxide was not purified but was further reacted to the azidohydrin by reaction with sodium azide at an elevated temperature. The opening of epoxides with nitrogen nucleophiles is also discussed in Section 1.5.1.6. More on the preparation of epoxides from carbon–carbon double bonds can be found in Section 3.10.4. (i)

(ii) 48% – 3 steps

45 Weintraub, P. M.; King, C.-H. R. The Journal of Organic Chemistry 1997, 62, 1560–1562. 46 Elango, S.; Yan, T.-H. Tetrahedron 2002, 58, 7335–7338. 47 Loiseleur, O.; Schneider, H.; Huang, G.; Machaalani, R.; Selles, P.; Crowley, P.; Hanessian, S. Organic Process Research & Development 2006, 10, 518–524.

11

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1 Aliphatic Nucleophilic Substitution

1.2.2.9

Reaction of Alcohols with Epoxides

Epoxides can be opened with nucleophilic alcohols in the presence of various activating agents. Despite a low degree of atom economy, NBS proved to be a very effective promoter in the following example.48 A catalytic quantity of an acid catalyst is often sufficient, however.

Re

In the following example from Loh and coworkers, a late-stage intramolecular epoxide opening by an alcohol is catalyzed by camphorsulfonic acid in dichloromethane to provide the desired furan as a single diastereomer in good yield.49 The γ-lactone resulting from intramolecular transesterification was observed as a minor by-product.

The specific case involving interconversion of two α,β-epoxy alcohols under basic conditions is known as the Payne rearrangement50 and is discussed in Section 7.2.2.3. The intermolecular ring-opening of epoxides by alcohol nucleophiles may be catalyzed by Lewis acids. The use of indium(III) chloride has proven to be particularly effective, as exemplified by Lee et al. in the following example.51 Here, both sterics (geminal methyls) and electronics (positive charge stabilization) direct the isopropanol nucleophile to the benzylic position.

1.2.2.10

The Reaction of Alcohols with Diazo Compounds

In a series of publications, Moody and coworkers have demonstrated the utility of Rh(II) catalyzed decomposition of α-diazo esters, sulfones, and phosphonates in the presence of various aliphatic and aromatic alcohols.52,53 The intramolecular variant of this method has found utility in the synthesis of functionalized cyclic ethers. Widespread application of the intermolecular reaction, however, has been hindered by the need for a large stoichiometric excess of the alcohol component to limit competitive hydrogen abstraction that leads to reduced product. Cat.

Reflux,

48 Iranpoor, N.; Firouzabadi, H.; Chitsazi, M.; Ali Jafari, A. Tetrahedron 2002, 58, 7037–7042. 49 Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis 2003, 755–764. 50 Payne, G. B. The Journal of Organic Chemistry 1962, 27, 3819–3822. 51 Lee, Y. R.; Lee, W. K.; Noh, S. K.; Lyoo, W. S. Synthesis 2006, 853–859. 52 Moody, C. J.; Taylor, R. J. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1989, 721–731. 53 Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E. R. H. B.; Kulagowski, J. J. Tetrahedron 1994, 50, 3195–3212.

1.2 Oxygen Nucleophiles

This example highlights the superiority of the Rh(II) trifluoroacetamide catalyst, as the more commonly employed Rh2 (OAc)4 afforded desired O–H insertion product in an inferior yield of 67% after 72 hours at reflux. Interestingly, photochemical decomposition of this diazo compound in isopropanol provided the product of hydrogen abstraction (i.e. reduction) exclusively in 90% yield. Complementary oxidative methods for the synthesis of related compounds are discussed in Section 10.3.4. 1.2.2.11

Preparation of Ethers via Dehydration of Alcohols

The direct formation of ethers from alcohol precursors is typically limited to the preparation of symmetrical ethers, as dehydration under the strongly acidic conditions employed generally occurs indiscriminately. In the following example, Ziyang et al. optimized a method for the production of solvent and one-time fuel additive methyl tert-butyl ether. In this method, a heated stream of tert-butanol and methanol are passed through a column packed with the strongly acidic resin Amberlyst-15.54 Reflux

1.2.2.12

Addition of Alcohols to Boron, Phosphorous, and Titanium

Borate esters can be prepared by direct reaction of alcohols with boron halides in the presence of a suitable base. In the following example, a 1,3,5-triol is reacted with boron trichloride and pyridine to yield a novel “tripod borate ester” in high yield. This compound is of particular interest due to the considerable distortion from planar geometry generally observed in borate esters.55

−

Phosphonate esters can be prepared in high yield by reaction of alcohols with diaryl halophosphates catalyzed by inorganic esters. As shown in the following, titanium(IV) t-butoxide was reported by Jones et al. to be the optimal catalyst.56

Phosphites and phosphonites are more commonly prepared by reaction of a metal alkoxide with a chlorophosphine derivative, as highlighted in the following example.57 These reactions are exothermic, so cooling is generally required. Furthermore, most phosphites and phosphonites are air and moisture sensitive, so care must be taken to avoid degradation. (i) (ii)

Due to the high oxophilicity of titanium(IV), titanates can be prepared through a process similar to the equilibrium-driven ligand exchange observed with organometallic complexes. For example, heating titanium(IV) 54 55 56 57

Ziyang, Z.; Hidajat, K.; Ray, A. K. Journal of Catalysis 2001, 200, 209–221. D’Accolti, L.; Fiorentino, M.; Fusco, C.; Capitelli, F.; Curci, R. Tetrahedron Letters 2007, 48, 3575–3578. Jones, S.; Selitsianos, D.; Thompson, K. J.; Toms, S. M. The Journal of Organic Chemistry 2003, 68, 5211–5216. Seebach, D.; Hayakawa, M.; Sakaki, J.; Schweizer, W. B. Tetrahedron 1993, 49, 1711–1724.

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1 Aliphatic Nucleophilic Substitution

ethoxide in the presence of the TADDOL ligand shown in the following initially provides an equilibrium mixture of titanium alkoxides. Complete exchange can be achieved by removal of ethanol by distillation.58 (i) (ii) Reflux, 5 h

1.2.3 1.2.3.1

Reactions with Carboxylates Alkylation of Carboxylic Acid Salts

Carboxylic acids can serve as effective nucleophiles toward a variety of electrophilic reagents if first converted to their carboxylate salts via deprotonation with a suitable base. The relatively low pK a of carboxylic acids allows very mild bases to be employed. A reliable, scalable method for the preparation of methyl esters involves preparation of the lithium carboxylate with LiOH, followed by treatment with dimethyl sulfate, as exemplified in the following.59 Note that methylation of the phenolic alcohol was avoided in this example through careful control of stoichiometry. Dimethyl sulfate may be replaced by iodomethane for most applications; however, this is less preferred due to the increased volatility of the latter reagent (bp 42.4 ∘ C). (i)

(ii)

The most common method for the synthesis of esters from acids utilizes alkyl halides, owing to the relatively easy access to these electrophiles. Cabri et al. demonstrated a high-yielding n-propyl ester preparation via the sodium carboxylate, which was obtained by treatment with NaHCO3 in N-methyl pyrrolidinone (NMP).60 Note that a tertiary amine was also quaternized under these conditions. For more on the alkylation of amines with alkyl halides, see Section 1.5.1.1.

This approach to the conversion of carboxylic acids to esters is complementary to the Fischer esterification, whereby the carboxylic acid is heated in an alcohol solvent in the presence of a strong acid with concomitant generation of water (see Section 2.31.1). 1.2.3.2

Iodolactonization

Iodolactonization is a useful and practical method for the stereocontrolled preparation of lactones. In the following example from House et al., the action of iodine upon the olefin provides an electrophilic intermediate iodonium ion. This highly reactive species is trapped in a stereospecific manner by the carboxylate nucleophile to provide a 1,2-anti relationship between the iodide and oxygen-bearing stereocenters.61

58 Von dem Bussche-Huennefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719–5730. 59 Chakraborti, A. K.; Nandi, A. B.; Grover, V. The Journal of Organic Chemistry 1999, 64, 8014–8017. 60 Cabri, W.; Roletto, J.; Olmo, S.; Fonte, P.; Ghetti, P.; Songia, S.; Mapelli, E.; Alpegiani, M.; Paissoni, P. Organic Process Research & Development 2006, 10, 198–202. 61 House, H. O.; Carlson, R. G.; Babad, H. The Journal of Organic Chemistry 1963, 28, 3359–3361.

1.2 Oxygen Nucleophiles

1.2.3.3

Preparation of Silyl Esters

The use of silyl esters as carboxylic acid protecting groups is an increasingly popular methodology due to the simplicity of preparation and relative ease of removal during workup. An attractive large-scale method for TMS ester preparation utilizes hexamethyldisilazane (HMDS) as both a base and TMS donor.62 This method also proved effective in forming a silyl ether from the secondary alcohol precursor. For more on the formation of silyl ethers, see Section 1.2.2.5.

The HMDS method described previously is clearly advantageous if a TMS ester is desired. Unfortunately, the corresponding triethylsilyl (TES), TBS, or TIPS analogs are inaccessible with this methodology. As a result, silyl esters are more generally prepared by treatment of carboxylate salts with silyl chlorides or triflates. In the following example, p-methoxy cinnamic acid is converted to its TBS ester in high yield via treatment with TBSCl and imidazole in DMF.63

The solvent employed for this reaction is often determined by the solubility of the intermediate carboxylate salt. Dichloromethane64 and THF65 have proven successful in many cases. Triethylamine is commonly used as a base in place of imidazole, and 4-dimethylaminopyridine (DMAP) may be added as a nucleophilic catalyst to activate the silyl electrophile in case of a sluggish reaction. In the following example, a TPS ester was prepared in high yield.66

1.2.3.4

Preparation of Mixed Organic–Inorganic Anhydrides

The reaction of carboxylic acid salts with phosphonic acid halides can provide the corresponding carboxylic acid-phosphonic acid mixed anhydrides in good yield. In the following example, a diethylphosphonate ester was prepared from a triethylammonium carboxylate under very mild conditions.67 62 Smith, A. B.; Safonov, I. G.; Corbett, R. M. Journal of the American Chemical Society 2002, 124, 11102–11113. 63 Ponticello, G. S.; Freedman, M. B.; Habecker, C. N.; Holloway, M. K.; Amato, J. S.; Conn, R. S.; Baldwin, J. J. The Journal of Organic Chemistry 1988, 53, 9–13. 64 Fache, F.; Suzan, N.; Piva, O. Tetrahedron 2005, 61, 5261–5266. 65 McNamara, L. M. A.; Andrews, M. J. I.; Mitzel, F.; Siligardi, G.; Tabor, A. B. The Journal of Organic Chemistry 2001, 66, 4585–4594. 66 Kim, W. H.; Hong, S. K.; Lim, S. M.; Ju, M.-A.; Jung, S. K.; Kim, Y. W.; Jung, J. H.; Kwon, M. S.; Lee, E. Tetrahedron 2007, 63, 9784–9801. 67 Procopiou, P. A.; Biggadike, K.; English, A. F.; Farrell, R. M.; Hagger, G. N.; Hancock, A. P.; Haase, M. V.; Irving, W. R.; Sareen, M.; Snowden, M. A.; Solanke, Y. E.; Tralau-Stewart, C. J.; Walton, S. E.; Wood, J. A. Journal of Medicinal Chemistry 2001, 44, 602–612.

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1 Aliphatic Nucleophilic Substitution

(i)

(ii)

1.2.3.5

Cleavage of Ethers with Acetic Anhydride

The cleavage of ethers with acetic anhydride in the presence of ferric chloride was first reported by Knoevenagel in 1914 for the conversion of diethyl ether to ethyl acetate.68 Ganem and Small followed years later with mechanistic studies and an examination of substrate scope for the method.69 In the following example, benzyl-n-butyl ether is converted to n-butyl acetate in high yield after several hours at 80 ∘ C. The benzyl acetate by-product was not quantified.

1.2.3.6

Alkylation of Carboxylic Acids and Enols with Diazo Compounds

One of the most efficient methods for the preparation of methyl esters from carboxylic acids involves reaction with a solution of diazomethane in ether.70 Esterification is generally rapid and highly chemoselective. Therefore, products can typically be isolated by simple evaporation of the volatile ether solvent. This method is not typically applied on large scale due to the serious hazards associated with the preparation and handling of diazomethane. However, with specialized equipment and proper engineering controls in place, methyl ester formation via treatment with diazomethane is sometimes the method of choice, as exemplified by the following example.71 These conditions are also effective for the methylation of sulfonic acids, as described in Section 1.2.1.4.

A safer, more practical alternative to the use of toxic and volatile diazomethane is provided by the commercially available reagent TMS diazomethane. In the following example, the enol form of a β-ketoaldehyde is converted to its methyl enol ether derivative in high yield and with excellent regioselectivity.72 A discussion of the mechanism of this interesting transformation has been published.73 For more on nucleophilic substitution reactions of enols and carbonyls, see Section 1.2.4.

68 Knoevenagel, E. Justus Liebigs Annalen der Chemie 1914, 402, 111–148. 69 Ganem, B.; Small, V. R., Jr. The Journal of Organic Chemistry 1974, 39, 3728–3730. 70 Arndt, F. Organic Syntheses 1935, 15, 3–5. 71 Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163–7169. 72 Coleman, R. S.; Tierney, M. T.; Cortright, S. B.; Carper, D. J. The Journal of Organic Chemistry 2007, 72, 7726–7735. 73 Kuehnel, E.; Laffan, D. D. P.; Lloyd-Jones, G. C.; Martinez del Campo, T.; Shepperson, I. R.; Slaughter, J. L. Angewandte Chemie, International Edition 2007, 46, 7075–7078.

1.2 Oxygen Nucleophiles

1.2.4 1.2.4.1

Reactions with Other Oxygen Nucleophiles Formation of Silyl Enol Ethers and Silyl Ketene Acetals

The formation of silyl enol ethers has been a topic of considerable study, due to the broad utility of these compounds in carbon–carbon bond-forming reactions. Silyl enol ethers are typically prepared by treatment of an enolizable carbonyl compound with a silyl halide or triflate in the presence of a suitable base. For unsymmetrical ketones, such as 2-methylcyclohexanone (shown in the following), regioisomeric enol ether products are possible, and methods for the selective preparation of both the kinetically favored and thermodynamically favored isomers have been developed.74,75 Treatment of ketones with a silyl chloride in the presence of a weak nitrogen base such as triethylamine provides the thermodynamically favored silyl enol ether (more substituted olefin) at or near room temperature in excellent yield.76

The use of anhydrous zinc dichloride is key to formation of Danishefsky’s diene.77 The zinc additive plays a dual role of Lewis acid and dehydrative agent in this enol ether formation. The use of freshly fused ZnCl2 is preferred and ensures a more robust outcome.

In contrast to the conditions described previously, enolization with a strong, bulky base at low temperature favors removal of the most sterically accessible α-proton to provide the kinetically favored enol ether upon silylation (less substituted olefin).78 In the following example, the dianion of a β-hydroxy ketone was formed with 2.2 equiv of lithium diisopropylamide (LDA) at −78 ∘ C. Silylation occurred with complete selectivity for the enol ether shown. (i) (ii)

In the following example from Aventis, a TMS enol ether was prepared in good yield despite the presence of a rather labile epoxide. Slow addition of the starting ketone into a cold solution of LDA and a careful isolation protocol proved to be important.79 (i) (ii)

As exemplified by Albrecht et al., treatment of a β-ketoester with 2 equiv of LDA yields a dienolate intermediate. Quenching the dienolate with two molar equivalents of chlorotrimethylsilane provides the silyl enol ether as well as a silyl ketene acetal in excellent yield.80 74 75 76 77 78 79 80

D’Angelo, J. Tetrahedron 1976, 32, 2979–2990. Heathcock, C. H. Modern Synthetic Methods 1992, 6, 1–102. Takasu, K.; Ishii, T.; Inanaga, K.; Ihara, M. Organic Syntheses 2006, 83, 193–199. Danishefsky, S.; Kitahara, T.; Schuda, P. F. Organic Syntheses 1983, 61, 147–151. Martin, V. A.; Albizati, K. F. The Journal of Organic Chemistry 1988, 53, 5986–5988. Larkin, J. P.; Wehrey, C.; Boffelli, P.; Lagraulet, H.; Lemaitre, G.; Nedelec, A.; Prat, D. Organic Process Research & Development 2002, 6, 20–27. Albrecht, U.; Nguyen, T. H. V.; Langer, P. The Journal of Organic Chemistry 2004, 69, 3417–3424.

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(i)

equiv

(ii)

A second example of the preparation of a silyl ketene acetal from an enolizable ester is included below.81 Note that the geometry of the newly formed double bond is not controlled, and a mixture of products is obtained. (i) (ii) (iii)

1.2.4.2

Formation of Enol Triflates

The increasing utility of enol trifluoromethanesulfonates (triflates) in metal catalyzed cross-coupling reactions has fueled the development of practical methods for their preparation. The synthesis of enol triflates is analogous to silyl enol ether formation. When the regioselectively of enolization is not a concern, enol triflates may be prepared by trapping the enol tautomers of carbonyl compounds with triflic anhydride (Tf2 O) in the presence of a mild nitrogen base. These reactions are commonly carried out in dichloromethane to avoid interactions between the strongly electrophilic Tf2 O and the solvent, although other non-Lewis basic media may be used. Due to the relative instability of enol triflates toward hydrolysis, manipulation during isolation and/or purification should be minimized, and cold storage is recommended. In the following example, the enol triflate is prepared in good yield by treatment of the ketone with triflic anhydride and a bulky pyridine base.82,83

The use of phenyl- or N-(2-pyridyl)-triflimide in place of Tf2 O can be advantageous, as described by Comins and coworkers.84 In general, triflimides may be used to trap metallo enolates with excellent regiospecificity. Therefore, careful choice of enolization conditions can provide a vinyl triflate with a high degree of regiocontrol. The Comins pyridyl triflimide is more reactive than its phenyl variant, is a solid at ambient temperature, and the by-products are more easily removed from reaction mixtures.85,86 In the following example, an LDA-derived lithium enolate was trapped with Comins’ chloropyridyl triflimide reagent to yield the vinyl triflate shown in high yield. It is notable that γ-deprotonation, leading to formation of the regioisomeric 1,3-diene, was not observed. (i)

(ii)

81 82 83 84 85 86

Mermerian, A. H.; Fu, G. C. Journal of the American Chemical Society 2005, 127, 5604–5607. Scott, W. J.; Crisp, G. T.; Stille, J. K. Organic Syntheses 1990, 68, 116–129. Cacchi, S.; Morera, E.; Ortar, G. Organic Syntheses 1990, 68, 138–147. McMurry, J. E.; Scott, W. J. Tetrahedron Letters 1983, 24, 979–982. Comins, D. L.; Dehghani, A. Tetrahedron Letters 1992, 33, 6299–6302. Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Organic Syntheses 1997, 74, 77–83.

1.2 Oxygen Nucleophiles

1.2.4.3

Formation of Oxonium Salts

Trialkyloxonium salts are powerful alkylating agents with broad utility. These reagents are generally effective under very mild reaction conditions, and often alkylate modest nucleophiles when others fail; alkylation of over 50 functional groups has been reported with trialkyloxonium salts. First reported by Meerwein (who was also responsible for the development of numerous applications), triethylammonium tetrafluoroborate provides access to ethyl enol ethers from carbonyl compounds (see Section 1.2.4.4). The synthesis of this reagent utilizes epichlorohydrin, boron trifluoride diethyletherate, and diethyl ether.87 In an analogous manner, trimethylammonium tetrafluoroborate is prepared from dimethyl ether.88

Reflux 85–95%

1.2.4.4

Reactions of Carbonyl Compounds with Oxonium Salts

Triethyloxonium tetrafluoroborate (Meerwein salt) is generally effective for the conversion of carbonyl compounds to their corresponding ethyl enol ether variants. For additional information regarding the synthesis of Meerwein salts, see Section 1.2.4.3. The reagent is an extremely powerful electrophile, and care must be taken to ensure worker safety and minimize environmental impact during its use. That said, the following example illustrates the high yields that are achievable with Et3 OBF4 under very mild conditions.89

1.2.4.5

Preparation of Hydroperoxides and Peroxyethers

Care should be taken in handling all peroxides due to their propensity to decompose violently when exposed to shock or heat. As a result, peroxy compounds are rarely utilized as synthetic intermediates on large scale. However, well-studied hydroperoxide reagents are sometimes employed. A common method for hydroperoxide synthesis involves reaction of an electrophile with hydrogen peroxide under acidic or basic catalysis. Although most commonly utilized in oxidation reactions, urea hydrogen peroxide (UHP) is an alternative form of H2 O2 that has proven useful in hydroperoxide synthesis. In the following example, moderate heating of an activated alkyl halide with UHP in DMF provides the hydroperoxide in excellent yield.90 Some of the practical advantages of UHP include the fact that it is a relatively stable, inexpensive, and easily handled solid.

In a manner analogous to the preparation of ethers from alcohols, peroxyethers can be prepared via treatment of hydroperoxides with a base in the presence of an alkyl halide or sulfonic acid ester (e.g. mesylate). These conditions are not always applicable however, as aliphatic peroxides containing α-hydrogens are prone to degradation under basic conditions. Nevertheless, when reactive electrophiles are used, appreciable yields and reaction rates can be seen at or near ambient temperature for many substrates. Reported methods involve the use of primary alkyl iodides in the

87 88 89 90

Meerwein, H. Organic Syntheses 1966, 46, 113–115. Curphey, T. J. Organic Syntheses 1971, 51, 142–147. Urban, F. J.; Anderson, B. G.; Orrill, S. L.; Daniels, P. J. Organic Process Research & Development 2001, 5, 575–580. Aoki, M.; Seebach, D. Helvetica Chimica Acta 2001, 84, 187–207.

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1 Aliphatic Nucleophilic Substitution

presence of silver oxide91,92 or, preferably bromides or sulfonates with potassium hydroxide base. In the latter method, polyethylene glycol is a recommended cosolvent. The addition of crown ethers or PEG-400 is thought to promote nucleophilicity through chelation to potassium ions and sometimes leads to superior yields.93

For less reactive or sterically hindered peroxides, cesium hydroxide has been shown to provide acceptable reaction rates in peroxyether formation at ambient temperature, thus avoiding a thermal degradation threat.94

1.2.4.6

Alkylation of Oximes

In most instances, oximes react with electrophiles such as aliphatic halides in a manner analogous to the corresponding reactions of alcohols. The following example outlines a typical procedure, in which an oxime is treated with an alkyl bromide and an inorganic base in a polar aprotic solvent.95

Takemoto and coworkers have employed oxime nucleophiles in palladium catalyzed allylic substitution reactions. Here, the electrophile is an intermediate palladium(II) π-allyl complex, and the base is potassium carbonate.96 The reaction proceeds in good yield to give the product of O-alkylation near ambient temperature, and at a reasonable rate, despite the poor solubility of K2 CO3 in dichloromethane. For more on metal-catalyzed allylic substitution with oxygen nucleophiles, see Section 6.16.3.

The following example highlights the ambiguous nature of an oxime’s ability to react at nitrogen, as opposed to oxygen, under certain conditions. In this instance, palladium(II) catalysis under solvent-free conditions provided the N-alkylated oxime as a mixture of geometrical isomers in moderate yield.

91 Ito, T.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J. Tetrahedron 2003, 59, 525–536. 92 Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Ono, K.; Ogura, N.; Wataya, Y. Journal of Medicinal Chemistry 2002, 45, 1374–1378. 93 Bourgeois, M. J.; Montaudon, E.; Maillard, B. Synthesis 1989, 700–701. 94 Dussault, P. H.; Eary, C. T. Journal of the American Chemical Society 1998, 120, 7133–7134. 95 Yamada, T.; Goto, K.; Mitsuda, Y.; Tsuji, J. Tetrahedron Letters 1987, 28, 4557–4560. 96 Miyabe, H.; Yoshida, K.; Reddy, V. K.; Matsumura, A.; Takemoto, Y. The Journal of Organic Chemistry 2005, 70, 5630–5635.

1.4 Sulfur Nucleophiles

In the following example, the oxygen atom of an oxime adds in a conjugate fashion to provide a stabilized anion for subsequent Horner–Wadsworth–Emmons reaction with nicotinaldehyde. Sodium hydride, which requires some additional handling precautions for large-scale applications, is employed as the base in this instance.97 This example is included to further illustrate the useful application of oxime nucleophiles. For more on nucleophilic addition of ROH to polarized carbon–carbon multiple bonds, see Section 3.3.2.

1.3 Phosphorus Nucleophiles 1.3.1

Preparation of Reagents for Wittig Reactions

Triarylphosphines may be reacted with alkyl halides to form the corresponding phosphonium salts.98 These products are generally stable, often crystalline, materials that serve as convenient precursors to phosphorous ylides, key participants in the Wittig reaction (see Section 2.18). The following example illustrates that triphenylphosphine preferentuially displaces iodide vs. chloride in reaction with chloroiodomethane. This Wittig salt was isolated via precipitation from the reaction mixture in modest yield but was bench stable when stored away from humidity, and could be further purified via recrystallization from ethanol. Subsequent Wittig reaction was achieved through treatment of the salt with t-BuOK in THF, followed by addition of the ketone. Reflux

–

Z : E = 3 :2

1.4 Sulfur Nucleophiles 1.4.1 1.4.1.1

Reactions with Thiols Preparation of Thioethers

Thioethers are generally prepared via reaction of thiols with electrophiles such as alkyl halides in the presence of an appropriate base. Thiols are not potent nucleophiles; however, SN 2 displacement reactions may frequently be accomplished near ambient temperature, as illustrated in the following example.99 In this instance, sterically encumbered trityl thiol is alkylated in high yield and at a reasonable rate with a reactive benzylic bromide.

97 Shen, Y.; Jiang, G.-F. Synthesis 2000, 502–504. 98 Caso, A.; Mangoni, A.; Piccialli, G.; Costantino, V.; Piccialli, V. ACS Omega 2017, 2, 1477–1488. 99 See Note 1.

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1 Aliphatic Nucleophilic Substitution

Cabri and coworkers described a highly efficient thioether formation in the synthesis of the ergot alkaloid derivative pergolide mesylate.100 Direct SN 2 displacement of the primary mesylate shown in the following was accomplished with commercially available sodium methanethiolate, which can also be generated in situ from methanethiol and sodium hydroxide. The latter method is generally not preferred due to the challenges associated with handling toxic, malodorous methanethiol gas (bp 6 ∘ C).

1.4.1.2

Cleavage of Arylmethyl Ethers

Another useful application of nucleophilic sulfur reagents involves the cleavage of arylmethyl ethers to afford the corresponding phenols.101 In the following example, an intermediate in the synthesis of a VEGFR inhibitor candidate was prepared in high yield by treatment of a methoxybenzothiophene derivative with 4 equiv of methionine in methanesulfonic acid.102 Me

1.4.2

Alkylation of Sulfides

Sulfides may be reacted directly with alkyl halides or activated primary alcohols, followed by a base, to afford sulfonium ylides. These compounds are typically prepared as reactive intermediates for further combination with electrophiles such as aldehydes, to yield epoxides. In the following example, from Aggarwal et al., a chiral sulfide is employed to provide enantioenriched products with excellent stereocontrol.103,104 Notably, the sulfides can often be recovered from the reaction mixture.

(i) (ii)

89%, 7 : 3 dr, 98% ee

1.4.3 1.4.3.1

Reactions with Other Sulfur Nucleophiles Preparation of Thiols

The preparation of thiols via direct displacement of alkyl halides with sodium sulfide is not straightforward due to low solubility of this sulfur reagent in most organic solvents. As a result, simple aliphatic thiols are most often prepared via the intermediacy of somewhat more elaborate precursors. In the following example, an isothiouronium salt is prepared 100 101 102 103 104

See Note 60. Linderberg, M. T.; Moge, M.; Sivadasan, S. Organic Process Research & Development 2004, 8, 838–845. Scott, R. W.; Neville, S. N.; Urbina, A.; Camp, D.; Stankovic, N. Organic Process Research & Development 2006, 10, 296–303. Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T. Angewandte Chemie International Edition 2003, 42, 3274–3278. Aggarwal, V. K.; Winn, C. L. Accounts of Chemical Research 2004, 37, 611–620.

1.4 Sulfur Nucleophiles

via reaction of an alkyl bromide with thiourea, followed by reaction with a nucleophilic amine.105 This method relies on distillation of the thiol product for isolation and purification and is therefore most applicable to the preparation of low-molecular-weight derivatives.

Di

Tr

Perhaps more generally, aliphatic thiols are prepared by reaction of alkyl halides with thioacetic acid salts, followed by thioester cleavage under alkaline conditions.106 The following example is a representative, although use of commercially available thioacetic acid sodium salt would be preferred due with free thioacids. (i)

(ii)

Independent of the method employed for their construction, thiols are a challenge to store and manipulate due to their stench and propensity to form disulfides in a mildly oxidizing environment such as air. As a result, the more stable disulfide dimers are sometimes targeted as thiol precursors. An attractive method for nucleophilic disulfide cleavage involves treatment with Cleland’s reagent (dithiothreitol, DTT), which liberates the thiol under mild aqueous conditions. Although this method would undoubtedly apply to a broad range of synthetic organic challenges, the use of DTT is dominated by its applications in biochemistry as a means to reduce thiolated DNA.106

A number of other chemical methods have been developed for disulfide cleavage, including the use of mild reducing agents such as phosphines, sodium borohydride, or zinc in acetic acid.107 A single example is included here, but for more on the preparation of thiols via reductive cleavage of disulfides, see Section 9.7.5.

105 Cossar, B. C.; Fournier, J. O.; Fields, D. L. The Journal of Organic Chemistry 1962, 27, 93–95. 106 Canaria, C. A.; Smith, J. O.; Yu, C. J.; Fraser, S. E.; Lansford, R. Tetrahedron Letters 2005, 46, 4813–4816. 107 Hartman, R. F.; Rose, S. D. The Journal of Organic Chemistry 2006, 71, 6342–6350.

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1 Aliphatic Nucleophilic Substitution

1.4.3.2

Formation of Bunte Salts

Salts of S-alkyl or S-aryl hydrogen thiosulfates are known as Bunte salts. They are frequently prepared as precursors to thiols or disulfides. Most commonly, Bunte salts are prepared from alkyl halides and sodium thiosulfate by heating in aqueous methanol.108

In the following example, a pyridinium Bunte salt was prepared from the aryl thiol, then converted into the corresponding thiocyanate in good yield.109 For a discussion on the preparation of aryl thiocyanates via electrophilic aromatic substitution, see Section 5.3.6.

(i) (ii)

pyridine

Reflux 80% – 3 steps

1.4.3.3

Alkylation of Sulfinic Acid Salts

Sulfinic acids react with common electrophiles upon treatment with a mild base. Various arene sulfinic acid derivatives are commercially available as their stable, crystalline salts, in contrast to the parent acids, which are somewhat prone to decomposition and dimerization. Sulfinic acid salts are generally nucleophilic at sulfur, as opposed to oxygen, although exceptions have been reported. In the following example, commercially available sodium benzenesulfinate is reacted with an allylic bromide in DMF to provide the sulfone in high yield.110,111

Another useful application of sulfinic acid nucleophiles is seen in palladium-catalyzed allylic substitution reactions. This mild methodology is useful for deprotection of allyl esters where standard acidic or alkaline hydrolysis would be incompatible with sensitive functionality and is generally amenable to large scale. The following examples, from the research groups of Trost et al.112 and Hegedus and coworkers,113 illustrate this reactivity toward π-allyl electrophiles. For more on metal-catalyzed allylic substitution, see Section 6.16. 108 Tseng, C. C.; Handa, I.; Abdel-Sayed, A. N.; Bauer, L. Tetrahedron 1988, 44, 1893–1904. 109 Alcaraz, M.-L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Organic Process Research & Development 2005, 9, 555–569. 110 Nilsson, Y. I. M.; Andersson, P. G.; Baeckvall, J. E. Journal of the American Chemical Society 1993, 115, 6609–6613. 111 Sellen, M.; Baeckvall, J. E.; Helquist, P. The Journal of Organic Chemistry 1991, 56, 835–839. 112 Trost, B. M.; Crawley, M. L.; Lee, C. B. Journal of the American Chemical Society 2000, 122, 6120–6121. 113 Sebahar, H. L.; Yoshida, K.; Hegedus, L. S. The Journal of Organic Chemistry 2002, 67, 3788–3795.

1.4 Sulfur Nucleophiles

1.4.3.4

Attack by Sulfite Ion

Sulfite ion (SO3 2− ) is sufficiently nucleophilic to participate in SN 2 displacement reactions with aliphatic alkyl halides to provide the corresponding sulfonic acids after an acidic workup. The following example from Chen et al. is a representative of typical reaction conditions and yields.114

Ac

In the following example, the reaction of sodium sulfite with a symmetrical dichloride yielded the corresponding disulfonate intermediate. This was not isolated, but rather converted into a sultone by treatment with acidic Amberlite resin at an elevated temperature.115 (i)

(ii) Reflux

1.4.3.5

(iii)

Preparation of Alkyl Thiocyanates

Thiocyanate salts (typically sodium or potassium) are ambident nucleophiles, capable of either sulfur- or nitrogen-centered SN 2 attack on electrophiles. Reaction at sulfur is more frequently observed, providing thiocyanate products (vs. isothiocyanates). In the following example, Sa et al. report a high-yielding preparation of allylic thiocyanates from allylic bromide precursors.116

In addition to the primary reactivity described previously, the authors also report measurable quantities of isothiocyanate products when the acrylate starting materials were alkyl substituted. Perhaps most interesting, the initially 114 Chen, Y. T.; Xie, J.; Seto, C. T. The Journal of Organic Chemistry 2003, 68, 4123–4125. 115 Snoddy, A. O. Organic Syntheses 1957, 37, 55–57. 116 Sa, M. M.; Fernandes, L.; Ferreira, M.; Bortoluzzi, A. J. Tetrahedron Letters 2008, 49, 1228–1232.

25

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1 Aliphatic Nucleophilic Substitution

observed thiocyanate : isothiocyanate mixture (7 : 1) equilibrated to favor the latter compound (1 : 6) after prolonged periods at ambient temperature.

1.5 Nitrogen Nucleophiles 1.5.1 1.5.1.1

Amine Alkylation Amine Alkylation with Alkyl Halides and Onium Salts

The alkylation of nitrogen with alkyl halides is one of the most commonly utilized transformations in target oriented synthetic chemistry. The inherently strong nucleophilicity of amines provides reliable, generally predictable reaction rates under mild conditions and in a variety of solvents. The nucleophilicity of an amine is strongly influenced by steric and inductive influences from substituents. A helpful discussion regarding the nucleophilicities of various primary and secondary amines has been published.117 In the following example, the primary amine is first protected as a ketimine derivative through dehydrative condensation with methyl isobutylketone before introduction of the alkyl chloride. This process prevents the formation of a mixture of N-alkylation products. To enhance the alkylation rate, the chloride is converted to its corresponding iodide in situ via reaction with potassium iodide (Finkelstein reaction; see Section 1.5.1.1).118 For further examples of ketimine formation, see Section 2.7.1. (i)

(ii)

For ease of handling, amines are often prepared and stored as crystalline, nonvolatile salts of a mineral acid. In most instances, these salts may be utilized directly in alkylation processes by introducing a stoichiometric quantity of a base. The salt is first broken to provide the corresponding “free base,” which then undergoes alkylation.119 These reactions are generally facile and efficient, providing the starting salt is sufficiently soluble in the reaction medium, and overalkylation is controlled through proper stoichiometry and reaction temperature.

The tendency of tertiary amines to react further with alkylating agents to provide quaternary ammonium salts is occasionally a complicating factor. There are examples, however, where tertiary amine quaternization has been utilized in a productive manner. In the Delépine reaction,120,121 primary alkyl halides are converted to the corresponding primary

117 Brotzel, F.; Chu, Y. C.; Mayr, H. The Journal of Organic Chemistry 2007, 72, 3679–3688. 118 Laduron, F.; Tamborowski, V.; Moens, L.; Horvath, A.; De Smaele, D.; Leurs, S. Organic Process Research & Development 2005, 9, 102–104. 119 Hashimoto, H.; Ikemoto, T.; Itoh, T.; Maruyama, H.; Hanaoka, T.; Wakimasu, M.; Mitsudera, H.; Tomimatsu, K. Organic Process Research & Development 2002, 6, 70–73. 120 Delepine, M. Bulletin de la Societe Chimique de France 1895, 13, 352–355. 121 Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajfez, F. Synthesis 1979, 161–176.

1.5 Nitrogen Nucleophiles

amines via treatment with hexamethylenetetramine, followed by hydrolysis. This sequence provides an inexpensive and reliable entry into aliphatic amines that can be conveniently isolated and handled as hydrochloride salts. The following example is a representative.122

When benzylic alkyl halides are treated in a similar fashion with excess hexamethylenetetramine, the product of hydrolysis is the aldehyde. This useful variation, known as the Sommelet reaction,123 provides fairly general access to aromatic aldehydes from benzylic halide precursors.124,125,126,127,128,129 For additional discussion on benzylic oxidation, see Sections 10.3.8.1 and 10.4.1.5.

In the following example, a spirocycle is formed through a series of intramolecular and intermolecular alkylation reactions.130 The amine could be isolated as its hydrochloride salt, or converted to the free base with sodium hydroxide to form the product illustrated in excellent overall yield. (i) (ii) (iii)

1.5.1.2

i

Amine Alkylation with Inorganic Esters

Amines typically react with inorganic esters in a manner analogous to their interaction with alkyl halides. As exemplified by the following scheme, reaction of an amine with an alkyl sulfonate (e.g. mesylate, tosylate, etc.) proceeds smoothly in a polar aprotic solvent to provide the substituted amine.131 Mild to moderate heating is often employed to decrease reaction time. One equivalent of a sulfonic acid is generated over the course of the reaction, so the product will require neutralization unless another base is included in the reaction.

122 Nodiff, E. A.; Hulsizer, J. M.; Tanabe, K. Chemistry and Industry 1974, 962–963. 123 Sommelet, M. Comptes Rendus de l’ Academie des Sciences Serie IIc:Chimie 1914, 157, 852–854. 124 Angyal, S. J.; Barlin, G. B.; Wailes, P. C. Journal of the Chemical Society 1953, 1740–1741. 125 Angyal, S. J.; Morris, P. J.; Rassack, R. C.; Waterer, J. A. Journal of the Chemical Society 1949, 2704–2706. 126 Angyal, S. J.; Morris, P. J.; Tetaz, J. R.; Wilson, J. G. Journal of the Chemical Society 1950, 2141–2145. 127 Angyal, S. J.; Penman, D. R.; Warwick, G. P. Journal of the Chemical Society 1953, 1742–1747. 128 Angyal, S. J.; Penman, D. R.; Warwick, G. P. Journal of the Chemical Society 1953, 1737–1739. 129 Angyal, S. J.; Rassack, R. C. Journal of the Chemical Society 1949, 2700–2704. 130 Golden, M.; Legg, D.; Milne, D.; Bharadwaj M, A.; Deepthi, K.; Gopal, M.; Dokka, N.; Nambiar, S.; Ramachandra, P.; Santhosh, U.; Sharma, P.; Sridharan, R.; Sulur, M.; Linderberg, M.; Nilsson, A.; Sohlberg, R.; Kremers, J.; Oliver, S.; Patra, D. Organic Process Research & Development 2016, 20, 675–682. 131 Srinivas, K.; Srinivasan, N.; Reddy, K. S.; Ramakrishna, M.; Reddy, C. R.; Arunagiri, M.; Kumari, R. L.; Venkataraman, S.; Mathad, V. T. Organic Process Research & Development 2005, 9, 314–318.

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1 Aliphatic Nucleophilic Substitution

Heterocyclic amines, such as the substituted imidazole in the following example from Dunetz et al., undergo N-alkylation under mild conditions with alkyl triflates.132 In this example, the base, solvent, and reaction temperature were all optimized to maximize regioselectivity and minimize racemization of the stereocenter.

2 equiv

er

In the following example, LaFrance and Caron optimized the identity of the sulfonate (Ns; 4-nitrobenzene sulfonate), in addition to base, solvent, and temperature, during development of a process to a DPP4 inhibitor candidate.133

For N-methylation of nitrogen-containing heterocycles, methyl tosylate provides an effective, low-cost alternative to the highly toxic, but commonly employed, reagents methyl iodide and dimethyl sulfate.134

When cyclic sulfates are employed, initial attack typically occurs at the less sterically encumbered carbon center to provide the intermediate amino sulfate. In the following example, a second equivalent of amine is introduced to promote a second displacement at the more substituted carbon center. Note that considerably more forcing conditions are required for the second alkylation and that this attack results in inversion of the stereocenter. The more sluggish reaction rate for the second addition often allows the use of two distinct amines in this stepwise reaction sequence.

Amines react analogously with cyclic sulfamates to provide 1,2-diamine products. In the following example, the coauthors state that the sulfamate intermediate could be isolated as a solid but was optimally deprotected with acid prior to further conversion to the desired lactam.135 132 Dunetz, J. R.; Berliner, M. A.; Xiang, Y.; Houck, T. L.; Salingue, F. H.; Chao, W.; Yuandong, C.; Shenghua, W.; Huang, Y.; Farrand, D.; Boucher, S. J.; Damon, D. B.; Makowski, T. W.; Barrila, M. T.; Chen, R.; Martinez, I. Organic Process Research & Development 2012, 16, 1635–1645. 133 Lafrance, D.; Caron, S. Organic Process Research & Development 2012, 16, 409–414. 134 Gal, M.; Feher, O.; Tihanyl, E.; Horvath, G.; Jerkovich, G. Tetrahedron 1982, 38, 2933–2938. 135 McLaughlin, M.; Belyk, K.; Chen, C.-Y.; Linghu, X.; Pan, J.; Qian, G.; Reamer, R. A.; Xu, Y. Organic Process Research & Development 2013, 17, 1052–1060.

1.5 Nitrogen Nucleophiles

(i) (ii)

Su

Trialkyloxonium tetrafluoroborate (Meerwein salts) have been used in the preparation of N-substituted pyrroles for pharmaceutical applications.136 In the following example, the 2-oxazoline-5-one derived from phenylalanine is N-ethylated to produce the reactive dipole 1,3-oxazolium-5-oxide (munchnone). In the presence of dimethyl acetylenedicarboxylate, a [3+2] cycloaddition takes place to provide the N-ethyl pyrrole after carbon dioxide is lost via retro [4+2]. The authors note that extremely reactive alkylating agents are required for this transformation; methyl iodide, dimethyl sulfate, and benzyl bromide are ineffective.

1.5.1.3

Amine Alkylation with Alcohols

Alcohols may serve as useful precursors to amines, although an activation step is required. Unfortunately, the activation step often involves the use of reagents that add considerable expense and/or waste to the process. For instance, if the amine nucleophile is suitably acidic, as is the case for the following Boc-protected sulfonamide, Mitsunobu conditions may be employed.137 Although this method can be effective for small scale applications, there is general agreement among process chemists that the phosphine, azodicarboxylate reagents, and the by-products they produce in the reaction decrease the utility of this method for large scale.

For more typical amine nucleophiles, such as simple unactivated primary amines, preactivation of the alcohol as its sulfonate ester (e.g. mesylate, tosylate, brosylate, etc.) is necessary.138 This method is preferable for bulk production, due to the lower expense of sulfonyl ester halides, and the ease of removal of sulfonic acid by-products via alkaline aqueous extraction. For more on the use of sulfonates in amine alkylation, see Section 1.4.1.2. (i) (ii)

(iii)

136 Hershenson, F. M.; Pavia, M. R. Synthesis 1988, 999–1001. 137 Nishino, Y.; Komurasaki, T.; Yuasa, T.; Kakinuma, M.; Izumi, K.; Kobayashi, M.; Fujiie, S.; Gotoh, T.; Masui, Y.; Hajima, M.; Takahira, M.; Okuyama, A.; Kataoka, T. Organic Process Research & Development 2003, 7, 649–654. 138 Conrow, R. E.; Dean, W. D.; Zinke, P. W.; Deason, M. E.; Sproull, S. J.; Dantanarayana, A. P.; DuPriest, M. T. Organic Process Research & Development 1999, 3, 114–120.

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1 Aliphatic Nucleophilic Substitution

More recent advances in the field have made the “Borrowing Hydrogen Approach” to direct coupling of alcohols and nucleophilic amines more practical. In this method, the alcohol is oxidized to the corresponding aldehyde through action of an appropriate transition metal catalyst complex. Upon nucleophilic addition of the amine, followed by elimination of water, the resulting imine is reduced to complete the catalytic cycle. The following example is a representative.139

1.5.1.4

Amine Alkylation with Diazo Compounds

As discussed in Section 1.2.3.5, the use of diazo compounds of low molecular weight is not preferred for large-scale applications. However, the reaction of activated amines with diazomethane to provide N-methylated products is a clean, high-yielding transformation that can be carried out quite reliably on laboratory scale in fit-for-purpose glassware.140

1.5.1.5

Transamination

The direct nucleophilic displacement of one aliphatic amine by another is not a widely employed transformation. The formal product of transamination can be obtained, however, under a range of reaction conditions. Although not technically a nucleophilic aliphatic substitution reaction, the following example highlights a formal transamination reaction. In this case, a series of elimination/conjugate addition reactions provide an efficient exchange of methylamine for tert-butylamine. Achieving a comparable transamination via direct SN 2 displacement with tert-butylamine would be very unlikely.141 So

1.5.1.6

Amine Alkylation with Epoxides

The ring-opening of epoxides with nitrogen nucleophiles is a facile, well-established transformation. The reaction will often proceed thermally, although the use of Lewis or Brønsted acid catalysis is common. In their multi-kilo scale synthesis of a 5-HT4 partial agonist, Widlicka et al. at Pfizer utilized the alkylation of a secondary amine with an epoxide in the last step to provide the active pharmaceutical ingredient (API) in 88% yield.142 Note the alkylation was accomplished by simply heating in i-PrOH.

139 Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. Organic Process Research & Development 2015, 19, 1400–1410. 140 Di Gioia, M. L.; Leggio, A.; Le Pera, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G. The Journal of Organic Chemistry 2003, 68, 7416–7421. 141 Amato, J. S.; Chung, J. Y. L.; Cvetovich, R. J.; Reamer, R. A.; Zhao, D.; Zhou, G.; Gong, X. Organic Process Research & Development 2004, 8, 939–941. 142 Widlicka, D. W.; Murray, J. C.; Coffman, K. J.; Xiao, C.; Brodney, M. A.; Rainville, J. P.; Samas, B. Organic Process Research & Development 2016, 20, 233–241.

1.5 Nitrogen Nucleophiles

(i) (ii) i (iii) Wa

®

In their synthesis of the anti-influenza drug oseltamivir (API in Tamiflu ), Rohloff et al. described a regioselective ring-opening of a key epoxide intermediate with sodium azide and ammonium chloride in aqueous ethanol. Although this reaction was performed at an elevated temperature, the authors warned against exceeding 80 ∘ C due to the potential explosivity of azides.143

The thermal and shock sensitivity of some azide-containing compounds has limited their use in large-scale synthesis. To address these issues for bulk production, Karpf and Trussardi have developed alternative conditions for the regioselective introduction of nitrogen to this substrate. The use of benzylamine, with magnesium bromide as a Lewis acid catalyst, provided the desired 1,2-amino alcohol in comparable yield and regioselectivity.144

For additional discussion on the use of azide nucleophiles, see Section 1.4.3.2. For another example of the reaction of an epoxide with sodium azide, see Section 1.2.2.8. Through inventive application of a Jocic-type Reaction, Henegar et al. prepared and utilized a dichloro epoxide in the regioselective and stereoselective alkylation of 3-fluoroaniline.145 The intermediate acyl chloride is further converted to the methyl ester by including MeOH as a cosolvent. The authors state that this product was formed in c. 75% in situ yield and was typically telescoped into the next synthetic step.

1.5.1.7

Amine Alkylation with Cyclic Carbonates

Reaction of nucleophilic amines with cyclic carbonates provides an attractive entry to 1,2-amino alcohols. Note that CO2 gas is liberated with this method, so care should be taken to account for pressure buildup in the reaction vessel. 143 Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. The Journal of Organic Chemistry 1998, 63, 4545–4550. 144 Karpf, M.; Trussardi, R. The Journal of Organic Chemistry 2001, 66, 2044–2051. 145 Henegar, K. E.; Lira, R.; Kim, H.; Gonzalez-Hernandez, J. Organic Process Research & Development 2013, 17, 985–990.

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In the following example, Riley et al. studied this reaction during efforts aimed at optimization of the manufacturing process to Tenofivir Disproxil Fumarate, a prodrug of the NRTI tenofivir.146 Reaction conditions were optimized for yield, as well as regioselectivity of N-alkylation. (i) 0.1 equiv KOH (ii) MeOH, i-PrOH

1.5.1.8

Preparation of 1∘ Amines via Hexamethyldisilazane

The direct nucleophilic displacement of aliphatic halides by HMDS has been demonstrated.147 The main advantages of this method for the synthesis of amines are the elimination of multialkylation issues and that TMS groups are easily removed by an acidic workup to liberate an ammonium salt. The method has not been widely adopted, however, due to the poor nucleophilicity of the sterically bulky HMDS. In most cases, reaction rates are slow, and yields are modest. In the following example, the displacement of a secondary chloride is assisted via participation by the neighboring boron atom, thus accelerating the reaction rate significantly.148 Note that participation by boron offsets the normal rate advantage offered by the primary bromide (vs. secondary chloride) and also provides a steric bias that influences the stereochemical course of the reaction.149 (i) (ii)

In order to eliminate oligomeric by-products observed in opening a terminal epoxide with ammonia, Schmidt et al. employed lithium hexamethyldisilazide (LiHMDS) as an ammonium surrogate.150 The reaction illustrated in the following scheme proceeded smoothly at room temperature in THF, liberating the primary amine for subsequent amide formation in a telescoped process. A corrected yield for the epoxide opening step was not reported, but the two-step sequence provided product in 84% prior to recrystallization.

1.5.1.9

Preparation of Isocyanides (“Isonitriles”)

The first synthesis of an isocyanide was reported by Lieke in 1859; allyl iodide was reacted with silver cyanide to yield allyl isocyanide. A second method involves reaction of a primary amine with dichlorocarbene (generated by treatment of chloroform with a strong base) and is known as the Hofmann carbylamine reaction. Weber et al. reported

146 Riley, D. L.; Walwyn, D. R.; Edlin, C. D. Organic Process Research & Development 2016, 20, 742–750. 147 Bestmann, H. J.; Woelfel, G. Chemische Berichte 1984, 117, 1250–1254. 148 Matteson, D. S.; Schaumberg, G. D. The Journal of Organic Chemistry 1966, 31, 726–731. 149 Wityak, J.; Earl, R. A.; Abelman, M. M.; Bethel, Y. B.; Fisher, B. N.; Kauffman, G. S.; Kettner, C. A.; Ma, P.; McMillan, J. L. et al. The Journal of Organic Chemistry 1995, 60, 3717–3722. 150 Schmidt, G.; Reber, S.; Bolli, M. H.; Abele, S. Organic Process Research & Development 2012, 16, 595–604.

1.5 Nitrogen Nucleophiles

an improvement to the latter method, wherein the use of phase transfer catalysis in dichloromethane-water solvent systems provides superior yields under milder conditions.151,152

However, isocyanides can be more generally prepared via dehydration of N-formyl precursors.153 A range of dehydrating agents are effective in the reaction, with phosphorous oxychloride (POCl3 ) used in the following representative example.154

1.5.1.10

Methylation of Amines, the Eschweiler–Clarke reaction

A special case of imine reduction is demonstrated in the Eschweiler–Clarke reaction, in which an amine is condensed with formaldehyde in the presence of formic acid to yield the N-methylated product. The reaction is most simply carried out in water at reflux, as demonstrated in the synthesis of citalopram.155 (i) (ii)

1.5.1.11

Preparation Sulfenamides

As illustrated by Walinsky et al. in their work toward the atypical antipsychotic drug ziprasidone, nucleophilic secondary amines react with disulfides via attack at sulfur to liberate sulfenamide products.156 These hydrolytically labile compounds may serve as amine precursors157 or intermediates in the preparation of heterocycles158 such as benzisothiazole shown in the following.

151 Weber, W. P.; Gokel, G. W. Tetrahedron Letters 1972, 1637–1640. 152 Weber, W. P.; Gokel, G. W.; Ugi, I. K. Angewandte Chemie, International Edition in English 1972, 11, 530–531. 153 Ugi, I.; Meyr, R. Angewandte Chemie, International Edition in English 1958, 70, 702–703. 154 Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400–402. 155 Elati, C. R.; Kolla, N.; Vankawala, P. J.; Gangula, S.; Chalamala, S.; Sundaram, V.; Bhattacharya, A.; Vurimidi, H.; Mathad, V. T. Organic Process Research & Development 2007, 11, 289–292. 156 Walinsky, S. W.; Fox, D. E.; Lambert, J. F.; Sinay, T. G. Organic Process Research & Development 1999, 3, 126–130. 157 Wuts, P. G. M.; Jung, Y. W. Tetrahedron Letters 1986, 27, 2079–2082. 158 Davis, F. A. International Journal of Sulfur Chemistry 1973, 8, 71–81.

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1.5.2 1.5.2.1

N-Alkylation of Amides, Lactams, Imides, and Carbamates Alkylation with Alkyl Halides

The alkylation of aryl amides with alkyl halides can be achieved under mild phase transfer conditions.159 In the following example, benzamide is converted to its N-butyl derivative through reaction with n-butyl bromide in the presence of tetra-n-butylammonium hydrogensulfate. The high concentration of sodium hydroxide prevents hydrolytic side reactions from occurring by promoting clear separation between aqueous and organic phases. Benzene can typically be replaced by toluene or dichloromethane to provide secondary amides with equal efficiency. The primary concern with this protocol is competing formation of tertiary amides via double alkylation. However, this issue can be addressed by careful control of stoichiometry, as the second alkylation is generally much slower than the first.

Be

Unfortunately, yields drop off somewhat when aliphatic amides are reacted under these conditions, and attempted introduction of a second alkyl group is generally unsuccessful. Primary sulfonamides can also be alkylated with these conditions, although doubly alkylated products are primarily obtained due to the increased acidity of this substrate class. In cases where the mild biphasic conditions described previously are ineffective, amides can typically be alkylated by deprotonation with a strong base under anhydrous conditions, followed by combination with an alkyl halide. In the alkylation of δ-valerolactam below, sodium hexamethyldisilazide (NaHMDS) in THF is utilized.160 The amide salts often exhibit poor solubility in solvents such as THF, however, so proper agitation, along with moderate heating may be required for successful reactions. (i) (ii)

20–60

Primary amides may be converted to iodo lactams via intramolecular alkylation of electrophilic iodonium species.161,162 The nucleophilic component in the following example is not the primary amide itself, but rather the N,O-bis(trimethylsilyl)imidate derivative shown in brackets. Silylation of the starting amide promotes the N-alkylation pathway and prevents competitive iodolactone formation, as originally reported by Ganem and coworkers.163

Pentane

During their pilot scale synthesis of an oxazolidinone antibacterial candidate, Lu et al. carried out a multikilogram carbamate alkylation as the first operation in a highly efficient three-step sequence.164 In this example, an N-aryl carbamate was reacted with a primary alkyl chloride in the presence of lithium t-butoxide. The desired alkylation product was obtained in high yield under these conditions, which also lead to subsequent acetate cleavage and oxazolidinone 159 Gajda, T.; Zwierzak, A. Synthesis 1981, 1005–1008. 160 Roenn, M.; McCubbin, Q.; Winter, S.; Veige, M. K.; Grimster, N.; Alorati, T.; Plamondon, L. Organic Process Research & Development 2007, 11, 241–245. 161 Knapp, S.; Levorse, A. T. The Journal of Organic Chemistry 1988, 53, 4006–4014. 162 Knapp, S.; Rodriques, K. E.; Levorse, A. T.; Ornaf, R. M. Tetrahedron Letters 1985, 26, 1803–1806. 163 Biloski, A. J.; Wood, R. D.; Ganem, B. Journal of the American Chemical Society 1982, 104, 3233–3235. 164 Lu, C. V.; Chen, J. J.; Perrault, W. R.; Conway, B. G.; Maloney, M. T.; Wang, Y. Organic Process Research & Development 2006, 10, 272–277.

1.5 Nitrogen Nucleophiles

formation. The use of lithium-derived bases was critical, as sodium and potassium counterions gave rise to isomeric by-products, as reported by Perrault during the development of structurally similar linezolid.165

In the following example from Augustine and coworkers, potassium succinimide is reacted with α-chloroacetophenone in DMF to provide an N-alkyl succinimide that served as a precursor to enantiomerically enriched 2-amino-1-phenylethanol.166 Consistent with their amide relatives, alkylation of imides most commonly occurs on nitrogen in the presence of a base, although O-alkylation can be a complicating side reaction. The use of a potassium counterion is generally effective for promoting nitrogen-centered attack.

1h

1.5.2.2

Alkylation with Alkyl Sulfonates and Derivatives

Acetamide derivatives undergo intramolecular N-alkylation reactions with alkyl sulfonates (e.g. mesylates, tosylates, etc.) in good yield.167 Sodium hydride in THF was employed in this example and is a common first choice for laboratory scale since the gaseous hydrogen by-product is easily removed and relatively inert. NaHMDS, which is safer and easier to handle on large scale, has also proven effective in some cases and should be considered.

Potassium tert-butoxide has also been successfully employed in amide alkylation reactions. In the following example, high yield of a bicyclic benzamide product was obtained via intramolecular mesylate displacement in THF.168

During development of synthetic methodology for the synthesis of oxacephem antibiotics, Chmielewski and coworkers reported an efficient intramolecular β-lactam alkylation with a primary tosylate.169 In this instance, a very mild base (sodium carbonate) was sufficient to promote the alkylation, so long as tetra-n-butylammonium bromide was included.

165 Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Organic Process Research & Development 2003, 7, 533–546. 166 Tanielyan, S. K.; Marin, N.; Alvez, G.; Augustine, R. L. Organic Process Research & Development 2006, 10, 893–898. 167 Hansen, M. M.; Bertsch, C. F.; Harkness, A. R.; Huff, B. E.; Hutchison, D. R.; Khau, V. V.; LeTourneau, M. E.; Martinelli, M. J.; Misner, J. W.; Peterson, B. C.; Rieck, J. A.; Sullivan, K. A.; Wright, I. G. The Journal of Organic Chemistry 1998, 63, 775–785. 168 Avenoza, A.; Cativiela, C.; Busto, J. H.; Fernandez-Recio, M. A.; Peregrina, J. M.; Rodriguez, F. Tetrahedron 2001, 57, 545–548. 169 Kaluza, Z.; Furman, B.; Krajewski, P.; Chmielewski, M. Tetrahedron 2000, 56, 5553–5562.

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1 Aliphatic Nucleophilic Substitution

Through creative use of a chiral cyclic sulfamidate, Rousseau et al. were able to accomplish efficient N-alkylation of a primary amide under mild, scale-friendly conditions.170

Sodium-t-amylate

1.5.3 1.5.3.1

Other Nitrogen Nucleophiles Nitrite Nucleophiles: Preparation of Nitro Compounds

The preparation of aliphatic nitro compounds can be accomplished by treatment of alkyl halides with sodium or potassium nitrite. Moderate heating in a polar solvent such as acetone, acetonitrile, DMF, or dimethylsulfoxide is generally required, and the formation of isomeric alkyl nitrites is competitive.171

Silver nitrite is superior to its sodium relative in many cases, affording moderate to good yields of nitro compounds in an aqueous environment.172 However, a significant excess of this expensive reagent is required to minimize competitive formation of alcohols. 1.5.3.2

Azide Nucleophiles

Due to a linear geometry that minimizes steric hindrance, azide ion is a highly effective nitrogen nucleophile. Azide has a nucleophilic constant (n)173 that is approximately equivalent to that of NH3 , while possessing a basicity closer to that of acetate ion.174 Furthermore, alkyl azides can be converted in a highly efficient manner to the corresponding amines via hydrogenolysis or via Staudinger reduction with a phosphine as the reducing agent (see Section 9.7.1.1). For these reasons, the use of azide ion as a nucleophile in organic synthesis is prevalent. In the following example, a primary alkyl tosylate is displaced by sodium azide in dimethylsulfoxide at 60 ∘ C to provide the primary alkyl azide in 95% yield.175

170 Rousseau, J.-F.; Chekroun, I.; Ferey, V.; Labrosse, J. R. Organic Process Research & Development 2015, 19, 506–513. 171 Singh, P. N. D.; Mandel, S. M.; Sankaranarayanan, J.; Muthukrishnan, S.; Chang, M.; Robinson, R. M.; Lahti, P. M.; Ault, B. S.; Gudmundsdottir, A. D. Journal of the American Chemical Society 2007, 129, 16263–16272. 172 Ballini, R.; Barboni, L.; Giarlo, G. The Journal of Organic Chemistry 2004, 69, 6907–6908. 173 Swain, C. G.; Scott, C. B. Journal of the American Chemical Society 1953, 75, 141–147. 174 Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A: Structure and Mechanisms; 4th ed.; Kluwer Academic/Plenum Publishers: Dordrecht, Netherlands, 2000. 175 Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Organic Process Research & Development 1997, 1, 26–38.

1.5 Nitrogen Nucleophiles

Sodium azide is similarly capable of displacing halides, as illustrated in the stereospecific reaction with the chiral secondary alkyl bromide shown in the following.176

n

It should be noted that sodium azide and many related compounds are toxic substances, and extreme care should be taken to minimize exposure while handling these reagents, reaction mixtures, and products. Furthermore, many azide compounds present an additional safety concern due to their tendency to aggressively decompose with concomitant nitrogen gas liberation. Many heavy metal azides are exceedingly shock sensitive, so handling of these compounds should be avoided. Finally, care must be taken during waste storage and disposal due to the propensity of azide ion to form explosive metal complexes with materials found in standard copper water pipes. For additional examples of C—N bond formation with azide nucleophiles, see Sections 1.2.2.8 and 1.5.1.6. 1.5.3.3

Isocyanates and Isothiocyanates as Nucleophiles

Isocyanate salts are commonly employed reagents for the introduction of urea or carbamate functionalities. Isocyanate ions are reasonably nucleophilic at nitrogen, but upon alkylation, the resulting N-substituted isocyanates are electrophilic at the central carbon atom. The following example illustrates how this dual reactivity can be utilized for the preparation of carbamates in a single reaction from potassium isocyanate, an alcohol and an alkyl halide.177

Magnus et al. reported a similar use of potassium isocyanate in their synthesis of NNRTI candidates for the treatment of HIV,178 although in this case, the carbonyl electrophile technically moves this example out of the scope of this chapter. For more on the addition of nitrogen nucleophiles to carbonyl carbon centers, see Chapter 2.

Isothiocyanate ions afford the same general reactivity, although competitive S-alkylation may be a minor complication. In the following example, the authors were able to isolate methallyl isothiocyanate prepared by refluxing an acetone solution of ammonium isothiocyanate with methallyl chloride in 80% yield. This product was converted to a thiourea derivative via treatment with alcoholic ammonia and to 2-butenamine via acidic hydrolysis.179 Ac

176 Pan, X.; Xu, S.; Huang, R.; Yu, W.; Liu, F. Organic Process Research & Development 2015, 19, 611–617. 177 Argabright, P. A.; Rider, H. D.; Sieck, R. The Journal of Organic Chemistry 1965, 30, 3317–3321. 178 Magnus, N. A.; Confalone, P. N.; Storace, L.; Patel, M.; Wood, C. C.; Davis, W. P.; Parsons, R. L., Jr. The Journal of Organic Chemistry 2003, 68, 754–761. 179 Young, W. G.; Webb, I. D.; Goering, H. L. Journal of the American Chemical Society 1951, 73, 1076–1083.

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1.6 Halogen Nucleophiles 1.6.1 1.6.1.1

Attack by Halides at Alkyl Carbon or Silicon Halide Exchange

The exchange of one halide for another, known as the Finkelstein reaction,180 is a thermodynamically driven process that can be influenced by the stoichiometric ratio of the two halides as well as relative solubilities of halide salts in the reaction medium. A halogen exchange reaction is commonly used to convert more stable, accessible, and inexpensive alkyl chlorides to their more reactive bromide or iodide analogs prior to an alkylation reaction. The Finkelstein reaction can frequently be carried out during an alkylation reaction, by adding a bromide or iodide salt to the reaction mixture. In the following example, an α-chloroamide is converted to the corresponding iodide through treatment with super-stoichiometric sodium iodide in acetone.181

With the activated halide highlighted in the aforementioned example, exchange occurs at an acceptable rate at ambient temperature; however, moderate heating is commonly employed to accelerate the conversion. In the following example, the less activated substrate required considerable heating and an extended reaction time to accomplish complete halide exchange.182

Most commonly, the halide exchange is carried out to enhance reactivity for a subsequent nucleophilic aliphatic substitution reaction, such as amine or carboxylate alkylation. In the following example, this exchange is carried out in situ, and since free halide is liberated upon N-alkylation, a stoichiometric excess of NaI is not required.183 Note that this two-stage reaction is run in water, where halide exchange is not facilitated by low solubility of NaCl in relation to NaI. equiv Water

1.6.1.2

Preparation of Halides from Sulfonic Acid Esters

Alkyl halides can be prepared from aliphatic alcohol precursors via the intermediacy of sulfonic acid esters such as mesylates, tosylates, or triflates. Preferred conditions involve heating the sulfonate with a halide salt in a polar aprotic solvent such as acetone, acetonitrile, or DMF. The reaction generally proceeds via direct SN 2 displacement to provide the product of stereochemical inversion, although subsequent halide–halide exchange may occur to yield an epimeric mixture. In the following example from Robins et al., clean inversion was achieved with lithium chloride in DMF.184 The corresponding bromide could be prepared in 85% yield under analogous conditions with lithium bromide.

180 181 182 183 184

Finkelstein, H. Berichte der Deutschen Chemischen Gesellschaft 1910, 43, 1528–1532. Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb, S. M. The Journal of Organic Chemistry 2006, 71, 2046–2055. Jensen, A. E.; Kneisel, F.; Knochel, P. Organic Syntheses 2003, 79, 35–42. Yang, F.; Wu, C.; Li, Z.; Tian, G.; Wu, J.; Zhu, F.; Zhang, J.; He, Y.; Shen, J. Organic Process Research & Development 2016, 20, 1576–1580. Robins, M. J.; Nowak, I.; Wnuk, S. F.; Hansske, F.; Madej, D. The Journal of Organic Chemistry 2007, 72, 8216–8221.

1.6 Halogen Nucleophiles

Interestingly, Lepore et al. have reported that certain sterically bulky arenesulfonates can be converted to the corresponding chlorides with retention of configuration by treatment with titanium tetrachloride in dichloromethane at −78 ∘ C.185 The method requires the use of an aryl sulfonic acid derivative that is capable of strong coordination to titanium. The authors propose an SN i-type mechanism to explain the observed stereochemical outcome.

With the steady increase in the number of fluorinated compounds being investigated in the pharmaceutical industry, numerous methods for the nucleophilic introduction of fluorine in a stereo- and regioselective manner have appeared.186 Both alkali metal fluorides and TBAF have been utilized successfully, but these reagents suffer from poor solubility and/or high basicity. A more general, albeit expensive, method for the direct nucleophilic displacement of halides (chlorides, bromides, and iodides) and sulfonates was introduced by DeShong and coworkers.187 As highlighted by the following example, treatment of a diastereomerically pure secondary mesylate with tetra-n-butylammonium (triphenylsilyl)difluorosilicate (TBAT) in refluxing acetonitrile provided the secondary fluoride in good yield, albeit as a mixture of diastereomers. Interestingly, when the triflate leaving group was utilized under identical conditions, the fluoride was obtained as a single syn-diastereoisomer in a slightly improved 76% yield. This result demonstrates that the substitution reaction occurs with clean inversion of stereochemistry and that erosion of diastereomeric purity does not occur via epimerization of the product under the reaction conditions, but rather through partial erosion of the mesylate starting material stereocenter.

Re

Reflux Si

1.6.1.3

Preparation of Alkyl Halides from Alcohols

Alcohols can serve as convenient precursors to halides, although direct displacement using hydrohalic acids is not always a practical operation due to competitive elimination and/or incompatibility with common functional groups. 185 Lepore, S. D.; Bhunia, A. K.; Mondal, D.; Cohn, P. C.; Lefkowitz, C. The Journal of Organic Chemistry 2006, 71, 3285–3286. 186 Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem: A European Journal of Chemical Biology 2004, 5, 637–643. 187 Pilcher, A. S.; Ammon, H. L.; DeShong, P. Journal of the American Chemical Society 1995, 117, 5166–5167.

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1 Aliphatic Nucleophilic Substitution

Instead, an activation step is carried out that renders the oxygen more reactive toward nucleophilic displacement. For large-scale applications, the reagents of choice for conversion of an aliphatic alcohol to its corresponding chloride are typically thionyl chloride, oxalyl chloride, or methanesulfonyl chloride. Each reagent has advantages and disadvantages when cost, atom economy, and handling issues are considered. As a result, reagent choice is often determined on a case by case basis. The following example highlights the use of thionyl chloride in the presence of catalytic N,N-dimethylformamide for the high-yielding conversion of a secondary benzylic alcohol to its chloride.188 The reaction proceeds cleanly in heptane to afford the desired product with minimal manipulation. The workup for this reaction generally involves a slow, cautious addition of water to carefully quench residual thionyl chloride (HCl generation), followed by neutralization, phase separation, and concentration to remove volatiles.

Alternatively, N-chlorosuccinimide (NCS) in combination with triphenylphosphine can be used to convert an alcohol to a chloride. The reaction on the chiral secondary alcohol shown in the following proceeded with inversion of stereochemistry and minimal erosion of enantiomeric excess.189 In contrast, the use of the more common reagents described previously would likely degrade the stereochemical integrity of the chiral center via reaction of the product with excess chloride.

For the simple preparation of alkyl halides from alcohols, few methods are as straightforward and reliable as the Appel reaction.190 Thus, treatment of an alcohol with carbon tetrabromide and triphenylphosphine provides the corresponding bromide, along with the stoichiometric triphenylphosphine oxide by-product.191 However, drawbacks associated with the use of this method include low atom economy, higher relative expense and additional challenges in purging phosphines and phosphine oxides from products. The latter can typically be accomplished via chromatography on silica gel or selective precipitation from a non-polar solvent.

1.6.1.4

Preparation of Alkyl Halides from Ethers

The action of the strong acids HI192 and HBr193 upon ethers provides one molar equivalent of an alkyl halide and another equivalent of an alcohol. If a stoichiometric excess of the acid is employed, the alcohol product is usually converted 188 Jacks, T. E.; Belmont, D. T.; Briggs, C. A.; Horne, N. M.; Kanter, G. D.; Karrick, G. L.; Krikke, J. J.; McCabe, R. J.; Mustakis, J. G.; Nanninga, T. N.; Risedorph, G. S.; Seamans, R. E.; Skeean, R.; Winkle, D. D.; Zennie, T. M. Organic Process Research & Development 2004, 8, 201–212. 189 Merschaert, A.; Boquel, P.; Van Hoeck, J.-P.; Gorissen, H.; Borghese, A.; Bonnier, B.; Mockel, A.; Napora, F. Organic Process Research & Development 2006, 10, 776–783. 190 Appel, R. Angewandte Chemie, International Edition in English 1975, 87, 863–874. 191 Woodin, K. S.; Jamison, T. F. The Journal of Organic Chemistry 2007, 72, 7451–7454. 192 See Note 101. 193 Giles, M. E.; Thomson, C.; Eyley, S. C.; Cole, A. J.; Goodwin, C. J.; Hurved, P. A.; Morlin, A. J. G.; Tornos, J.; Atkinson, S.; Just, C.; Dean, J. C.; Singleton, J. T.; Longton, A. J.; Woodland, I.; Teasdale, A.; Gregertsen, B.; Else, H.; Athwal, M. S.; Tatterton, S.; Knott, J. M.; Thompson, N.; Smith, S. J. Organic Process Research & Development 2004, 8, 628–642.

1.6 Halogen Nucleophiles

to its corresponding alkyl halide as well. This method is not commonly utilized to prepare alkyl halides from mixed ethers due to the lack of selectivity in the cleavage to halide and alcohol. R

R′

R

X

R′

R′

R

R

R′

Conversely, there is broad utility for this method in the cleavage of alkyl aryl ethers (anisole derivatives), which liberate the alkyl halide and phenol preferentially (see Section 1.5.1.6). In this case, the goal is deprotection of the phenol rather than synthesis of the alkyl halide, although the latter is a consequence. 1.6.1.5

Preparation of Alkyl Halides from Epoxides

Epoxides are commonly prepared via intramolecular nucleophilic displacement of halides by vicinal alcohols (see Section 1.2.2.8). The inverse reaction can also be carried out; epoxides can be opened via nucleophilic attack by halide ions. Allevi reported that the treatment of a terminal epoxide with sodium iodide and acetic acid in THF provides the primary alkyl iodide (via anti-Markovnikov attack) in high yield at room temperature.194

The ring-opening of epoxides with halide salts to produce halohydrins can also be promoted by either Lewis or Brønsted acids. The following example is representative of the stereochemical course of the reaction, which obeys the Fürst–Plattner rule,195 providing the anti-halohydrin via backside attack on the epoxide.196 The selectivity for the favored constitutional isomer is controlled in this case by steric factors, although electronic factors can also strongly influence the product distribution. The latter is especially true when strong Lewis or Brønsted acids are employed.

In the following interesting example, from Seçen and coworkers, a cyclic epoxide was opened in a highly stereoselective manner to afford the 1,4-syn-haloacetate.197 The authors proposed that this reaction may proceed through a semiconcerted transition state, where partial acylation of the epoxide occurs concurrently with SN 2′ attack of halide ion. Note that under these reaction conditions, the acetonide was also converted to a diacetate.

Another example of opening an allylic epoxide with halide ions is shown in the following.198 In this case, halohydrin formation was promoted by magnesium bromide in cold acetonitrile. The ratio of isomers is presumably a reflection of increased carbocation stabilization at the allylic position, since sterics would appear to offer little influence.

194 195 196 197 198

Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2004, 15, 2091–2096. Furst, A.; Plattner, P. A. Helvetica Chimica Acta 1949, 32, 275–283. Eipert, M.; Maichle-Moessmer, C.; Maier, M. E. Tetrahedron 2003, 59, 7949–7960. Baran, A.; Kazaz, C.; Secen, H. Tetrahedron 2004, 60, 861–866. Ha, J. D.; Kim, S. Y.; Lee, S. J.; Kang, S. K.; Ahn, J. H.; Kim, S. S.; Choi, J.-K. Tetrahedron Letters 2004, 45, 5969–5972.

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Epoxides can also be ring-opened in a highly stereoselective manner by hydrogen fluoride-pyridine complex.199 It is notable that preferential attack by fluoride occurred away from the vinyl substituent in this example.

In a study aimed at identifying scale-friendly conditions for the preparation of enantioenriched 3-fluoromethyl-γbutyrolactone, Zutter and coworkers evaluated a range of reported methods, concluding that use of KHF2 in the presence of a phase-transfer catalysis (PTC) at elevated temperature was optimal.200 2 equiv KHF t

t

Tri

Doyle and coworkers have reported on nucleophilic opening of epoxides with fluoride ions, catalyzed by cobalt(II) salen complexes.201 The method may be utilized for kinetic resolution of terminal racemic epoxides, as in the following example, and also for asymmetric desymmetrization of meso epoxides.202

t

t t

t

ee

1.6.1.6

Cleavage of Alkyl Ethers with Halide Ion

The cleavage of arylmethyl ethers with halide ion to form the corresponding phenols is a common practice in the pharmaceutical industry. In the following example from Jacks et al., hydrogen bromide in acetic acid gave good conversion and high yield of a catechol intermediate.203 199 Ayad, T.; Genisson, Y.; Broussy, S.; Baltas, M.; Gorrichon, L. European The Journal of Organic Chemistry 2003, 2903–2910. 200 Adam, J.-M.; Foricher, J.; Hanlon, S.; Lohri, B.; Moine, G.; Schmid, R.; Stahr, H.; Weber, M.; Wirz, B.; Zutter, U. Organic Process Research & Development 2011, 15, 515–526. 201 Shaw, T. W.; Kalow, J. A.; Doyle, A. G. Organic Syntheses 2012, 89, 9–18. 202 Kalow, J. A.; Doyle, A. G. Journal of the American Chemical Society 2010, 132, 3268–3269. 203 See Note 188.

1.6 Halogen Nucleophiles

Hydrogen chloride is generally less effective than hydrogen iodide or hydrogen bromide, although when used as a pyridine salt, high yields have been reported for demethylation of certain anisole derivatives. In the following example, the starting coumarin derivative was treated with pyridine hydrochloride in the absence of solvent at high temperature. The reagent cleaves two methyl ethers and an acetyl protecting group in excellent yield, although the required reaction temperature was quite high.204 Py

The use of strong mineral acids is often incompatible with organic substrates, however. Therefore, preferable methods for large-scale applications often utilize reagents such as boron tribromide,205 boron trichloride,206 or aluminum trichloride207,208 despite the challenges associated with safe handling of these materials. In these reactions, ionization of the departing alcohol is promoted by complexation of the boron or aluminum to the ether oxygen. The use of BBr3 in dichloromethane has proven to be effective for the cleavage of a range of arylmethyl ethers.209

Arylmethyl ethers can also be converted to phenols by treatment with iodotrimethylsilane, which liberates iodomethane as a stoichiometric by-product. This mild method can be further improved by utilizing the less expensive chlorotrimethylsilane in combination with sodium iodide.210

Perhaps the most attractive protocol for demethylation on large scale involves nucleophilic attack on the methyl group by a mild sulfur nucleophile such as methionine211 or a simple aliphatic thiol.212 This reaction is discussed in Section 1.4.1.2.

204 Li, X.; Jain, N.; Russell, R. K.; Ma, R.; Branum, S.; Xu, J.; Sui, Z. Organic Process Research & Development 2006, 10, 354–360. 205 Lim, C. W.; Tissot, O.; Mattison, A.; Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Organic Process Research & Development 2003, 7, 379–384. 206 Cai, S.; Dimitroff, M.; McKennon, T.; Reider, M.; Robarge, L.; Ryckman, D.; Shang, X.; Therrien, J. Organic Process Research & Development 2004, 8, 353–359. 207 See Note 188. 208 Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King, S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.; Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang, W. Organic Process Research & Development 2004, 8, 897–902. 209 Zhang, W.; Yamamoto, H. Journal of the American Chemical Society 2007, 129, 286–287. 210 Wack, H.; France, S.; Hafez, A. M.; Drury, W. J., III; Weatherwax, A.; Lectka, T. The Journal of Organic Chemistry 2004, 69, 4531–4533. 211 See Note 102. 212 See Note 101.

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1.6.1.7

Cleavage of Silyl Ethers and Silyl Enol Ethers with Halide Ion

Silicon-based protecting groups play a central role in complex target-oriented synthesis. As a result, numerous mild and effective methods have been developed for efficient cleavage of silicon oxygen bonds. Nevertheless, the use of TBAF remains the most commonly employed reagent for this task. In their multikilogram scale, preparation of vitamin D3 analogs, Shimizu et al. were successful in removing two TBS protecting groups in high yield with TBAF in refluxing THF.213

If mild reaction temperatures and appropriate stoichiometry are utilized, more labile silyl enol ethers may be selectively cleaved in the presence of a silyl ether with TBAF. The following example is particularly impressive, as the bulky TIPS group resides at each position in the starting material.214

2h

It should be noted that TBAF is strongly basic and is manufactured as a water-wet substance. As a result, the addition of a suitable acid (often acetic acid) is typical when base-sensitive substrates are involved. Furthermore, hydrogen fluoride is a highly toxic and corrosive substance, so extreme caution should be taken to minimize exposure during handling of TBAF or related materials. For the desilylation of compounds where high pH must be avoided, the use of aqueous hydrofluoric acid may be considered. In the following example, two secondary TBS ethers are cleaved with high efficiency by utilizing 40% aqueous hydrofluoric acid in acetonitrile at ambient temperature.215

It should be noted that HF has been demonstrated to etch glass at low concentrations,216,217,218,219 so care must be taken when choosing equipment for the laboratory or plant. Fluorinated polymers (e.g. Teflon-PTFE) have been shown to 213 Shimizu, H.; Shimizu, K.; Kubodera, N.; Mikami, T.; Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.; Shimizu, M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.; Kobayashi, M.; Kigawa, M.; Kato, M.; Kozono, T.; Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M. Organic Process Research & Development 2005, 9, 278–287. 214 Outten, R. A.; Daves, G. D., Jr. The Journal of Organic Chemistry 1987, 52, 5064–5066. 215 Baumann, K.; Bacher, M.; Steck, A.; Wagner, T. Tetrahedron 2004, 60, 5965–5981. 216 Spierings, G. A. C. M. Journal of Materials Science 1991, 26, 3329–3336. 217 Spierings, G. A. C. M.; Van Dijk, J. Journal of Materials Science 1987, 22, 1869–1874. 218 Spierings, G. A. C. M. Journal of Materials Science 1993, 28, 6261–6273. 219 Tso, S. T.; Pask, J. A. Journal of the American Ceramic Society 1982, 65, 360–362.

1.6 Halogen Nucleophiles

offer good corrosion resistance and are generally the preferred materials of construction for HF-resistant laboratory equipment, while alloys of nickel and copper (e.g. Alloy 400, C71500, C70600, etc.) comprise the preferred materials of construction for commercial reactors that are routinely exposed to hydrofluoric acid.220 Other attractive options for large-scale silyl ether cleavage are triethylamine trihydrofluoride,221 ammonium bifluoride,222,223 and hydrogen fluoride pyridine complex.224,225 As described in the following example, hydrogen fluoride–pyridine complex has been utilized for the selective cleavage of a primary silyl ether in the presence of a secondary silyl ether in high yield under very mild conditions. The cleavage of silyl ethers with acids or bases in an aqueous or alcoholic environment is discussed in Sections 1.2.1.8 and 1.2.2.6, respectively.

1.6.1.8

Cleavage of Carboxylic Acid and Sulfonic Acid Esters with Halide Ion

In a series of seminal publications, Krapcho reported that heating β-ketoesters, malonate esters or α-cyanoesters in water-wet dimethylsulfoxide in the presence of chloride or cyanide ions provided the products of dealkoxycarbonylation.226 A BAL 2 type mechanism (i.e. nucleophilic attack by chloride on the alkyl group of the ester to provide an alkyl chloride and sodium carboxylate) is generally accepted, although Krapcho demonstrated that certain dealkoxycarbonylations are more likely to proceed through a BAC 2 pathway. Dealkoxycarbonylation in the absence of salts was also reported, although both rate and yield improve with added chloride ion for most substrates.227 Nonetheless, the “Krapcho decarboxylation” has demonstrated utility in synthetic organic chemistry, as highlighted by the following example from Hoekstra et al. during development of a multikilogram synthesis of the anticonvulsant pregabalin.228 The major disadvantage of the classic Krapcho conditions is that a temperature in excess of 130 ∘ C is generally required, which presents challenges for substrate compatibility and worker safety on large scale.

Through related transformations, nucleophilic cleavage of aliphatic esters has also been reported with cyanide229,230, or thiolate anions.233,234,235,236,237 These latter methods are typically employed for the ring-opening of cyclic esters (lactones) and therefore incorporate the nucleophiles into the product as nitriles or thioethers, respectively.

231,232

220 Schillmoller, C. M. Chemical Engineering Progress 1998, 94, 49–54. 221 Joubert, N.; Pohl, R.; Klepetarova, B.; Hocek, M. The Journal of Organic Chemistry 2007, 72, 6797–6805. 222 Hu, X. E.; Kim, N. K.; Grinius, L.; Morris, C. M.; Wallace, C. D.; Mieling, G. E.; Demuth, T. P., Jr. Synthesis 2003, 1732–1738. 223 Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T. Synlett 1995, 609–611. 224 See Note 72. 225 Shin, Y.; Fournier, J.-H.; Brueckner, A.; Madiraju, C.; Balachandran, R.; Raccor, B. S.; Edler, M. C.; Hamel, E.; Sikorski, R. P.; Vogt, A.; Day, B. W.; Curran, D. P. Tetrahedron 2007, 63, 8537–8562. 226 Krapcho, A. P. Synthesis 1982, 893–914. 227 Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E., Jr.; Lovey, A. J.; Stephens, W. P. The Journal of Organic Chemistry 1978, 43, 138–147. 228 See Note 175. 229 Stanetty, P.; Froehlich, H.; Sauter, F. Monatshefte fur Chemie 1986, 117, 69–88. 230 Anjanamurthy, C.; Rai, K. M. L. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1985, 24B, 502–504. 231 Goya, S.; Takadate, A.; Tanaka, T.; Tsuruda, Y.; Ogata, H. Yakugaku Zasshi 1980, 100, 819–825. 232 Miller, A. W.; Stirling, C. J. M. Journal of the Chemical Society [Section] C: Organic 1968, 2612–2617. 233 Kelly, T. R.; Dali, H. M.; Tsang, W. G. Tetrahedron Letters 1977, 3859–3860. 234 Traynelis, V. J.; Love, R. F. The Journal of Organic Chemistry 1961, 26, 2728–2733. 235 Kresze, G.; Schramm, W.; Cleve, G. Chemische Berichte 1961, 94, 2060–2072. 236 Farrar, M. W. The Journal of Organic Chemistry 1958, 23, 1065–1066. 237 Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Bankert, R. A.; Beears, W. L.; Prendergast, M. G. Journal of the American Chemical Society 1949, 71, 661–663.

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Sulfonic acid esters may also be converted to the parent sulfonic acids through nucleophilic attack by halide ion at carbon. In the following example, sodium iodide in acetone solvent provided the sodium sulfonate via a mild, high-yielding transformation.238

1.6.1.9

Preparation of Halides from 𝛂-Diazo Carbonyl Compounds

Treatment of α-diazo carbonyl compounds with a haloacid can efficiently provide the α-halo derivative. In the following example, a diazoketone is reacted with aqueous HBr in THF at 0 ∘ C to yield the corresponding bromoketone in high yield.239

α-Halo carbonyl compounds can also be prepared from α-amine precursors via diazotization in situ followed by reaction with a halide. Treatment of the amino carbonyl compound with a halide salt in the presence of sodium nitrite and in aqueous sulfuric acid provides the product at or near room temperature. When applied to α-amino carboxylic acids, this transformation has been shown to proceed in high yields, and with net retention of configuration, as illustrated in the example that follows.240

This stereochemical outcome is specific to α-amino acids, as the mechanism involves the intermediacy of an α-lactone. The analogous reaction with amino ketones, esters, or amides would proceed with inversion of stereochemistry. Complementary methods for the synthesis of α-halo carbonyl compounds are discussed in Section 10.3.3. 1.6.1.10

Preparation of Cyanamides

The reaction of an amine with cyanogen bromide yields cyanamide products of the general formula R1 R2 N–CN. When the reaction is carried out on a tertiary amine, one of the C—N bonds of the initially formed quaternary amine is cleaved through nucleophilic attack at carbon by bromide ion (von Braun reaction).241 The reaction may be carried out with a wide range of tertiary amines, although at least one substituent on the amine must be aliphatic, as aromatic groups are not cleaved after amine quaternization.242,243 An illustrative example from Reinhoudt and coworkers is provided in the following.244

238 See Note 8. 239 Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. The Journal of Organic Chemistry 2002, 67, 3169–3178. 240 Dutta, A. S.; Giles, M. B.; Gormley, J. J.; Williams, J. C.; Kusner, E. J. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1987, 111–120. 241 von Braun, J. Berichte der Deutschen Chemischen Gesellschaft 1900, 33, 1438–1452. 242 Cooley, J. H.; Evain, E. J. Synthesis 1989, 1–7. 243 Hageman, H. Organic Reactions (New York) 1953, VII, 198–262. 244 Verboom, W.; Visser, G. W.; Reinhoudt, D. N. Tetrahedron 1982, 38, 1831–1835.

1.7 Carbon Nucleophiles

1.7 Carbon Nucleophiles 1.7.1 1.7.1.1

Attack by Carbon at Alkyl Carbon Direct Coupling of Alkyl Halides

The direct coupling of alkyl halides via treatment with a metal or mixture of metals is known as the Wurtz reaction. Although it has been suggested that the initial stages of the Wurtz reaction are radical in nature,245 the bond formation step is believed to consist of an SN 2 displacement of an alkyl halide with an aliphatic anion.246 The reaction is not typically amenable to large-scale applications, since specialized equipment is required. Furthermore, substrate scope is generally limited to homocoupling of activated halides, and yields are typically low to moderate due to competitive alkene formation of the presumed radical intermediate. However, the homocoupled products can be useful and might otherwise require multistep synthesis.247 The following example is noteworthy, given the substantial steric congestion associated with creating adjacent quaternary carbon centers.

Unsymmetrical Wurtz couplings can be promoted by manganese and copper co-catalysts, as reported by Chan and Ma.248 It is noteworthy that these reactions are carried out in an aqueous solvent system, thus avoiding the challenges associated with handling moisture sensitive reagents and intermediates. In addition, this methodology proved applicable to unactivated aliphatic alkyl bromides and iodides. In the following example, a significant quantity of 1,5-hexadiene by-product was formed, which called for a stoichiometric excess of allyl bromide. However, the desired acid could be easily separated from this nonpolar hydrocarbon. Note that for this particular substrate, a copper promoted SN 2′ displacement of the allylic bromide cannot be ruled out. 4 equiv allyl bromide

For small-scale applications, electrochemical Wurtz coupling methods may be applicable, although specialized equipment is required.249 For more on the coupling of allylic halides, see Section 1.6.1.3.

Reflux

1.7.1.2

Reactions of Organometallic Reagents with Alkyl Halides

The nucleophilic displacement of an alkyl halide with an organometallic reagent has been the subject of considerable research by the synthetic organic community. A wide variety of organometallic reagents have proven effective for this transformation, and their preparation is the subject of Chapter 12. A concern when choosing the appropriate methodology for a given system is the ability of many organometallic reagents to act as bases; deprotonation of the electrophile can lead to undesired elimination products. The relatively high basicity of alkyl lithium compounds makes their use in halide displacement reactions quite challenging. As a result, transmetalation from readily accessible but somewhat capricious alkyl lithiums to more predictable organometallic derivatives is common. Perhaps the most highly utilized method was co-developed by the laboratories of Corey, House, Posner, and Whitesides.250 This method consists of the reaction of a lithium dialkylcuprate (Gilman reagent), formed by treatment of an 245 246 247 248 249 250

Richards, R. B. Transactions of the Faraday Society 1940, 36, 956–960. LeGoff, E.; Ulrich, S. E.; Denney, D. B. Journal of the American Chemical Society 1958, 80, 622–625. Fouquey, C.; Jacques, J. Synthesis 1971, 306. Ma, J.; Chan, T.-H. Tetrahedron Letters 1998, 39, 2499–2502. Nedelec, J. Y.; Mouloud, H. A. H.; Folest, J. C.; Perichon, J. The Journal of Organic Chemistry 1988, 53, 4720–4724. Posner, G. H. Organic Reactions (New York) 1975, 22, 253–400.

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alkyl lithium with copper iodide in THF at −78 ∘ C, with a suitable alkyl halide to afford the desired product. The scope of this methodology is generally limited to primary or activated alkyl halides. A notable drawback to the use of Gilman reagents is that 2 equiv of the alkyl lithium are required, but only 1 equiv is incorporated into the product. In 1983, Lipshutz et al. reported a valuable extension of this method: the facile coupling of higher order cyanocuprates with a range of alkyl halide electrophiles.251 These reagents have an advantage over traditional Gilman reagents in that they can be prepared from more stable, easily accessible alkyl bromides or chlorides. However, they are somewhat less reactive, so higher than cryogenic temperatures are often utilized for the coupling step. For more on the use of cyanocuprates as nucleophiles, see Section 1.6.1.7. In the following example, a high yield of the substituted pyridine product is obtained after three hours at −50 ∘ C in THF.

The displacement of alkyl halides with aliphatic Grignard reagents has also been reported; however, these methods are often complicated by functional group incompatibility and/or elimination. The use of the non-Lewis basic solvent dichloromethane allowed Eguchi and coworkers to couple Grignard reagents with tertiary halides with moderate success.252 The authors suspect competitive elimination was responsible for the lower yield observed with t-butyl chloride; elimination is prohibited by Bredt’s rule for adamantyl chloride. A single electron transfer (radical) mechanism likely competes with an SN 2 pathway for these substrates.

1.7.1.3

Couplings of Allylic and Propargylic Halides

Allylic and propargylic halides are reactive electrophiles due to their ability to offer resonance stabilization to growing positive charge at the allylic/propargylic carbon during ionization of the carbon–halogen bond. This effect also allows for insertion of low-valent metals into the carbon–halogen bond, which produces nucleophilic organometallic compounds. As a result, the addition of a metal in its lowest oxidation state, such as zinc, magnesium, or iron, to a solution of an allylic or propargylic halide will typically yield significant quantities of dimerization products (Wurtz coupling).253

Reflux

The following example illustrates that this reductive dimerization is also effective with secondary allylic halides, although the rate and yield often decline for such systems.254

251 Lipshutz, B. H.; Parker, D.; Kozlowski, J. A.; Miller, R. D. The Journal of Organic Chemistry 1983, 48, 3334–3336. 252 Ohno, M.; Shimizu, K.; Ishizaki, K.; Sasaki, T.; Eguchi, S. The Journal of Organic Chemistry 1988, 53, 729–733. 253 Rao, G. S. R. S.; Bhaskar, K. V. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1993, 2813–2816. 254 Voegtle, F.; Eisen, N.; Franken, S.; Buellesbach, P.; Puff, H. The Journal of Organic Chemistry 1987, 52, 5560–5564.

1.7 Carbon Nucleophiles

55–65%

For an additional example of the Wurtz coupling of an allylic halide, see Section 1.6.1.1. 1.7.1.4

Couplings of Organometallic Reagents with Sulfonate Esters

Most organometallic carbon nucleophiles (Grignards, cuprates, etc.) react with aliphatic sulfonate ester electrophiles in a manner analogous to that observed with alkyl halides (see Section 1.6.1.2). In the following example, an aliphatic Grignard reagent is modified by the addition of copper(I) bromide to allow smooth displacement of a primary tosylate in THF at ambient temperature.255

Grignard reagents are frequently used without conversion to copper complexes in cases where allylic or propargylic carbon nucleophiles are involved. In the following example, a high yield of the alkylation product was obtained under mild conditions when an excess of 2-methallylmagnesium chloride was allowed to react with either the primary tosylate or iodide.256 Benzenesulfonate derivatives typically outperform mesylates, as the latter contain acidic α-protons that may quench basic carbon nucleophiles.

1.7.1.5

Couplings Involving Alcohols

Because hydroxide ion is a relatively poor leaving group, the direct SN 2 displacement at an alcohol-bearing carbon center is rare. Instead, alcohols are typically subjected to an activation step such as conversion to the corresponding halide257 or inorganic ester258,259,260,261 (see Sections 1.5.1.3 and 1.7.1.2). A few methods for direct alcohol displacement have been reported, however. One particularly mild method, the treatment of benzylic alcohols with a catalytic quantity of InCl3 (5 mol%) in the presence of allyl, propargyl, or alkynyl silanes, was reported by Baba and coworkers.262

255 Yadav, J. S.; Rao, K. V.; Prasad, A. R. Synthesis 2006, 3888–3894. 256 Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Diez, D.; Basabe, P.; Garcia, N.; Moro, R. F.; Broughton, H. B.; Mollinedo, F.; Urones, J. G. The Journal of Organic Chemistry 2003, 68, 7496–7504. 257 See Note 188. 258 See Note 56. 259 Shan, Z.; Xiong, Y.; Zhao, D. Tetrahedron 1999, 55, 3893–3896. 260 See Note 57. 261 See Note 58. 262 Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angewandte Chemie, International Edition 2004, 43, 1414–1416.

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Cat

Aliphatic Grignard reagents have also been coupled with alcohols in the presence of titanium(IV) isopropoxide, although the scope appears to be limited to activated (e.g. allylic) alcohols.263 1.7.1.6

Reactions of Organometallic Reagents with Allylic Esters and Carbonates

Allylic esters and carbonates possess unique reactivity amongst aliphatic electrophiles in that they may be alkylated at either the 1- or 3-position of the allylic system via formal SN 2 or SN 2′ displacement of the leaving group. In the absence of a catalyst, the two modes of attack may be competitive, resulting in a product distribution that varies with substrate. In the following example, an allylic acetate was reacted with n-butyl magnesium bromide in the presence of CuCN to yield a mixture of regioisomers favoring the branched (SN 2′ -type) alkylation product.264 n

More commonly, reactions of allylic electrophiles are catalyzed by an organometallic complex that provides a π-allyl intermediate via oxidative addition. The choice of metal and ligand set influences the sterics and electronics of the π-allyl intermediate, and therefore, the product distribution. The metal catalyzed allylic substitution reaction falls outside the scope of this chapter but is discussed thoroughly within Section 6.16. 1.7.1.7

Reactions of Organometallic Reagents with Epoxides

The opening of epoxides with nonenolate carbon nucleophiles is traditionally accomplished with higher order mixed organocuprate reagents “R2 Cu(CN)Li2 ” generated in situ from 2 equiv of the corresponding organolithium and 1 equiv of copper cyanide, as reported by Lipshutz et al. These reagents often outperform the related Gilman-type reagents “R2 CuLi” and “RCu(CN)Li,” presumably due to decreased basicity and enhanced nucleophilicity. Furthermore, cyanocuprates exhibit increased thermal stability compared to classical Gilman reagents, which allows reactions to be carried out at or above ambient temperature. In the following example, the reagent generated from n-propyllithium and copper cyanide provided the desired ring-opened product in high yield under mild conditions in THF. The same transformation carried out with n-PrCu(CN)Li proceeded in only 15–30% yield and required ethyl ether solvent to minimize competitive reagent complexation with the THF solvent.265

Alam et al. have reported on the development of a highly regioselective, scale-friendly variation that takes advantage of the broad commercial availability of Grignard reagents.266 The protocol, exemplified in the following scheme, employs a small stoichiometric excess of the Grignard in THF in combination with a catalytic amount of copper(I) chloride, providing products in high yield.

263 264 265 266

Kulinkovich, O. G.; Epstein, O. L.; Isakov, V. E.; Khmel’nitskaya, E. A. Synlett 2001, 49–52. Erdik, E.; Kocoglu, M. Tetrahedron Letters 2007, 48, 4211–4214. Lipshutz, B. H.; Kozlowski, J.; Wilhelm, R. S. Journal of the American Chemical Society 1982, 104, 2305–2307. Alam, M.; Wise, C.; Baxter, C. A.; Cleator, E.; Walkinshaw, A. Organic Process Research & Development 2012, 16, 435–441.

1.7 Carbon Nucleophiles

1.7.1.8

Alkylation of Malonate and Acetoacetate Derivatives

A carbon bearing at least one hydrogen atom and two to three electronegative substituents can be deprotonated to provide a stabilized carbanion that may be alkylated with a broad range of electrophiles under very mild conditions. The most common examples in this class are resonance stabilized salts of malonic acid derivatives (e.g. dimethylmalonate) and acetoacetate esters (e.g. ethyl acetoacetate). These compounds have found broad utility in transition metal-catalyzed allylic alkylation methodology pioneered by Tsuji and coworkers267,268 and Trost and Verhoeven269 as well as in the Knoevenagel condensation270 to provide α,β-unsaturated carbonyl compounds. These reactions fall outside the scope of this chapter but are discussed in Chapters 2 and 6, respectively. Salts of β-dicarbonyl compounds can also be alkylated with alkyl halides,271 epoxides,272 and alkyl sulfonates.273 In the following representative example, dibenzyl malonate was treated with sodium hydride in THF to provide a sodiomalonate that reacted with an alkyl bromide in high yield.274

In the second example, an enantiomerically enriched secondary tosylate is displaced by the sodium salt of di-tert-butyl malonate to provide the alkylation product in good yield. The product was formed with clean inversion of stereochemistry, in support of an SN 2 mechanism.

1.7.1.9

Alkylation of Aldehydes, Ketones, Nitriles, and Carboxylic Esters

The α-alkylation of aldehyde enolates is plagued by self condensation by-products, as aldehydes are reactive electrophiles. An elegant solution was introduced by Stork, as highlighted by the following example.275 Condensation of an enolizable aldehyde with a primary amine provides the corresponding imine, which is far less prone to self condensation. Subjecting the imine to reaction with a base provides the metalated enamine, which can be reacted with mild electrophiles such as alkyl halides. Of particular note is that ethyl magnesium bromide is employed as a base in this particular example, and no addition of the Grignard reagent to the imine is observed. The resulting bromomagnesium counterion works in combination with the bulky t-butyl substituent on the imine nitrogen to provide excellent Cvs. N-alkylation selectivity. A simple aqueous hydrochloric acid workup hydrolyzes the imine to release the aldehyde function for further elaboration. (i) (ii) (iii)

In what has become the definitive example of stereocontrolled enolate alkylation under chiral phase transfer catalysis, Dolling et al. reported the following enantioselective methylation of an aryl ketone enolate.276 The cinchona alkaloid 267 Minami, I.; Shimizu, I.; Tsuji, J. Journal of Organometallic Chemistry 1985, 296, 269–280. 268 Tsuji, J. Organic Synthesis with Palladium Compounds; Springer-Verlag: Berlin, 1980. 269 Trost, B. M.; Verhoeven, T. R. Journal of the American Chemical Society 1980, 102, 4730–4743. 270 Davis, A. P.; Egan, T. J.; Orchard, M. G.; Cunningham, D.; McArdle, P. Tetrahedron 1992, 48, 8725–8738. 271 Kaltenbronn, J. S.; Hudspeth, J. P.; Lunney, E. A.; Michniewicz, B. M.; Nicolaides, E. D.; Repine, J. T.; Roark, W. H.; Stier, M. A.; Tinney, F. J. et al. Journal of Medicinal Chemistry 1990, 33, 838–845. 272 Takasu, H.; Tsuji, Y.; Sajiki, H.; Hirota, K. Tetrahedron 2005, 61, 8499–8504. 273 Larcheveque, M.; Petit, Y. Synthesis 1991, 162–164. 274 See Note 271. 275 Stork, G.; Dowd, S. R. Organic Syntheses 1974, 54, 46–49. 276 Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Journal of the American Chemical Society 1984, 106, 446–447.

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derived phase transfer catalyst blocks one face of the enolate to provide a substantial rate advantage over the racemic background alkylation. In their account of this work, Dolling et al. reported that several variables, including solvent polarity, reaction concentration, sodium hydroxide concentration, and catalyst loading were critical to optimizing yield and enantioselectivity.

Ketone enolates are readily generated by treatment with strong base.277 When only one enolate is possible, as is the case with aryl ketones, a wide variety of bases can be used. In the following example, a chloroketone was treated with 2 equiv of potassium t-butoxide in THF, to promote intramolecular alkylation and provide the cyclopropyl ketone in excellent yield.278

The generation and cyanation of ketone enolates obtained by treatment with lithium diisopropylamide in THF at −78 ∘ C has been reported by Kahne and Collum.279 The use of p-toluenesulfonyl cyanide as the cyanide source proved to be critical, as did inverse addition of the enolate into a cold THF solution of p-TsCN. For more on the addition of carbon based nucleophiles to nitriles, see Sections 2.41–2.43. (i) (ii)

–78 °C –78 °C

It is also possible to deprotonate the position α to an aliphatic nitrile with LDA. In the following example, reaction of the deprotonated nitrile with an alkyl bromide provided the expected alkylation product in good yield.280 (i) (ii)

The alkylation of nitriles is often complicated by incomplete conversion and over-alkylation. In the following example from Taber et al., however, a rather complex nitrile is further elaborated via deprotonation with LDA at −78 ∘ C, and subsequent treatment with an alkyl iodide.281 277 278 279 280 281

See Note 74,75. Chang, S.-J.; Fernando, D. P.; King, S. Organic Process Research & Development 2001, 5, 141–143. Kahne, D.; Collum, D. B. Tetrahedron Letters 1981, 22, 5011–5014. Wu, L.; Hartwig, J. F. Journal of the American Chemical Society 2005, 127, 15824–15832. Taber, D. F.; Bhamidipati, R. S.; Yet, L. The Journal of Organic Chemistry 1995, 60, 5537–5539.

1.7 Carbon Nucleophiles

(i) (ii)

Taber and Joerger have also reported on the use of epoxides for the alkylation of nitrile enolates. In the following example shown, n-butyllithium is utilized for the deprotonation step, and an allylic epoxide serves as the electrophile. Of note is the apparent lack of regioisomeric products that could arise from attack at the other epoxide-bearing carbon or the less-substituted allylic terminus (SN 2′ ).282

The use of strong bases derived from HMDS is becoming increasingly popular for both small- and large-scale applications. The lithium, sodium, and potassium hexamethyldisilazides (KHMDSs) are relatively stable, commercially available materials, and provide a convenient option for investigating counterion effects on rate and/or selectivity in a given reaction. In the following example, LiHMDS in THF was employed for the selective formation of the kinetically favored (Z)-ester enolate at a temperature of −23 ∘ C. The subsequent addition of allyl iodide provided a 23 : 1 ratio of diastereoisomers in excellent yield.283 Interestingly, KHMDS also provided the (Z)-ester enolate, although the opposite diastereoisomer was favored during the alkylation. The authors propose an internal ester chelation mechanism for the potassium enolate that is not operable for the lithium enolate.

dr

dr

LiHMDS in THF/DMPU has been used for an ester enolate formation on multikilogram scale. The enolization and subsequent tosylate displacement were carried out below −40 ∘ C in order to conserve the stereochemical integrity of the benzylic chiral center.284

282 Taber, D. F.; Joerger, J.-M. The Journal of Organic Chemistry 2007, 72, 3454–3457. 283 Humphrey, J. M.; Bridges, R. J.; Hart, J. A.; Chamberlin, A. R. The Journal of Organic Chemistry 1994, 59, 2467–2472. 284 O’Shea, P. D.; Chen, C.-Y.; Chen, W.; Dagneau, P.; Frey, L. F.; Grabowski, E. J. J.; Marcantonio, K. M.; Reamer, R. A.; Tan, L.; Tillyer, R. D.; Roy, A.; Wang, X.; Zhao, D. The Journal of Organic Chemistry 2005, 70, 3021–3030.

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In a process to the HMG CoA reductase inhibitor simvastatin, lithium pyrrolidide has been used as a base for ester enolization, which allowed for the introduction of a challenging acyclic geminal methyl substituent.285 Of significance is the lack of competitive amide methylation observed under these conditions. The authors were able to optimize reaction temperature and methyl iodide stoichiometry to minimize this side reaction, presumably aided by the high pK a of the amide α-protons after initial lithium imidate formation. (i) hexanes

(ii)

1.7.1.10

Alkylation of Carboxylic Acid Salts

The action of 2 equiv of strong base on carboxylic acids produces a dianion that is capable of reaction with electrophiles to provide α-substitution products (the Krapcho method).286 Although the second deprotonation is considerably more challenging than the initial carboxylate salt formation, aggregate effects render the effective pK a of lithium carboxylates in THF solvent just a few units higher than the corresponding carboxylic esters.287 In the following example, treatment of an enolizable carboxylic acid with 2 equiv of LDA at −75 ∘ C in THF provided the dianion. Subsequent addition of methyl iodide, followed by a hydrolytic workup, afforded the α-methylation products in high yield as a mixture of diastereoisomers favoring axial substitution.288 (i) 2 equiv LDA, THF, −75 °C (ii) Mel, THF, −75 °C to rt dr 73 : 27

1.7.1.11

Alkylation 𝛂 to a Heteroatom

In a series of seminal publications, Corey and Seebach described the use of 1,3-dithianes as acyl anion synthons.289,290,291 Soon after, Seebach introduced the term umpolung (German for “reversed polarity”), whereby a chemical transformation carried out on a functional group changes the inherent reactive polarity of that group. The use of dithianes as umpolung synthons has been reviewed.292 The example below clearly illustrates the umpolung concept, as the carbon in the 2-position of the starting 1,3-dithiane is derived from formaldehyde, which is typically electrophilic at carbon. Through conversion to the dithiane and deprotonation with n-butyllithium, this carbon becomes a nucleophilic center. Subsequent addition of 1-bromo-3-chloropropane provides the 3-chloropropyl alkylation product. In this example, an additional charge of n-BuLi led to intramolecular alkylation, which afforded dithiane protected cyclobutanone in good yield. One major drawback of this methodology is the typical use of mercury(II) salts to promote conversion of the dithiane to the free carbonyl.293,294 However, a handful of alternative methods for this conversion have been reported.295,296 For more on the oxidation of sulfides, see Section 10.8.5. 285 286 287 288 289 290 291 292 293 294 295 296

Askin, D.; Verhoeven, T. R.; Liu, T. M. H.; Shinkai, I. The Journal of Organic Chemistry 1991, 56, 4929–4932. Krapcho, A. P.; Dundulis, E. A. Tetrahedron Letters 1976, 2205–2208. Gronert, S.; Streitwieser, A. Journal of the American Chemical Society 1988, 110, 4418–4419. Krapcho, A. P.; Dundulis, E. A. The Journal of Organic Chemistry 1980, 45, 3236–3245. Corey, E. J.; Seebach, D. Angewandte Chemie, International Edition in English 1965, 4, 1075–1077. Corey, E. J.; Seebach, D. Angewandte Chemie, International Edition in English 1965, 4, 1077–1078. Corey, E. J.; Seebach, D. Organic Syntheses 1970, 50, 72–74. Groebel, B. T.; Seebach, D. Synthesis 1977, 357–402; Seebach, D. Synthesis 1969, 1, 17–36. Seebach, D.; Beck, A. K. Organic Syntheses 1971, 51, 76–81. Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale, K. J. Organic Letters 2006, 8, 4477–4480. Firouzabadi, H.; Hazarkhani, H.; Hassani, H. Phosphorus, Sulfur and Silicon and the Related Elements 2004, 179, 403–409. Walsh, L. M.; Goodman, J. M. Chemical Communications 2003, 2616–2617.

1.7 Carbon Nucleophiles

(i) (ii) (iii)

–20 –75

2–3 h –75 65–84%

The dithiane alkylation reaction can also be used for the preparation of acyl silanes for further elaboration.297 As described in the following scheme, the dithiane was deprotonated at the 2-position by n-BuLi in THF-hexanes and then reacted with chlorotrimethylsilane to afford the quaternary silane product in excellent yield.

C-alkylation of TMS cyanohydrins has emerged as an excellent method for homologation of aldehydes at the carbonyl carbon. As described in the following example, the TMS cyanohydrin prepared from furfuraldehyde and TMS cyanide was treated with LDA at low temperature in THF to afford the carbon-centered anion. The addition of 4-bromo-1-butene followed by warming to room temperature provided the C-alkylated product in excellent yield. The cyanohydrin product was then subjected to triethylamine trihydrofluoride, which led to desilylation and loss of cyanide, and provide the ketone in high yield.298 (i) (ii)

Hydrazones have also been shown to be effective acyl anion equivalents, as highlighted by the pioneering work of Baldwin et al.299,300,301 In the following example, the t-butyl hydrazone of acetaldehyde was treated with n-butyllithium in THF to provide the expected lithiated intermediate at −20 ∘ C. Subsequent reaction with o-bromobenzylbromide at 15 ∘ C provided exclusively the product of C-alkylation in 77% yield.302 The use of the sterically bulky tert-butyl substituent minimizes competitive N-alkylation.

Dieter and coworkers have extended this methodology through the use of organocuprates derived from lithiated hydrazones in reactions with Michael acceptors. This reaction is useful for the preparation of β-substituted carbonyl compounds.303 The use of copper additives enhances the selectivity for C- vs. N-alkylation of these ambident nucleophiles and expands the substrate scope to include cyclic α,β-unsaturated ketones. Alkoxy vinyl lithium reagents are another useful class of acyl anion equivalents. First reported by Baldwin et al., the methyl enol ether of acetaldehyde can be deprotonated with tert-butyl lithium at the vinyl carbon bearing oxygen.304 297 Huckins, J. R.; Rychnovsky, S. D. The Journal of Organic Chemistry 2003, 68, 10135–10145. 298 Fischer, K.; Huenig, S. The Journal of Organic Chemistry 1987, 52, 564–569. 299 Baldwin, J. E.; Adlington, R. M.; Bottaro, J. C.; Jain, A. U.; Kohle, J. N.; Perry, M. W. D.; Newington, I. M. Journal of the Chemical Society, Chemical Communications 1984, 1095–1096. 300 Baldwin, J. E.; Adlington, R. M.; Bottaro, J. C.; Kolhe, J. N.; Perry, M. W. D.; Jain, A. U. Tetrahedron 1986, 42, 4223–4234. 301 Baldwin, J. E.; Adlington, R. M.; Newington, I. M. Journal of the Chemical Society, Chemical Communications 1986, 176–178. 302 Wang, S. F.; Warkentin, J. Canadian Journal of Chemistry 1988, 66, 2256–2258. 303 Alexander, C. W.; Lin, S.-Y.; Dieter, R. K. Journal of Organometallic Chemistry 1995, 503, 213–220. 304 Baldwin, J. E.; Hoefle, G. A.; Lever, O. W., Jr. Journal of the American Chemical Society 1974, 96, 7125–7127.

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1 Aliphatic Nucleophilic Substitution

The resulting vinyl anions can be alkylated with various electrophiles. Both tert-butyl lithium and alkoxy vinyl lithium reagents are highly reactive substances, which may limit practical use on a large scale; however, a number of improvements to the original synthesis of these reagents have been made, and several useful applications have been reported. In the example below from Denmark et al., n-butyl vinyl ether is deprotonated with tert-butyllithium in THF. Following transmetalation with CuCN, the resulting vinyl cuprate was treated with allyl bromide to afford the alkylation product in good yield.305 (i) (ii) (iii) Allyl bromide

Meyers and coworker have communicated that the use of tetrahydropyran (THP) is superior to THF for the efficient preparation of these reagents via deprotonation by t-BuLi.306 Meyers’ group has also demonstrated the utility of α-ethoxyvinyl lithium in a diastereoselective conjugate addition to α,β-unsaturated oxazolines. Although not an aliphatic nucleophilic substitution reaction, an example is provided below for illustrative purposes.307 The addition of carbon nucleophiles to polarized carbon–carbon multiple bonds is the subject of Section 3.5. (i)

(ii)

Alkoxyvinyl lithium derivatives have also found utility in nucleophilic additions to carbonyl centers such as carboxylic esters.308 1.7.1.12

Alkylation 𝛂 to a Masked Carboxylic Acid

Elaboration at the α-position of carboxylic acid derivatives has been the subject of considerable research. Although much has been reported on the direct alkylation of carboxylate dianions, it is often preferable to employ carboxylic acid surrogates in bond-forming operations and then deprotect later in a multistep synthesis. In a series of seminal publications, Meyers et al. introduced 2-substituted 4,4-dimethyloxazolines as carboxylic acid synthons that can be easily elaborated via alkylation of their stabilized anion derivatives. The following example illustrates the deprotonation of 2-propyl oxazoline by n-butyllithium, followed by reaction with an alkyl iodide to provide the alkylated product.309 The carboxylic acid moiety can be conveniently liberated under either acidic (3 N HCl) or alkaline (MeI, then 1 N NaOH) conditions. The latter method was utilized here to preserve the acid sensitive acetal functionality. (i) (ii)

hexane

(i) (ii)

Stereoselective alkylation of masked carboxylic acids in the form of chiral oxazolidinone auxiliaries has been extensively studied by Evans et al.310 The method has been applied to numerous complex total syntheses and is considered a foundational synthetic methodology. In the following example, Michida et al. utilize the Evans stereoselective alkylation 305 306 307 308 309 310

Denmark, S. E.; Guagnano, V.; Dixon, J. A.; Stolle, A. The Journal of Organic Chemistry 1997, 62, 4610–4628. Shimano, M.; Meyers, A. I. Tetrahedron Letters 1994, 35, 7727–7730. James, B.; Meyers, A. I. Tetrahedron Letters 1998, 39, 5301–5304. Li, Y.; Drew, M. G. B.; Welchman, E. V.; Shirvastava, R. K.; Jiang, S.; Valentine, R.; Singh, G. Tetrahedron 2004, 60, 6523–6531. Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. The Journal of Organic Chemistry 1974, 39, 2778–2783. Evans, D. A.; Ennis, M. D.; Mathre, D. J. Journal of the American Chemical Society 1982, 104, 1737–1739.

1.7 Carbon Nucleophiles

to construct a key stereocenter in their synthesis of a renin inhibitor.311 The alkylation illustrated below was carried out as a part of a four-step telescoped sequence that performed in 63% overall yield.

Hoestra et al. at Parke–Davis reported the use of an Evans asymmetric alkylation for the preparation of an enantiomerically pure anticonvulsant candidate.312 In order to apply this methodology on multi-hundred kilogram scale, the auxiliary was recycled in a recovery yield of 64%. (i) (ii)

tBu, THF dr

1.7.1.13

tBuO

Alkylation at Alkynyl Carbon

Terminal alkynes can be converted to their acetylide anions by deprotonation with a strong base such as n-butyllithium. The acetylide formation and subsequent reaction with electrophiles are typically carried out in THF at temperatures near −78 ∘ C. In a few cases, additives such as HMPA or DMPU313 are included to accelerate the overall reaction rate via coordination to lithium cations, resulting in deaggregation. An interesting study on the implications of HMPA additives on solution kinetics has been reported.314 It should be noted that HMPA is a demonstrated health hazard, and extreme care should be taken to avoid exposure during handling. If a strongly coordinating additive is desired, DMPU should be used preferentially, due to a superior safety profile. The following example is demonstrative of typical conditions for deprotonation and alkylation of terminal alkynes.315

Epoxides are also suitable alkylating agents for lithium acetylides when the reaction is carried out in the presence of an oxophilic Lewis acid. In the following example, nucleophilic attack occurred at the less sterically encumbered position in the presence of boron trifluoride diethyl etherate.316 he

311 Michida, M.; Takayanagi, Y.; Imai, M.; Furuya, Y.; Kimura, K.; Kitawaki, T.; Tomori, H.; Kajino, H. Organic Process Research & Development 2013, 17, 1430–1439. 312 See Note 175. 313 Mukhopadhyay, T.; Seebach, D. Helvetica Chimica Acta 1982, 65, 385–391. 314 Collum, D. B.; McNeil, A. J.; Ramirez, A. Angewandte Chemie, International Edition 2007, 46, 3002–3017. 315 Patil, N. T.; Wu, H.; Yamamoto, Y. The Journal of Organic Chemistry 2007, 72, 6577–6579. 316 Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron 2007, 63, 11011–11015.

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Trost et al. reported the use of catalytic diethylaluminum chloride as a Lewis acid on a closely related system to obtain the enantiomerically enriched alcohol in quantitative yield.317 (ii) (iii)

(i)

Under analogous conditions, acetylides can be alkylated with oxetane via catalysis by BF3 ⋅OEt2 , as described by Wessig et al.318 hexanes

Copper-promoted acetylinic alkylation reactions have also been reported. The mild conditions described in the following example are advantageous compared to methods that require cryogenic temperatures and pyrophoric reagents.319

Acetylenes can be reacted with activated aziridines to afford homopropargylic amine derivatives in good yield.320 It has been reported that potassium tert-butoxide base in dimethylsulfoxide is optimal for these systems.

1.7.1.14

Alkylation of Cyanide Ion – Preparation of Nitriles

The use of cyanide anion for the preparation of nitriles (or amines via nitrile reduction) is a useful and commonly employed operation in target-directed synthesis. Despite the serious health hazards presented by hydrogen cyanide, sodium and potassium cyanide salts are utilized extensively as nucleophiles under basic conditions. Highly sensitive HCN detection monitors are available to provide an early warning to scientists working in the vicinity of cyanide-containing reactions. Diligence in the use of these detectors, in addition to personal protective equipment and proper engineering controls, is essential to maintaining a safe working environment. A cyanide poisoning antidote kit should be readily available before beginning any laboratory work.321 In the following example, 2,4,6-triisopropylbenzyl chloride was converted to the corresponding benzylic nitrile in a biphasic solvent system via phase transfer catalysis.322 This nucleophilic substitution reaction requires heating, presumably due to considerable steric obstruction from the isopropyl substituents. For some substrates, the more expensive, but also commercially available, tetrabutylammonium cyanide may provide a rate advantage over the catalytic method described here. However, this reagent is exceedingly hygroscopic, which complicates storage and handling.

317 318 319 320 321 322

Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. Journal of the American Chemical Society 2005, 127, 10028–10038. Wessig, P.; Mueller, G.; Kuehn, A.; Herre, R.; Blumenthal, H.; Troelenberg, S. Synthesis 2005, 1445–1454. Alegret, C.; Santacana, F.; Riera, A. The Journal of Organic Chemistry 2007, 72, 7688–7692. Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586–9593. Hall, A. H.; Saiers, J.; Baud, F. Critical Reviews in Toxicology 2009, 39, 541–552. Dozeman, G. J.; Fiore, P. J.; Puls, T. P.; Walker, J. C. Organic Process Research & Development 1997, 1, 137–148.

1.7 Carbon Nucleophiles

Cyanide salts can also be reacted with alkyl sulfonates to provide the expected nitriles in high yield. In the following example, a primary alcohol was converted to its mesylate under standard conditions. The subsequent reaction of sodium cyanide in dimethylsulfoxide-toluene provided the nitrile in excellent overall yield on multigram scale.323 (i)

(ii)

Acetone cyanohydrin can also be employed as a convenient source of nucleophilic cyanide in the presence of a base. In the following example, an enantiomerically enriched secondary tosylate is converted to the corresponding nitrile in high yield and with clean inversion of stereochemistry. The authors reported that proper choice of base and solvent were critical to achieving high yield and reaction rate while preserving the stereochemical integrity of the product.324 Optimal conditions included lithium hydroxide in a mixture of THF and 1,3-dimethyl-2-imidazolidinone (DMI).

In the following example, the action of tetrabutylammonium hydroxide on acetone cyanohydrin produced tetrabutylammonium cyanide in situ. This underwent a smooth, high-yielding conjugate addition to the enone to afford the β-cyanoketone in high yield.325 This methodology was successfully scaled to approximately 10 kg during the preparation of an endothelin antagonist candidate. Although this example does not satisfy the definition of a nucleophilic aliphatic substitution reaction, it is included here to illustrate the utility of in situ derived tetrabutylammonium cyanide, as the isolated compound is exceedingly hygroscopic and difficult to handle. For more discussion on the nucleophilic addition of cyanide to polarized carbon–carbon multiple bonds, see Section 3.5.6.

323 Wu, G.; Wong, Y.; Steinman, M.; Tormos, W.; Schumacher, D. P.; Love, G. M.; Shutts, B. Organic Process Research & Development 1997, 1, 359–364. 324 Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Ohta, C.; Nakabayashi, K.; Okamoto, M.; Hamano, M.; Takahashi, K.; Ohuchida, S.; Hamada, Y. Organic Process Research & Development 2005, 9, 774–781. 325 Ellis, J. E.; Davis, E. M.; Brower, P. L. Organic Process Research & Development 1997, 1, 250–252.

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1.8 Nucleophilic Substitution at a Sulfonyl Sulfur Atom 1.8.1 1.8.1.1

Attack by Oxygen Hydrolysis of Sulfonic Acid Derivatives

Sulfonyl halides are readily hydrolyzed to the parent sulfonic acids or sulfonate salts under acidic or basic conditions, respectively. In fact, most sulfonyl halides will hydrolyze in an aqueous environment in the absence of an additive, as the acidic products are themselves catalysts.326

Sulfonic acid esters are also susceptible to hydrolysis. However, nucleophilic attack by water generally takes place at the carbon center, with concomitant displacement of the sulfonate moiety, as discussed in Section 1.2.1.4. Basic conditions are typically employed, and elimination is a concern. In a few rare cases, nucleophilic attack may occur at the sulfur center, as evidenced by net stereochemical retention at carbon in the following example.327 The product is consistent with hydrolysis of the sulfonate, although steps were taken to ensure that water was not present in the reaction mixture. Deprotonation and subsequent formation of the sulfene was not ruled out as an alternative mechanism.

Attack by water at the sulfur center is likely operative during the hydrolysis of aryl sulfonate esters, although examples of this reaction are rare.328,329 Sulfonamides can be converted to the corresponding sulfonic acids via hydrolysis promoted by strong acids. Alkaline hydrolysis is typically ineffective, although a few special exceptions have been reported.330 In the following example, N-methyl saccharin was treated with hydrochloric acid at reflux temperature to provide the methylammonium salt of the sulfonic acid resulting from complete hydrolysis of the mixed sulfonamide. The authors advise that the initial hydrolysis product is the N-methylsulfonamide, which reacts further with water to provide the sulfonic acid.331

Reflux, 5 h

326 327 328 329 330 331

Hoffart, D. J.; Cote, A. P.; Shimizu, G. K. H. Inorganic Chemistry 2003, 42, 8603–8605. Chang, F. C. Tetrahedron Letters 1964, 305–309. Suh, J.; Suh, M. K.; Cho, S. H. Journal of the Chemical Society, Perkin Transactions 2 1990, 685–688. Kano, K.; Nishiyabu, R.; Asada, T.; Kuroda, Y. Journal of the American Chemical Society 2002, 124, 9937–9944. Cuvigny, T.; Larcheveque, M. Journal of Organometallic Chemistry 1974, 64, 315–321. Meadow, J. R.; Cavagnol, J. C. The Journal of Organic Chemistry 1951, 16, 1582–1587.

1.8 Nucleophilic Substitution at a Sulfonyl Sulfur Atom

1.8.1.2

Formation of Sulfonate Esters

Sulfonic acid esters are most commonly prepared by reaction of alcohols with sulfonyl halides under basic conditions. The use of methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl) is commonplace, as these reagents are employed in the activation step during conversion of alcohols to other functionalities (for an example, see Section 1.6.1.4). In the following example, a diol intermediate was differentially protected with TsCl and p-nitrobenzenesulfonyl chloride (NsCl) by taking advantage of the relative acidities of the two alcohols.332 This selective protection sequence was used in the authors’ synthesis of the muscarinic receptor antagonist tolterodine. (i)

(ii)

1.8.2 1.8.2.1

Attack by Nitrogen Formation of Sulfonamides

The reaction of primary and secondary amines with sulfonyl halides is analogous to the corresponding reaction with oxygen nucleophiles, although the superior nucleophilicity of most amines makes the formation of sulfonamides a milder, more efficient transformation.333 During the development of novel COX-2 inhibitors for the treatment of pain and related inflammatory disorders, Caron et al. reported the preparation of an aryl sulfonamide via treatment of an aniline derivative with tosyl chloride and pyridine in dichloromethane.

In the following example from Han et al., the hydrochloride salt of (R)-phenylglycine methyl ester was treated with tosyl chloride in the presence of the mild base sodium bicarbonate to afford the sulfonamide in excellent yield at room temperature.334 The authors were able to employ ethyl acetate as the solvent in this example, which is preferred for large-scale applications due to its decreased environmental impact.

1.8.3 1.8.3.1

Attack by Halogen Formation of Sulfonyl Halides

Sulfonic acids or their salts can be converted to the corresponding sulfonyl halides with methods analogous to the conversion of carboxylic acids or carboxylate salts to carboxylic acid halides (see Section 2.26). Sulfonyl chlorides are most commonly prepared by treatment with thionyl chloride335 or phosphorus pentachloride,336 with the former preferred for large-scale applications due to the ease of reagent removal by distillation. In the following example, treatment of 332 De Castro, K. A.; Ko, J.; Park, D.; Park, S.; Rhee, H. Organic Process Research & Development 2007, 11, 918–921. 333 Caron, S.; Vazquez, E.; Stevens, R. W.; Nakao, K.; Koike, H.; Murata, Y. The Journal of Organic Chemistry 2003, 68, 4104–4107. 334 Han, Z.; Krishnamurthy, D.; Senanayake, C. H. Organic Process Research & Development 2006, 10, 327–333. 335 Morikawa, A.; Sone, T.; Asano, T. Journal of Medicinal Chemistry 1989, 32, 42–46. 336 Ponticello, G. S.; Freedman, M. B.; Habecker, C. N.; Lyle, P. A.; Schwam, H.; Varga, S. L.; Christy, M. E.; Randall, W. C.; Baldwin, J. J. Journal of Medicinal Chemistry 1987, 30, 591–597.

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an acetonitrile suspension of a sulfonic acid sodium salt with thionyl chloride in the presence of DMF provided the sulfonyl chloride in excellent yield.337

Likewise, sulfonyl bromides can be prepared from sulfonic acid salts by utilizing phosphorous pentabromide,338 or preferably, via treatment with triphenylphosphine and bromine or NBS.339 In the following example, the tetrabutylammonium salt of a sulfonic acid was converted to the corresponding sulfonyl bromide with triphenylphosphine and bromine. As sulfonyl bromides are generally unstable, the product was not isolated, but rather converted immediately to the isopropyl sulfonate ester by quenching the reaction with isopropanol and triethylamine.

A less frequently utilized method involves treatment of sulfonyl hydrazines with bromine.340 As a relatively large number of sulfonyl chlorides are commercially available, a convenient method for the preparation of sulfonyl bromides involves treatment of sulfonyl chlorides with sodium sulfite, followed by bromine, as described in the following example.341 (i)

(ii)

Sulfonyl fluorides are also most easily prepared from their sulfonyl chloride analogs through halogen exchange with potassium fluoride342 or TBAF.343 In the following representative example, a sulfonyl fluoride was obtained in high yield via treatment of a sulfonyl chloride with KF in refluxing THF. The sulfonyl fluoride products typically require purification through distillation, which can be damaging to glass and is better carried out in specialized equipment.

Reflux

337 Ikemoto, N.; Liu, J.; Brands, K. M. J.; McNamara, J. M.; Reider, P. J. Tetrahedron 2003, 59, 1317–1325. 338 Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R.; Laffitte, J. A.; Wall, A. Journal of the American Chemical Society 1986, 108, 4568–4580. 339 Huang, J.; Widlanski, T. S. Tetrahedron Letters 1992, 33, 2657–2660. 340 Palmieri, G. Tetrahedron 1983, 39, 4097–4101. 341 See Note 338. 342 Hyatt, J. A.; White, A. W. Synthesis 1984, 214–217. 343 Sun, H.; DiMagno, S. G. Journal of the American Chemical Society 2005, 127, 2050–2051.

1.8 Nucleophilic Substitution at a Sulfonyl Sulfur Atom

1.8.4 1.8.4.1

Attack by Carbon Preparation of Sulfones

The range of carbon-centered nucleophiles that can react with sulfonyl halide electrophiles to afford sulfone products with reasonable efficiency is rather limited. One complicating factor is that sulfone products typically have a lower pK a than the carbanion nucleophiles used to prepare them, so β-disulfonylation products dominate. Stoichiometry may be adjusted to partially address this issue, as can enhancement of sulfone electrophilicity through formation of sulfonyl fluorides, as described in the following example.344,345 Scope is generally limited to arylsulfones. (1) (2)

The addition of vinyl carbon nucleophiles to sulfonyl chlorides has also been accomplished under transition metal catalysis.346 The example below from Labadie is a representative and involves the use of stoichiometric organostannane.

Nevertheless, the synthesis of alkyl sulfones is best accomplished via oxidation of sulfide or sulfoxide precursors (see Section 10.8.5).

344 Grunewald, G. L.; Dahanukar, V. H.; Jalluri, R. K.; Criscione, K. R. Journal of Medicinal Chemistry 1999, 42, 118–134. 345 Frye, L. L.; Sullivan, E. L.; Cusack, K. P.; Funaro, J. M. The Journal of Organic Chemistry 1992, 57, 697–701. 346 Labadie, S. S. The Journal of Organic Chemistry 1989, 54, 2496–2498.

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2 Addition to Carbon-Heteroatom Multiple Bonds Prantik Maity and Rajappa Vaidyanathan Biocon Bristol-Myers Squibb R&D Center, Bangalore, India

CHAPTER MENU Introduction, 66 Addition of Water to Aldehydes and Ketones: Formation of Hydrates, 66 Addition of Bisulfite to Aldehydes and Ketones, 67 The Addition of Alcohols to Aldehydes and Ketones: Acetal Formation, 69 The Addition of Thiols to Aldehydes and Ketones: S,S-Acetal Formation, 71 Reductive Etherification, 72 Addition of NH3 , RNH2 , and R2 NH, 74 Formation of Hydrazones, 79 Formation of Oximes, 80 The Formation of gem-Dihalides from Aldehydes and Ketones, 80 The Aldol Reaction, 82 Allylorganometallics: Stannane, Borane, and Silane, 92 The Nozaki–Hiyama–Kishi Reaction, 97 Addition of Transition Metal Alkynylides to Carbonyl Compounds, 99 Addition of Organometallic Reagents to Carbonyls, 100 Addition of Conjugated Alkenes to Aldehydes: the Baylis–Hillman Reaction, 103 The Reformatsky Reaction, 104 The Wittig Reaction, 106 Horner–Wadsworth–Emmons Reaction, 108 Peterson Olefination, 109 Julia–Lythgoe Olefination, 110 Tebbe Methylenation, 112 The Mannich Reaction, 113 The Strecker Reaction, 115 Hydrolysis of Carbon–Nitrogen Double Bonds, 117 Conversion of Carboxylic Acids to Acyl Chlorides, 118 Synthesis of Acyl Fluorides from Carboxylic Acids, 122 Formation of Amides from Carboxylic Acids, 123 Formation of Amides from Esters, 130 Hydrolysis of Acyl Halides, 132 Conversion of Carboxylic Acids to Esters, 132 Hydrolysis of Amides, 136 Conversion of N-Acyloxazolidinones to Other Carboxyl Derivatives, 139 Alcoholysis of Amides, 140 Hydrolysis of Esters, 141 Transesterification, 143 Alkyl Thiol Addition to Esters, 144 Addition of Organometallic Reagents to Carboxylic Acid Derivatives, 145 The Kulinkovich Cyclopropanation, 149 Synthesis of Acyl Cyanides, 150 The Ritter Reaction, 151 Thorpe Reaction, 154 Addition of Organometallic Reagents to Nitriles, 155 Conversion of Nitriles to Amides, Esters, and Carboxylic Acids, 155 Conversion of Nitriles to Thioamides, 158 The Addition of Ammonia or Amines to Nitriles, 160 Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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2 Addition to Carbon-Heteroatom Multiple Bonds

The Addition of Alcohol to Nitriles, 161 Alkyl Thiol Addition to Nitriles, 162 The Blaise Reaction, 162 The Addition of Alcohols to Isocyanates, 163 The Addition of Amines and Amides to Isocyanates, 164 The Formation of Xanthates, 165 The Addition of Amines to Carbon Dioxide, 166 The Addition of Amines to Carbon Disulfide, 167 Addition of Organometallic Reagents to Carbon Dioxide, 167

2.1 Introduction Additions to carbon-heteroatom multiple bonds will be presented in this chapter. The majority of the discussion will focus on additions to carbon–oxygen double bonds, carbon–nitrogen double bonds, and carbon–nitrogen triple bonds. Additions to carbon–sulfur double bonds are far less common and will be briefly discussed. The polarity of the C=O, C=N, and C≡N bonds makes prediction of their reactivity fairly simple. With the exception of isocyanides, the carbon atom is typically the more electropositive center, so nucleophiles generally attack the carbon atom, while the more electronegative heteroatom (O or N) generally attacks electrophiles. The relative stereochemistry of addition (syn or anti) across carbon-heteroatom double bonds is neither known nor of any consequence. However, the relative stereochemistry of addition across carbon–nitrogen triple bonds can be determined by examining the product (E or Z isomer). The more interesting stereochemical aspect is the facial selectivity of nucleophilic attack onto C=O and C=N moieties. If R1 and R2 (the groups flanking the C=X center) are different, the resultant molecule after nucleophilic addition is chiral. In the absence of chirality in R1 , R2 , or the nucleophile, the products are racemic mixtures. The absolute configuration at the chiral center may be controlled by either of the R groups, the nucleophile, or more importantly, catalysts used to affect these reactions. The use of asymmetric catalysts to influence the stereochemical outcome of these reactions has revolutionized this area, and several examples will be presented. In the specific case of nucleophilic attack on carbon–oxygen double bonds, substitution or addition-derived products can arise. The mode of reactivity is determined by the nature of the groups flanking the carbonyl carbon. Aldehydes and ketones cannot undergo substitution reactions owing to the poor leaving group ability of H, alkyl, and aryl groups. However, carboxylic acids and their derivatives undergo substitution reactions since OH, OR, and NR2 groups are better leaving groups. The chapter is divided into additions to aldehydes or ketones (see Sections 2.2–2.22), additions to carbon–nitrogen double bonds (see Sections 2.23–2.25), additions to carboxylic acid derivatives (see Sections 2.26–2.40), additions to nitriles (see Sections 2.41–2.49), and miscellaneous C=X additions (see Sections 2.50–2.55)

2.2 Addition of Water to Aldehydes and Ketones: Formation of Hydrates The net addition of water across a carbonyl results in a hydrate. They are virtually useless from a synthetic standpoint, and hence are seldom intentionally synthesized. Hydrates occur readily in most aqueous solvent systems, but they are usually not isolable unless the carbonyl is sufficiently electron-deficient (e.g. di- and tri-carbonyl compounds, α-haloaldehydes, etc.). A few instances where hydrates of oxalates are formed are shown in the following scheme. Both examples involve formation of electrophilic 1,2-dicarbonyl compounds, which results in the concomitant formation of a hydrate. In the first example, treatment of the fluoro-phenyl ketone with HBr in dimethyl sulfoxide (DMSO) leads to the corresponding dibromide, which is then converted to the aldehyde during the workup1 . In the second example, oxidative periodate-mediated cleavage of diethyl tartarate furnished 2 equiv of ethyl glyoxaldehyde, which readily converts to a stable hydrated form in the presence of water.2 1 Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Soug, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U. -H.; Grabowski, E. J. J.; Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. J. Org. Chem. 2002, 67, 6743–6747. 2 Bailey, P. D.; Smith, P. D.; Pederson, F.; Clegg, W.; Rosair, G. M.; Teat, S. J. Tetrahedron Letters 2002, 43, 1067–1070.

2.3 Addition of Bisulfite to Aldehydes and Ketones

O

O

aq HBr, DMSO

Me

OH

55 °C

F

OH

F

76%

H H

CO2Et OH OH CO2Et

OH

aq NaIO4

OEt

HO

CH2Cl2

O

94%

2.3 Addition of Bisulfite to Aldehydes and Ketones Bisulfite formation is a valuable, chemoselective derivatization procedure used for the protection and/or purification of carbonyl compounds (generally aldehydes), or for the removal of unwanted/residual aldehydes from reaction mixtures. In the most commonly utilized method, the aldehyde is treated with sodium bisulfite to afford the sodium salt of the bisulfite adduct. These charged adducts are often highly water soluble; however, careful solvent selection can allow for isolation or removal of the bisulfite adduct via precipitation. Regeneration of the aldehyde can be accomplished by treatment with aqueous base or in some cases, by heating in water.3 Bisulfite adduct formation is heavily utilized in beer and wine production, where inhibition of oxidation of acetaldehyde (to form acetic acid) is critical. Brewing research scientists from the Sapporo Corporation formed the bisulfite adduct of acetaldehyde by mixing sodium bisulfite and acetaldehyde, thereby lengthening the shelf-life of their product.4

NaHSO3, H2O

O Me

HO Me

H

90%

H SO3Na

Kjell et al. utilized an alternative approach for the regeneration of an aldehyde from the bisulfite adduct during their work to produce the oncolytic agent, LY231514⋅Na.5 In this case, the alcohol impurities could be removed from the mixture by conversion of the aldehydes to the corresponding bisulfite adducts. Bisulfite adducts form slowly on hindered substrates, and as a result, the less-hindered aldehyde was enriched in the process. Anhydrous regeneration of the aldehyde was necessary in order to avoid inefficient extraction of the aldehyde from the aqueous layer. This was achieved by treatment of the bisulfite adducts with an excess of trimethylsilyl chloride (TMSCl) in acetonitrile. CO2Me

CO2Me

CO2Me

CO2Me NaHSO3

+

+

H O 90%

EtOH, H2O EtOAc

Me O

H 5%

OH 5%

CO2Me

CO2Me TMSCl +

SO3Na OH 75–80%

Me HO

SO3Na

MeCN Quant.

H O

95%

34 Gharpure, S. J.; Prasad, J. V. K. The Journal of Organic Chemistry 2011, 76, 10325–10331. 35 Kalutharage, N.; Yi, C. S. Organic Letters 2015, 17, 1778–1781. 36 Banks, A.; Breen, G. F.; Caine, D.; Carey, J. S.; Drake, C.; Forth, M. A.; Gladwin, A.; Guelfi, S.; Hayes, J. F.; Maragni, P.; Morgan, D. O.; Oxley, P.; Perboni, A.; Popkin, M. E.; Rawlinson, F.; Roux, G. Organic Process Research & Development 2009, 13, 1130–1140.

2.7 Addition of NH3 , RNH2 , and R2 NH

In their work toward avermectin, Cvetovich et al. found that standard conditions showed only a small amount of desired product and a significant amount of 1,4-addition by-product.37 As a result, they developed a Lewis acid approach to favor formation of the desired product. The procedure with ZnCl2 and TMSONH2 provided the desired oxime in good isolated yield. OMe

MeCONH Me

O

OMe

Me

O

Me

H

O Me

O

H

O

Me O

O

Me

Me Me

O O OH

OMe

O

O Me

OMe

MeCONH

H

O

Me O O

R

H

Me

O

Me

NH2OTMS, ZnCl2

O OH

i-PrOAc 80%

Me

O

O

H

O

H

Me Me R

Me N

OH

En route to a novel prostaglandin receptor agonist, Hida et al. utilized an oxime formation/reduction sequence for installation of the requisite amine.38 Clean transformation to the O-methyl oxime was accomplished by dissolving the ketone in ethanol and adding equimolar amounts of the O-methyl hydroxyl amine salt and pyridine and heating to reflux. Acid/base aqueous workup and silica gel chromatography were necessary to isolate clean O-methyl hydroxyl amine. The oxime was transformed to the free amine by dissolution in diglyme with aluminum trichloride and then slow addition of an excess of sodium borohydride. Me Me

O

MeONH2 • HCl

O OEt

Pyridine EtOH reflux

OMe N O

Me Me

NaBH4 AlCl3 OEt

Me Me

Diglyme

NH2 O OEt

82%

Another method for conversion of a ketone to a primary amine is shown in the following scheme.39 O

O OMe

N •HCl

NH3(g) NaOAc AcOH toluene i-PrOH 65 °C 89%

NH2 O OMe N

NH2 O

NaBH4 AcOH THF −5 °C

OMe N

74%

A chiral auxiliary controlled diastereoselective reductive amination was used in the synthesis of leukocyte inhibitor DMP 777.40 Imine formation (2 : 1 E:Z) was accomplished using titanium tetrachloride, triethylamine (TEA), and toluene. In the Raney Ni reduction, the E isomer is quickly reduced with good diastereoselectivity, while the less 37 Cvetovich, R. J.; Leonard, W. R.; Amato, J. S.; DiMichele, L. M.; Reamer, R. A.; Shuman, R. F.; Grabowski, E. J. J. The Journal of Organic Chemistry 1994, 59, 5838–5840. 38 Hida, T.; Mitsumori, S.; Honma, T.; Hiramatsu, Y.; Hashizume, H.; Okada, T.; Kakinuma, M.; Kawata, K.; Oda, K.; Hasegawa, A.; Masui, T.; Nogusa, H. Organic Process Research & Development 2009, 13, 1413–1418. 39 Cohen, J. H.; Bos, M. E.; Cesco-Cancian, S.; Harris, B. D.; Hortenstine, J. T.; Justus, M.; Maryanoff, C. A.; Mills, J.; Muller, S.; Roessler, A.; Scott, L.; Sorgi, K. L.; Villani, F. J., Jr.; Webster, R. R. H.; Weh, C. Organic Process Research & Development 2003, 7, 866–872. 40 Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L., Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Organic Process Research & Development 2002, 6, 54–63.

75

76

2 Addition to Carbon-Heteroatom Multiple Bonds

reactive Z isomer isomerizes to the E isomer, which in turn is reduced to the desired product. The sequence is finished by standard hydrogenolysis to remove the chiral auxiliary. Me H2N

O O

Ph

Me

TiCl4, Et3N

Me

O

Toluene EtOH

O

Me

H2 Raney Ni

Me

NH

O

Toluene EtOH

O

Me

O

NH3Cl

NH2

Pd/C, H2 AcOH

N

O

Toluene

O

Ph

Ph

Me

HCl

O

i-PrOH toluene

O

Me

Potassium carbonate has been used as a dehydrating agent in the formation of imines from aldehydes. The basic conditions suppressed the unwanted aldol-type side reactions, and more importantly, the base was removed from the reaction by simple filtration to give the imine in high purity. Also noteworthy in this example is the use of Zn(BH4 )2 (generated in situ from ZnCl2 and NaBH4 ) for the subsequent reduction step.41 K2CO3 THF

O

O

+

N

H

N NH2

O

O N

N

rt, 1 h

N

ZnCl2, NaBH4 THF −15 °C, 2 h

O

O N

N HN

O

84% (2 steps)

Reductive amination of a cyclobutanone with piperidine was accomplished using NaBH(OPiv)3 . This reagent was prepared in situ from NaBH4 and pivalic acid; the slight excess of pivalic acid used in the preparation of the reagent promoted the imine formation, while the bulky hydride reagent led to high diastereoselectivity in the reduction step.42 N N O

N N

piperidine, NaBH(OPiv)3

O

O

N

PivOH, toluene, 0– 5 °C, 16 h 99%

O

O

N

N 55:1

In another example of stereoinduction during the reductive amination reaction, the process group at Merck obtained high diastereoselectivities in the reductive amination involving a highly functionalized pyranone with a mesylated pyrazole. The reduction was accomplished by using NaBH(OAc)3 .43 F NHBoc

BocN

N

NMs

CF3CO2H 0 °C

TFA • HN

N

F NMs

O

F NHBoc

O

DMAc, Et3N, −15 °C NaBH(OAc)3 NH4OH 85–90%

F

O 30 :1 dr

N

N NMs

41 Crawford, J. B.; Chen, G.; Gauthier, D.; Wilson, T.; Carpenter, B.; Baird, I. R.; McEachern, E.; Kaller, A.; Harwig, C.; Atsma, B.; Skerlj, R. T.; Bridger, G. J. Organic Process Research & Development 2008, 12, 823–830. 42 Kallemeyn, J. M.; Ku, Y.-Y.; Mulhern, M. M.; Bishop, R.; Pal, A.; Jacob, L. Organic Process Research & Development 2014, 18, 191–197. 43 Chung, J. Y. L.; Scott, J. P.; Anderson, C.; Bishop, B.; Bremeyer, N.; Cao, Y.; Chen, Q.; Dunn, R.; Kassim, A.; Lieberman, D.; Moment, A. J.; Sheen, F.; Zacuto, M. Organic Process Research & Development 2015, 19, 1760–1768.

2.7 Addition of NH3 , RNH2 , and R2 NH

Amides can react with ketones under the appropriate conditions to provide enamides. In the following example, the use of catalytic sulfuric acid led to clean enamide formation. The desired (Z)-enamide was isolated by crystallization.44 O

O

Me

N

Me

SO2Me

O

NH2

10 mol% H2SO4 toluene, 130 °C, 48 h

Me

H N

Me N

SO2Me

70%

A particularly appealing application of the reaction of amides with ketones is the Guareschi–Thorpe reaction. In the following example from Boehringer–Ingelheim, a convergent coupling of cyclopentyl dioxobutanoate with cyanoacetamide followed by acidic decyanation led to an isonicotinic acid core in 69% yield over two steps.45 EtO

O

EtO

O

O

H2N

O

HO CN

CN

O

N H

O

30% HCl 100 °C, 22 h

O

69% (2 steps)

N H

O

Reaction of aldehydes and ketones with Ellman’s sulfinamide reagent followed by either alkylation or reduction provides an efficient entry into chiral, nonracemic amines. The first step, namely, the reaction of the sulfinamide with the carbonyl compound is generally promoted by anhydrous copper(II) sulfate.46

t-Bu

O S

+ NH2

O H

O

CuSO4 anh N

Toluene, 50 °C 85%

2.7.2

t-Bu

O S H

N O

N

Redox Neutral Amination

Metal-catalyzed “redox neutral” methods for conversion of an alcohol into an amine have recently been developed. It is postulated that these complexes (generally Ru- or Ir-based) generate the carbonyl component in situ, followed by imine formation and reduction of the imine by the metal hydride species formed during the imine formation. Hence, these reactions are sometimes referred to as “borrowing hydrogen” methods. This method is particularly useful when aldehyde or ketone instability precludes standard reductive amination conditions. Berliner et al. used the Ir-catalyzed version of this methodology for the synthesis of PF-03463275. Using (Cp*IrCl2 )2 , the redox neutral amination reaction was optimized to achieve catalyst loadings lower than 0.05 mol% iridium (S/C g 2000) while retaining reasonable reaction rates.47

44 Reeves, J. T.; Tan, Z.; Reeves, D. C.; Song, J. J.; Han, Z. S.; Xu, Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; Mahaney, P. E.; Lee, H.; Busacca, C. A.; Senanayake, C. H. Organic Process Research & Development 2014, 18, 904–911. 45 Schmidt, G.; Bolli, M. H.; Lescop, C.; Abele, S. Organic Process Research & Development 2016, 20, 1637–1646. 46 Zhang, W.-Y.; Hogan, P. C.; Chen, C.-L.; Niu, J.; Wang, Z.; Lafrance, D.; Gilicky, O.; Dunwoody, N.; Ronn, M. Organic Process Research & Development 2015, 19, 1784–1795. 47 Berliner, M. A.; Dubant, S. P. A.; Makowski, T.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y. Organic Process Research & Development 2011, 15, 1052–1062.

77

78

2 Addition to Carbon-Heteroatom Multiple Bonds

Cl F OH H

H2N

2.5 mol% catalyst 5% K2CO3

H Cl

N CH3

NH

Toluene, 3% H2O 100 °C, 5 h

F

H

95%

N CH3

Catalyst

Cl

Ir

Cl Ir Cl

H

Cl

The use of diols instead of alcohols leads to a net double reductive amination. In the case of 1,5-diols, a formal annulation to form a piperidine ring is accomplished.48

Cl NH2

HO

+

Ir

Cl Ir Cl

Cl

N

OH

K2CO3, toluene 17 h 80%

Me

NH2 CO2Me +

HO

OH

2.5 mol% catalyst 5% NaHCO 3

Me

Toluene 125 °C, 18 h

N CO2Me

56%

The Williams laboratories successfully applied a ruthenium p-cymene complex to the reaction shown in the following scheme.49 Cl

OH

H2N +

N

Cl Ru Ru Cl Cl

2.5 mol%

PPh2 Fe PPh2 dppf 5 mol%

H N

N

K2CO3 11 mol% 3Å MS Toluene, reflux, 24 h quantitative

Racemic secondary alcohols can be converted to the corresponding chiral, nonracemic amines using this methodology. Commercially available Ru-Macho promoted the formation of α-chiral tert-butanesulfinylamines from racemic secondary alcohols and Ellman’s chiral tert-butanesulfinamide, and the reactions proceeded with high diastereoselectivity (>95 : 5).50

48 Fujita, K.; Fujii, T.; Yamaguchi, R. Organic Letters 2004, 6, 3525–3528; Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. Organic Process Research & Development 2015, 19, 1400–1410. 49 Hamid, M. H. S. A.; Williams, J. M. J. Chemical Communications (Cambridge, United Kingdom) 2007, 725–727. 50 Oldenhuis, N. J.; Dong, V. M.; Guan, Z. Journal of the American Chemical Society 2014, 136, 12548–12551.

2.8 Formation of Hydrazones

OH Me

+

H2N

N

O S

1 mol% Ru-Macho t-Bu

15 mol% KOH Toluene, 120 °C, 7 h 80%

Ru-Macho H

HN

O S

t-Bu

Me N

PPh2

H N Ru CO Cl PPh2

This approach was extended to the synthesis of chiral, nonracemic 1,2-amino alcohols from racemic terminal 1,2-diols. The use of a chiral ligand and catalytic organic acid led to an effective reductive amination of the primary alcohol and a dynamic resolution of the secondary center.51 OH OH +

O

5 mol% [RuCl2(p-cymene)] 2 6 mol% Josiphos

N H

20 mol% PhCO2H Toluene, 100 °C, 7 h

OH

O N

95%, 89% ee

2.8 Formation of Hydrazones Hydrazines condense with aldehydes and ketones to afford the corresponding hydrazones. Typically, hydrazine itself reacts only with aromatic ketones to produce hydrazones, whereas higher hydrazine homologs exhibit broader substrate scope.52 Me

O

H2N N

Me

aq NH2NH2 EtOH, reflux Cl

81– 88%

Cl

Reaction of hydrazine with aldehydes often leads to the bis-addition products (azines).53 However, protected hydrazones can be synthesized by the treatment of aldehydes with protected hydrazines.54 CHO N

BocNHNH2 toluene i-PrOH 80–85 °C

N

NHBoc

N

85%

The use of p-tosylhydrazine yields p-tosylhydrazones, which are substrates for the Wolff–Kischner (see Section 9.3.4) and Shapiro reaction as a particularly useful method for the synthesis of olefins from ketones (see Section 8.2.8).55 51 Yang, L.-C.; Wang, Y.-N.; Zhang, Y.; Zhao, Y. ACS Catalysis 2017, 7, 93–97. 52 Nenajdenko, V. G.; Korotchenko, V. N.; Shastin, A. V.; Balenkova, E. S.; Brinner, K.; Ellman, J. A. Organic Syntheses 2005, 82, 93–98. 53 Newkome, G. R.; Fishel, D. L. The Journal of Organic Chemistry 1966, 31, 677–681. 54 Xu, Z.; Singh, J.; Schwinden, M. D.; Zheng, B.; Kissick, T. P.; Patel, B.; Humora, M. J.; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes, J. E.; Pudipeddi, M.; Lindrud, M. D.; Srivastava, S. K.; Kronenthal, D. R.; Mueller, R. H. Organic Process Research & Development 2002, 6, 323–328. 55 Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. The Journal of Organic Chemistry 2001, 66, 5772–5782.

79

80

2 Addition to Carbon-Heteroatom Multiple Bonds

Me Me

Br

O

NH2NHTs TsOH

Me Me

Br

N

MeOH 77%

Me Me

N H

Ts

Me Me

In an interesting example, the bromo acetal in the following scheme was used as a masked aldehyde functionality and condensed with benzyl carbazate in the presence of phosphoric acid. This procedure afforded the Cbz-protected hydrazine in excellent yields.56 OMe H2N NHCbz +

Br

H3PO4, water

OMe

21–45 °C, 12–18 h

Br

83%

CbzHN

N

2.9 Formation of Oximes The addition of hydroxylamine to aldehydes or ketones leads to oximes. In general, hydroxylamine is conveniently added as its hydrochloride salt; hence, an equivalent amount of external base is required to neutralize the acid. Two representative examples illustrating the formation of an aldoxime57 and a ketoxime58 from the respective carbonyl compounds are given here. OMe SMe H

N N

O

O

OMe

(i) H2NOH•HCl, NaOH (4 N) EtOH, 50 °C (ii) recrystallization, MeOH 87%

N

NH2OH•HCl, pyridine

SMe H

N N

N

OH

OH

MeOH, 20 °C, 1 h 97%

2.10 The Formation of gem-Dihalides from Aldehydes and Ketones Aldehydes and ketones can be converted to gem-dichlorides by treatment with PCl5 . This procedure was used to synthesize dichloromethylmesitylene from the corresponding aldehyde in excellent yield.59 Me

Me

O H

Me

Me

PCl5 CH2Cl2 91%

Cl Cl

Me

Me

In some instances, the transformation has been achieved using a mixture of PCl3 and PCl5 , as exemplified by the synthesis of 2,2-dichloronorbornane from norcamphor.60 56 Zheng, B.; Conlon, D. A.; Corbett, R. M.; Chau, M.; Hsieh, D.-M.; Yeboah, A.; Hsieh, D.; Müslehiddino˘glu, J.; Gallagher, W. P.; Simon, J. N.; Burt, J. Organic Process Research & Development 2012, 16, 1846–1853. 57 López-Ogalla, J.; Saiz, G.; Palomo, F. E. Organic Process Research & Development 2013, 17, 120–126. 58 Breitenmoser, R. A.; Fink, T.; Abele, S. Organic Process Research & Development 2012, 16, 2008–2014. 59 Yakubov, A. P.; Tsyganov, D. V.; Belen’kii, L. I.; Krayushkin, M. M. Tetrahedron 1993, 49, 3397–3404. 60 Ashby, E. C.; Sun, X.; Duff, J. L. The Journal of Organic Chemistry 1994, 59, 1270–1278.

2.10 The Formation of gem-Dihalides from Aldehydes and Ketones

Cl

PCl3, PCl5

O

0 °C 75%

Cl

There are very few examples of gem-dibromides synthesized using PBr5 . As previously mentioned, the same substrate was converted to 2,2-dibromonorbornane using PBr3 and Br2 . Br

PBr3, Br2

O

0 °C 53%

Br

gem-Difluorides are the most commonly synthesized dihalides. While these compounds were typically prepared using SF4 -HF and diethylaminosulfur trifluoride (DAST) in the past, safety concerns over these reagents led to the development and use of bis(2-methoxyethyl)aminosulfur trifluroide (Deoxo-Fluor) as the fluorinating agent of choice.61 O Cl

F O

S

N Boc

Cl

Deoxo-Fluor

S

Toluene, 70 °C, 21 h 62%

F O N Boc

Mase et al. described the conversion of a ketone to a gem-difluoride using Deoxo-Fluor. While 2.5 equiv of Deoxo-Fluor were originally required to achieve an 80% yield, the authors found that the addition of small amounts of Lewis acids such as BF3 ⋅OEt2 (5–10 mol%) led to much cleaner (albeit slower) reactions and higher yields, while allowing for the use of fewer equivalents (1.4) of Deoxo-Fluor.62 t-Bu

O O

O

Ph

BF3 • OEt 2, PhCH3 90%

O

O

O

Deoxo-Fluor

Ph

t-Bu

O

F

F

Another class of reagents which has come to the forefront in fluorination reactions are the XtalFluor reagents developed in the laboratories of Omegachem.63 These reagents hold advantages over the others due to their safer preparation (no distillation of reagent), better safety profile, and the ability to use them in borosilicate (i.e. glass) vessels. Important for good reaction yield with this reagent is order of addition and use of the TEA⋅3HF complex, as shown in the following example using XtalFluor. O

XtalFluor-E, TEA • 3HF N CBZ

F

F

TEA, CH2Cl2, rt 91%

XtalFluor-E

Et Et

N CBZ +

N SF2

BF4−

61 DeBaillie, A. C.; Jones, C. D.; Magnus, N. A.; Mateos, C.; Torrado, A.; Wepsiec, J. P.; Tokala, R.; Raje, P. Organic Process Research & Development 2015, 19, 1568–1575. 62 Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. The Journal of Organic Chemistry 2001, 66, 6775–6786. 63 L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; La Flamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. The Journal of Organic Chemistry 2010, 75, 3401–3411.

81

82

2 Addition to Carbon-Heteroatom Multiple Bonds

More recently, 4-t-butyl-2,6-dimethylphenylsulfur trifluoride and its analogs have been developed as useful deoxofluorinating reagents. These compounds do not appear to possess the same thermal liabilities as DAST, and hence are easier to handle.64 SF3 Me

Me

O

F F t-Bu

CO2Et

CH2Cl2, EtOH (cat.) rt, 24 h

CO2Et

85%

2.11 The Aldol Reaction The aldol reaction is the addition of an enol or enolate nucleophile to an aldehyde, resulting in a β-hydroxycarbonyl product. The power of the aldol reaction lies in its formation of a carbon–carbon bond in a stereochemically predictable manner. Control of enolate geometry, catalyst selection, solvent choice, and reaction conditions all lead to varied and generally predictable product diastereo- and (in some cases) enantioselectivities. Nearly every nuance of this powerful reaction has been studied and rationalized.65 In the following sections are examples of the ways to unleash its potential and some lead references to aid in the application to other substrates of interest.

O

Base H2C

R

H3C

O

O−M+

OH O

H

R′

R

R

R′

Enolate

In the absence of any stereochemical control elements in enolate, aldehyde, or catalyst, the aldol reaction is nonselective in its stereochemical outcome and generates a racemic product. This construct is the key step in the synthesis of the Novartis cardiovascular drug fluvastatin.66 In this case, use of excess base to form the keto-ester dianion ensures the desired regiochemical outcome. (1) (i) NaH, 20–25 °C, THF (ii) n-BuLi, 20–25 °C O

Me H

N Me

Me

O

O

Me

Me Ot-Bu

(2) THF, 20–25 °C 80%

Ot-Bu

N Me

Me

OH O

O

Use of an ethyl ketone (or propionate if R′ =alkoxy) highlights the ability of the starting material to give rise to syn or anti aldol products. Addition of an E or Z enolate to the aldehyde gives complementary products with excellent selectivity.67

64 65 66 67

Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. Journal of the American Chemical Society 2010, 132, 18199–18205. Heathcock, C. H. Science 1981, 214, 395–400; Heathcock, C. H. Science 1995, 267, 116–118. Fuenfschilling, P. C.; Hoehn, P.; Mutz, J.-P. Organic Process Research & Development 2007, 11, 13–18. Heathcock, C. H. Modern Synthetic Methods 1992, 6, 1–102.

2.11 The Aldol Reaction

O O−M+ Me

R′

R

OH R

R′

Z

Me syn O

O−M+ E

R′

O

H

R

O H

OH

R′

R Me anti

Me

The Brown group68,69,70,71,72 has demonstrated conditions for selective formation of either E or Z-enolborinates, which translate into syn or anti product geometries, respectively. These reactions are tuned through variation of the size of the alkylborane and use of a complimentary base to enable selection of the desired E or Z enolborinate. Then, addition of the aldehyde and standard oxidative workup gives the β-hydroxy ketone product.

O

(c-hex)2BCl

Me

Ph

O Me

Et3N

(c-hex)2BCl Ph

i-Pr2EtN

PhCHO −78 °C

OB(c-hex)2 Ph Me E (>97%)

MeOH, H2O2 97%

OB(c-hex)2 Me

Ph

Z (>97%)

OH O

OH O Ph +

Ph

Ph

Me 97

OH O

OH O Ph +

Ph Me >97

Ph

Ph Me 98 ee

82%

The catalyst system described previously represents a class that is considered “privileged,” in that it can be used for numerous asymmetric transformations, e.g. aldol, allylation, and Diels–Alder reactions.91,92 More recently, L-proline–derived catalysts have been used to promote asymmetric aldol reactions. In the following example, researchers at Sumitomo applied this methodology for the stereoselective aldol reaction of 4-benzyloxybutanal with ethyl glyoxalate. The product was isolated in >95% ee, with a >10/1 dr.93 O

BnO + H

O

OEt

H O

Cat. A (3 mol%) THF/H2O 20 °C MeOH (5 equiv)

H

BnO H

OH OEt O

O

N H

Ph Ph OH Cat. A

73%

90 91 92 93

Keck, G. E.; Krishnamurthy, D. Journal of the American Chemical Society 1995, 117, 2363–2364. Krauss, R.; Koert, U. Organic Synthesis Highlights IV 2000, 144–154. Wabnitz, T.; Reiser, O. Organic Synthesis Highlights IV 2000, 155–165. See Note 13.

2.11 The Aldol Reaction

Aldehydes and ketones can be cross-coupled with α-thioacetal aldehydes in the presence of L-proline. The reactions proceed with high enantio- and diastereocontrol and allow access to highly oxidized, versatile synthons that can be further elaborated.94 O H

Bn +

O H

O

L-Proline, DMF

S

rt

S

OH S

H Bn

S

73%, 97% ee >20 : 1 (anti/syn)

Imidazolidinones have also been utilized as efficient catalysts for the direct enantioselective aldol reaction.95 O Me

H

O

+

MeO

Amberlyst-15, MeOH 4 °C, 24 h

H

Me

81% 97% ee 5 :1 (anti/syn)

2.11.1

O

OMe OH

20 mol% catalyst, Et2O

Ph

N

Me

N H

•TFA Me

Me Me

Catalyst

Ketene and Silyl Enol Ether Addition to Aldehydes

One standard method for ensuring clean aldol reactions is through preformation of the nucleophile via ketene and silyl enol ethers. When traditional enolate aldol conditions are employed, other acidic functionality in the reactants can interfere with the desired reaction; it is necessary to rely on the inherent pK a differences of the substrates to ensure desired reaction. For example, if the aldehyde has an α-hydrogen that is more acidic than the reacting ketone enolate, proton transfer can occur, leading to undesired reactions such as aldehyde self-condensation. Another reason for use of silyl enol ether or ketene silyl acetal nucleophiles is their utility with Lewis acid catalysts, which complements the basic conditions of lithium enolate aldols. This can be a desirable alternative with certain base-sensitive substrates. Although the initial product is a β-silyloxy aldol, the silyl ether is frequently cleaved during aqueous workup. These nucleophiles have been used extensively in both methodological and total synthesis applications of the aldol reaction. 2.11.2

Silyl Enol Ether Addition to Aldehydes: The Mukaiyama Aldol

Kelly and Vanderplas developed a titanium-mediated silyl enol ether aldol reaction that provided the desired product on large scale in good yield. This method was found to be more successful than either lithium enolate or enamine alternatives.96 O

OTMS + OTMS

OH Ph

TiCl4

O Ph

H

−78 °C CH2Cl2

OH

92%

In another example, Kuroda et al. utilized boron trifluoride etherate as the Lewis acid of choice for addition of an enol ether to an α,β-unsaturated aldehyde.97 OSiMe3 Ph

Me

+

O

O

BF3•E t2O

H n-Bu

−78 °C CH2Cl2

OH

Ph Me

n-Bu

92%

94 95 96 97

Ian Storer, R.; MacMillan, D. W. C. Tetrahedron 2004, 60, 7705–7714. Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angewandte Chemie International Edition 2004, 43, 6722–6724. Kelly, S. E.; Vandeplas, B. C. The Journal of Organic Chemistry 1991, 56, 1325–1327. Kuroda, H.; Hanaki, E.; Izawa, H.; Kano, M.; Itahashi, H. Tetrahedron 2004, 60, 1913–1920.

87

88

2 Addition to Carbon-Heteroatom Multiple Bonds

The use of indium triiodide as a catalyst promoted the direct conversion of esters to β-hydroxycarbonyl compounds via reaction with silyl enolates. A hydrosilane was used to reduce the esters to the corresponding oxocarbenium species (or the aldehyde) in situ.98 O +

OMe

Me

OSiMe3

InI3 (5 mol%), HSiMe2Ph

OH O

Me

OMe

CH2Cl2, rt, 2 h

Me Me

OMe

92%

Mukaiyama-type condensations have also been carried out using dimethylacetals as aldehyde surrogates. The reaction of silyl enol ethers with dimethylacetals derived from enolizable aldehydes in the presence of FeCl3 ⋅6H2 O led to β-methoxy ketones with excellent yields.99 OSiMe3

OMe

+

OMe

OMe O

FeCl3• 6H2 O (5 mol%) CH2Cl2 0 °C to rt, 30 min 99%

Through careful choice of enolsilane geometry, Lewis acid, and reaction conditions, the Evans group was able to achieve excellent diastereoselectivity for a key bond formations that lead to the synthesis of both 6-deoxyerythronolide B and oleandolide.100 Me Me O O

O

O

Me Me

O

O H +

N Bn

Me

Me

Me3SiO Me

OR OTBS Me Me

Me

O

−78 °C CH2Cl2

Me

O

BF3•E t2O

O

O

OH O

N Bn

82% >95% dr

R = PMB

O

Me

Me

Me

Me

OR OTBS Me Me

Me

The next two examples show catalytic asymmetric variants of the Mukaiyama aldol reaction. Yamamoto and coworkers developed a catalyst derived from tryptophan that works exceptionally well for a variety of silyl enol ethers in condensations with benzaldehyde.101 OSiMe3 Ph

O

+

H

O

Catalyst (5 mol%) Ph

−78 °C propionitrile 99% 94% ee

Ph

OH Ph

H N

O

O N H

CF3 B

Catalyst

CF3

The Evans group was able to expand the scope of this asymmetric transformation with their cationic scandium pybox catalyst system.102 As seen in the following example, with the gem-dimethyl silyl enol ether and ethyl glyoxalate, good yield and excellent enantioselectivity are achieved. The key for asymmetric induction in this catalyst system is the two-point coordination of the catalyst to the aldehyde. This manifests itself in the necessity for an alpha Lewis basic

98 Inamoto, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. Organic Letters 2012, 14, 1168–1171. 99 Rodríguez-Gimeno, A.; Cuenca, A. B.; Gil-Tomás, J.; Medio-Simón, M.; Olmos, A.; Asensio, G. The Journal of Organic Chemistry 2014, 79, 8263–8270. 100 Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. Journal of the American Chemical Society 1998, 120, 5921–5942. 101 Ishihara, K.; Kondo, S.; Yamamoto, H. The Journal of Organic Chemistry 2000, 65, 9125–9128. 102 Evans, D. A.; Masse, C. E.; Wu, J. Organic Letters 2002, 4, 3375–3378.

2.11 The Aldol Reaction

functional group in the aldehyde starting material. Another key difference in this catalyst system is its ability to effectively catalyze reactions with electron deficient aldehydes.

Ph

OSiMe3 Me + Me

O

O

Catalyst (10 mol%)

H

CO2Et

−78 °C, CH2Cl2

Ph

85% 95% ee

OH

Me Me

CO2Et +

SbF6− O

O N t-Bu

N Sc Cl Cl

t-Bu

Catalyst

The Kobayashi group has developed a catalytic asymmetric hydroxymethylation of silicon enolates using aqueous formaldehyde in the presence of a chiral bismuth complex. While Bi(OTf )3 itself is unstable in water, the complex formed by Bi with the ligand is stable in aqueous media.103 Bi(OTf)3 (1 mol%) Ligand (3 mol%), Bipy (5 mol%)

OSiMe3 aq HCHO

Me

+

O

Me

H2O/DME (1/4), 0 °C, 22 h

HO

81%, 95% ee t-Bu

N

N

OH

t-Bu

HO Ligand

The reaction of silyl enol ethers containing a β′ -hydroxy substituent with aldehydes has been harnessed in the synthesis of highly functionalized THP-4-ones. This methodology was extended to the enantioselective synthesis of cyanolide A and its aglycone.104

Me

OH OH OTBS Me + OHC Me

O

BF3•Et 2O Ph

CH2Cl2, −78 °C, 4 h

OH Me

Me Me

O

97%

Ph

MacMillan and coworker developed a synthetic strategy for the expeditious construction of differentially protected monosaccharides based on aldol coupling of three aldehydes in two steps. In this protocol, the first step (not shown here) is the dimerization of an -oxyaldehyde catalyzed by L-proline to give the homoaldol adduct. This step is followed by a Lewis acid–catalyzed tandem Mukaiyama aldol addition–cyclization sequence with a silyl enol ether. This methodology has been used to access differentially protected hexose stereoisomers.105

H

OTMS OAc

O +

OH OTIPS

H OTIPS

TiCl4•(THF) 2 CH2Cl2, −40 °C, 96%, 95% ee, >19 :1 dr

TIPSO

O

TIPSO

OH OAc

OH

103 Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.; Manabe, K. Organic Letters 2005, 7, 4729–4731. 104 Tay, G. C.; Gesinski, M. R.; Rychnovsky, S. D. Organic Letters 2013, 15, 4536–4539. 105 Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752–1755.

89

90

2 Addition to Carbon-Heteroatom Multiple Bonds

2.11.3

Ketene Silyl Acetal and Thioacetal Addition to Aldehydes

The next few examples illustrate ketene silyl acetal additions with a variety of substrates and Lewis acids. In the first, Keck et al. used an attenuated titanium species in order to realize a good yield for formation of the desired hydroxyl-ester.106 Use of this Lewis acid was based on the lability of the p-methoxy benzyl ether. Low temperatures are critical with preformed nucleophiles (e.g. silyl ketene acetals); in this example, a pre-cooled solution of Lewis acid is added to a cold solution of aldehyde, followed by addition of the nucleophile. The reactions need to be quenched at a low temperature and allowed to warm up to room temperature for optimal stereoselectivity and yield.

PMBO

TiCl2(O-i-Pr)2

St-Bu

H

+

O

OSiMe3

St-Bu OH O

PMBO

Toluene −78 °C 95% 41 : 1 dr

In the second example, stereochemistry is again directed through chelation controlled addition of the ketene silyl acetal. In this case, the more robust benzyl ether protecting group allows for use of the stronger catalyst titanium tetrachloride.107 Me H

BnO

St-Bu

BnO

CH2Cl2 − 80 °C

OTBS

O

Me

TiCl4

St-Bu

+

OH O

94% 97 : 3 dr

Finally, Shiina and Fukui extended this methodology by incorporating a third stereocenter and setting the stereocenters via an open chained (Felkin–Ahn) model that capitalizes on the steric bulk of the substrates to dictate facial selectivity.108 Me

TBSO H

Me

SEt

+

OSiMe3

O

SnCl4 CH2Cl2 −78 °C 67%

TBSO

Me SEt

Me OH O

Single stereoisomer

The remainder of this section presents examples of catalytic asymmetric aldol reactions using ketene silyl acetals. In their work toward cholesterol absorption inhibitor, Wu and Tormos found that a valine-derived sulfonamide catalyst performed well to effect the reaction with the protected cyclohexyl silyl ketene acetal.109 OTMS

O

EtO2C OH

Catalyst (40 mol%)

OEt + H

O

106 107 108 109

O

OBn

−78 °C, EtCN 90% 91% ee

O O

Keck, G. E.; Welch, D. S.; Vivian, P. K. Organic Letters 2006, 8, 3667–3670. Zanato, C.; Pignataro, L.; Hao, Z.; Gennari, C. Synthesis 2008, 2158–2162. Fukui, H.; Shiina, I. Organic Letters 2008, 10, 3153–3156. Wu, G.; Tormos, W. The Journal of Organic Chemistry 1997, 62, 6412–6414.

OBn O O S N H B O Catalyst

i-Pr O

2.11 The Aldol Reaction

Huang et al. used a catalyst developed in the Masamune labs in their synthesis of the marine anticancer natural product psymberin.110 In this process, the catalyst is preformed at low temperature, and then, the ketene acetal is added. Finally, the aldehyde is added over a few hours.

EtO

OTMS Me Me

O +

OH

Catalyst (20 mol%) OBn

H

EtO2C

OBn

Me Me

−78 °C, EtCN 95% >98% ee

OMe OMe

O O S Me N H B O O Catalyst

Me

Thioketene acetals (formed from thioesters) are also frequently utilized. Bulky alkyl groups (e.g. t-butyl, phenyl) generally lead to better selectivity. The following schemes are examples of an asymmetric system developed by the Evans group. The first scheme highlights the application of the pybox tin and copper catalysts in the synthesis of phorboxazole B and an extended methodology evaluation.111,112 The final scheme is a related example from Larionov and De Meijere in their work toward the belactosins.113 O N

Ph

H +

O

St-Bu OTMS

Catalyst (10 mol%) CH2Cl2, −80 °C

OH O Ph

N

St-Bu

O

91% 94% ee

Me Me O

O

N N Sn Ph TfO OTf Ph Catalyst

O BnO

H

+

St-Bu OTMS

Catalyst (10 mol%) CH2Cl2, −80 °C

OH O BnO

St-Bu

91% ee

Me Me O

O N

N

Cu t-Bu TfO OTf t-Bu Catalyst

110 Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Organic Letters 2007, 9, 2597–2600. 111 Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. Journal of the American Chemical Society 2000, 122, 10033–10046. 112 Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. Journal of the American Chemical Society 1999, 121, 669–685. 113 Larionov, O. V.; De Meijere, A. Organic Letters 2004, 6, 2153–2156.

91

92

2 Addition to Carbon-Heteroatom Multiple Bonds

O +

H

EtO2C

SPh

Me Me

OTMS

Catalyst (10 mol%) CH2Cl2, −78 °C 99% >40: 1 syn:anti 99% ee

OH Me Me

EtO2C O

SPh Me Me O

O N

N

Sn Bn TfO OTf Bn Catalyst

The following system, initially put forward by the Keck labs, does not necessitate a Lewis basic center functional group at the α-center and uses inexpensive and easily handled reagents, but reaction times can be longer. These reactions generally work better in the presence of molecular sieves.114 O H

+

St-Bu OTMS

Ti(O-i-Pr)4 (20 mol%) (R)-Binol (20 mol%)

OH O

4 Å MS Et2O, reflux

St-Bu

89% 89% ee

2.12 Allylorganometallics: Stannane, Borane, and Silane In this section, we will discuss the more common types of allylation reactions, focusing on nucleophiles containing silicon, boron, and tin. Allylation provides a few advantages over the classic aldol reaction: 1. An alkene is embedded in the resultant providing a handle for further elaboration. 2. The nucleophiles (e.g. allylsilanes) are generally stable species amenable to storage. 3. The Lewis acidic metal embedded in the nucleophile leads to enhanced reactivity via coordination with the Lewis basic carbonyl. 4. The ability to place chiral ligands on the metal center, which translates to a net enantioselective reaction after removal of the ligand in the reaction workup. SnBu3 H

OH

Lewis Acid

O

Transmetalation can change the reactivity and stereochemical outcome (see Chapter 12). A complication with use of these nucleophiles, however, is removal of the resultant stannous, borate, or silyl by-products. With careful operations, these by-products can be effectively purged, but this can be a challenge (e.g. coordination of borane by-products to the desired product, removal of toxic organostannane reagents, etc.).

2.12.1

Allylsilane Additions

The first class of allyl organometallic reagents described are allylsilanes. Although attenuated in reactivity compared to other allylorganometallics, these reagents offer significant advantages in terms of reduced toxicity and ease of handling. 114 Dalgard, J. E.; Rychnovsky, S. D. Organic Letters 2004, 6, 2713–2716.

2.12 Allylorganometallics: Stannane, Borane, and Silane

Jervis and Cox used this classic allylsilane reaction to build the THF core of aureonitol.115 By tethering the allylsilane, this intramolecular reaction proceeds with good stereoselectivity and yield to give the desired THF. SiMe3

MeSO3H

O TBDPSO

CHCl3 −60 °C

CHO

O

O

+

TBDPSO

TBDPSO

OH

86%

OH

(8 :1)

Chemler and Roush developed a trifluorocrotylsilane reagent that gives good selectivity for the elusive anti:anti bond construction.116 Selectivity in this system is dictated by the reactive trifluorosilane. It is proposed that the reaction proceeds via a Zimmerman–Traxler-like transition state where the silicon of the allylsilane coordinates with both the aldehyde and β-hydroxyl group in the substrate to lock the reaction conformation. TBDPSO

OH O

Me H

Me

SiF3

TBDPSO

OH OH

i-Pr2NEt, CH2Cl2 0 °C, 4 Å MS

Me

Me

Me

Me

93 :6 : 1

75%

In the next two examples, work from the Panek laboratories shows the versatility of chiral crotylsilane reactions. In the first, Kesavan et al. performed this enantioselective crotylation to give, after treatment with methyl sulfate, the desired syn-methyl ether in good yield and with excellent diastereoselectivity.117 Me

O

CO2Me SiMe2Ph

H Br

OMe CO2Me Br

TMSOMe, TfOH −78 °C

Me >20:1 dr

80%

In the second example, Arefolov and Panek used a titanium-catalyzed crotylsilane addition in their approach to the total synthesis of discodermolide.118 Me Me

O H

TBDPSO Me

CO2Me SiMe2Ph

OH Me TBDPSO

TiCl4, CH2Cl2 −78 °C

CO2Me Me

Me >30:1 dr

85%

Allyl silane nucleophiles can formally add to aromatic aldehydes or acetals in the presence of 2,2′ -bipyridyl and TMSOTf. The addition is chemoselective and works only for aromatic aldehydes but not for aliphatic ones.119 O H + MeO

TMSO Me

Me

2,2′-bipyridyl TMS

CH2Cl2, 3 h, 0 °C TMSOTf 99%

MeO

115 Jervis, P. J.; Cox, L. R. The Journal of Organic Chemistry 2008, 73, 7616–7624. 116 Chemler, S. R.; Roush, W. R. The Journal of Organic Chemistry 1998, 63, 3800–3801. 117 Kesavan, S.; Panek, J. S.; Porco, J. A., Jr. Organic Letters 2007, 9, 5203–5206. 118 Arefolov, A.; Panek, J. S. Journal of the American Chemical Society 2005, 127, 5596–5603. 119 Kawajiri, T.; Kato, M.; Nakata, H.; Goto, R.; Aibara, S.-Y.; Ohta, R.; Fujioka, H.; Sajiki, H.; Sawama, Y. The Journal of Organic Chemistry 2019, 84, 3853–3870.

93

94

2 Addition to Carbon-Heteroatom Multiple Bonds

TMSO

O

Me

O +

O

2,2ʹ-bipyridyl TMS

Cl

CH2Cl2, 24 h, 0 °C TMSOTf 96%

Me

MeO

Denmark et al. developed a Lewis base catalyzed allylsilylation using a chiral bisphosphoramide.120,121 This reaction was used in a sequence for the synthesis of the natural product papulacandin. SiCl3 Me

Me

Me

H

Catalyst (1 mol%)

Me

Me

Me

i-Pr2NEt, CH2Cl2 −70 °C

O

OH

88% (96:4 dr)

H H H

P

O N Me Catalyst

2.12.2

CH2 2

Allylborane Additions

One strength of allylborane additions to carbonyls is excellent reactivity and selectivity due to the oxophilicity of boron. Another relies on the fact that many chiral ligands can be tethered to the borane nucleophile. A downside to this class of reagents is difficulty sometimes encountered in releasing the desired products from borane-derived by-products. Ramachandran and Chatterjee used a difluoro allylborane reagent for the synthesis of a gem-difluoro alkene.122 The reagent was prepared from trifluoroethanol. They found good yields in difluroallylation of a variety of substrates. One conclusion of their work was the finding that the benzyl-protected allyl borane had much better reactivity than the tosyl variant initially investigated. They also were able to extend this methodology to a variety of aliphatic, aromatic, and substituted aldehyde substrates. OBn F

O H

B(O-i-Pr)2

OH OBn

F F F

Pentane 82%

Thadani and Batey developed the (Z)-crotyl trifluoroborate salt in the following scheme, which has the distinct advantage of tolerating a biphasic aqueous solvent system.123 Phase transfer reagents are necessary for this transformation, but the allyl trifluoroborate reagent can be stored for long periods of time and is stable to air and water. BF3K O Me Me

H Me

OH

Me n-Bu4NI CH2Cl2, H2O 96%

120 121 122 123

Me Me

Me

Me

>98:2 dr

Denmark, S. E.; Regens, C. S.; Kobayashi, T. Journal of the American Chemical Society 2007, 129, 2774–2776. Denmark, S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.; Wong, K.-T.; Nishigaichi, Y. The Journal of Organic Chemistry 2006, 71, 3904–3922. Ramachandran, P. V.; Chatterjee, A. Organic Letters 2008, 10, 1195–1198. Thadani, A. N.; Batey, R. A. Organic Letters 2002, 4, 3827–3830.

2.12 Allylorganometallics: Stannane, Borane, and Silane

Indium metal has been shown to promote the addition of allyltrifluoroborate to α,β-epoxy ketones. The addition is chemoselective, providing the tertiary alcohols in high yields and diastereoselectivities, without competing ring-scission of the epoxide.124 Me OH Me

Me

H O

Me OH

BF3K

Me

In (1.0 equiv) CH2Cl2/H2O, 5–25 h, rt

H

O

Me

H HO

96:4 dr, 91%

H

O

En route to the macrocyclic depsipeptide natural products kitastatin and respirantin, the Batey group developed and successfully utilized a diastereoselective multigram scale montmorillonite K10-catalyzed prenylation of N-Boc-L-leucinal.125 O Me

Me

H NHBoc

Me

+

Me

OH

Mont. K10 BF3K

Me

CH2Cl2/H2O, 16 h 0 °C to rt

Me NH Me Me Boc dr 85:15

74%

Allyl dioxazaborolidines, which are air-stable and often crystalline organoboranes, can react with aldehydes and ketones to afford the corresponding adducts. Brønsted acids such as trifluoroacetic acid activate allyl dioxazaborolidines to generate the reactive allyl-transfer reagents in situ. E- and Z-crotyl reagents react diastereoselectively with carbonyl compounds to produce anti and syn adducts, respectively.126 O TBDPSO

O B NH+ O

CF3CO2H

−

CO2Me +

TBDPSO

CH2Cl2, rt, 12–18 h

HO

CO2Me

95%

Smith and Zheng used classic Roush crotylboration conditions in a key bond-forming sequence for their salicylihalamide A synthesis.127 These reactions were performed by adding a solution of the allylborane to a low temperature slurry of aldehyde and molecular sieves. One advantage of this series of reagents is that in general, the crotylborane nucleophile overrides the inherent facial selectivity of the chiral aldehyde. CO2i-Pr Et

Et

O

O

O B

Me

O H

O

CO2i-Pr

Et

Et O

Toluene, −78 °C

O

OH Me

88% (90% de)

Va and Roush modified the crotylborane nucleophile with the γ-silylallylborinate shown in the following scheme.128

OPMB H O

124 125 126 127 128

Me

PhMe2Si

O B

CO2 i-Pr O

CO2 i-Pr

Toluene, 4 Å MS, −78 °C

PhMe2Si

OPMB OH Me

90% 9: 1 dr

Nowrouzi, F.; Janetzko, J.; Batey, R. A. Organic Letters 2010, 12, 5490–5493. Beveridge, R. E.; Batey, R. A. Organic Letters 2014, 16, 2322–2325. Reilly, M. K.; Rychnovsky, S. D. Organic Letters 2010, 12, 4892–4895. Smith, A. B.; Zheng, J. Tetrahedron 2002, 58, 6455–6471. Va, P.; Roush, W. R. Tetrahedron 2007, 63, 5768–5796.

95

96

2 Addition to Carbon-Heteroatom Multiple Bonds

Scientists at Boehringer–Ingelheim utilized an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by (S)-3,3′ -F2-BINOL under solvent-free and metal-free conditions as the key transformation in the synthesis of an 11-β-HSD inhibitor.129 O Ph

Cl

+

OH

(S)-3,3′-F2-BINOL (5 mol%)

Me Bpin

Ph

t-Amyl alcohol, 9 h, 35–40 °C

Me

Cl

87:13 er, 95%

Hoveyda and coworkers developed a broadly applicable method for the enantioselective synthesis of fluoroalkylsubstituted Z-homoallylic tertiary alcohols. Ketones containing a fluoroalkyl group reacted with unsaturated organoboronates in the presence of Zn(OMe)2 and a valine-derived aminophenol catalyst to provide the target tertiary alcohols in high de and ee.130 CF3

O CF3 + F3C

Bpin Me

Ligand (0.5 mol%)

HO

Zn(OMe)2 (1 mol%), MeOH toluene, 22 °C, 1.5 h

F3C Me

92% yield, 98% ee 98: 2 α:γ, 94 : 6 Z:E

i-Pr N H OH SiPh3

2.12.3

NMe2 O

Ligand

Allylstannane Additions

Even with the detriment of tin toxicity, the literature is full of examples of various allyl tin additions to aldehydes. This is due to the fact that the reagent’s toxicity is balanced with higher reactivity at lower temperatures and their ability to coordinate with Lewis bases and transmetallate with the Lewis acid reactants. The latter qualities can lead to excellent stereoselectivity. In their synthesis of mycalamide A, Rawal and coworkers utilized prenyl stannane with zinc dibromide to catalyze the transformation.131 After precomplexation of the aldehyde in methylene chloride, prenylation proceeded with excellent yield and greater than 50 : 1 diastereoselectivity. Allylation with this and other metal variants is a common method for the installation of the gem-dimethyl functionality. Me MOMO TBDPSO

O H OMOM

SnBu3 Me ZnBr2

CH2Cl2, −78 to 0 °C 90%

MOMO TBDPSO

OH

MOMO Me Me >50:1 dr

The Cossy laboratories demonstrated a nonchelation controlled crotylstannane reaction.132 In their synthesis of spongidepsin, through use of an E-crotyl stannane, the silyl protected aldehyde and BF3 ⋅OEt2 , they set the syn, syn bond construction required for the natural product. 129 Zhang, Y.; Wu, J.-P.; Li, G.; Fandrick, K. R.; Gao, J.; Tan, Z.; Johnson, J.; Li, W.; Sanyal, S.; Wang, J.; Sun, X.; Lorenz, J. C.; Rodriguez, S.; Reeves, J. T.; Grinberg, N.; Lee, H.; Yee, N.; Lu, B. Z.; Senanayake, C. H. The Journal of Organic Chemistry 2016, 81, 2665–2669. 130 van der Mei, F. W.; Qin, C.; Morrison, R. J.; Hoveyda, A. H. Journal of the American Chemical Society 2017, 139, 9053–9065. 131 Sohn, J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. Journal of the American Chemical Society 2005, 127, 7290–7291. 132 Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Organic Letters 2006, 8, 3441–3443.

2.13 The Nozaki–Hiyama–Kishi Reaction

Me Me

BF3 OEt2

H

TBDPSO

SnBu3 •

CH2Cl2, −78 °C

O

Me

Me TBDPSO

OH

76%

87:13 dr

Using chiral stannanes, Marshall and Welmaker obtained good diastereoselectivity in the reaction with the enal ester.133 Key for good selectivity in this transformation was use of the unsaturated aldehyde and silyl protection in the chiral stannane. Also of note is that use of the enantio- and regio-divergent reagent gave the opposite product enantiomer. Bu3Sn

OTBS

n-C10H21

OTBS

BF3•OEt 2

H

EtO2C O

EtO2C

n-C10H21

CH2Cl2, −78 °C

OH

79% Bu3Sn

>95:5 dr >95% ee

OTBS

n-C10H21 BF3•OEt 2

H

EtO2C O

OTBS EtO2C

n-C10H21

CH2Cl2, −78 °C

OH

77%

The final example shows a standard application of catalytic asymmetric allylstanylation. In the synthesis of bryostatin A, Keck et al. using utilized asymmetric allylation for several key stereochemical bond formations.134 Preformation of the catalyst using BINOL, titanium isopropoxide, molecular sieves and trifluoroacetic acid in methylene chloride was followed by the addition of the aldehyde and allylstannane. With this reaction system, the desired product was obtained in excellent enantioselectivity and yield.

EtO2C

H O

(i) (S)-BINOL, 4Å MS (i-PrO)4Ti, TFA CH2Cl2 (ii)

EtO2C OH

SnBu3 −78 to −20 °C

99% ee

97%

2.13 The Nozaki–Hiyama–Kishi Reaction The reaction of aldehydes with an allyl or vinyl halide (to give allylic or homoallylic alcohols) in the presence of Cr and/or Ni compounds is called the Nozaki–Hiyama–Kishi reaction. In recent times, new synthetic methodologies have evolved, which employ ketones as well as other vinyl or allyl species (such as triflates) as coupling partners in this reaction. In the following example, the vinyl triflate shown was treated with 3-phenylpropanal in the presence of stoichiometric CrCl2 and catalytic NiCl2 to furnish the adduct. The toxic nature of Cr species makes this protocol unattractive for large-scale or routine use.135 133 Marshall, J. A.; Welmaker, G. S. The Journal of Organic Chemistry 1994, 59, 4122–4125. 134 See Note 106. 135 Takai, K.; Sakogawa, K.; Kataoka, Y.; Oshima, K.; Utimoto, K. Organic Syntheses 1995, 72, 180–188.

97

98

2 Addition to Carbon-Heteroatom Multiple Bonds

Me

+

OTf

O

CrCl2, cat. NiCl2

H

Ph

Ph

Me

DMF, 25 °C 30 min

OH

94%

The Fürstner group developed a catalytic version of this reaction, where the active Cr2+ species is constantly regenerated using Mn powder as the stoichiometric reductant.136,137 CrCl2 (7 mol%) Mn-dust, TMSCl

O

Br

+

H

Me

OTMS Me

THF, rt, 6 h 78%

This methodology was extended to the synthesis of 1,4-dioxygenated compounds by means of a homoaldol reaction between aldehydes and 3-bromopropenyl acetate (used as a masked homoenolate) in the presence of CrCl3 and Mn.138 O H O

+ OAc

O

OH

CrCl3(10 mol%), 15 mol% Et3N

Br

TMSCl/Mn THF, rt, 20 h, TBAF

O

OAc O

96%

Asymmetric versions of this reaction have been developed, wherein the presence of a chiral, nonracemic ligand furnishes the desired products in high enantioselectivity.139,140,141 Ph Me Me

CHO

Cr-ligand (10 mol%) Mn-dust,TMSCl

+ Br Me

H OBn

DIPEA, TBAF THF, rt 94%, 97% dr

O H

+

Me Br

10 mol% CrCl3, 10 mol% L 20 mol% Et3N, TMSCl, Mn-dust, THF, 0 °C, 24 h

Ph

Me Me HO

Me

H OBn

O

N

N H

N

O

i-Pr i-Pr Ligand

HO

Me Me

L=

Me O N

Me O N H

BocN

73%, 91% ee

The intramolecular version of this reaction was successfully utilized to provide the key cyclized intermediate in the synthesis of eribulin mesylate.142

136 137 138 139 140 141 142

Fürstner, A.; Shi, N. Journal of the American Chemical Society 1996, 118, 2533–2534. Fürstner, A.; Shi, N. Journal of the American Chemical Society 1996, 118, 12349–12357. Kang, J. Y.; Connell, B. T. Journal of the American Chemical Society 2010, 132, 7826–7827. Inoue, M.; Suzuki, T.; Nakada, M. Journal of the American Chemical Society 2003, 125, 1140–1141. Miller, J. J.; Sigman, M. S. Journal of the American Chemical Society 2007, 129, 2752–2753. Lee, J.-Y.; Miller, J. J.; Hamilton, S. S.; Sigman, M. S. Organic Letters 2005, 7, 1837–1839. Fukuyama, T.; Chiba, H.; Takigawa, T.; Komatsu, Y.; Kayano, A.; Tagami, K. Organic Process Research & Development 2016, 20, 100–104.

2.14 Addition of Transition Metal Alkynylides to Carbonyl Compounds

H PhO2S MeO TBSO TBSO

O H O TBSO

H OTBS OTBS

I

O O

Me

MeO TBSO TBSO

Mn, Cp2ZrCl2, THF, rt, 3 h O

O

H

PhO2S

di-t-Bu-bipy (10 mol%) CrCl3 (10 mol%), Ni-neo (10 mol%)

O

O H TBSO

O O

97%

Me O

H OTBS OTBS OH

H

2.14 Addition of Transition Metal Alkynylides to Carbonyl Compounds Metalated terminal alkynes (i.e. alkynylides) add to a wide range of C=O bonds to provide the corresponding propargylic alcohols or amines. The reaction of lithium and magnesium acetylides with carbonyl compounds is discussed in Sections 2.15.1 and 2.15.2. This section will cover the addition of transition metal alkynylides (generated in situ) to carbonyl compounds. Carreira and coworkers developed a protocol for the in situ generation of zinc alkynylides and their subsequent addition to C=O and C=N bonds. The electrophiles in this case were aldehydes, ketones, hydrazones, or nitrones.143 O Ph

H

Zn(OTf)2 (10 mol%)

Ph

Zn OTf

OH

Ph

CH2Cl2, rt 80%

i-Pr2NEt i-Pr2NEt•HOTf

Subsequently, asymmetric versions of this reaction were developed employing chiral, nonracemic ligands to furnish the required propargylic alcohols in high ee and yields.144,145 CHO

+

Ph

Zn(OTf)2, Et3N (+)-N-methylephedrine

OH Ph

Toluene, 23 °C, 4 h 98%, 99% ee

Me

CHO Me

OTMS +

Me Me

Zn(OTf)2 (20 mol%) (+)-N-methylephedrine (22 mol%) Et3N, toluene, 60 °C, 5 h 77%, 98% ee

OH Me Me

OTMS Me Me

Asymmetric alkynylation of aldehydes has also been accomplished using an In(III)-BINOL complex as the catalyst. The success of this protocol is attributed to the dual activation of the alkyne (soft nucleophile) and the aldehyde (hard electrophile) components by indium(III).146 143 144 145 146

Frantz, D. E.; Fässler, R.; Carreira, E. M. Journal of the American Chemical Society 1999, 121, 11245–11246. Frantz, D. E.; Fässler, R.; Carreira, E. M. Journal of the American Chemical Society 2000, 122, 1806–1807. Anand, N. K.; Carreira, E. M. Journal of the American Chemical Society 2001, 123, 9687–9688. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. Journal of the American Chemical Society 2005, 127, 13760–13761.

99

100

2 Addition to Carbon-Heteroatom Multiple Bonds

O H

+

Ph

InBr3 (10 mol%), (R)-BINOL (10 mol%)

OH

Cy2NMe (50 mol%) CH2Cl2, 40 °C, 22 h

Ph

85%, 98% ee

A chiral-at-ruthenium catalyst was employed successfully for the enantioselective synthesis of the anti-HIV drug, efavirenz. The key alkynylation reaction of a trifluoromethyl ketone proceeded in very high selectivity and yield with only 0.2 mol% of the ruthenium catalyst.147 2+ 2PF6− Me

O Cl

CF3 Cl

N

Ru-Catalyst (0.2 mol%) Et3N (20 mol%) THF, 60 °C, 16 h 99%, 95% ee

Cl

N

F3C OH

N

N N Mes NMes

Ru N

Me

N

Cl Ru-Catalyst

2.15 Addition of Organometallic Reagents to Carbonyls Grignard and organolithium additions are one of the classic methods for carbon–carbon bond formation. They perform well in addition to carbonyl compounds due to their ability to coordinate with the carbonyl or transmetallate to form other organometallic compounds. The highly basic nature of these reagents should be taken into consideration when designing a synthesis, but there are examples where relatively sensitive functionality (e.g. a stereocenter adjacent to a carbonyl) can be tolerated. There are a few challenges with carrying out effective organolithium or organomagnesium (Grignard) reactions. Both nucleophiles are very basic: for example, butyllithium is on the order has a pK a of 48 and phenylmagnesium bromide a pK a of approximately 35.148 Therefore, care has to be taken to ensure reaction of the desired components; proton transfer can easily compete with the desired reaction. In organolithium additions, unintended cross-coupling such as the Wurtz reaction (see Section 1.7.1.1) should be anticipated; this particular side reaction can be circumvented by avoiding alkyl iodides. Appropriate care must be taken for the exclusion of water and oxygen. Other obstacles exist in the formation of Grignard reagents.149 Grignard reagents are formed from the reaction of magnesium metal and an organohalide, typically in an ethereal solvent (to aid solubility). Given the biphasic nature of the metal and organohalide, care must be taken upon reaction due to the ability to have an activation period followed by rapid exothermic reaction. One method to manage this is the use of activators (e.g. iodine, dibromomethane) to help minimize the onset period. Other techniques include the use of activated magnesium turnings and starting with a partial charge, instead of a full charge of the organohalide. The reaction of organolithium and organomagnesium reagents with aldehydes and ketones is presented in this section. Reactions of these compounds with carboxylic acid derivatives and nitriles are presented in Sections 2.38 and 2.43, respectively. 2.15.1

Using Organolithium Reagents

Zhang et al. prepared 2-lithiofuran by metalation with n-butyllithium, and this reagent was in turn added to a nonenolizable aryl ketone.150 Upon reaction completion, the mixture was quenched with an aqueous ammonium chloride solution and standard workup ensued to give an excellent yield of the desired alcohol. 147 Zheng, Y.; Zhang, L.; Meggers, E. Organic Process Research & Development 2018, 22, 103–107. 148 Bordwell, F. G. Accounts of Chemical Research 1988, 21, 456–463; Silverman, G. S.; Rakita, P. E.; Editors Handbook of Grignard Reagents. [In: Chemical Industries (Dekker), 1996; 64], 1996. 149 Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angewandte Chemie International Edition 2003, 42, 4302–4320. 150 Zhang, P.; Kern, J. C.; Terefenko, E. A.; Fensome, A.; Unwalla, R.; Zhang, Z.; Cohen, J.; Berrodin, T. J.; Yudt, M. R.; Winneker, R. C.; Wrobel, J. Bioorganic & Medicinal Chemistry Letters 2008, 16, 6589–6600.

2.15 Addition of Organometallic Reagents to Carbonyls

O O Br

O

HO n-BuLi, THF

C2F5

Br

C2F5

−78 °C to 0 °C >90%

NH2

NH2

Caron and Do151 explored the effect of temperature, solvent, and character of the electrophile in their work toward the optimization of reactions with dibromobenzene. Choice of reaction solvent and low temperatures was the key to optimizing the yield for this lithiation–addition sequence. Br

(i) n-BuLi, THF −78 °C

Br Br

OH

(ii) O 98%

Moseley and coworkers at AstraZeneca used similar conditions for their synthesis of several neurokinin antagonists.152 Both Grignard and aryllithium reagents were investigated, with the latter providing cleaner addition products. MeO OMe

MeS

(i) n-BuLi, THF −70 °C MeS

(ii) O

Br

N

OH

N Cbz

Cbz

−78 °C to rt 89%

Modeling work in the Corey lab, Pierce et al. developed an asymmetric variant of an organolithium addition in their work on the HIV candidate efavirenz.153 In this reaction sequence, the ephedrine-derived ligand, butyl lithium, and the cyclopropyl acetylene are premixed and cooled to −50 ∘ C prior to addition of the trifluoro methyl ketone. Enantioselectivity of this transformation was optimized through temperature control, variation of substituents at the aniline, and careful consideration of the ligand chirality. (i) n-BuLi, THF, 0 °C

H

HO

N

Ph

Me

(ii)

Cl

O Cl N H

CF3 PMB

HO

N H

CF3 PMB

THF, −55 °C 91% (99.5% ee)

151 Caron, S.; Do, N. M. Synlett 2004, 1440–1442. 152 Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Organic Process Research & Development 2004, 8, 33–44. 153 Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.-Y.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.; Reamer, R.; Reider, P. J. The Journal of Organic Chemistry 1998, 63, 8536–8543.

101

102

2 Addition to Carbon-Heteroatom Multiple Bonds

As mentioned earlier, the high basicity of organolithiums could preclude their use in the presence of sensitive functional groups. Premixing an organolithium (RLi) with TiCl4 leads to the formation of RTiCl3 , which is a good nucleophile and a poor base. In the following example, CH3 TiCl3 (derived from CH3 Li and TiCl4 ) was found to react chemoselectively with the ketone (and not the nitrile) to provide the tertiary alcohol in excellent yield.154 N

N

TiCl4, MeLi Anisole −10 to −5 °C, 1 h

Me O

84%

2.15.2

Me Me

OH

Using Organomagnesium Reagents

Katzenellenbogen and coworker constructed tamoxifen and its analogs through the phenyl Grignard addition to the ketone in the following.155 In their synthesis, phenyl Grignard was generated by subjection of a portion of the bromobenzene to magnesium turnings in diethyl ether. After initiation commenced, the remainder of the bromide was added slowly so as to maintain a gentle reflux of the solvent. The phenyl Grignard solution was then added slowly to a cooled solution of the diaryl ketone. After aqueous workup, the reaction mixture was concentrated to give an oil, which upon subjection to alcoholic HCl generated the desired triaryl alkene. (i)

NMe2

O

NMe2

O

Br

O

Br MgBr (ii) HCl/MeOH

Me

Me

84%

The O-benylated benzhydryl ether in the following scheme was a key intermediate en route to ertugliflozin. This was synthesized by the reaction of 5-bromo-2-chlorobenzaldehyde with 4-ethoxyphenylmagnesium bromide followed by treatment with benzyl alcohol in the presence of H2 SO4 .156 Cl H

Br

OEt

Br

BrMg

O

Cl

OEt

+

Cl

H2SO4 BnOH 2-MeTHF 75% (2 steps)

OH

OEt

Br OBn

Magnesium ate complexes (R3 MgLi) derived from organomagnesium species and alkyllithiums have been successfully shown to add to carbonyl compounds. The R group in these reagents is more nucleophilic and less basic than the corresponding organomagnesium or organolithium species.157 In the following example, the ate complex was chemoselectively added to the keto functionality in the presence of the ester.158 O

N F

MgLi 3

(i) THF, −20 to 0 °C

+ CO2i-Pr

(ii) MeOH EtNH2 in MeOH

OH

N F

CONHEt

55% 154 Weiberth, F. J.; Gill, H. S.; Lee, G. E.; Ngo, D. P.; Shrimp, F. L.; Chen, X.; D’Netto, G.; Jackson, B. R.; Jiang, Y.; Kumar, N.; Roberts, F.; Zlotnikov, E. Organic Process Research & Development 2015, 19, 806–811. 155 Robertson, D. W.; Katzenellenbogen, J. A. The Journal of Organic Chemistry 1982, 47, 2387–2393. 156 Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E. C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.; Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C. L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Organic Process Research & Development 2014, 18, 66–81. 157 Hatano, M.; Matsumura, T.; Ishihara, K. Organic Letters 2005, 7, 573–576. 158 Hawkins, J. M.; Dubé, P.; Maloney, M. T.; Wei, L.; Ewing, M.; Chesnut, S. M.; Denette, J. R.; Lillie, B. M.; Vaidyanathan, R. Organic Process Research & Development 2012, 16, 1393–1403.

2.16 Addition of Conjugated Alkenes to Aldehydes: the Baylis–Hillman Reaction

2.16 Addition of Conjugated Alkenes to Aldehydes: the Baylis–Hillman Reaction The addition of the α-carbon of an α,β-unsaturated carbonyl compound to an aldehyde is referred to as the Baylis–Hillman reaction. The product of this reaction is an allylic alcohol. Nucleophiles such as tertiary amines and phosphines catalyze this reaction.159 The use of asymmetric catalysts can lead to optically enriched products. A classic example, by Basavaiah and Suguna Hyma in the following scheme.160 Hexanal and methyl acrylate are mixed neat with a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give a good yield of the desired allylic alcohol. As illustrated in this example, neat or very concentrated reaction conditions are frequently beneficial for this reaction. O

Me H

O +

OH O

DABCO OMe

Me

rt, 6 days

OMe

85%

Dunn et al. at Pfizer used the Baylis–Hillman reaction as the first step for the large-scale production of sampatrilat.161 Use of aqueous acetonitrile with 2 equiv of aldehyde and an equivalent of 3-quinuclidinol was found to give complete and clean conversion to the allyic alcohol. During the process run, the 3-quinuclidinol was dropped to a catalytic amount due to cost considerations. This optimization work (excess aldehyde in a polar solvent) supports the second-order kinetics observed in the laboratories of McQuade.162 Using this process, 80 kg of the allylic alcohol were produced. HO

OH N

t-BuO

t-BuO

CH2O, MeCN

O

O

81%

Aggarwal and Mereu have demonstrated that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is a much superior catalyst than either DABCO or 3-hydroxyquinuclidine in the Baylis–Hillman reaction.163 O Me + O

O H

OH O

DBU Ph

Ph

6 h, rt

O

Me

89%

Key examples for the asymmetric Baylis–Hillman reaction include use of an optically active Lewis acid complex as well as chiral auxiliaries and optically active catalysts. Chen and coworkers used chiral lanthanide complexes to successfully perform the addition; unfortunately, high enantioselectivities were observed only with electron poor aromatic aldehydes.164 Leahy et al., obtained success with a wider scope of substrates in their chiral auxiliary and chiral catalyst approaches. Use of the Oppolzer sultam with a catalytic amount of DABCO gave excellent yield and high enantioselectivity.165 Me

Me

O O N

S O O

159 160 161 162 163 164 165

DABCO MeCHO 85%

O Me

O

Me

>99% ee

Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001–8062. Basavaiah, D.; Suguna Hyma, R. Tetrahedron 1996, 52, 1253–1258. Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Organic Process Research & Development 2003, 7, 244–253. Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. The Journal of Organic Chemistry 2005, 70, 3980–3987. Aggarwal, V. K.; Mereu, A. Chemical Communications 1999, 2311–2312. Yang, K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K. The Journal of Organic Chemistry 2003, 68, 915–919. Brzezinski, L. J.; Rafel, S.; Leahy, J. W. Tetrahedron 1997, 53, 16423–16434.

103

104

2 Addition to Carbon-Heteroatom Multiple Bonds

Hatakeyama and coworkers expanded chiral Baylis–Hillman methodology through use of the activated alkene and the chiral quinidine (β-ICD).166 Although yields are moderate and in most cases a small amount of the lactone dimer is observed, the aldehyde scope is broad, and the enantioselectivity is excellent. Ph O

O Ph

+

H

CF3 O

OH O

β-ICD

CF3

Ph

DMF −55 °C

Me

OH

CF3 O

+

CF3

Ph

50% 92% ee

O

O

O O

N N

β-ICD

Essentially identical conditions were used to synthesize the key intermediate en route to the indole alkaloid, andranginine. The reaction proceeded in 64% yield, and high enantioselectivity.167 O H

O O

N

+

O

CF3 O

CF3

HO

β-ICD (cat) F3C

DMF, 4 Å MS, −55 °C

N

O CF3 O

64%, 98% ee

A β-iodo Baylis–Hillman reaction was employed to prepare the Z-vinyl iodide in the synthesis of aruncin B. Treatment of methyl propiolate with in situ generated MgI2 and tert-butyl dimethylsilyl (TBS)-protected aldehyde furnished the Bayliss–Hillman adduct in excellent yield.168

+ MeO

O

H

I

Mg (turnings), I2

OTBS

CH2Cl2/ Et2O, −20 to 0 °C

O

96%

MeO

OTBS O

OH

2.17 The Reformatsky Reaction The Reformatsky reaction is the reaction of a zinc enolate with an aldehyde or ketone. Zinc enolates are less basic than magnesium or lithium enolates. This decreased basicity allows a wider range of functional group toleration in the reaction substrates. One challenge for this reaction is the requirement of activated zinc. Multiple methods are published that accomplish this task, and a few variants are described in this section. Hallinan et al. used classic conditions for the formation of the requisite di-flouro compound shown in the following.169 Starting with freshly etched (rinsed with strong acid) zinc in THF, the zinc enolate was formed from the α-bromo ester, then allowed to react with the aldehyde. F F EtO2C

Br

OH

(i) Zn, THF (ii) OHC

EtO2C N

N

F F

93% 166 Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. Journal of the American Chemical Society 1999, 121, 10219–10220. 167 Tooriyama, S.; Mimori, Y.; Wu, Y.; Kogure, N.; Kitajima, M.; Takayama, H. Organic Letters 2017, 19, 2722–2725. 168 Ribaucourt, A.; Hodgson, D. M. Organic Letters 2016, 18, 4364–4367. 169 Hallinan, E. A.; Hagen, T. J.; Husa, R. K.; Tsymbalov, S.; Rao, S. N.; vanHoeck, J. P.; Rafferty, M. F.; Stapelfeld, A.; Savage, M. A.; Reichman, M. Journal of Medicinal Chemistry 1993, 36, 3293–3299.

2.17 The Reformatsky Reaction

Siegel and coworker found a mixture of copper chloride, zinc powder, and sulfuric acid to be effective for the Reformatsky reaction.170 In this case, the zinc–copper couple was formed by making a suspension of copper chloride and zinc powder in THF. To this suspension was added a catalytic amount of sulfuric acid, and the solution was heated. The ketone was added followed by the bromo-ester. Following this procedure, the group obtained the desired hydroxy-ester (as a mixture of diastereomers) in excellent yield. (i) Zn (1.7 equiv) CuCl (0.2 equiv), THF H2SO4 (0.2 equiv)

Br Me

MeO2C

(ii) O

Me OH

MeO2C

OMe OMe 92%

A selective coupling of an α-bromo pyrimidine and a triazole ketone was the key transformation in the synthesis of voriconazole.171 For these substrates, activation of zinc metal was initially found to be dependent on lead content in the zinc and continuous addition of iodine, alkyl bromide, and ketone to the slurry of zinc. Additional investigation revealed that they did not have to dope with lead if they instead had a continuous stream of iodine added with their substrates to the zinc slurry. Temperature control was also important to maintain selectivity; optimal selectivity was observed at reaction temperatures at or below 5 ∘ C. N

N

N Me

Cl Br

N N

N Zn, I2

+

F

O F

F

N

N

F

F

Me

N

+

Cl

THF 90%

N

N

OH N F

N

N

OH N

Cl F

F

Me

F

10.3 :1

A highly diastereoselective aza-Reformatsky reaction was developed for the synthesis of enantiopure alkynyl N-sulfinylimines from N-t-butanesulfinimines. A variety of aldimines and ketimines bearing differently substituted alkynyl groups can participate in this reaction to provide the desired products. Excellent diastereoselectivities were obtained by the use of AlMe3 as the Lewis acid. Interestingly, the use of TBSOTf as the Lewis acid promoter provided complementary diastereoselectivity. Thus, this protocol was used for the stereodivergent asymmetric synthesis of β-alkynyl-β-amino acids from the same sulfinimines by the appropriate choice of the Lewis acid.172

HN

O

O

S

S

t-Bu

N

Zn-dust, TBSOTf THF, −78 °C

Ph

O

Ot-Bu

86%, >93:7 dr

H Ph

O t-Bu

+ Br

O

HN

Zn-dust, AlMe3 Ot-Bu

S

t-Bu

THF, −78 °C 88%, >98:2 dr

Ph

O

Ot-Bu

Samarium iodide has been utilized instead of zinc to effect Reformatsky-type reactions. In their synthesis of (±)-chlorizidine A, Mhaske and coworker successfully employed a samarium iodide-mediated Reformatsky reaction to synthesize the β-hydroxyketone intermediate; the zinc-mediated protocol afforded only trace amounts of product in this case.173

170 Scherkenbeck, T.; Siegel, K. Organic Process Research & Development 2005, 9, 216–218. 171 Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Organic Process Research & Development 2001, 5, 28–36. 172 Fernández-Sánchez, L.; Fernández-Salas, J. A.; Maestro, M. C.; García Ruano, J. L. The Journal of Organic Chemistry 2018, 83, 12903–12910. 173 Mahajan, J. P.; Mhaske, S. B. Organic Letters 2017, 19, 2774–2776.

105

106

2 Addition to Carbon-Heteroatom Multiple Bonds

O

H N

Cl

O MeO

Br

+

N

H

SmI2, THF

Cl

MeO

Cl

Cl

Reflux, 1 h

H N

Cl

O

N MeO

Cl

70%

HO MeO Cl Cl

An asymmetric SmI2 -mediated Reformatsky reaction was employed to access the stereogenic center in the key β-hydroxyester intermediate in the synthesis of prostaglandin E2 methy ester. Treatment of the oxazolidinonesubstituted bromide with the propargylic alcohol shown in the following scheme in the presence of SmI2 led to the desired product in high yield and diastereoselectivity.174 O O Ph

O

O N

Br

O

+

Ph Me

SPh

H

Me

SmI2 Ph

THF, −78 °C 88%, >90% de

O N

O

Ph Me

OH

Me

SPh

2.18 The Wittig Reaction The reaction of a Wittig reagent (phosphorous ylide) with an aldehyde or ketone gives an alkene product and triphenylphosphine oxide. E vs. Z olefin selectivity is a complex function of ylide stability, counterion effects, solvent, etc. and the subject has been well reviewed.175 Taber and Nelson used potassium hydride in paraffin as the base in the otherwise standard Wittig reaction depicted in the following scheme.176 O

−

Br PPh3

+

H

+

KH (paraffin)

OBn

OMe

THF, 0 °C

OBn

OMe

80%

Stuk et al. used a preformed Wittig ylide in the synthesis of pagoclone.177 Heating the ylide with a hydroxy-isoindolinone in refluxing xylenes for 24 hours enabled smooth conversion, via the ring-opened aldehyde, to the initial enone product, which then underwent a Michael addition of the amide nitrogen to reform the isoindolinone. A solvent exchange from xylenes into isopropanol allowed for the isolation of a good yield of the desired product. Me O N OH

Ph3P N

N

Cl

O

Me O

xylenes, reflux 24 h 85%

N Me Me

N

N

Cl

O

After exploring multiple methods for the olefination of the 6-methoxytetralone, Ainge et al. found the Wittig reaction to be most effective.178 They investigated several variants: use of the preformed ylide, different orders of addition, different bases, and different solvents. For this substrate, the reaction was optimized for overall yield and the ratio of exocyclic vs. endocyclic olefin. The optimized procedure involved premixing the ketone and phosphonium bromide 174 Huang, K.-H.; Huang, C.-C.; Isobe, M. The Journal of Organic Chemistry 2016, 81, 1571–1584. 175 Maryanoff, B. E.; Reitz, A. B. Chemical Reviews 1989, 89, 863–927. 176 Taber, D. F.; Nelson, C. G. The Journal of Organic Chemistry 2006, 71, 8973–8974. 177 Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Organic Process Research & Development 2003, 7, 851–855. 178 Ainge, D.; Ennis, D.; Gidlund, M.; Stefinovic, M.; Vaz, L.-M. Organic Process Research & Development 2003, 7, 198–201.

2.18 The Wittig Reaction

in THF, followed by slow addition of a cold THF solution of potassium t-butoxide. After reaction completion, it was necessary to remove the reaction solvent in order to precipitate the triphenyl phosphine oxide by-product. Washing the product with water and solvent exchange into t-butanol allowed for near quantitative isolation of product. O MeO

MeO

Ph3PMeBr THF, t-BuOK 97%

In the next two reactions, the use of a stabilized Wittig reagent is demonstrated. In the first, Prasad Raju et al. utilized the stabilized-Wittig reaction in their synthesis of lacidipine.179 Generation of the Wittig ylide was accomplished with sodium hydroxide at 0 ∘ C. After reaction completion, heptanes were added to the solution to allow for precipitation of triphenyl phosphine oxide. Following filtration, the product was used without further purification in the subsequent reaction to form the isolated dihydropyridine product.

Br − (Ph)3P+

CO2t-Bu

CHO

NaOH

CO2t-Bu

(Ph)3P

−5 to 0 °C CH2Cl2, H2O

CHO

NH2 CO2t-Bu

EtO2C

CHO

Me

CO2t-Bu CO2Et

EtO2C

i-PrOH, TFA

Me

52%

N H

Me

In the second example, Chen et al. generated the reactive aldehyde by treating the primary alcohol with pyridine-sulfur trioxide complex and an excess of pyridine (to remove excess sulfuric acid in the complex).180 The aldehyde was then treated with the stabilized Wittig ylide to give the α,β unsaturated ester as a single olefin isomer. O

BocNH

O

NH

pyr • SO3 DMSO

NH

DIEA CH2Cl2

OH

O

BocNH

O Et3P=CHCO2Et 86%

H

BocNH

NH

CO2Et

Researchers at Eli Lilly employed the Wittig reaction to synthesize the olefin shown in the following scheme en route to the preparation of a glucokinase activator. The product was isolated as a 55 : 45 mixture of E:Z isomers.181 O

O

O

LiHMDS, THF

OEt + S

O

O

+

PPh3 I

−

OEt

0–5 °C, S

O

89% 2 steps

OH S

O

+ PPh 3O

179 Prasada Raju, V. V. N. K. V.; Ravindra, V.; Mathad, V. T.; Dubey, P. K.; Pratap Reddy, P. Organic Process Research & Development 2009, 13, 710–715. 180 Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. Organic Process Research & Development 2006, 10, 163–164. 181 DeBaillie, A. C.; Magnus, N. A.; Laurila, M. E.; Wepsiec, J. P.; Ruble, J. C.; Petkus, J. J.; Vaid, R. K.; Niemeier, J. K.; Mick, J. F.; Gunter, T. Z. Organic Process Research & Development 2012, 16, 1538–1543.

107

108

2 Addition to Carbon-Heteroatom Multiple Bonds

2.19 Horner–Wadsworth–Emmons Reaction The Horner–Wadsworth–Emmons reaction involves reaction of a phosphonate ester with an aldehyde or ketone. Due to the stabilized nature of the ylide, the E-olefin geometry is formed predominantly. In the synthesis of cefovecin, Norris et al. used the Horner–Wadsworth–Emmons reaction as a key bond-forming step.182 In their process, the group built the phosphonate ester via the α-chloro ester. Iodide-catalyzed phosphite displacement and treatment with Hunig’s base in methylene chloride resulted in an intramolecular Horner–Wadsworth–Emmons reaction. O Ph

H N

S

O

Ph

CH2Cl2

N

O

O

NaI P(OMe)3 LiCl

O

H N

O

Ph DIPEA

S

O

Cl

O

N

O

77%

O O

S N O

O

OPNB

O P(OMe)2

H N

OPNB

O OPNB

For Alimardanov et al. at Wyeth, the Horner–Wadsworth–Emmons reaction proved critical for synthesis of the desired E alkene in their synthesis of a trifluoromethyl alkene.183 Key to reaction success was the use of K3 PO4 (NaH was less effective) and aging the reaction in ethanol. Potassium phosphate provided moderate E:Z selectivity (83 : 17), whereas NaH was essentially nonselective (53 : 47). Further aging of the reaction in ethanol (20 hours) provided enhancement of the E:Z selectivity to 95 : 5. EtO

F

F

PO(OEt)2 O

CF3

F O

CF3

F

K3PO4 then H2O

EtO

83%

O

Despite obtaining four different isomeric alkenes in their first attempt at the reaction shown in the following scheme, Zanka et al. were able to develop conditions for the preparation of the desired α,β-unsaturated ester.184 When the initial NaH/DMSO reaction provided a complex mixture, the group examined different solvents and bases to fine-tune the reaction. This optimization work led them to a combination of sodium hydroxide and potassium carbonate in 1,2-dimethoxyethane (DME), which provided an excellent yield of the desired product and minimal amounts of isomeric by-products. O

O O N N N N

OtBu

O t-BuO2C

N N

PO(OEt)2

NaOH, K2CO3 DME 78%

N N

A modification of the Horner–Emmons reaction initially developed by Still and Gennari allows for the isolation of the Z-alkene instead. In their synthesis of the enantiomer of Kallolide B, Marshall et al. used the Still modification of the Horner–Emmons to append their furan intermediate to the (Z)-conjugated ester in excellent yield.185

182 Norris, T.; Nagakura, I.; Morita, H.; McLachlan, G.; Desneves, J. Organic Process Research & Development 2007, 11, 742–746. 183 Alimardanov, A.; Nikitenko, A.; Connolly, T. J.; Feigelson, G.; Chan, A. W.; Ding, Z.; Ghosh, M.; Shi, X.; Ren, J.; Hansen, E.; Farr, R.; MacEwan, M.; Tadayon, S.; Springer, D. M.; Kreft, A. F.; Ho, D. M.; Potoski, J. R. Organic Process Research & Development 2009, 13, 1161–1168. 184 Zanka, A.; Itoh, N.; Kuroda, S. Organic Process Research & Development 1999, 3, 394–399. 185 Marshall, J. A.; Bartley, G. S.; Wallace, E. M. The Journal of Organic Chemistry 1996, 61, 5729–5735.

2.20 Peterson Olefination

Me

O

O

(CF3CO)2OP

O

H

EtO

OEt

Me

Me

Me

O O

KHMDS, THF 18-C-6

Me HO

Me

86%

HO

A Horner–Wadsworth–Emmons reaction between the piperidone and phosphonate ester shown in the following scheme was the key step in the synthesis of a SERT/5-HT1a inhibitor. The use of t-BuOK as the base led to clean product formation.186 O

Br MeO

O

Br

KOt-Bu (in THF)

O + P(Oi-Pr)2

N Boc

Toluene, −7 °C to 5 °C 7–8 h

MeO

NBoc

O

Mathur et al. developed a convenient one-pot protocol for acetal hydrolysis, followed by an olefination of the intermediate aldehyde using K2 CO3 as the base.187 OMe

TsOH, THF-H2O

MeO

BnO

H

91%

HO

O

O

O P(OMe)2

K2CO3, rt

HO

75%

O BnO HO

2.20 Peterson Olefination The Peterson olefination involves formation of an alkene through elimination of a β-hydroxysilane. The hydroxyl silane is typically formed by addition of an α-silyl carbanion to an aldehyde or ketone. E vs. Z selectivity is dependent on the stereochemistry of the β-hydroxysilane and whether acidic or basic conditions are utilized to effect elimination. Key to the Denmark and Yang synthesis of brasilenyne was a Peterson olefination for the installation of the sensitive Z-enyne.188 The lithiated silyl precursor was formed by treating a cold THF solution of the disilyl alkyne with n-butyllithium. To this solution was added the aldehyde, and upon slow warming, the desired enyne was formed in good yield and 6 : 1 Z:E selectivity. TIPS

TIPS TBSO O O

H Me

TBSO

n-BuLi, THF −78 °C to rt 83% 6:1 Z : E

O TIPS

Me

Tius and coworker utilized a Peterson olefination early in their formal synthesis of roseophilin.189 The t-butylimine was first α-silylated with lithium diisopropylamide (LDA) and TMSCl. A second lithiation and condensation with isobutyraldehyde formed the α,β-unsaturated imine, and treatment with aqueous oxalic acid in THF delivered the desired aldehyde in 71% isolated yield. 186 Ueno, A.; Ae, N.; Terauchi, H.; Fujimoto, K.; Fujiwara, Y. Organic Process Research & Development 2015, 19, 1030–1037. 187 Mathur, A.; Wang, B.; Smith, D.; Li, J.; Pawluczyk, J.; Sun, J.-H.; Wong, M. K.; Krishnananthan, S.; Wu, D.-R.; Sun, D.; Li, P.; Yip, S.; Chen, B.-C.; Baran, P. S.; Chen, Q.; Lopez, O. D.; Yong, Z.; Bender, J. A.; Nguyen, V. N.; Romine, J. L.; Laurent, D. R. S.; Wang, G.; Kadow, J. F.; Meanwell, N. A.; Belema, M.; Zhao, R. The Journal of Organic Chemistry 2017, 82, 10376–10387. 188 Denmark, S. E.; Yang, S.-M. Journal of the American Chemical Society 2002, 124, 15196–15197. 189 Harrington, P. E.; Tius, M. A. Organic Letters 1999, 1, 649–651.

109

110

2 Addition to Carbon-Heteroatom Multiple Bonds

Me Me N Me H

(i) LDA, TMSCl, THF −78 to 10 °C (ii) LDA, i-PrCHO −78 to 10 °C

O H Me

(iii) (COOH)2 THF, H2O

Me

71%

O’Shea and coworker demonstrated highly tunable stereoselective aza-Peterson olefinations with bench-stable bis-(trimethylsilanes) and imine electrophiles. The stereoselectivity of the product alkene was shown to be completely dependent on the nature of the imine employed. N-Aryl imines preferentially afforded the E-stilbenes, while N-t-butanesulfinyl imines provided Z-stilbenes as the predominant products.190 Ph OMe

N

MeO

MeO

OMe

MeO

Me3SiOK/Bu4NCl THF, −20 to 0 °C, 3 h 84%, E/Z = 1:99

OMe

MeO

OMe

H

OMe

Me3Si

SiMe3

HO

O N S t-Bu H

MeO MeO

Me3SiOK/Bu4NCl THF, −20 to −10 °C, 3 h 87%, Z/E = 95:5

OMe

OH OMe

In their synthesis of maritimol, Deslongchamps and coworkers utilized a Peterson olefination to enable the formation of the required Z olefin.191 The reactive boronate was formed by treatment of a lithiated solution of trimethylsilylacetonitrile with triisopropylborate. To this cooled reagent was added a solution of aldehyde, providing a 79% yield of the desired alkene. CHO

CN

Me O

TMS

CN CN

B(Oi-Pr)2

Me

CN THF, −78 °C

Me Me

O

79% 6:1 Z:E

Me Me

The Peterson olefination reaction was used to access a variety of α-CF3 akenes from the corresponding trifluoromethyl ketones. The reaction sequence was demonstrated both in batch mode and flow mode, with the latter providing significantly higher yields.192,193 O CF3 t-Bu

HO

Me3SiCH2MgCl THF, 50 °C 30 min

SiMe3 CF3

t-Bu

TMSOTf 9:1 CH 2Cl2/hex rt, 10 min

CF3 t-Bu

Batch mode 65% Flow mode 90%

2.21 Julia–Lythgoe Olefination Julia olefinations involve α-metalation of an alkyl sulfone and addition to an aldehyde or ketone. The resulting alcohol is activated (e.g. by acylation) and then reductively eliminated to form the olefin (see Section 9.5.2). Keck et al. used modified Julia–Lythgoe conditions in their synthesis of rhizoxin.194 They found that their target triene product was incompatible with standard Na(Hg) reduction conditions due to reduction to form a 1,5-diene. Pursuing 190 191 192 193 194

Das, M.; O’Shea, D. F. Organic Letters 2016, 18, 336–339. Toro, A.; Nowak, P.; Deslongchamps, P. Journal of the American Chemical Society 2000, 122, 4526–4527. Hamlin, T. A.; Lazarus, G. M. L.; Kelly, C. B.; Leadbeater, N. E. Organic Process Research & Development 2014, 18, 1253–1258. Hamlin, T. A.; Kelly, C. B.; Cywar, R. M.; Leadbeater, N. E. The Journal of Organic Chemistry 2014, 79, 1145–1155. Keck, G. E.; Savin, K. A.; Weglarz, M. A. The Journal of Organic Chemistry 1995, 60, 3194–3204.

2.21 Julia–Lythgoe Olefination

observations of Kende and other workers, they studied the use of samarium diiodide as an alternative reductant with good success. They found that the β-acetoxy sulfone adduct could be eliminated to a vinyl sulfone, which was efficiently reduced by SmI2 in a THF-N,N′ -dimethylpropyleneurea (DMPU)-MeOH solvent mixture to selectively give the desired E-olefin. In deuterium-labeling studies, they found that SmI2 appears to reduce β-acetoxy sulfones directly to olefins, whereas a Na(Hg) reduction appears to proceed via a vinyl sulfone (i.e. a stepwise elimination/reduction sequence).

Ph

(i) n-BuLi, THF, −78 °C (ii) PhCHO

SO2Ph

OAc Ph

DBU

Ph SO2Ph

(iii) Ac 2O 82%

SmI2 (8 equiv) DMPU

Ph Ph

THF, MeOH

SO2Ph

Ph

Ph

92%

Danishefsky and coworkers utilized a standard Julia olefination in their total synthesis of indolizomycin.195 The lithiated allylic sulfone was added to the aldehyde and acetylated to form a mixture of diastereomers in high yield (86%), and reduction with Na(Hg) generated the desired E,E,E-triene with excellent efficiency (89%). (1) (i) −78 °C, THF Me SO2Ph Me

OTBS

OTBS

Li

O

(ii) Ac2O

O

N R

86% N R

(2) Na(Hg), MeOH −20 °C 89%

CHO

Me

Me

The Kocienski modification of the Julia–Lythgoe olefination allows for the removal of the one-electron reductant through use of a benzothiazole sulfone. The first step is the same as with the standard Julia–Lythgoe protocol. Deprotonation α to the sulfone and addition to the aldehyde occur to generate a metal alkoxide, which adds to the thiazole to generate an intermediate that collapses to give the desired olefin.

N S

O S O

N

Me (i) PhCHO

S

(ii) n-BuLi

O

S

O

−O

S

Li+ −

Ph

O

Me

S

O O

Ph

N Me

Ph

Me

Waykole and coworkers at Novartis found two procedural changes that are key for achieving the Kocienski modification of the Julia olefination for their substrates: heating the reaction post sulfone addition to the aldehyde and addition of an additive such as TMSCl or BF3 ⋅Et2 O.196 Initial experiments showed less than 10% conversion to the desired olefin, although the aldehyde was consumed. While heating a failed reaction to remove solvent, the group noticed desired product formed, suggesting that elimination (rather than addition) was rate-limiting. This led them to identify the successful modification, which provided the desired alkene in 45% yield on 170 g scale. t-Bu

O

O O S N

O S

+

O OMe

H O

O

Me Me

(i) n-BuLi THF, MeCN (ii) TMSCl (iii) H2O (iv) MTBE

O O t-Bu

OMe O

O

Me Me

195 Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. Journal of the American Chemical Society 1993, 115, 30–39. 196 Xu, D. D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee, G. T.; Liu, W.; Szewczyk, J.; Vargas, K.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 2003, 7, 856–865.

111

112

2 Addition to Carbon-Heteroatom Multiple Bonds

Hobson et al. utilized a variant of the Julia–Lythgoe olefination in which a phenyltetrazolyl sulfone served as the nucleophile.197 Examination of several reaction parameters indicated that aging temperature was critical to E:Z selectivity. The optimized process involved metalation with LiHMDS at −70 ∘ C, then warming to −10 ∘ C and aging for one hour prior to quench. With this protocol, an average yield of 80% with 99.9 area % purity was realized on 27 kg scale (>100 : 1 E:Z selectivity).

F

H

O

Me Me Me Me

Me Me

N

N

CO2tBu

O

N N

O

O S O

+

Me

Ph N

Me

N

CO2tBu

O (i) LiHMDS THF −70 to 0 °C

F

Me

(ii) 10% Aq KHCO3 (iii) EtOH, H2O (3 : 2) 74%

N N

O

Me N

N N

N

Me

Me

A similar tetrazolyl sulfone was used in the synthesis of (−)-leiocarpin A. Interestingly, the use of LiHMDS was critical to obtaining a high E/Z ratio (92 : 8). Sodium or potassium bases led to diminished E/Z ratios.198 Me

Me

Ph O O O S N N N N

O

O

+

Ot-Bu

O Ph

Me

LiHMDS/THF

O

THF, −75 °C, 2 h

H

Me O

O

Ph

Ot-Bu

85%, E/Z 92:8

The synthesis of a key Z-trisubstituted olefin intermediate toward phormidolides B and C was efficiently accomplished by the reaction of a 1-(t-butyl)tetrazolyl sulfone with an appropriately substituted aldehyde.199 TBDPSO TBSO

O Me N N N N

O

OTIPS Me

+

S O O t-Bu

O t-BuO

OTIPS O H

LDA, THF, rt HMPA (additive) 61%, Z/E 97:3

TBDPSO TBSO

OTIPS Me

Me

t-BuO O

OTIPS

2.22 Tebbe Methylenation The Tebbe reagent, which can be made from trimethylaluminum and dicyclopentyl titanocene, is used for methylenation of an aldehyde, ketone, ester, or amide.200 There are a few advantages to the Tebbe Lewis acid reagent. The reagent is highly reactive and can be used with sterically demanding substrates. It can also be used to olefinate carbonyls with an α-stereocenter without epimization. Another added benefit is the trade of phosphine oxide side products common to the Wittig and Horner–Emmons olefinations for titanium oxide. A modification was made by Petasis in the production of the titanocene reagent by replacing trimethyl aluminum (original Tebbe) with methyl lithium. This reagent procedure produces a reagent with similar reactivity but better handling and storage properties.201 The next two examples showcase the ability of the Tebbe reagent to accomplish methylenation of hindered and sensitive substrates. In the first example, the Sinay group append their hindered glycoside using the Tebbe reagent.202 197 Hobson, L. A.; Akiti, O.; Deshmukh, S. S.; Harper, S.; Katipally, K.; Lai, C. J.; Livingston, R. C.; Lo, E.; Miller, M. M.; Ramakrishnan, S.; Shen, L.; Spink, J.; Tummala, S.; Wei, C.; Yamamoto, K.; Young, J.; Parsons, R. L. Organic Process Research & Development 2010, 14, 441–458. 198 Meruva, S. B.; Rao K, R.; Mohammed, A.; Dahanukar, V. H.; Kumar, U. K. S.; Dubey, P. K. Synthetic Communications 2016, 46, 187–196. 199 Lorente, A.; Albericio, F.; Álvarez, M. The Journal of Organic Chemistry 2014, 79, 10648–10654. 200 Cannizzo, L. F.; Grubbs, R. H. The Journal of Organic Chemistry 1985, 50, 2386–2387. 201 Petasis, N. A.; Bzowej, E. I. Journal of the American Chemical Society 1990, 112, 6392–6394. 202 Marra, A.; Esnault, J.; Veyrieres, A.; Sinay, P. Journal of the American Chemical Society 1992, 114, 6354–6360.

2.23 The Mannich Reaction

The acetate was dissolved in 5 : 1 pyridine:THF, cooled to −60 ∘ C, treated with the Tebbe reagent, and warmed to 0 ∘ C. Following quench and workup, the desired product was isolated in excellent yield. OBn

pyr, THF (5 :1) CP2TiMe2

O

BnO BnO

OBn

O

O

Toluene −60 to 0 °C

Me

OBn O

BnO BnO

OBn

O Me

90%

In the second example, Howell and Blauvelt were able to methylenate a challenging β-lactone substrate.203 The lactone substrate in toluene was treated with the Tebbe reagent, and after precipitation of titanium by-products, the product was purified by silica gel chromatography. This is an impressive reaction because it has an α-stereocenter, is hindered by the trityl group, and is sensitive to ring opening.

TrHN

O

Cp2TiMe2

O

TrHN

Toluene, 80 °C

O

CH2

60%

Using the Petasis modification of Tebbe reagent formation, the Merck team utilized methyl magnesium chloride and dichlorocyclopentadienyl titanocene for effective production of the necessary dimethyltitanocene reagent.204 Payack et al. used the Petasis-modified Tebbe reaction for the preparation of aprepitant. The olefination was clean in this case, but excess Tebbe reagent caused product deterioration if it was not quenched immediately. This issue was overcome by addition of a small amount of sacrificial ester to intercept excess Tebbe reagent. The reaction was quenched and filtered through diatomaceous earth (to remove titanium by-products) to provide a 91% yield of the desired enol ether. CF3 O

CF3

CF3 O

O

CF3 O

Cp2TiMe2 Toluene, 80 °C

N Ph

91%

F

O

N Ph

F

In the following example, treatment of the α-benzyloxy ketone with Tebbe reagent provided a mixture of diastereomers epimeric at the benzyloxy center. The temperature and order of addition were deemed important: addition of Tebbe reagent to the ketone at −78 ∘ C resulted in a 1 : 1 ratio of epimers, while the addition of the ketone to the Tebbe reagent at ambient temperature minimized epimerization (9 : 1 ratio of epimers observed).205 OBn O Et

Me O Et

O

12

OBn

Tebbe reagent (2 equiv) rt, 6 h 81%, 9 : 1

O Et

OBn Me

O Et

12

+

O Et

Me O

12

Et

2.23 The Mannich Reaction The Mannich reaction is the condensation of a carbonyl compound, an amine and a carbon nucleophile. The nitrogen nucleophile may be a primary or secondary amine, or ammonia; however, anilines do not participate in the Mannich 203 Blauvelt, M. L.; Howell, A. R. The Journal of Organic Chemistry 2008, 73, 517–521. 204 Payack, J. F.; Huffman, M. A.; Cai, D.; Hughes, D. L.; Collins, P. C.; Johnson, B. K.; Cottrell, I. F.; Tuma, L. D. Organic Process Research & Development 2004, 8, 256–259. 205 Lu, X.; Arthur, G.; Bittman, R. Organic Letters 2005, 7, 1645–1648.

113

114

2 Addition to Carbon-Heteroatom Multiple Bonds

reaction. The carbon nucleophile is typically a second carbonyl compound with an enolizable α-proton. The reaction proceeds via activation of the aldehyde via formation of a Schiff base with the nitrogen nucleophile, followed by attack of the carbon nucleophile to afford the product, as described in the scheme following scheme.

O R1

R3

H N

R3

R4

R2

R4

N

R1

O

R6

R5

R4 R3 N O 2 R R1 R5 6 R

H

R2

The simplest manifestation of the Mannich reaction entails stirring a nucleophilic amine, paraformaldehyde, and an enolizable carbon nucleophile in the presence of an acid at an elevated temperature. A few representative examples are given here.206,207,208 Me2NH • HCl (CH2O)n

O

S

Me

O

S

i-PrOH aq HCl

NMe2

88%

I BnHN O

I

O

(CH2O)n

N Bn

AcOH, HCl 100%

Me2NH•HCl (CH2O)n

O Me

O NMe2

EtOH Conc. HCl 83%

The Mannich reaction was used to construct the core for the manufacture of carmegliptin. In this sequence, the cyclic anhydride was converted to 3-oxo-glutaric acid mono methyl ester and then treated with the iminium hydrochloride to furnish the 2-substituted-tetrahydroisoquinoline after decarboxylation. Using formaldehyde, followed by treatment of the adduct with NH4 OAc provided the racemic core for further elaboration to carmegliptin.209 MeO O

O

O

O

EtOH, heptane O

HO2C

rt

CO2Et

MeO

MeO

N

CO2Et MeO

NH • HCl

MeO

OH CO2Et

MeO

NaOAc, MeOH/H2O, rt 81–86%

NH2

O

N•HCl

CO2Et

NH4OH MeOH, 50 °C 70% in 2 steps

MeO

N

aq HCHO MeOH/H2O, rt

MeO

206 Fujima, Y.; Ikunaka, M.; Inoue, T.; Matsumoto, J. Organic Process Research & Development 2006, 10, 905–913. 207 Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. Journal of the American Chemical Society 2003, 125, 1587–1594. 208 Kellogg, R. M.; Nieuwenhuijzen, J. W.; Pouwer, K.; Vries, T. R.; Broxterman, Q. B.; Grimbergen, R. F. P.; Kaptein, B.; La Crois, R. M.; de Wever, E.; Zwaagstra, K.; van der Laan, A. C. Synthesis 2003, 1626–1638. 209 Abrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes, A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Organic Process Research & Development 2011, 15, 503–514.

2.24 The Strecker Reaction

Several excellent examples of intramolecular Mannich condensations can be found in Heathcock’s synthesis of lycopodium alkaloids. In the following scheme, treatment of the amino bis-acetal starting material with HCl led to acetal hydrolysis followed by an intramolecular Mannich reaction to produce the tricyclic aminoketone in 63% yield.210 O

O 3 N HCl

H2N

O

MeOH 14 d

Me

O

Me

N H O

63%

Recent advances in the development of asymmetric versions of the Mannich reaction have been extensively reviewed.211,212 An asymmetric Mannich reaction was utilized to set the stereocenter in the synthesis of ipatasertib. Treatment of the Evans’ oxazolidinone adduct with an iminium generated in situ from the N-Boc aminal led to the Mannich product in high diastereoselectivity.213

Cl

O

O N

Bn

O

(i) TiCl4 (in toluene) DIPEA, CH2Cl2, −20 °C

Cl

O N

(ii) CH2Cl2, –20 °C Me MeO

O

BocN

Bn

Me

N Me Boc

O

(i) LiOH, 30% H2O2 THF/H2O, 0 °C

Cl

(ii) Aq Na2SO3, Aq KHSO4 (iii) toluene

O OH BocN Me

Me

> 20 :1 dr

2.24 The Strecker Reaction The Strecker synthesis can be viewed as a variant of the Mannich reaction (2.39), where cyanide plays the role of the carbon nucleophile. The original Strecker reaction was a “one-step” method using ammonia as the nitrogen source, where all three components were mixed together at the start of the reaction. More recent versions of this reaction involve preformation of the imine (using amines), followed by addition of the cyanide nucleophile. The Strecker reaction is perhaps the oldest known nonbiosynthetic method to synthesize α-amino acids. These compounds are formed by hydrolysis of the intermediate α-aminonitrile. O R1

R3NH2 R2

HCN

R2 R1

NHR3 CN

Hydrolysis

R2 R1

NHR3 COOH

R3NH2 R3 R1

HCN N R2

One of the simplest methods to carry out the Strecker reaction is to combine the carbonyl compound and the amine with a cyanide source (preferably KCN or NaCN), and stir the mixture until the product is formed. A nice example of the use of the Strecker reaction was provided by Mehrotra et al.214 210 Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S. Journal of the American Chemical Society 1982, 104, 1054–1068. 211 Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chemical Reviews 2007, 107, 5471–5569. 212 Shi, Y.; Wang, Q.; Gao, S. Organic Chemistry Frontiers 2018, 5, 1049–1066. 213 Remarchuk, T.; St-Jean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.; Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Organic Process Research & Development 2014, 18, 1652–1666. 214 Mehrotra, M. M.; Heath, J. A.; Smyth, M. S.; Pandey, A.; Rose, J. W.; Seroogy, J. M.; Volkots, D. L.; Nannizzi-Alaimo, L.; Park, G. L.; Lambing, J. L.; Hollenbach, S. J.; Scarborough, R. M. Journal of Medicinal Chemistry 2004, 47, 2037–2061.

115

116

2 Addition to Carbon-Heteroatom Multiple Bonds

O

KCN MeNH2 MeOH H2O 94%

N Ph

MeHN CN

N Ph

A slight variation of this procedure was used for the reaction of (R)-phenylglycinol with KCN and glutaraldehyde.215

Ph

OH NH2

+

OHC

CHO

(i) KCN aq citric acid CH2Cl2

Ph NC

(ii) ZnBr 2

N

O

65–70%

The use of alkali metal cyanides invariably necessitates the use of water, and this can be deleterious in some cases. For example, in the synthesis of carfentanil, it was found that the α-aminonitrile (formed via the reaction of N-benzyl-4-piperidone with aniline and KCN in aqueous acetic acid) underwent a retro-Strecker reaction when heated in the presence of aqueous acid. Under these conditions, only 71% of the desired product was isolated; however, the use of trimethylsilyl cyanide (TMSCN) in glacial acetic acid (anhydrous conditions) furnished the product in 81% yield. The difference in yields was more pronounced when 2-fluoroaniline was used as the amine component. The aqueous Strecker afforded the product in 12% yield, while the anhydrous modification yielded 72% of the desired product.216 O

TMSCN PhNH2

PhHN CN

N

AcOH

N

81%

Ph

Ph

Lewis acids are also known to promote the formation of α-aminonitriles from ketones. A diastereoselective Strecker reaction was performed on a highly substituted cyclopentanone using NH3 , Ti(Oi-Pr)4 and TMSCN.217 Ph Ph

OH

F CO2Me

O O

H

NH3/MeOH Ti(O-i-Pr)4 TMSCN 80%

Ph Ph

OH O

F CONH2

H H2N CN

Several asymmetric modifications of the Strecker reaction have been developed and utilized to synthesize a host of optically enriched, structurally diverse unnatural α-amino acids. These nonproteinogenic amino acids have found extensive use as key building blocks in the pharmaceutical industry. Recent developments in the area of catalytic enantioselective Strecker reactions have been chronicled in reviews.218,219 Jacobsen and coworkers developed an asymmetric version of the Strecker reaction using amido-thiourea catalysts for the synthesis of enantiomerically enriched nonnatural amino acids. For instance, treatment of the pivalaldehyde-derived imine with KCN and the amido-thiourea catalyst, followed bynitrile hydrolysis, and Boc protection led to Boc-protected (R)-tert-leucine in >98% ee.220

215 216 217 218 219 220

Bonin, M.; Grierson, D. S.; Royer, J.; Husson, H. P. Organic Syntheses 1992, 70, 54–59. Feldman, P. L.; Brackeen, M. F. The Journal of Organic Chemistry 1990, 55, 4207–4209. See Note 19. Groeger, H. Chemical Reviews 2003, 103, 2795–2827. Wang, J.; Liu, X.; Feng, X. Chemical Reviews 2011, 111, 6947–6983. Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461, 968.

2.25 Hydrolysis of Carbon–Nitrogen Double Bonds

Catalyst (0.5 mol%) KCN, AcOH

Ph N t-Bu

Ph

H2O, toluene 0 °C, 4–8 h

H

Ph HN t-Bu

Ph CN

(i) H2SO4, HCl, 44–68 h (ii) NaOH, NaHCO3, (iii) Boc2O, dioxane,16 h (iv) Recrystallize

Me N Me

O

t-Bu

CO2H

65% (2 steps) 99% ee

CF3 Me

NHBoc

t-Bu S N H

N H

CF3

Catalyst

2.25 Hydrolysis of Carbon–Nitrogen Double Bonds The carbon–nitrogen double bond can be hydrolyzed to a carbon–oxygen double bond by the reaction of the substrate in aqueous acidic, aqueous basic, or under oxidative conditions. The oxidative methods will not be covered here; some examples are the use of pyridinium dichromate(PDC), o-iodoxybenzoic acid (IBX), Dess–Martin periodinane, and ozone (see Chapter 10 for C—N oxidation strategies). The ease of hydrolysis varies with the substitution on the nitrogen and also on the ability of the substrate to tolerate changes in pH. In general, it is more difficult to convert hydrazones and oximes back to the respective aldehyde and ketone than imines. In the first example, after the Friedel–Crafts reaction with the sesamol nitrile, the resultant imine is converted to the ketone by heating an acidic aqueous solution for a few hours.221 OH

O NC

O

HO

OH

OH

HCl, ZnCl2

NH

O O

HO

OH

OH O

10% HCl 80% 2 steps

O O

HO

OH

It can be difficult to maintain the imine functionality unless rigorous care is taken to maintain an anhydrous environment. As with other generally sensitive functionality such as acid chlorides, some compounds in this class are more hydrolytically stable and can even be chromatographed. A common method for the hydrolysis of hydrazones or oximes involves the use of a transfer agent. In the following examples, acetone and formaldehyde are used to trap the hydrazine or hydroxylamine when they are released from the substrate of interest. This works well when two factors are present: (i) The substrate can tolerate exposure to an abundance of the sacrificial aldehyde or ketone (formaldehyde or acetone in this case) without deleterious side reactions, and (ii) there is an easy method for separation of the acetyl or formyl by-product after the reaction. In the first example, the Fuchs group used boron trifluoride etherate and acetone to effect the transfer of the tosyl hydrazone to the acetyl hydrazone.222 The tosyl hydrazone by-product was easily removed by precipitation with hexanes or through degradation and separation by stirring with a basic aqueous wash. Tos N

NH

BF3•OEt 2

O

Acetone, H2O 94%

Another option is the use of a formaldehyde trap in a binary aqueous hydrochloric acid/THF solution.223 This reaction was stirred at room temperature with a 35% HCl solution until completion. The product may then be isolated by extraction. 221 Hastings, J. M.; Hadden, M. K.; Blagg, B. S. J. The Journal of Organic Chemistry 2008, 73, 369–373. 222 Sacks, C. E.; Fuchs, P. L. Synthesis 1976, 456–457. 223 Severin, T.; Lerche, H. Synthesis 1982, 305–307.

117

118

2 Addition to Carbon-Heteroatom Multiple Bonds

OBn

N EtO

CH2O, HCl

O EtO

H2O, THF

Me O

Me O

79%

When functionality is present that is sensitive to strongly acidic or basic reagents, there are other options available for oxime or hydrazone hydrolysis. Mildly acidic reagents (i.e. pH 4–7) may be used for hydrolysis. In the first example, Ziegler and Becker was able to successfully degrade the Enders (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) hydrazone using copper acetate in THF and water.224 The subsequent ketone was isolated in moderate yield after distillation. In the second example, the hydrazone was converted to the aldehyde in excellent yield by treatment with CuCl2 .225 Et Et Me

Me

N N

Me F3C Ts

N H

Et

Cu(OAc)2 OMe

Et

H 2O

O Me

Me

Me F3C

O

56% O CuCl2 t-BuOH, H2O

N

OHC

95%

OMe

OMe

Likewise, Mitra and Reddy was able to reveal the latent ketone in the alkenyl hydrazine depicted in the following scheme. This substrate and others with THP and acetal functionality were stirred in THF/water (10/1 v/v) with silica gel at room temperature.226 The reaction was then concentrated to dryness, and the product (absorbed onto the sililca gel) was chromatographed to give the desired product. N Me

NMe2

O

Silica gel Me

Me

THF, H2O

Me

73%

One final example shows the use of dichloramine-T (N,N-dichloro-4-toluenesulfonamide, DCT). This slightly acidic solution allowed the removal of the oxime without scrambling of the (E)-α,β-unsaturated system.227 O O S NCl2 Me (dichloramine-T) H

N OH

MeCN, H2O

H

O

79%

2.26 Conversion of Carboxylic Acids to Acyl Chlorides This section will deal with the synthesis of acid chlorides from carboxylic acids; the synthesis of acyl bromides and iodides will not be discussed in this chapter, while the synthesis of acyl fluorides is discussed in Section 2.27. One of 224 225 226 227

Ziegler, F. E.; Becker, M. R. The Journal of Organic Chemistry 1990, 55, 2800–2805. Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Organic Process Research & Development 2007, 11, 1015–1024. Mitra, R. B.; Reddy, G. B. Synthesis 1989, 694–698. Gupta, P. K.; Manral, L.; Ganesan, K. Synthesis 2007, 1930–1932.

2.26 Conversion of Carboxylic Acids to Acyl Chlorides

the most common methods to activate carboxylic acids toward nucleophilic attack at the carboxyl center is to convert them to acyl halides, generally acyl chlorides. The reaction is typically performed by treatment of the carboxylic acid with a halogenating agent such as thionyl chloride or oxalyl chloride, optionally with a catalytic amount of dimethylformamide. Vilsmeier reagent (derived from reaction of thionyl chloride or oxalyl chloride with dimethylformamide) has also been used. Representative examples and relative merits of these protocols are discussed in the following sections.

2.26.1

Procedures Using Oxalyl Chloride in the Absence of DMF

It is generally possible to treat a carboxylic acid with oxalyl chloride in an organic solvent to form the acid chloride. The advantage of using oxalyl chloride is that by-products of the reaction (CO, CO2 , and HCl) are volatile and can be easily removed from the reaction mixture. In any event, they rarely interfere with subsequent reactions of the acid halides, rendering oxalyl chloride one of the top reagents of choice to effect this transformation. Interestingly, DBU has been found to be an effective catalyst for this transformation. Treatment of the carboxylic acid with 2 equiv of oxalyl chloride and 0.06 equiv of DBU in THF at room temperature led to clean conversion to the acid chloride (yield not mentioned). Subsequent reaction of the acid chloride with hydroxylamine furnished the hydroxamic acid in 61% overall yield after recrystallization.228 Me

Me

Me

OH

O

S ON

O

Me Cl

O

S ON

(COCl)2, DBU

Me O

O

S ON

aq NH2OH

OH

O

61% overall

THF O

Me H N

O

O

O

O

O

Acid chlorides are rarely isolated but are rather carried on directly to the subsequent transformation (most often reaction with amines or alcohols to produce amides or esters). However, in the following scheme, the hydrochloride salt of the pyrrolidine acid was converted to the hydrochloride salt of the corresponding acid chloride, which was isolated after crystallization from THF.229 O N •HCl

(i) (COCl)2, CH2Cl2, 30 °C OH

(ii) THF (dry), 0 °C

O N •HCl

Cl

90%

2.26.2

Procedures Using Thionyl Chloride in the Absence of DMF

In general, treatment of carboxylic acids with thionyl chloride affords the corresponding acyl chlorides. The by-products of the reaction are SO2 and HCl. The reaction can be carried out in the absence of an organic co-solvent (i.e. in neat thionyl chloride).230 The excess thionyl chloride can be conveniently removed from the reaction mixture by distillation due to its relatively low boiling point (79 ∘ C), thereby avoiding complications in subsequent steps. Cl Me

Cl

SOCl2 CO2H

Cl

Me O

Cl

L-Glutamine

82% overall

H N

Me O

CONH2 CO2H

228 Frampton, G. A.; Hannah, D. R.; Henderson, N.; Katz, R. B.; Smith, I. H.; Tremayne, N.; Watson, R. J.; Woollam, I. Organic Process Research & Development 2004, 8, 415–417. 229 Ronn, M.; Zhu, Z.; Hogan, P. C.; Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D. K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, X.-Y. Organic Process Research & Development 2013, 17, 838–845. 230 Sano, T.; Sugaya, T.; Inoue, K.; Mizutaki, S.-I.; Ono, Y.; Kasai, M. Organic Process Research & Development 2000, 4, 147–152.

119

120

2 Addition to Carbon-Heteroatom Multiple Bonds

The reaction has also been carried out in organic solvents such as THF, as exemplified here.231 O N

HO Me

NH

1.5 equiv. SOCl2 THF, rt ~100%

O Me

O N

Cl Me

NH

O Me

This transformation may also be carried out in the presence of a base. In the following example, the acid chloride was synthesized by treating the carboxylic acid with thionyl chloride and TEA in toluene/methyl-t-butyl ether (MTBE). The acid chloride was taken on to the Boc-protected amine via a Curtius rearrangement (see Section 7.2.3.2) in 73% overall yield.232 SOCl2, Et3N HO2C CO2t-Bu

PhCH3/MTBE

ClOC CO2t-Bu

BocHN CO2t-Bu 73% overall

In the following example, the thionyl chloride reaction was originally carried out in ethyl acetate, followed by reaction of the acid chloride with an amine under Schotten–Baumann conditions. Since hydrolysis of ethyl acetate was a major problem in the Schotten–Baumann reaction, the authors switched to iso-propyl acetate for both of the transformations.233 CO2Bn CO2Bn

CO2Bn HN

O

SOCl2, i-PrOAc 76–82 °C, 1 h O

OH

K2CO3-H2O O

Cl

85%

N

Me Me

O

N N

Me Me

O

It is to be noted that the use of SOCl2 in MTBE in the absence of a base is particularly hazardous. The HCl liberated in reactions using SOCl2 could lead to decomposition of MTBE and generate iso-butylene gas.234 2.26.3

Procedures Using a Halogenating Agent and DMF

A small amount of N,N-dimethylformamide (DMF) typically catalyzes the reaction of a carboxylic acid with a chlorinating agent such as oxalyl chloride or thionyl chloride. This is presumably due to the in situ generation of the Vilsmeier reagent (see Section 2.26.4). One major drawback of utilizing DMF in chlorodehydroxylation reactions is the unwanted coproduction of dimethylcarbamoyl chloride (DMCC). This compound is a known animal carcinogen and a potential human carcinogen.235 Due to these toxicological concerns, adequate containment measures must be taken while performing reactions involving DMF and chlorinating agents, especially in the pharmaceutical industry. With that note of caution, here are a few examples of reactions using this reagent combination. 231 Stoner, E. J.; Stengel, P. J.; Cooper, A. J. Organic Process Research & Development 1999, 3, 145–148. 232 Varie, D. L.; Beck, C.; Borders, S. K.; Brady, M. D.; Cronin, J. S.; Ditsworth, T. K.; Hay, D. A.; Hoard, D. W.; Hoying, R. C.; Linder, R. J.; Miller, R. D.; Moher, E. D.; Remacle, J. R.; Rieck, J. A., III; Anderson, D. D.; Dodson, P. N.; Forst, M. B.; Pierson, D. A.; Turpin, J. A. Organic Process Research & Development 2007, 11, 546–559. 233 Bret, G.; Harling, S. J.; Herbal, K.; Langlade, N.; Loft, M.; Negus, A.; Sanganee, M.; Shanahan, S.; Strachan, J. B.; Turner, P. G.; Whiting, M. P. Organic Process Research & Development 2011, 15, 112–122. 234 Grimm, J. S.; Maryanoff, C. A.; Patel, M.; Palmer, D. C.; Sorgi, K. L.; Stefanick, S.; Webster, R. R. H.; Zhang, X. Organic Process Research & Development 2002, 6, 938–942. 235 Levin, D. Organic Process Research & Development 1997, 1, 182.

2.26 Conversion of Carboxylic Acids to Acyl Chlorides

In the following two examples, oxalyl chloride was used in the presence of catalytic DMF to convert the acids to the corresponding acyl chlorides.236,237 N O N

HO

O O S

O

(COCl)2 DMF (cat)

N

Cl

O

O O S

CO2Et

CO2H

DMF (cat.) 2-MeTHF

CO2Et

H2N CONMe2 Me

Hunig’s base 2-MeTHF

COCl

Me

CF3

CO2Et

(COCl)2 Me

O

Me

CF3

O O S OEt

74% overall

O

CF3

N

N H

(ii) HCl, EtOH

OEt

Me

HO

(i) NH2OH (aq)

THF

OEt O

N

N

O Me

CO2Et N H

CONMe2

CF3

O Me

CO2H N H

(i) 1 N NaOH, 5 min (ii) 2 N HCl (pH 1–2) 85% (over 3 steps)

CONMe2

Reaction of alkali metal carboxylate salts with (COCl)2 and DMF also provides the acyl chlorides in quantitative yields.238 N N Me

O

OK

Me

MeCN, 0–5 °C

O

N N

(COCl)2, DMF (cat.)

O

Cl O

100%

Clean conversion to the acid chloride can also be achieved using SOCl2 in the presence of catalytic DMF in toluene, as exemplified by the following scheme. Since the acid chloride was being converted to the amide under Schotten–Baumann conditions (using aqueous NaOH) in the next step, it was not necessary to remove the excess thionyl chloride after the acid chloride formation.239 Cl OH OH O Me

N Me

Cl

SOCl2 DMF (cat)

Cl

N Me

NH2 Cl

Toluene Me

O Me

O

Toluene pH ≥ 7.5 88% overall

NH Me

O

O

Me

236 Slade, J. S.; Vivelo, J. A.; Parker, D. J.; Bajwa, J.; Liu, H.; Girgis, M.; Parker, D. T.; Repic, O.; Blacklock, T. Organic Process Research & Development 2005, 9, 608–620. 237 Eisenbeis, S. A.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. Organic Process Research & Development 2015, 19, 244–248. 238 Humphrey, G. R.; Pye, P. J.; Zhong, Y.-L.; Angelaud, R.; Askin, D.; Belyk, K. M.; Maligres, P. E.; Mancheno, D. E.; Miller, R. A.; Reamer, R. A.; Weissman, S. A. Organic Process Research & Development 2011, 15, 73–83. 239 Burks, J. E., Jr.; Espinosa, L.; LaBell, E. S.; McGill, J. M.; Ritter, A. R.; Speakman, J. L.; Williams, M.; Bradley, D. A.; Haehl, M. G.; Schmid, C. R. Organic Process Research & Development 1997, 1, 198–210.

121

122

2 Addition to Carbon-Heteroatom Multiple Bonds

2.26.4

Procedures Using Vilsmeier Reagent

The reaction of DMF with a halogenating agent such as SOCl2 , POCl3 , or oxalyl chloride leads to formation of Vilsmeier reagent (N,N-dimethylchloromethyleneammonium chloride). This reagent is commercially available and has been used in the conversion of carboxylic acids to acid chlorides. A representative example is provided here.240 OMe

OMe H

OH O

BnO

Cl N

Me

+

Cl

H2N

−

Me

Cl

THF, 0 °C

O

BnO

OMe

O NHMe t-Bu N-Methylmorpholine THF, 23 °C

H N BnO

O

O NHMe t-Bu

98% overall

2.27 Synthesis of Acyl Fluorides from Carboxylic Acids One of the most commonly used reagents for the conversion of carboxylic acids to acyl fluorides is DAST.241 The reaction is carried out at near-ambient conditions. Fmoc

H N

O OH

DAST, pyridine CH2Cl2

Me

Fmoc

O F

Me

80%

Me

H N

Me

One major drawback with DAST is its well-documented thermal instability. From this perspective, bis(2-methoxyethyl) aminosulfur trifluroide (Deoxo-Fluor) is a better choice due to its enhanced thermal stability.242 O

O Deoxo-Fluor

OH

F

CH2Cl2 96%

Efficient conversion of acids to acyl fluorides can also be achieved using 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride).243 F Me

Me OH

BocHN O

N F

N N

F

Pyridine, CH2Cl2 97%

Me

Me F

BocHN O

Aminodifluorosulfinium tetrafluoroborate salts in conjunction with an exogenous fluoride source (Et3 N⋅3HF in this case) are efficient deoxofluorinating reagents that can provide acyl fluorides from carboxylic acids. These salts are crystalline and exhibit enhanced thermal stability over dialkylaminosulfur trifluorides. In addition, they do not react violently with water, unlike DAST and Deoxo-Fluor.244 240 241 242 243 244

Koch, G.; Kottirsch, G.; Wietfeld, B.; Kuesters, E. Organic Process Research & Development 2002, 6, 652–659. Wipf, P.; Wang, Z. Organic Letters 2007, 9, 1605–1607. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. The Journal of Organic Chemistry 1999, 64, 7048–7054. Suaifan, G. A. R. Y.; Mahon, M. F.; Arafat, T.; Threadgill, M. D. Tetrahedron 2006, 62, 11245–11266. Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A. Organic Letters 2009, 11, 5050–5053.

2.28 Formation of Amides from Carboxylic Acids

Et O Ph

Et OH

−

+

BF4

N SF2

O Ph

Et3N•3HF, CH2Cl2

F

94%

A particularly convenient protocol for the transformation of aliphatic and aromatic carboxylic acids to acyl fluorides involves the use of (Me4 N)SCF3 . The reagent is a bench-stable solid, and the reactions are carried out at ambient temperature.245 O

+

F3C S

OH

CH2Cl2

− +

NMe4

O

rt, 0.5–1 h

(1.2 equiv)

F

89%

A recent report details the development of a practical method for the conversion of carboxylic acids to acyl fluorides. This protocol employed Ph3 P, N-bromosuccinimide (NBS), and Et3 N⋅HF; Brønsted acidic conditions were found to be essential for this transformation.246 Me

Me

Me

Me

(i) PPh3/NBS, CH2Cl2 0 °C to rt, 15 min OH (ii) Et N•3HF, CH Cl , rt, 2 h 3 2 2

Me O

80%

Me

Me

Me

Me

F

Me O

2.28 Formation of Amides from Carboxylic Acids Amides may be formed either by direct coupling of carboxylic acids (by activation in situ) with amines or in a two step process via activation of the carboxylic acid followed by reaction of an amine with the activated intermediate. 2.28.1

Direct Coupling of Carboxylic Acids and Amines

Carbodiimides such as dicyclohexylcarbodiimide (DCC) are the most commonly utilized class of reagents for the direct coupling of acids and amines. The major drawback with these reagents is the formation of urea by-products that are typically separable only by chromatography. This problem can be alleviated by the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC),247 wherein the urea by-product is water soluble and can be conveniently removed through extractive workup or a water wash. In most cases, these reactions require catalysis by 1-hydroxybenzotriazole (HOBt). Thus, the need to use a stoichiometric amount of EDC, coupled with the known hazards of HOBt,248 makes this protocol less desirable for large-scale applications. F HN

O

O OH

HN

+

EDC, HOBt DMAP, DMA

H N

H2N

CO2Bn

O

EDC =

Me

N Me

• HCl

C

N

Me

O

O N H

77%

N

HN

0 to 5 °C HN

CO2Bn

N

F

HOBt =

O HN

CO2Bn

N N

CO2Bn

N N OH

245 Scattolin, T.; Deckers, K.; Schoenebeck, F. Organic Letters 2017, 19, 5740–5743. 246 Munoz, S. B.; Dang, H.; Ispizua-Rodriguez, X.; Mathew, T.; Prakash, G. K. S. Organic Letters 2019, 21, 1659–1663. 247 Ormerod, D.; Willemsens, B.; Mermans, R.; Langens, J.; Winderickx, G.; Kalindjian, S. B.; Buck, I. M.; McDonald, I. M. Organic Process Research & Development 2005, 9, 499–507. 248 Dunn, P. J.; Hoffmann, W.; Kang, Y.; Mitchell, J. C.; Snowden, M. J. Organic Process Research & Development 2005, 9, 956–961.

123

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2 Addition to Carbon-Heteroatom Multiple Bonds

In an interesting application, the EDC/HOBt conditions were used in conjunction with a surfactant in water to selectively convert unprotected amino alcohols to amides via reaction with carboxylic acids. These conditions obviate the need to protect the hydroxy functionality prior to the amidation reaction.249 O

OH

NH2 OH

+

EDC (1.5 equiv), HOBt (1.2 equiv) NMI (3.0 equiv)

OH

TPGS-750-M 2 wt% in H2O (0.25 M) 40 °C, 20 h

Br

95%

=

O

MeO

O

O n n = ~15

Hydrophilic

Br

Me

O TPGS-750-M

H N

O

Me

O Me

Me

Me

Me Me

Me

Linker

Lipophilic

Another example of selective reaction of an amine with a carboxylic acid in the presence of multiple unprotected functionalities is provided in the following scheme. Amphotericin B was coupled with (l)-histidine methyl ester dihydrochloride, in the presence of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) to produce the corresponding amide. This procedure was successfully carried out on a 100 g scale.250 OH Me HO

O O Me

OH OH

O OH

OH

OH OH O

Me

N Me

O

HO

OH NH2

OH OMe

OH O

O

H2N

NH

PyBOP, Et3N DMSO, 23–25 °C, 24 h

Me HO

O O Me

OH OH

OH

OH H N

OH OH O

O OMe

O

Me O

O

HO

97%

Me

N

NH

OH NH2

A particularly convenient and “green” protocol for the synthesis of amides involves the direct reaction of a carboxylic acid and an amine in the presence of catalytic boric acid with azeotropic removal of water. This reaction was shown to be successful with a variety of primary and secondary aliphatic amines as well as anilines.251 Ph

MeHN

O OH

MeO

Ph

+ OBn

Br

86%

MeHN

O

Ph

PhB(OH)2 5 mol%

+

MeO

Ph

Br

86%

MeO

N Me

OBn

O

Xylene, 30 h OBn

OBn

O

Xylene, 30 h

Br

OH MeO

PhB(OH)2 5 mol%

Br

N Me

Tetrakis(dimethylamido)diboron and tetrahydroxydiboron were recently reported as new catalysts for the synthesis of amides from carboxylic acids and amines. This method also relies upon the azeotropic removal of water to push the reaction to completion. In addition to aryl carboxylic acids, this method was also useful for the reaction of N-protected amino acids with aliphatic amines.252 249 Parmentier, M.; Wagner, M. K.; Magra, K.; Gallou, F. Organic Process Research & Development 2016, 20, 1104–1107. 250 Flores-Romero, J. D.; Rodríguez-Lozada, J.; López-Ortiz, M.; Magaña, R.; Ortega-Blake, I.; Regla, I.; Fernández-Zertuche, M. Organic Process Research & Development 2016, 20, 1529–1532. 251 Tang, P. Organic Syntheses 2005, 81, 262–272. 252 Sawant, D. N.; Bagal, D. B.; Ogawa, S.; Selvam, K.; Saito, S. Organic Letters 2018, 20, 4397–4400.

2.28 Formation of Amides from Carboxylic Acids

Me2N Me O BocHN

Me NHBn

+

OH

H2 N

B

B

NMe2 Me

NMe2 Me2N (5 mol%) Dry toluene 7 h, reflux

O

Me NHBn

O BocHN

N H

O

70%

Tetramethyl orthosilicate (TMOS) has also been proven to be an effective reagent for the direct amidation of aliphatic and aromatic carboxylic acids using alkyl and aryl amines. The reaction is facilitated by the distillative removal of methanol and usually provides the product in excellent yields.253 O Me Me Me

OH

H

+

H

H HO

O Me Me

Si(OMe)4

H2N Me

H

N H

H

H HO

93%

H

Me

Toluene reflux, 5 h

H

Me

H

H

POCl3 has also been used for the conversion of carboxylic acids to amides. The reaction does not require any additional base and presumably proceeds via the acid chloride. In the instance shown in the following scheme, treatment of the enantiomerically pure tetrahydroisoquinolone carboxylic acid with 5-amino-2-fluoro-benzonitrile and POCl3 in acetonitrile at reflux led to the efficient formation of the desired amide on a multigram scale.254 CF3 O CF3 O N

POCl3

+ CN

CO2H

N

N

NH2

F

MeCN, reflux

N

O

NH

91% CN F

The use of n-propanephosphonic acid anhydride (T3P) for the direct coupling of acids with amines has gained widespread application in recent years. This reagent is available as a solution in various solvents and is particularly convenient to use on scale. The by-product from this transformation is water soluble and can be easily removed via aqueous washes. Even weakly nucleophilic anilines react efficiently with carboxylic acids under these conditions to furnish amides.255 O OH N N

N

+ H2N

CF3

CO2Bn

N

O 1.5 equiv T3P (50% in EtOAc) 2 equiv pyridine, EtOAc, 0 °C 16–20 h, then aq HCl 85%

N N

CO2Bn

N H

CF3

In an interesting application of this reagent, Petterson et al. utilized T3P to form an amide bond between an optically enriched carboxylic acid and a secondary amine. Heating of the reaction mixture with an excess of T3P also led to dehydration of a primary carboxamide in the molecule to a nitrile functionality in 97% overall yield.256 253 Braddock, D. C.; Lickiss, P. D.; Rowley, B. C.; Pugh, D.; Purnomo, T.; Santhakumar, G.; Fussell, S. J. Organic Letters 2018, 20, 950–953. 254 Wang, Z.; Barrows, R. D.; Emge, T. J.; Knapp, S. Organic Process Research & Development 2017, 21, 399–407. 255 Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Organic Letters 2011, 13, 5048–5051. 256 Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Boehler, E.; Irdam, E.; Osterhout, M. H. Organic Process Research & Development 2009, 13, 900–906.

125

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2 Addition to Carbon-Heteroatom Multiple Bonds

O

H2N HN

O BocHN

H2H O

F (1.1 equiv)

OH

F

BocHN

T3P (1.5 equiv) DIPEA, EtOAc 40–50 °C

F

2.28.2

•TsOH O T3P (1.5 equiv)

N

75–80 °C

F F

CN

O BocHN

F

97% (2 steps)

F

N

F

F

Via Acid Chlorides

A common approach to the synthesis of amides is via the reaction of amines with acid chlorides in the presence of a base. When sodium hydroxide is used as the base, the reaction is called the Schotten–Baumann reaction. Organic bases such as TEA have also been employed in this transformation. In some cases, the reactions are accelerated by the addition of a small quantity of 4-(dimethylamino)pyridine (DMAP). This is a convenient and fairly general method for amide formation when the acid chlorides are readily available (see Section 2.26 for the preparation of acid chlorides from carboxylic acids). Despite the convenience and practicality it affords, this method has a few limitations. The coproduction of HCl in the coupling reaction can lead to undesired side reactions such as unwanted removal of certain acid-labile protecting groups. Moreover, the base used to scavenge the HCl could lead to racemization of enolizable acid chlorides, especially when applied to peptide synthesis where epimerizable centers are abundant. In the following example, the use of a mild base (sodium bicarbonate) led to smooth amidation while preserving stereochemistry and avoiding hydrolysis of the ester functionalities.257 O

OMe

O Me

Cl Me

+

OMe

H2N

O

NaHCO3 DMF, H2O 88%

OMe

O Me Me

O

N H

OMe O

In the following example, the acid chloride was formed in quantitative yield by treatment of the carboxylic acid with thionyl chloride. The amidation reaction was then performed using imidazole as the base.258 The use of imidazole circumvented self-condensation and consequent polymerization of the intermediate acid chloride – a problem observed when several other bases were used. Me O

O N

Cl Me

H N

O Me

NH

Me

O

OH

Ph Me

NH2 Ph

Imidazole, EtOAc, 0 °C to rt

H N

O Me

O

OH

Ph O

Ph

N H Me

N

NH

O Me

87–95%

2.28.3

Via Acyl Imidazoles (Imidazolides)

N,N′ -Carbonyldiimidazole (CDI) is a convenient and widely used reagent for the formation of amides. The carboxylic acid is activated with CDI to produce the intermediate acyl imidazole, which is then coupled with the desired amine in the subsequent step. This protocol was successfully used to synthesize a key intermediate in the manufacture of sildenafil.259 257 Ager, D. J.; Babler, S.; Erickson, R. A.; Froen, D. E.; Kittleson, J.; Pantaleone, D. P.; Prakash, I.; Zhi, B. Organic Process Research & Development 2004, 8, 72–85. 258 See Note 231. 259 Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Organic Process Research & Development 2000, 4, 17–22.

2.28 Formation of Amides from Carboxylic Acids

OEt O OH

(i) CDI, EtOAc reflux (ii)

Me

S O N O

N

OEt O

NH2

O

H2N

N H2N

N Me

N H

Me N

O

Pr

Pr

Me

N

S O O

90%

Since imidazole is produced in this sequence of reactions, there is no need to utilize additional base for the coupling reaction. Moreover, salts of amines may be directly used without the need to generate the free-base prior to the reaction. The by-products of amidations using CDI, namely, imidazole and carbon dioxide, are fairly innocuous. It has been shown that the CO2 evolved in the activation step catalyzes the subsequent amidation step.260,261 Fe(CO)3 O

Me

(i) CDI (ii) HN(Me)OMe, CO2

OH

Fe(CO)3 O

Me

N Me MeO

92%

One minor drawback of the CDI protocol is that acyl imidazoles are slightly less reactive than the corresponding acid chlorides, and hence, couplings involving either sterically hindered carboxylic acids or weakly nucleophilic amines tend to be sluggish. This problem may be overcome by the use of a catalyst such as 2-hydroxy-5-nitropyridine. The safety hazards and efficiencies of such catalysts have been thoroughly investigated.262 The reaction of acyl imidazoles with anilines is catalyzed by imidazole⋅HCl, which functions as a proton source for acid catalysis. This method is particularly useful for electron-deficient anilines.263 O OH

NO2

O

(i) CDI, rt

N H

(ii) Im • HCl, 50 °C, ~5 h NO2

H2N ~90%

An alternative nucleophilic catalysis pathway has also been exploited for this transformation, wherein DBU functions as the nucleophilic catalyst.264 O Ph Me Me

OH

CDI, 2-MeTHF 23 °C

H2N

O Ph Me Me

NO2 DBU

N N

2-MeTHF, 80 °C

O

NO2

Ph

N Me Me H

82%

2.28.4

Via Acyl Imidazolium Ions

A particularly useful method for the synthesis of amides from sterically hindered carboxylic acids and relatively nonnucleophilic amines involves the use of N,N,N′ ,N′ -tetramethylchloroformamidinium hexafluorophosphate (TCFH) in 260 Williams, I.; Kariuki, B. M.; Reeves, K.; Cox, L. R. Organic Letters 2006, 8, 4389–4392. 261 Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas, S. P. The Journal of Organic Chemistry 2004, 69, 2565–2568. 262 Bright, R.; Dale, D. J.; Dunn, P. J.; Hussain, F.; Kang, Y.; Mason, C.; Mitchell, J. C.; Snowden, M. J. Organic Process Research & Development 2004, 8, 1054–1058. 263 Woodman, E. K.; Chaffey, J. G. K.; Hopes, P. A.; Hose, D. R. J.; Gilday, J. P. Organic Process Research & Development 2009, 13, 106–113. 264 Larrivée-Aboussafy, C.; Jones, B. P.; Price, K. E.; Hardink, M. A.; McLaughlin, R. W.; Lillie, B. M.; Hawkins, J. M.; Vaidyanathan, R. Organic Letters 2010, 12, 324–327.

127

128

2 Addition to Carbon-Heteroatom Multiple Bonds

conjunction with N-methylimidazole (NMI). These reactions proceed through the in situ generation and subsequent reaction of highly reactive acyl imidazolium ions. Remarkably, the reactions exhibited a high degree of stereoretention at chiral centers α to the carboxylic acid.265

Me

Me

Ph

− Cl PF6 Me Me + N N Me Me

OH

N

O

Me Ph

N Me

CN

N

Me Ph

Me H N O

O

CH3CN, 23 °C

2.28.5

Me

H2N

Me N+

CN

93%

Acyl imidazolium

Via Anhydrides

Symmetrical anhydrides are rarely used as the acyl component in amide-formation reactions because only one half of the acid is used in the coupling reaction while the other half is “wasted.” This method is attractive only when the anhydride is cheap and commercially available (e.g. acetic anhydride). The reaction of primary amines with cyclic anhydrides leads to imides. The phthalimido group is commonly used as a protecting group for amines and is installed via reaction with phthalic anhydride.266 O

O

O Me

Me

S

CO2Me NH3

+ Cl−

CO2Me

S N

O

O

Et3N toluene 80%

Mixed anhydrides have been widely used to form amides. Mixed anhydrides can be categorized into two types, namely, mixed carboxylic anhydrides and mixed carbonic anhydrides. The most widely used example of a mixed carboxylic anhydride is pivalic anhydride. The carboxylic acid is treated with pivaloyl chloride (trimethylacetyl chloride) in the presence of a base (tertiary amine), and the resultant anhydride is coupled with an amine in the next step. The steric hindrance provided by the t-butyl group forces the amine to react preferentially at the distal carboxyl center, and thus, regioselectivity is obtained.267 Other mixed carboxylic anhydrides are plagued with regioselectivity issues and hence are less commonly used. O

OMe

O n-Bu Me

N H

OH O

O

t-BuCOCl NMM EtOAc

H2N

OMe

CN

O n-Bu Me

O

N

N H

O O

t-Bu O

54%

OMe

O n-Bu Me

N H

H N O

N CN

NMM = N-methylmorpholine

Mixed carbonic anhydrides are extensively used for amide formation. These compounds can be readily accessed by treatment of a carboxylic acid with an alkyl chloroformate in the presence of a base (typically a tertiary amine). Regiochemistry of amine attack is primarily dictated by electronic factors in these cases. The reaction preferentially occurs at the more electrophilic carboxylic site rather than the carbonate site. The by-products from these reactions, namely the hydrochloride salt of the base, CO2 , and the alcohol from the chloroformate, are fairly innocuous and render this protocol attractive for large-scale applications. 265 Beutner, G. L.; Young, I. S.; Davies, M. L.; Hickey, M. R.; Park, H.; Stevens, J. M.; Ye, Q. Organic Letters 2018, 20, 4218–4222. 266 Meffre, P.; Durand, P.; Le Goffic, F. Organic Syntheses 1999, 76, 123–132. 267 See Note 257.

2.28 Formation of Amides from Carboxylic Acids

In a typical reaction, the chloroformate is added to a mixture of the carboxylic acid and the base to form the mixed anhydride, which is treated with an amine in the next step to afford the amide.268 (i) i-BuOC(O)Cl, TEA

O BocHN

OH

Me

O

NH2 • HCl

(ii) MeO2C

BocHN

91%

Me

N H Me

Me

CO2Me

Interestingly, when the same protocol was applied for the following transformation, significant amounts of the symmetrical anhydride were formed in the activation step due to reaction of the carboxylic acid with the activated species. This problem was circumvented by modifying the order of addition: A mixture of the carboxylic acid and base was added to a solution of iso-butylchloroformate in toluene. The choice of base is noteworthy. N,N-Dimethylbenzylamine was extracted from the aqueous layers after the workup, and recycled.269 BocHN

CO2H

(i) i-BuOC(O)Cl N,N-dimethylbenzylamine toluene

O BocHN

N Me

(ii) MeHN 100%

In instances where free hydroxyl groups are also present in the molecule (e.g. mandelic acid), the pivaloyl group can be used as a protecting group for the alcohol functionality while simultaneously activating the carboxylic acid moiety. Treatment of (R)-mandelic acid with excess PivCl led to the hydroxy-protected anhydride, which upon reaction with an amine provided the amide. The hydroxy group was liberated via an aqueous base-promoted deprotection reaction.270 (i) PivCl, Et 3N, CH2Cl2 OH

OH O

H2N (i)

OPiv

OH

NO2

OPiv

(ii) H2O reflux

(ii) aq NaOH

O

O

92%, overall

H N NO2

Another method to form mixed carbonic anhydrides is to treat the carboxylic acid with 2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline (EEDQ). The main disadvantage of this method compared to the chloroformate protocol is the production of stoichiometric quinoline as the by-product. F F

H2N

CO2Bn

+ BocHN

CO2H

EEDQ CH2Cl2 20 °C

CO2Bn

H N

BocHN

CO2Bn

O

92%

CO2Bn

O Me Me

N

O O

EEDQ

Mixed carbonic-sulfonic anhydrides can be synthesized in situ by the treatment of carboxylic acids with sulfonyl chlorides (such as methanesulfonyl- and p-toluenesulfonyl chloride). These intermediates can be converted to amides by 268 Chen, J.; Corbin, S. P.; Holman, N. J. Organic Process Research & Development 2005, 9, 185–187. 269 Prashad, M.; Har, D.; Hu, B.; Kim, H.-Y.; Girgis, M. J.; Chaudhary, A.; Repic, O.; Blacklock, T. J.; Marterer, W. Organic Process Research & Development 2004, 8, 330–340. 270 Zhang, Q.-L.; Zhuang, Z.-Y.; Liu, Q.-D.; Zhang, Z.-M.; Zhan, F.-X.; Zheng, G.-X. Organic Process Research & Development 2016, 20, 1993–1996.

129

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2 Addition to Carbon-Heteroatom Multiple Bonds

reaction with amines. In the following example, the N-protected proline compound was efficiently transformed to an amide via the intermediacy of a mixed carbonic-sulfonic anhydride generated using MsCl. The amidation reaction was carried out at lower temperatures to minimize epimerization of the asymmetric center in the proline fragment.271 Boc N

O OH

+

F

H2N

N N

MsCl (1.0 equiv) NMI, DMF, −10 °C

Boc N

O

N

N H

then −10 to 20 °C

(in DMF)

N

F

77%

In a similar fashion, the mixed carbonic-sulfonic anhydride derived from a 4-arylpyridine-3-carboxylic acid and p-TsCl was allowed to react with a secondary amine to afford the secondary amide. In this case, the secondary amine was added as its MsOH salt; the excess base (NMI) used in the reaction effectively neutralized the salt and made the amine available for the reaction.272 Me N

Me N

O

CO2H

+

Br

HN

MeO

N Boc

O

p-TsCl, NMI, MeTHF/MeCN −20 to 20 °C

Me

Br

N

83%

3

O

N Boc

•MsOH

Me MeO

(in CH2Cl2)

3

Several other reagents have been developed for the formation of amide bonds, and the literature in this area has been extensively reviewed.273 Most of these reagents such as phosphonium salts and uronium salts are very effective; however, they are unattractive for large-scale applications because of extensive by-product formation. These methods may be applicable in extreme cases should the aforementioned protocols fail to produce the desired results.

2.29 Formation of Amides from Esters The direct coupling of alkyl esters with an amine is an attractive method to form amides. The reaction may be catalyzed by a mild Brønsted acid such as 2-hydroxypyridine.274 O H

HN

OMe

N H

Me N Me

H2N

O

2-hydroxypyridine HOCH2CH2OH 110 °C 85%

H

H N

Me N Me

N H

HN

The coupling of esters with amines to form amides is also catalyzed by Lewis acids such as magnesium halides. This procedure has been used to amidate the ester at the 2-position of indoles and pyridines, presumably due to complexation of the metal with the nitrogen atom. It has also been shown to work with other unactivated esters.275 271 Liu, Y.; Prashad, M.; Ciszewski, L.; Vargas, K.; Repiˇc, O.; Blacklock, T. J. Organic Process Research & Development 2008, 12, 183–191. 272 Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.; Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Organic Process Research & Development 2011, 15, 1138–1148. 273 Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–10852. 274 Ashford, S. W.; Henegar, K. E.; Anderson, A. M.; Wuts, P. G. M. The Journal of Organic Chemistry 2002, 67, 7147–7150. 275 Guo, Z.; Dowdy, E. D.; Li, W. S.; Polniaszek, R.; Delaney, E. Tetrahedron Letters 2001, 42, 1843–1845.

2.29 Formation of Amides from Esters

H N O

OMe

OMe O

0.5 equiv. MgBr2

O N H

O

N H

THF

OMe

N

91% H N O

O

0.5 equiv. MgCl2 OMe

N

THF 98%

Another Lewis acid that has been utilized to convert esters to amides is lanthanum trifluoromethanesulfonate. The reactions generally proceed with 5 mol% of the catalyst at temperatures ranging from ambient to 70 ∘ C. In the example shown in the following scheme, the amidation occurred preferentially at the 2-pyridyl ester moiety than at the ester functionality in the phenyl alanine component. In addition, no epimerization of the stereogenic center was detected.276 Ph

O OEt N

+

OEt

H2 N

rt, 24 h

O

Ph

O

La(OTf)3 (1 mol %)

N H

N

OEt O

91%, 99% ee

Organocatalysts have also been used for the conversion of esters to amides. Keiswetter et al. have demonstrated the use of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as an effective catalyst for this transformation. Significantly, no epimerization was observed with a substrate such as lactic acid.277 O Me

BnNH2 Me +

O OH

TBD (10 mol%) Toluene 80 °C, 2.5 h 97%

O Me OH

N H

Bn

Retention of configuration

A mild procedure for the transformation of unactivated esters and amino alcohol derivatives to the corresponding amides involves the use of catalytic t-butylamino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP). The reaction is highly general in nature and proceeds at ambient temperature.278 Cl

Cl

O OMe

Br

HN

+

MeCN, rt, 15 h

HO Et t-Bu N N Et P Me Me N N

O

10 mol% BEMP

92%

N Br

HO

BEMP

276 Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima, T. Organic Letters 2014, 16, 2018–2021. 277 Kiesewetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.; Hedrick, J. L.; Waymouth, R. M. The Journal of Organic Chemistry 2009, 74, 9490–9496. 278 Caldwell, N.; Campbell, P. S.; Jamieson, C.; Potjewyd, F.; Simpson, I.; Watson, A. J. B. The Journal of Organic Chemistry 2014, 79, 9347–9354.

131

132

2 Addition to Carbon-Heteroatom Multiple Bonds

2.30 Hydrolysis of Acyl Halides The hydrolysis of acyl halides leads to carboxylic acids. This is a reaction that typically works extremely and almost equally well in the absence of a skilled chemist or in the presence of a careless one. Most acyl halides are formed from the corresponding carboxylic acids, and the reverse reaction is rarely attempted deliberately. Several acid halides are water-sensitive and therefore need to be stored under anhydrous conditions to prevent hydrolysis. Nevertheless, if one desperately needs to effect this transformation, it can be easily accomplished by treating the acyl halide with water (or hydroxide, in some rare instances). Note that the reaction could be exothermic and will lead to the coproduction of 1 equiv of HX.

2.31 Conversion of Carboxylic Acids to Esters Carboxylic acids can be converted to esters in two different ways. Alkylation of the carboxylate oxygen with a suitable electrophile will lead to esters. In this case, both of the oxygen atoms in the carboxylic acid are retained in the ester formed, and this type of transformation is covered in Section 1.2.3.1. A complementary method is via treatment of the acid with an oxygen nucleophile in the presence of an appropriate catalyst or activating agent. The oxygen atom from the nucleophile is incorporated into the ester formed, and this type of transformation is covered in this section. 2.31.1

Fisher Esterification

The conversion of carboxylic acids to esters via treatment with alcohols in the presence of a protic acid catalyst is referred to as the Fisher esterification reaction. This is essentially an equilibrium reaction and is generally driven to the right by the use of one of the reagents in excess, or removal of water (either by distillation or the use of a suitable desiccant/dehydrating agent). O R1

OH

H+

R2OH

+

O R1

+

OR2

H2O

In the case of esterification reactions to form simple esters such as methyl and ethyl esters, the alcohol is used in large excess, usually as the solvent.279,280 Note that in the second example, the strongly acidic conditions led to the removal of the Boc-protecting group as well. Me

Me

O

O

OH MeOH, H2SO4 O

OMe O

91%

NHBoc

NH2

2HCl

MeOH, HCl CO2H

N

83%

N

CO2Me

When the alcohol cannot be used as the solvent, the reaction is generally driven to completion by azeotropic removal of water.281 OH O HO

OH O

OH

+

PhCH2OH

p-TsOH•H2O PhCH3, 130 °C

OH O Ph

O

O O

Ph

OH

94% 279 Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Organic Process Research & Development 2007, 11, 1015–1024. 280 Boesch, H.; Cesco-Cancian, S.; Hecker, L. R.; Hoekstra, W. J.; Justus, M.; Maryanoff, C. A.; Scott, L.; Shah, R. D.; Solms, G.; Sorgi, K. L.; Stefanick, S. M.; Turnheer, U.; Villani, F. J.; Walker, D. G. Organic Process Research & Development 2001, 5, 23–27. 281 Furuta, K.; Gao, Q.-Z.; Yamamoto, H. Organic Syntheses 1995, 72, 86–94.

2.31 Conversion of Carboxylic Acids to Esters

The use of catalytic SOCl2 in the presence of an alcohol is another convenient method for the preparation of esters.282 The thionyl chloride reacts with methanol to form HCl and thus serves as a convenient source of anhydrous HCl. Acetyl chloride is also frequently used for this purpose. HO2C

CO2H

MeOH, SOCl2

NO2

Cl

MeO2C

CO2Me Cl

95%

NO2

The Fisher esterification protocols are effective when primary or secondary alcohols are used. Tertiary alcohols typically undergo elimination under these conditions, and hence, esters of tertiary alcohols are seldom prepared using this method (see Section 2.31.2). While this procedure is operationally simple, the need for strong acids is a limitation when acid-labile functionality is present in the molecule(s). 2.31.2

Widmer’s Method for the Synthesis of t-Butyl Esters

A particularly convenient method for the formation of t-butyl esters is Widmer’s method, wherein a carboxylic acid is treated with DMF di-tert-butyl acetal. While the original procedure utilized benzene as the reaction solvent,283 toluene has been found to be an acceptable alternative.284 CO2H

CO2t-Bu (t-BuO)2CHNMe2 Toluene, 80 °C

Br

2.31.3

Br

60%

Via Acid Chlorides

Carboxylic acids can easily be transformed to the corresponding esters via acid chlorides (see Section 2.26 for the conversion of carboxylic acids to acid chlorides). As in the case of amidation reactions, esterifications via acid chlorides generate an equivalent of HCl and hence require an equivalent of base in order to proceed to completion. These reactions are generally catalyzed by the addition of small quantities of DMAP.285 OH O

OH BnO2C

CO2Bn

+

MeO

Cl

CO2Bn

BnO2C OMe

O

Et3N, DMAP (cat) MeO

CH2Cl2

OH

O OMe

97%

2.31.4

Via Acyl Imidazoles (Imidazolides)

Carboxylic acids can be converted to the corresponding esters through a two-step sequence that proceeds via an acyl imidazole. In a typical reaction, the acid is activated with CDI to afford the acyl imidazole, which is then treated with an alcohol to furnish the ester.286 Since the by-product in this transformation is imidazole, no additional base is required. O

O OH CDI, EtOAc

N

O BnOH

N N

N

94%

OBn N

282 Gurjar, M. K.; Murugaiah, A. M. S.; Reddy, D. S.; Chorghade, M. S. Organic Process Research & Development 2003, 7, 309–312. 283 Widmer, U. Synthesis 1983, 135–136. 284 Tagat, J. R.; McCombie, S. W.; Nazareno, D. V.; Boyle, C. D.; Kozlowski, J. A.; Chackalamannil, S.; Josien, H.; Wang, Y.; Zhou, G. The Journal of Organic Chemistry 2002, 67, 1171–1177. 285 See Note 281. 286 Couturier, M.; Le, T. Organic Process Research & Development 2006, 10, 534–538.

133

134

2 Addition to Carbon-Heteroatom Multiple Bonds

Alkyl imidazole carbamates has also been employed for the synthesis of esters from carboxylic acids. In the example illustrated in the following scheme, treatment of the carboxylic acid with methyl imidazole carbamate (MImC) in acetonitrile furnished the methyl ester. While the mechanistic details of this transformation are yet to be unequivocally established, one of the postulated pathways involves the intermediacy of an acyl imidazole species.287 O N

N

CO2H

OMe MImC

CO2Me

MeCN, 80 °C, 24 h

Br

93%

2.31.5

Br

Using Carbodiimides

The use of carbodiimides is a convenient method for the synthesis of esters from acids. The most commonly used carbodiimides are DCC288,289 and EDC.290 Under these conditions, sterically demanding substrates as well as weakly nucleophilic alcohols such as phenols react to produce the corresponding esters. However, since most of the urea by-products arising from the carbodiimides are separable only by chromatography, this method is less favored than the ones listed previously. H

CO2H +

H

EtO2C

CH2Cl2 0 °C to rt, 3 h 81%

Me

HO OH Br

H

DCC, DMAP

t-BuOH

+

EtO2C

CO2t-Bu H

DCC, DMAP

O

Me

O

CH2Cl2 Br

Me

O

92%

Me

O Me

O Me DMTrO

O

NH N

O

+ HO

OH

EDC, DMAP O

DMTrO

O

CH2Cl2 97%

NH N

O

O O

DMTr = Dimethoxytrityl

2.31.6

Via Anhydrides

As discussed in the amidation section (Section 2.28.5), symmetrical anhydrides are rarely used as the acyl component in ester formation reactions because only one half of the anhydride gets incorporated into the product. Alcoholysis of symmetrical anhydrides is typically performed only when the anhydride is inexpensive and readily available (e.g. acetic anhydride). This kind of transformation is generally useful for the protection of alcohols as esters. 287 Heller, S. T.; Sarpong, R. Organic Letters 2010, 12, 4572–4575. 288 Neises, B.; Steglich, W. Angewandte Chemie International Edition in English 1978, 17, 522–524. 289 Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Organic Syntheses 2003, 79, 72–83. 290 de Koning, M. C.; Ghisaidoobe, A. B. T.; Duynstee, H. I.; Ten Kortenaar, P. B. W.; Filippov, D. V.; van der Marel, G. A. Organic Process Research & Development 2006, 10, 1238–1245.

2.31 Conversion of Carboxylic Acids to Esters

Most commonly, the alcohol is treated with an anhydride in the presence of a base to afford the ester. A catalytic amount of DMAP is often added to enhance the reaction rate. Two representative examples using propionic anhydride291 and iso-butyric anhydride292 are given in the following scheme. O OH O

Me

O

I

N

O

Me i-Pr

Me

O

(EtCO)2O, Et3N

F

N

O OEt

N

NH

F

N

HO

F

N H2N

H2N

F

F

O

Me i-Pr

O

F

OEt

F

N Me

O

O

O

I

DMAP, CH2Cl2 96%

F

O

O

O

F

OEt

(i-PrCO)2O DBU, NMP 93% O (over 3 steps)

N

N

O Me Me

F

N H2N F

Several Lewis acid catalysts have been shown to promote the alcoholysis of anhydrides. For example, it has been demonstrated that the addition of very small quantities (90%

OH H

Me S

N

O

HO

O

O

H N

CO2H

N CO2H O

If the reaction of an amine with CO2 is carried out in the presence of an alkylating agent and a base, it is possible to trap the intermediate adduct and produce carbamates. For example, the three-component coupling between valine ester, benzylchloride, and CO2 led to the corresponding carbamate in excellent yield.423 Me

OMe

+

H3N Cl

−

Me

Me

O

BnCl, CO2, Cs2CO3 Bu4N+I−, DMF, 24 h

H Ph

O

Me OMe

N O

O

92%

Similarly, treatment of amines with phenacyl bromide and CO2 furnished the corresponding phenacyl urethanes. The reaction was found to be broadly applicable, allowing for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in good to excellent yields.424 O N H

+

Br

(i) Cs 2CO3, CO2, DMSO, 1 h (ii) 1.1 equiv phenacyl bromide, 5 min 99%

N O

O O

419 Hampe, E. M.; Rudkevich, D. M. Chemical Communications (Cambridge, U. K.) 2002, 1450–1451. 420 Katritzky, A. R.; Faid-Allah, H.; Marson, C. M. Heterocycles 1987, 26, 1333–1344. 421 Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. The Journal of Organic Chemistry 1995, 60, 6218–6220. 422 Williams, J. M.; Brands, K. M. J.; Skerlj, R. T.; Jobson, R. B.; Marchesini, G.; Conrad, K. M.; Pipik, B.; Savary, K. A.; Tsay, F.-R.; Houghton, P. G.; Sidler, D. R.; Dolling, U.-H.; DiMichele, L. M.; Novak, T. J. The Journal of Organic Chemistry 2005, 70, 7479–7487. 423 Salvatore, R. N.; Shin, S. I.; Nagle, A. S.; Jung, K. W. The Journal of Organic Chemistry 2001, 66, 1035–1037. 424 Speckmeier, E.; Klimkait, M.; Zeitler, K. The Journal of Organic Chemistry 2018, 83, 3738–3745.

2.55 Addition of Organometallic Reagents to Carbon Dioxide

2.54 The Addition of Amines to Carbon Disulfide Amines add to carbon disulfide (analogous to the reaction with CO2 , Section 2.53) to form dithiocarbamic acids or their salts. The reaction is facile and occurs under fairly mild conditions.425 F

NH2

N H

F

CS2

H N

+

N H H

EtOAc 0 °C 87%

S− S

Again, similar to the reaction of amines with CO2 (see Section 2.53) and the reaction of alcohols with CS2 (see Section 2.52), the intermediate adduct can be trapped with an alkylating agent to furnish S-alkyldithiocarbamates.426

Me

O

(i) CS2, Et3N (ii) MeI

O OH

Me

EtOH, H2O

NH2

OH S

HN

93%

SMe

In an interesting variant of this reaction, a four-component coupling reaction between an imine, an acid chloride, and amine and CS2 provided the dithiocarbamate in very good yields.427

N

Me Me

S

NH

Me + Me

O +

Ph

N

CS2, Et3N, DCM Cl

S

S Me Me

0 °C to rt, 20 h 75%

Ph N S

O Me Me

The addition of Boc2 O to the dithiocarbamate formation reaction leads to desulfurylation to provide the corresponding isothiocyanates in very good yields.428 O

O NH2

t-BuO

CS2, Et3N, Boc2O

t-BuO

N

C

0 °C to rt,

S

81%

2.55 Addition of Organometallic Reagents to Carbon Dioxide The addition of an organometallic species to carbon dioxide furnishes the corresponding carboxylic acid.429 H N

i-Pr O

Me F I

(i) p-TolMgCl in THF −10 to 0 °C, 30 min (ii) i-PrMgCl in THF −10 to 0 °C, 20 min

H N

i-Pr O

Me F CO2H

(iii) CO2, −10 to 15 °C, 20 min 85% 425 Kruse, L. I.; Kaiser, C.; DeWolf, W. E.; Finkelstein, J. A.; Frazee, J. S.; Hilbert, E. L.; Ross, S. T.; Flaim, K. E.; Sawyer, J. L. Journal of Medicinal Chemistry 1990, 33, 781–789. 426 Vaillancourt, V. A.; Larsen, S. D.; Tanis, S. P.; Burr, J. E.; Connell, M. A.; Cudahy, M. M.; Evans, B. R.; Fisher, P. V.; May, P. D.; Meglasson, M. D.; Robinson, D. D.; Stevens, F. C.; Tucker, J. A.; Vidmar, T. J.; Yu, J. H. Journal of Medicinal Chemistry 2001, 44, 1231–1248. 427 Schlüter, T.; Ziyaei Halimehjani, A.; Wachtendorf, D.; Schmidtmann, M.; Martens, J. ACS Combinatorial Science 2016, 18, 456–460. 428 Munch, H.; Hansen, J. S.; Pittelkow, M.; Christensen, J. B.; Boas, U. Tetrahedron Letters 2008, 49, 3117–3119. 429 See Note 351.

167

169

3 Addition to Carbon–Carbon Multiple Bonds John A. Ragan Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 169 Hydrogen–Halogen Addition (Hydrohalogenation), 169 Hydrogen–Oxygen Addition, 173 Hydrogen–Nitrogen Addition (Hydroamination), 178 Hydrogen–Carbon Addition (Hydroalkylation), 180 Halogen–Halogen Addition, 191 Hydroxy–Halogen Addition, 192 Amino–Halogen Addition, 194 Carbon–Halogen Addition, 194 Oxygen–Oxygen Addition, 196 Oxygen–Nitrogen Addition, 202 Nitrogen–Nitrogen Addition, 204 Carbon–Oxygen Addition, 206 Carbon–Nitrogen Addition, 211 Carbon–Carbon Addition, 212

3.1 Introduction Functionalization of olefins, acetylenes, and 1,3-dienes constitutes some of the most important transformations in organic synthesis. A rough approximation is that 10 of the 110 Nobel Prizes awarded in chemistry between 1901 and 2018 have included in significant portion the development or utilization of such reactions in the prize winner’s research. The list of chemists in this analysis includes several leading and historical figures in organic synthesis (e.g. Alder, Brown, Corey, Diels, Heck, Noyori, Sharpless, Suzuki, Woodward). This chapter is organized according to the nature of the elements being added to an olefin (or acetylene). Sections 3.2–3.5 cover addition of H-X, and Sections 3.6–3.15 cover addition of X-Y (where X and Y are elements other than hydrogen).

3.2 Hydrogen–Halogen Addition (Hydrohalogenation) 3.2.1

Hydrohalogenation of Olefins

Direct addition of HX to an olefin is known, and in some cases is a preparatively useful method for the synthesis of alkyl halides. Polarized olefins (e.g. α,β-unsaturated carbonyl compounds, terminal olefins, styrene derivatives, or 1,1-disubstituted olefins) are particularly good substrates for this reaction. However, nonpolarized olefins can yield problematic mixtures of regioisomers. Note that in general, alkyl halides are more readily prepared from alcohols (see Section 1.5.1.3). The examples that follow are arranged in the sequence of addition of HF, HCl, HBr, and HI. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

170

3 Addition to Carbon–Carbon Multiple Bonds

For hydrofluorinating alkenes and other substrates, Olah developed a mixture of anhydrous HF and pyridine (Olah reagent).1 The corrosive nature of this reagent is an issue, however, and other methods for installation of fluorine are often preferred (e.g. fluoride ion displacement of alkyl sulfonates, Section 1.6.1.2).2,3 Hydrochlorination can be an efficient process. In the first example, Markovnikov addition to a trisubstituted olefin is achieved with TMSCl and water.4 In the second example, HCl addition occurs in a conjugate fashion with concomitant acetal formation of the aldehyde.5 TMSCl H2O

Me Me

Me

Me

98%

Me

HCl HOCH2CH2OH Bu 4NCl

CHO

Me

Cl

Me

Me

O Cl

>95%

O

Carreira and coworker have developed a cobalt-catalyzed hydrochlorination of unactivated olefins with p-toluenesulfonyl chloride and phenylsilane serving as the source of HCl.6 This method provides remarkable levels of regioselectivity with either terminal or trisubstituted olefins, as shown in the following two examples. The catalytic cycle proceeds via a Co(II)/Co(III) radical process. An Organic Syntheses preparation of the catalyst ligand (2-(3,5-di-tert-butyl-2-hydroxybenzylideneamino)-2,2-diphenylacetic acid potassium salt, or SALDIPAC) and chlorination of 4-phenyl-1-butene has been reported.7

O

Co(BF 4)2•6H2O Cat B (10 mol%) t-BuOOH (30 mol%) PhSi H3, EtOH

O

O

94%

O

Me Me

TBDPSO

Cat A: Me

O t-Bu

1 2 3 4 5 6 7

75%

Co

t-Bu

Me

Me Cl

TBDPSO

Ph

t-Bu

N O

Cl

Cat B:

Me Me Me

N t-Bu

Cat A (5 mol%) PhSi H3, EtOH

Me

N

t-Bu

OH

Ph

O

OK

t-Bu

Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. The Journal of Organic Chemistry 1979, 44, 3872–3881. Percy, J. M. Topics in Current Chemistry 1997, 193, 131–195. Resnati, G. Tetrahedron 1993, 49, 9385–9445. Boudjouk, P.; Kim, B.-K.; Han, B.-H. Synthetic Communications 1996, 26, 3479–3484. Kawashima, M.; Fujisawa, T. Bulletin of the Chemical Society of Japan 1988, 61, 3377–3379. Gaspar, B.; Carreira, E. M. Angewandte Chemie, International Edition 2008, 47, 5758–5760. Gaspar, B.; Waser, J.; Carreira, E. M. Organic Syntheses 2010, 87, 88–94.

3.2 Hydrogen–Halogen Addition (Hydrohalogenation)

Hydrobromination of methyl acrylate is similarly effected; use of bromine-free HBr is an important factor for this reaction. A radical inhibitor (hydroquinone) is utilized to quench any radicals formed, which can lead to anti-Markovnikov addition products.8

CO2Me

HBr Et 2O 0–25 °C 80–84%

Br

CO2Me

Landini and Rolla have utilized a tetraalkylphosphonium salt as a phase-transfer catalyst for the hydrohalogenation (HCl, HBr, and HI) of terminal olefins; this allows for the use of aqueous (48%) HBr in place of HBr gas. The regioselectivity reflects Markovnikov’s rule. The reaction is run neat in olefin at 115 ∘ C.9 C10H21

aq HBr C16H33PBu 3Br

Br Me

86%

C10H21

Hydroiodination can be effected with HI, or more practically, by in situ formation of HI from an iodide salt (e.g. KI and H3 PO4 ).10 KI H3PO4

I

88–90%

Terminal olefins can be selectively converted to the primary halide by hydrozirconation followed by trapping of the C—Zr bond with an electrophilic halogen source (further examples of hydrozirconation can be found in Section 12.2.12). The following examples utilize iodine to generate the alkyl iodide.11,12 (i) Cp 2ZrHCl PhH, 25 °C, 9 h (ii) I2

Me TBSO

Me TBSO

90% (i) Cp 2ZrHCl toluene

I

(ii) I2, toluene

Ph

I

I I

Ph

Silver-catalyzed debromofluorination of alkylboronates and boronic acids has been reported, allowing for the net hydrofluorination of an olefin when coupled with a hydroboration, as shown in the following.13 O O BPi n Me Me

O

AgNO 3 (cat ) SelectFluor F

TFA H2O, CH2Cl 2 82%

O F

F

Me Me

8 Mozingo, R.; Patterson, L. A. Organic Syntheses 1940, 20, 64–65. 9 Landini, D.; Rolla, F. The Journal of Organic Chemistry 1980, 45, 3527–3529. 10 Stone, H.; Schechter, H. Organic Syntheses 1951, 31, 66–67. 11 Evans, D. A.; Bender, S. L.; Morris, J. Journal of the American Chemical Society 1988, 110, 2506–2526. 12 Meijboom, R.; Moss, J. R.; Hutton, A. T.; Makaluza, T.-A.; Mapolie, S. F.; Waggie, F.; Domingo, M. R. Journal of Organometallic Chemistry 2004, 689, 1876–1881. 13 Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. Journal of the American Chemical Society 2014, 136, 16439–16443.

171

172

3 Addition to Carbon–Carbon Multiple Bonds

3.2.2

Hydrohalogenation of Alkynes

Preparation of vinyl halides by addition of HX to acetylenes is not generally the most practical route to these compounds. An exception is polarized alkynes, such as propynoic acid derivatives; these substrates will react with halide salts to generate β-haloacrylic acid derivatives.14 The reaction shows useful levels of Z-selectivity with esters, amides, and nitriles, but not with ketones. LiX, AcOH CH3CN, 90 °C

O

X

O NHEt

NHEt X=I

91%

X = Br

85%

X = Cl

91%

For unactivated acetylenes, addition of HCl can be effected with triethylammonium hydrogen dichloride (Et3 NH+ HCl2 − ), although isomeric mixtures are typically observed.15 More useful is the addition of HBr to terminal acetylenes with tetraethylammonium hydrogen dibromide, which generates the 1-alkyl-1-bromo olefins in useful yields on 5–10 g scale.16

R

Et 4N+ HBr 2– CH2Cl 2

R Br

R = alkyl, hydroxyalkyl 65–91% yields

Hydrozirconation of alkynes followed by trapping of the C—Zr bond with an electrophilic halogen source can be useful for the regio- and stereoselective preparation of vinyl halides. The reaction is generally selective for the syn-addition of H-X and can be remarkably sensitive to steric differences in the acetylene substrate.17 The high regioselectivity has been shown to arise via Zr-catalyzed equilibration of the isomers; the initial kinetic selectivity is modest. The examples shown in the following are taken from total syntheses of discodermolide18 and FK506,19 respectively, and demonstrate the utility of this reaction for the stereo- and regioselective preparation of trisubstituted olefins. OTBS

TMS

BnO Me

Cp 2ZrHCl I2, THF 92%

Me

Me OMe OTIPS

Cp 2ZrHCl NBS, PhH 86%

OTBS I

BnO Me

Br

Me

TMS

OMe Me

OTIPS

14 Ma, S.; Lu, X.; Li, Z. The Journal of Organic Chemistry 1992, 57, 709–713. 15 Cousseau, J.; Gouin, L. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1977, 1797–1801. 16 Cousseau, J. Synthesis 1980, 805–806. 17 Hart, D. W.; Blackburn, T. F.; Schwartz, J. Journal of the American Chemical Society 1975, 97, 679–680. 18 Arefolov, A.; Panek, J. S. Journal of the American Chemical Society 2005, 127, 5596–5603. 19 Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. Journal of the American Chemical Society 1990, 112, 5583–5601.

3.3 Hydrogen–Oxygen Addition

3.3 Hydrogen–Oxygen Addition 3.3.1 3.3.1.1

Addition of H–OH (Hydration) Hydration of Olefins

Direct hydration of olefins to generate alcohols is usually not a practical process, but indirect, metal-mediated methods are common. Three of the most commonly used are covered in this section: hydroboration, hydrosilylation, and oxymercuration. Hydroboration Hydroboration is a useful indirect method for hydration of olefins via oxidation of the C—B bond result-

ing from the initial hydroboration. This is a widely utilized method for anti-Markovnikov addition of water to an olefin (steric and electronic factors favor boron addition to the less substituted carbon, and thus lead to formation of the less substituted alcohol after oxidation). The complex of borane and tetrahydrofuran (borane ⋅ THF) is commercially available and can serve as a convenient source of borane on laboratory scale. There are potential handling and stability issues with this reagent, however.20,21 These can be avoided through in situ formation of borane. One of the most useful methods for this is the reaction of sodium borohydride with BF3 ⋅ Et2 O, as shown in the following example.22 Me

(i) NaBH 4, BF3 • Et 2O

Me

(ii) H2NOSO3H, 100 °C (iii) H 3PO4

Me Me

NH2 • H3PO4 Me Me

42%

Dialkylboranes such as disiamylborane ((Me2 CHCHMe)2 BH, prepared in situ by reaction of BH3 ⋅ THF with 2-methyl-2-butene) can exhibit useful levels of regio- and stereocontrol. In the following example, a triene is selectively hydroborated at the terminal olefin to give the primary alcohol following oxidation.23

Me

(i) (Me2CHCHMe)2BH

Me

Me

(ii) H2O2, NaOH, THF

Me

Me

88–91%

Me OH

Diastereoselectivity is another useful feature of hydroborations, with syn addition of the borane reagent from the less hindered face of the olefin predominating. The following example illustrates this for a bicyclic olefin, with the borane reagent approaching from the less hindered face. This procedure also illustrates the use of sodium perborate, a safe and convenient alternative to hydrogen peroxide for oxidation of the intermediate organoborane.24 Me

(i) BH3 • THF

Me

(ii) NaBO3 • 4 H2O H 2O

Me Me

91–92%

OH Me Me

Enantioselective hydroboration is a challenging transformation. In selected cases, it can be achieved with the use of chiral, nonracemic dialkylborane reagents. In the following example, the two olefins are enantiotopic, and the chiral reagent selectively reacts with one olefin to generate the product alcohol with useful levels of enantioselectivity after 20 21 22 23 24

am Ende, D. J.; Vogt, P. F. Organic Process Research & Development 2003, 7, 1029–1033. Potyen, M.; Josyula, K. V. B.; Schuck, M.; Lu, S.; Gao, P.; Hewitt, C. Organic Process Research & Development 2007, 11, 210–214. Rathke, M. W.; Millard, A. A. Organic Syntheses 1978, 58, 32–36. Leopold, E. J. Organic Syntheses 1986, 64, 164–174. Kabalka, G. W.; Maddox, J. T.; Shoup, T.; Bowers, K. R. Organic Syntheses 1996, 73, 116–122.

173

174

3 Addition to Carbon–Carbon Multiple Bonds

an oxidative workup (albeit in modest yield, 27–31% overall for the alkylation/hydroboration sequence from cyclopentadienyl sodium).25 Me CO2Me

(i) Me

Me

BH 2

CO2Me

HO

(ii) H2O2, NaOH 27–31%

Acyclic olefins can also be good substrates for diastereoselective hydroboration, as first noted by Still and Barrish.26 The following example from Evans et al. is representative.27 O

OH OH

O N

O

Bn

Me

Me

(i) 9-BBN, THF (ii) H2O2, MeOH aq pH 7 buffer

O O

73%

Me

O

OH OH OH

N Bn

Me

Me

Me

85 : 15 diastereoselectivity

Hydroboration of olefins with catecholborane catalyzed by rhodium or iridium has been developed by Evans et al., and provides products complimentary to the uncatalyzed reaction in terms of regio- and stereocontrol. For example, the catalyzed hydroboration shown in the following provides the syn product (93 : 7 selectivity), whereas the uncatalyzed hydroboration with 9-BBN provides predominantly the anti product (87 : 13 selectivity, not shown).28 OTBS Me n-Pr

(i) CB (3 equiv), (Ph 3P)3RhCl (3 mol%) THF, 20 °C; (ii) H2O2, EtOH aq pH 7 buffer 79%

CB = Catecholborane =

O

OTBS HO

Me n-Pr

93 : 7 diastereoselectivity BH

O

Cyclic olefins also exhibit this complementarity, with the 1,3-anti product favored with catalyzed hydroboration, vs. the 1,2-anti product in the uncatalyzed variant. Coordinating substituents such as a phosphinite or an amide have a dramatic impact on the stereo- and regiochemical outcome. For example, allylic cyclohexenols provide the 1,3-anti product with a noncoordinating group (TBSO), whereas the 1,2-syn product predominates with a coordinating group (Ph2 PO). Amides also serve as directing groups in this reaction.28 OTBS

(i) CB (3 equiv), (Ph 3P)3RhCl (3 mol%) THF, 20 °C

OTBS

(ii) H2O2, EtOH

OH

aq pH 7 buffer 79% dr = 86 : 14

OPPh 2

(i) CB (6 equiv), (Ph 3P)3RhCl (1.1 equiv) THF, 20 °C (ii) H2O2, EtOH, aq pH 7 buffer (iii) Ac 2O

25 26 27 28

OAc

OAc

55% dr = 91 : 9

Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. Organic Syntheses 1985, 63, 44–56. Still, W. C.; Barrish, J. C. Journal of the American Chemical Society 1983, 105, 2487–2489. Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. Journal of the American Chemical Society 1998, 120, 5921–5942. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Journal of the American Chemical Society 1992, 114, 6671–6679.

3.3 Hydrogen–Oxygen Addition

Hydrosilylation Hydrosilylation of an olefin followed by oxidation of the C—Si bond achieves the overall hydration of

the olefin, similar to hydroboration/oxidation. In the following intramolecular example, this reaction is highly selective for the 2,3-syn triol.29 OCH2OMe C6H13

Pt[(CH2 = CHSiMe 2)2O] 2 C6H13 Hexane, 25 °C

OSiMe 2H

O

OCH2OMe

30% H2O2 KF, KHCO 3 MeOH

SiMe 2

58–66% overall

OCH2OMe C6H13 OH OH

Oxymercuration Oxymercuration of olefins followed by reduction of the C—HgX bond effects net hydration of the

olefin. The regioselectivity of this method is generally excellent, providing the Markovnikov addition product, and it is thus complementary to hydroboration (see Section “Hydroboration”). The generation of a stoichiometric organomercurial intermediate and resulting mercury waste streams makes this method impractical on large scale, but for laboratory applications, it can be useful. In the example shown, 1-methylcyclohexene is oxymercurated and reduced with sodium borohydride to generate 1-methylcyclohexanol.30 NaBH 4 aq NaOH Et 2O

OH

Hg(OAc) 2 Me Et O, H O 2 2

Me

71–75%

Hg(OAc)

3.3.1.2

Me OH

Hydration of Acetylenes

Addition of water to an acetylene formally generates an enol, which tautomerizes to the carbonyl form. Gold catalysts have emerged as a useful method for effecting this transformation, as shown in the following preparatively useful example.31 Hayashi has provided a Discussion Addendum to his original Organic Syntheses procedure.32 These catalysts supplant the mercury salts that were frequently used for this reaction and avoid the associated waste handling concerns. CH3Au(PPh 3) aq H2SO4 86%

O

O

Me

Me

Terminal alkynes can also be hydrated to give the alternative regioisomer (i.e. the aldehyde). Wakatsuki and coworkers have reported the Ru-catalyzed hydration of terminal acetylenes to provide the anti-Markovnikov product, an attractive alternative to stoichiometric hydroboration/oxidation (see in the following).33 The catalyst (RuCpCl(dppm))34 is commercially available.

C6H13

RuCpCl(dppm) 2 mol % aq i-PrOH sealed tube, 100 °C

O C6H13

H

93% dppm = (P h 2P)2CH2

29 30 31 32 33 34

Tamao, K.; Nakagawa, Y.; Ito, Y. Organic Syntheses 1996, 73, 94–109. Jerkunica, J. M.; Traylor, T. G. Organic Syntheses 1973, 53, 94–97. Mizushima, E.; Cui, D.-M.; Nath, D. C. D.; Hayashi, T.; Tanaka, M. Organic Syntheses 2006, 83, 55–60. Hayashi, T. Organic Syntheses 2012, 89, 126–130. Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Organic Letters 2001, 3, 735–737. Ashby, G. S.; Bruce, M. I.; Tomkins, I. B.; Wallis, R. C. Australian Journal of Chemistry 1979, 32, 1003–1016.

175

176

3 Addition to Carbon–Carbon Multiple Bonds

The initial enol product can also be isolated as an enol ester, as shown in the following Rh-catalyzed example, which proceeds with high regio- and stereoselectivity.35,36 (i) [Rh(COD)acac] (2 mol%) DPPMP (2 mol%) THF, 50 °C

O Ph

O Ph

(ii) 1-octyne, 110 °C

OH

O C6H13

93%

Hydroboration of alkynes also provides the anti-Markovnikov hydration product, via oxidation of the initially formed terminal vinyl organoborane. The example shown in the following converts 1-hexyne to hexanal.37 (i) Me2CHCMe2BH 2 diglyme, 0 °C (ii) H2O2, aq NaOH

C4H9

H

C4H9 O

82%

Internal (unsymmetrical) acetylenes generally give mixtures of regioisomers with mercury or gold catalysts.38 There is a report of regioselective addition of methanol to methylisopropylacetylene catalyzed by a cationic gold(I) complex,39 although no yield and limited experimental details are provided. Me

Me

(Ph 3P)AuMe MeSO3H

Me

MeOH

MeO

OMe i-Pr

Me

It is reported that the regioselective hydration of an unsymmetrical alkyne can be achieved indirectly via hydroboration, although no experimental details are provided.40

3.3.2.1

S O

91%

n-C5H11

3.3.2

Me

(i) Hydroboration (ii) Oxidation

SMe

n-C5H11

Addition of H–OR (Hydroalkoxylation) Addition of H–OR to Olefins

Polarized olefins can be reacted with alcohols under more practical conditions. One such example is shown in the following, in which catalytic sodium is used to generate the catalytic alkoxide.41 An earlier reference for the addition of simpler, less expensive alcohols to acrylate esters (e.g. methanol, ethanol) is also provided.42

+

EtO2C

NHBoc

HO

Cat. Na THF 25 °C

EtO2C

81%

O

NHBoc

Unsaturated lactones can also serve as electrophiles for this conjugate addition, as in the following example.43

O OTs

O

NaOCH2CH=CH2 HOCH2CH=CH2 –40 to 0 °C

OCH2CH=CH2

87%

CO2CH2CH=CH2 O

35 Lumbroso, A.; Vautravers, N. R.; Breit, B. Organic Letters 2010, 12, 5498–5501. 36 Ganss, S. Organic Syntheses 2016, 93, 367–384. 37 Zweifel, G.; Brown, H. C. Journal of the American Chemical Society 1963, 85, 2066–2072. 38 Norman, R. O. C.; Parr, W. J. E.; Thomas, C. B. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1976, 1983–1987. 39 Teles, J. H.; Brode, S.; Chabanas, M. Angewandte Chemie, International Edition in English 1998, 37, 1415–1418. 40 Trost, B. M.; Martin, S. J. Journal of the American Chemical Society 1984, 106, 4263–4265. 41 Reddy, D. S.; Vander Velde, D.; Aube, J. The Journal of Organic Chemistry 2004, 69, 1716–1719. 42 Rehberg, C. E.; Dixon, M. B.; Fisher, C. H. Journal of the American Chemical Society 1946, 68, 544–546. 43 Roth, B.; Baccanari, D. P.; Sigel, C. W.; Hubbell, J. P.; Eaddy, J.; Kao, J. C.; Grace, M. E.; Rauckman, B. S. Journal of Medicinal Chemistry 1988, 31, 122–129.

3.3 Hydrogen–Oxygen Addition

As in the oxymercuration of olefins to form alcohols (see Section “Oxymercuration”), mercury(II) salts can effect addition of alcohols to olefins (alkoxymercuration) to generate the corresponding ethers following reduction of the C—HgX bond with NaBH4 .44,45 Due to the generation of stoichiometric mercury metal as a by-product, this method is not practical on any significant scale, however; appropriate caution should be utilized even on modest laboratory scale. Highly polarized olefins can be directly reacted with an alcohol and acid catalyst. Two such examples can be found in alcohol protecting group chemistry. Addition of an alcohol to dihydropyran generates the corresponding tetrahydropyranyl (THP) ether,46 an excellent blocking group for strong base chemistry (note that a chiral center is generated in the product, such that a chiral alcohol will generate a pair of diastereomeric THP ethers). p-TsOH

O OH

78–92%

O

O

Isobutylene can also be condensed with an alcohol under strongly acidic conditions to generate the corresponding tert-butyl ether.47 Addition of carboxylic acids to olefins is also known. Formation of tert-butyl esters from isobutylene falls in this category and represents another example of protecting group chemistry.48 Intramolecular addition of carboxylic acids to olefins can also be a useful route to lactones. This transformation is frequently effected by iodolactonization (see Section 1.2.3.2) followed by reduction of the carbon–iodine bond; but in certain cases, the transformation can be realized directly by treatment with acid, such as toluenesulfonic acid in the following example (note that in this example, the preference for Markovnikov addition and the kinetic preference for five- vs. six-membered ring formation are aligned to provide a single regioisomer).49 Triflic acid in nitromethane has also been utilized to generate several fiveand six-membered lactones.50

Me

p-TsOH

Me CO2Me

3.3.2.2

O

COOH Toluene reflux, 1 h 75%

Me

O Me

Me CO2Me

Addition of H–OR to Acetylenes

Alcohols will also add to polarized acetylenes to generate β-alkoxy acrylate derivatives, as shown in the following example.51 Phenols will also add in a similar fashion.52

CO2Me

CO2Me

44 45 46 47 48 49 50 51 52

MeOH, Et 3N Et 2O, 25 °C 90% PhOH N-Me-morpholine THF, 0 °C 82%

MeO

PhO

CO2Me

CO2Me

Brown, H. C.; Kurek, J. T.; Rei, M. H.; Thompson, K. L. The Journal of Organic Chemistry 1984, 49, 2551–2557. Brown, H. C.; Kurek, J. T.; Rei, M. H.; Thompson, K. L. The Journal of Organic Chemistry 1985, 50, 1171–1174. Earl, R. A.; Townsend, L. B. Organic Syntheses 1981, 60, 81–87. Ireland, R. E.; O’Neil, T. H.; Tolman, G. L. Organic Syntheses 1983, 61, 116–121. Strube, R. E. Organic Syntheses 1957, 37, 34–36. Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, 6251–6262. Coulombel, L.; Dunach, E. Synthetic Communications 2005, 35, 153–160. Ireland, R. E.; Wipf, P.; Xiang, J. N. The Journal of Organic Chemistry 1991, 56, 3572–3582. Glorius, F.; Neuhurger, M.; Pfaltz, A. Helvetica Chimica Acta 2001, 84, 3178–3196.

177

178

3 Addition to Carbon–Carbon Multiple Bonds

3.4 Hydrogen–Nitrogen Addition (Hydroamination) 3.4.1

Hydroamination of Olefins

Direct hydroamination of unactivated olefins is challenging and is an active area of research in organometallic catalysis.53 Mercury salts will catalyze the addition of amines to olefins (similar to the oxymercuration discussed in Section “Oxymercuration”). Markovnikov’s rule predicts the regioselectivity of this reaction. As with oxymercuration, a significant drawback to this approach is the generation of mercury metal in the subsequent reduction of the carbon–mercury bond.54 Hydroboration followed by treatment of the organoborane with a chloroamine is an indirect approach to this transformation.55 Another variant on this approach is shown in the following, in which the intermediate organoborane is oxidized with hydroxylamine-O-sulfonic acid to provide the corresponding primary amine56 (note that this method for in situ generation of borane is also useful for hydroborations to generate alcohols, as shown earlier in Section “Hydroboration”). Me

Me

(i) NaBH 4, BF3•Et 2O (ii) H2NOSO3H, 100 °C (iii) H 3PO4

Me Me

NH2•H3PO4 Me Me

42%

Alkyl azides can also be coupled with alkylboranes to affect the net hydroamination of the olefin substrate. The following two examples are from H. C. Brown et al.57 and D. A. Evans and A. E. Weber.58 In the first example, the chiral dichloroalkylborane is prepared by asymmetric hydroboration of 1-methylcyclopentene with di- or mono-isopinocampheylborane and formation of the dichloroborane by treatment with HCl-Me2 S. The second example, from Evans’ synthesis of echinocandin d, is particularly interesting as it involves a diastereoselective hydroboration followed by internal coupling of an alkylazide to form the pyrrolidine. (i) IpcBH 2; crystallize (ii) CH3CHO

Me

Me BCl 2•Me2S

(iii) LiAlH4 (iv) HCl, Me2S

Me N3

H N

ClCH 2CH2Cl 60 °C 72% OH

OH MeO2C

Me

N3

(c-C 6H11)2BH

MeO2C

CH2Cl 2

+

N2

OH Me

N

B– R2

(–N2) aq HCl 72%

Me

MeO2C HCl•H

N

In contrast to unactivated olefins, amines readily add to highly polarized olefins such as α,β-unsaturated esters. Care must be taken to avoid polymerization, but with proper choice of conditions, this can be a useful synthesis of β-aminoesters, as shown in the following example, where two molecules of ethyl acrylate condense with 3-hydroxy-1-aminopropane (this is the first step in a preparation of azetidine).59 Cupric acetate has been used as a catalyst for mono-addition of 2-chloroaniline to acrylonitrile.60 HO

NH2

CO2Et Neat, reflux

HO

N

CO2Et CO2Et

99%

53 54 55 56 57 58 59 60

Ryu, J.-S.; Li, G. Y.; Marks, T. J. Journal of the American Chemical Society 2003, 125, 12584–12605. Griffith, R. C.; Gentile, R. J.; Davidson, T. A.; Scott, F. L. The Journal of Organic Chemistry 1979, 44, 3580–3583. Kabalka, G. W.; McCollum, G. W.; Kunda, S. A. The Journal of Organic Chemistry 1984, 49, 1656–1658. See Note 22. Brown, H. C.; Salunkhe, A. M.; Singaram, B. The Journal of Organic Chemistry 1991, 56, 1170–1175. Evans, D. A.; Weber, A. E. Journal of the American Chemical Society 1987, 109, 7151–7157. Wadsworth, D. H. Organic Syntheses 1973, 53, 13–16. Heininger, S. A. Organic Syntheses 1958, 38, 14–16.

3.4 Hydrogen–Nitrogen Addition (Hydroamination)

Additions to α,β-unsaturated amides are also useful, and the following experimental is offered on more typical laboratory scale and in ethanol solvent (3.6 g product, isolated via chromatography).61 Me

Me

O N Me

Ph Ph

Ph

Me

NH2

Ph

EtOH, reflux

Me

O

N H

98%

N Me

Ph Ph

A detailed procedure for the following sequence has also been described, using a similar chiral auxiliary for the addition of a secondary amine to an unsaturated ester.62 Me O Me

Ph

Me

N H

Ot-B u

Ph

Ph Me

n-BuLi, THF –75 °C

Me

Ph

N

(i) H2, Pd(OH) 2/C MeOH 83%

O

NH2 O

Ot-B u (ii) TFA, DCM HCl, (iii) Ion-exchange chromatography 88 to 93%

Me

89%

Me

OH Me

MacMillan and coworkers have applied imidazolidinone organic catalysis to the conjugate addition of O-silyl hydroxylamines to enals.63 Me

N

t-Bu

Me

O

O

N H • TFA

Ph Boc

(20 mol%) BocNHOTBS

OTBS

Me

CHCl 3, –20 °C

O 92% ee

85%

3.4.2

N

Hydroamination of Acetylenes and Allenes

Hydroamination of alkynes (and allenes) can be a useful approach to the synthesis of alkyl amines.64 A variety of catalysts for effecting this transformation have been developed. Doye and coworkers have reported dimethyltitanocene as a catalyst for the intermolecular hydroamination of acetylenes.65 In the following example, nitrogen adds to the carbon β to the aromatic ring; the initial imine product is then hydrogenated to generate the primary amine through hydrogenation of the C=N bond and hydrogenolysis of the benzyhydryl group. Ph

Ph NH2 +

Ph

61 62 63 64 65

Ph Cp 2TiMe 2 (3 mol%)

n-Pr

PhCH 3 110–120 °C

N Ph

Ph n-Pr

H2, Pd/C THF 70%

NH2 Ph

n-Pr

Gutierrez-Garcia, V. M.; Lopez-Ruiz, H.; Reyes-Rangel, G.; Juaristi, E. Tetrahedron 2001, 57, 6487–6496. Davies, S. G. F., Ai M.; Roberts, Paul M. Organic Syntheses 2010, 87, 143. Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. Journal of the American Chemical Society 2006, 128, 9328–9329. Pohlki, F.; Doye, S. Chemical Society Reviews 2003, 32, 104–114. Haak, E.; Siebeneicher, H.; Doye, S. Organic Letters 2000, 2, 1935–1937.

179

180

3 Addition to Carbon–Carbon Multiple Bonds

Bergman and coworker have reported that tetrakis(amido) titanium complexes effect intramolecular hydroaminations of alkynes and allenes; the reaction temperature is somewhat reduced with this catalyst.66 Ts N NMe 2 Ti N NMe2 Ts

NH2

(5 mol%)

N

PhH, 75 °C F

Me

F

93%

In the final example, Livinghouse utilized an amido titanocene complex to effect the intramolecular hydroamination of an acetylene in his synthesis of monomorine.67 O

CpTiCl 3 (20 mol%)

O

Me Me NH2

Me

N

O

Et 3N, THF 25 °C 93%

O Me

Gold complexes have also been used as catalysts for hydroamination of alkynes. Both intra-68 and intermolecular69 examples are shown in the following. Na[AuCl4] (5 mol%) CH3CN, 79 °C

Br +

Ph

H2N

N

92%

NH2

(Ph 3P)AuMe (0.01 mol%) H3PW12O40 (0.05 mol%) 70 °C

Br N

Crystallization from hexanes 85%

Ph

Me

Direct addition of amines to polarized acetylenes is generally an efficient process, as shown in the following example where proline ethyl ester adds to ethyl propynoate.70

CO2Et NH

+

CO2Et

Heptane reflux 15 mi n >90%

CO2Et N

CO2Et

3.5 Hydrogen–Carbon Addition (Hydroalkylation) 3.5.1

Direct Hydrogen-Alkyl Addition

There are few preparatively useful reactions for the direct hydroalkylation of unactivated olefins. (Note that indirect methods that proceed via hydrometalation, e.g. carboalumination, are covered in Chapter 12). One notable exception is 66 67 68 69 70

Ackermann, L.; Bergman, R. G. Organic Letters 2002, 4, 1475–1478. McGrane, P. L.; Livinghouse, T. The Journal of Organic Chemistry 1992, 57, 1323–1324. Fukuda, Y.; Utimoto, K. Synthesis 1991, 975–978. Mizushima, E.; Hayashi, T.; Tanaka, M. Organic Letters 2003, 5, 3349–3352. Walter, P.; Harris, T. M. The Journal of Organic Chemistry 1978, 43, 4250–4252.

3.5 Hydrogen–Carbon Addition (Hydroalkylation)

the cascade cyclization of polyenes to generate steroid and terpene-like structures. The majority of these reactions fall in the category of carbon–carbon addition to an olefin (see Section 3.15.8). The following cyclization, a Friedel–Crafts addition to a conjugated dienone, provides an example of a formal hydroalkylation of an olefin.71 OMe

OMe OMe

OMe

Me

Me

BF 3 • Et 2O CH2Cl 2 reflux 80%

O Me

O Me

A similar example was utilized in the cyclization shown in the following.72 This reaction can also be viewed as a Lewis acid–mediated ene reaction (see Section 3.5.2). Me

Me Me

CO2Me

Me Me H

BF 3 • Et 2O Benzene

Me

Me Me CO2Me

93%

Another example of hydroalkylation is the dimerization of styrene to generate 1-methyl-3-phenylindane.73 Me

H2SO4 H2O Reflux 77–81%

3.5.2

Ph

Hydrogen–Allyl Addition (Alder Ene Reaction)

The Alder ene reaction, a [2,3]-sigmatropic process, effects the net addition of hydrogen and an allyl group across an olefin. The reaction can be effected thermally, as exemplified in the following.74 O

+

Ph

O O

1,2-Cl 2C6H4

O Ph

O

180 °C

O

37–48%

Lewis acid catalysis has also been utilized to effect ene reactions at lower temperatures. The following cyclization is representative and proceeds with high diastereoselectivity (>30 : 1).75 Me Me MeO2C

Me CO2Me

71 72 73 74 75

FeCl 3 /Al 2O3 (10 mol%) CH2Cl 2 –78 to 20 °C 71–77%

Me MeO2C

Me CO2Me

Majetich, G.; Liu, S.; Fang, J.; Siesel, D.; Zhang, Y. The Journal of Organic Chemistry 1997, 62, 6928–6951. Schmidt, C.; Chishti, N. H.; Breining, T. Synthesis 1982, 391–393. Rosen, M. J. Organic Syntheses 1955, 35, 83–84. Rondestvedt, C. S., Jr. Organic Syntheses 1951, 31, 85–87. Tietze, L. F.; Beifuss, U. Organic Syntheses 1993, 71, 167–174.

181

182

3 Addition to Carbon–Carbon Multiple Bonds

An enantioselective ene cyclization was reported in the synthesis of (−)-α-kainic acid.76 Although 2 equiv of the ligand and metal reagents are required, the reaction proceeds in good yield and enantioselectivity. Note that appropriate precautions should be taken when handling perchlorate salts. Me

Me

N

N

O Me

EtO2C O

Me

O

Ph

Ph

MgCl O4 (2 equiv) CH2Cl 2

N COPh

EtO2C

72%

Me

O

N COPh

>95 : 5 cis:trans 66% ee

A similar transformation can occur wherein the ene component is the enol of a carbonyl compound. This transformation is known as a Conia reaction.77 The following example is from Paquette’s synthesis of modhephene. While efficient (85% yield on 500 mg scale), the reaction does require extreme temperatures.78 O

H 360 °C decalin

Me

85%

Me

3.5.3

H O

Me

O

Me

Me

Me

Me

Hydrogen–Malonate/Enolate Addition (Michael Reaction)

Active methylene compounds such as malonates and β-keto esters readily add to activated olefins (enones, acrylates). This can be coupled with a subsequent saponification/decarboxylation to give the acid corresponding to conjugate addition of an acetic acid dianion equivalent. The following example is from a Paquette Organic Syntheses preparation of 4-methyltricyclo[2.2.2.03,5 ]octane-2,6-dione.79 O

CH2(CO2Et)2 Na, EtOH 74–76%

Me

O CO2Et Me CO2Et

(i) KOH (ii) HCl, reflux

O

O CO2H

O

79% Me

Me

Merck reported the multikilogram reaction of dimethylmalonate and methyl vinyl ketone to form a keto bis-ester, which served as a trans-aminase substrate en route to an enantiomerically pure piperidine intermediate.80

Me

+ O

MeO2C

CO2Me

K 2CO3 MeCN 80%

CO2Me Me

CO2Me O

Me HN • CSA

OH

76 Xia, Q.; Ganem, B. Organic Letters 2001, 3, 485–487. 77 Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003–9031. 78 Schostarez, H.; Paquette, L. A. Tetrahedron 1981, 37, 4431–4435. 79 Poupart, M.-A.; Lassalle, G.; Paquette, L. A. Organic Syntheses 1990, 69, 173–179. 80 Girardin, M.; Ouellet, S. G.; Gauvreau, D.; Moore, J. C.; Hughes, G.; Devine, P. N.; O’Shea, P. D.; Campeau, L.-C. Organic Process Research & Development 2012, 17, 61–68.

3.5 Hydrogen–Carbon Addition (Hydroalkylation)

Malonate anions also add to acetylenes, albeit with modest E/Z selectivity. In the following example, triethylamine catalyzes the addition to alkynoate with 3 : 1 E/Z selectivity; the paper includes several examples with enones, which exhibit more modest selectivity (1–2 : 1). Phoramidites (e.g. HMPT = (Me2 N)3 P) also catalyze this reaction.81 Me CO2Et

Me

+

Me

Et 3N

CO2Et

CH3CN

CN

CO2Et

Me

NC CO2Et

95%

75 : 25 E/Z

Heathcock and coworkers have extensively studied the stereoselectivity of enolate additions to Michael acceptors. The two examples shown in the following exhibit high regio- and stereoselectivity; the latter is not the case for many other examples. Both examples involve addition of a preformed lithium enolate of a propionamide to an α,β-unsaturated ketone.82 O Me +

N

Me

O Me Me

Me

O

Me

N

+

THF –78 to 25 °C 87%

t-B u

Et

Me

O

N Me

THF –78 °C 86%

Me

Me

>95 : 5 diastereoselectivity >97 : 3 regioselectivity Et

O

LDA

O

Me

O

LDA

O t-Bu

Me N

93 : 7 diastereoselectivity >97 : 3 regioselectivity

Enol silanes can also add to activated olefins (Mukaiyama–Michael addition). Several useful variants of this reaction have been developed; a preparatively useful enantioselective example from the Evans lab is shown in the following.83

OTMS N

Me +

Cu cat :

EtO2C

O t-Bu

N

O Cu

N

EtO O

5 mol% Cu cat O

2+

Me Me N

O

O

2 SbF 6–

(CF3)2CHOH CH2Cl 2 –20 °C 97%

N

O

O

O N

Me

O

99 : 1 diastereoselectivity 97% ee

t-Bu

81 Grossman, R. B.; Comesse, S.; Rasne, R. M.; Hattori, K.; Delong, M. N. The Journal of Organic Chemistry 2003, 68, 871–874. 82 Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H. The Journal of Organic Chemistry 1990, 55, 132–157. 83 Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. Journal of the American Chemical Society 2001, 123, 4480–4491.

183

184

3 Addition to Carbon–Carbon Multiple Bonds

Electron-rich aromatic rings can also function as nucleophiles in these reactions. For example, MacMillan and coworkers have applied organocatalysis to effect addition of furan84 and pyrrole85 nucleophiles to enals. An example from the second reference is shown in the following. Me Me

+

N Me

O

N

•TFA

Me N H Ph (20 mol%)

Ph

O

N Me

aq THF –30 °C, 42 h 87%

O Ph

Nitroalkanes can also serve as effective nucleophiles in conjugate additions, as shown in the following example for an α,β-unsaturated ester.86 Me Me Boc N

Me

Me Me

O CO2Me

CH3NO2 TBD (0.4 eq) 99%

Me

Boc N

O

Me Me

NO2

N

TBD = N H

CO2Me

N

Trialkyl phosphines can catalyze a vinylogous Baylis–Hillman reaction, which is essentially the addition of the α-carbon of an enone to a Michael acceptor. The following two examples come from Roush and coworkers87 and Krische and coworkers.88 Each cyclization proceeds with high diastereoselectivity (10 : 1 and >19 : 1, respectively). TBSO

CHO

TBSO

CHO

PBu 3 (30 mol%) CH3CN, 25 °C 90%

TBSO TBSO

O

Me

OBn OBn

3.5.4

CHO

O Me OBn

O

CHO

PBu 3 (20 mol%) t-BuOH, 84 °C

Me OBn

O Me

81%

OBn OBn

Hydrogen–Alkyl Addition, Stork Enamine Reaction

When condensed with secondary amines (e.g. pyrrolidine), enolizable aldehydes and ketones generate enamines, which are excellent nucleophiles for conjugate addition to Michael acceptors such as methyl vinyl ketone. The following two 84 85 86 87 88

Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. Journal of the American Chemical Society 2003, 125, 1192–1194. Paras, N. A.; MacMillan, D. W. C. Journal of the American Chemical Society 2001, 123, 4370–4371. Hanessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomley, M. The Journal of Organic Chemistry 2005, 70, 6746–6756. Frank, S. A.; Mergott, D. J.; Roush, W. R. Journal of the American Chemical Society 2002, 124, 2404–2405. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. Journal of the American Chemical Society 2002, 124, 2402–2403.

3.5 Hydrogen–Carbon Addition (Hydroalkylation)

examples are representatives.89,90 In both cases, Mannich cyclization of the initial product generates a cyclohexenone product.

CHO

N H

(i) MeC(O)CH=CH2 (ii) NaOAc, AcOH

N

(iii) aq NaOH

94%

44–49% O

HN Me

Me

Me

Me

Me

CHO

O

O

N Me

94–95%

O

Me Me

HCl 71–85%

N

Me Me

Use of a chiral secondary amine such as (S)-proline can generate chiral, nonracemic products, as in the classic preparation of the Wieland–Miescher ketone shown in the following.91 O

Me

O MeC(O)CH=CH2

Me

aq AcOH

O

3.5.5

MeO

O Me

(S)-proline (5 mol%) DMSO

O

O

57%

Hydrogen–Alkyl Addition, Metal-Catalyzed

The first example in this category is narrow in scope, being limited to malonate nucleophiles, but is remarkably atom economical and efficient (e.g. no solvent, and just 2 mol% of an inexpensive catalyst).92 O

CO2Et +

FeCl3 • 6 H2O (2 mol%) neat

O Me

O

91–93%

O CO2Et

Me

Addition of cuprate reagents (R2 CuLi) to electron-deficient olefins is well known; copper-catalyzed addition of Grignard reagents effects a similar transformation. The example below comes from a synthesis of (−)-8-phenylmenthol.93 (i) PhMgBr, CuBr Et 2O, –20 °C

Me

Me

(ii) 2 N HCl O Me

Me

(iii) KOH, EtOH reflux 79–91%

O Me

Me Ph

87 : 13 diastereoselectivity 89 90 91 92 93

Kane, V. V.; Jones, M., Jr. Organic Syntheses 1983, 61, 129–133. Chan, Y.; Epstein, W. W. Organic Syntheses 1973, 53, 48–52. Buchschacher, P.; Fuerst, A. Organic Syntheses 1985, 63, 37–43. Christoffers, J. Organic Syntheses 2002, 78, 249–253. Ort, O. Organic Syntheses 1987, 65, 203–214.

185

186

3 Addition to Carbon–Carbon Multiple Bonds

Another useful variant is shown in the following and utilizes catalytic MnCl2 in addition to CuCl.94 Note that the decreased diastereoselectivity is due to the absence of the KOH-EtOH equilibration step. n-BuMgCl MnCl 2 (30 mol%) CuCl (3 mol%)

Me

THF, 0 °C 94%

O Me

Me

Me

O Me Me n-Bu

62 : 38 diastereoselectivity

A nice example from Bristol-Myers Squibb is shown in the following, in which use of a bis-phosphine ligand facilitates very low levels of copper catalyst.95 MeMgCl CuCl (5 mol%) DPPP (7 mol%)

O

Me

O

TMSCl THF

O

Me

O

Me

60–65% distilled

Recently, Pd-catalyzed conjugate addition of arylboronic acids to enones has been developed, as shown in the following example from Stoltz.96 O

Cl + Me

Pd(OCOCF 3)2 (5 mol%) (S)-tert-BuPyOx (6 mol%) NH4PF6 (0.30 equiv) Water ClCH 2CH2Cl 40 °C

(HO)2B

(S)-tert-BuPyOx =

Cl Me

93% ee 87–91 % yield

O

N

O

N t-B u

Several metal-mediated conjugate additions have been developed more recently, similar to conjugate addition of cuprate or Grignard reagents. Nickel catalyzes the conjugate addition of vinylzirconium reagents to enones, as shown in the following.97 O

Me

Cp 2ZrHCl THF 15–25 °C

n-Hex

ZrCp 2Cl

O

Ni(acac) 2 (10 mol%) THF 25–50 °C 59%

n-Hex

94 Alami, M.; Marquais, S.; Cahiez, G. Organic Syntheses 1995, 72, 135–146. 95 Young, I. S.; Haley, M. W.; Tam, A.; Tymonko, S. A.; Xu, Z.; Hanson, R. L.; Goswami, A. Organic Process Research & Development 2014, 19, 1360–1368. 96 Holder, J. Organic Syntheses 2015, 92, 247–266. 97 Sun, R. C.; Okabe, M.; Coffen, D. L.; Schwartz, J. Organic Syntheses 1993, 71, 83–88.

3.5 Hydrogen–Carbon Addition (Hydroalkylation)

Copper can catalyze the conjugate addition of alkylzirconium reagents to enones. The following example proceeds in 73% yield on 1 g scale (the product was isolated as the dinitrophenylsulfonylhydrazone).98 (i) CuCN (3 mol%) Et 2O, 25 °C O N Me

Cp 2ZrHCl

Me

Me Me

ZrCp 2Cl

THF, 40 °C

NHSO2Ar

(ii) ArSO2NHNH2 EtOH 73%

Me Me Me

NO2

Ar =

NO2

The following example is similar to the preceding one but does not involve isolation of the intermediate vinylzirconium reagent.99

(i) Cp2ZrHCl THF, 40 °C Me

Ph

(ii) CuI·0.75 Me2S THF, 40 °C

n-Bu

O Me

O Ph

Me 97%

In situ alcohol protection as a borate ester facilitated the conjugate addition of 4-penten-1-ol to cyclohexanone.100 (i) B(OH)3 (0.3 equiv) toluene (ii) Cp2ZrHCl toluene-THF OH

(iii) CuBr·Me2S

O

OH

O

66%

98 Wipf, P.; Xu, W.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50, 1935–1954. 99 El-Batta, A.; Hage, T. R.; Plotkin, S.; Bergdahl, M. Organic Letters 2004, 6, 107–110. 100 Arnold, D. M.; Krainz, T.; Wipf, P. Org. Synth. 2015, 92, 277–295.

187

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3 Addition to Carbon–Carbon Multiple Bonds

3.5.6

Hydroformylation/Hydroacylation

Addition of H—C(O)X can be a useful process and is frequently executed with a metal catalyst using CO and H2 (for X=H) or CO and XH (where X=OR, NR2 , etc.). The following example is coupled with an in situ TEMPO oxidation to deliver exo-norbornyl-2-carboxylic acid on kilo lab scale (11 kg, 80% yield).101

Rh(CO) 2(acac) (0.15 mol%) DPPF (0.2 mol%)

CHO

CO/H2, t-BuOH 45 psi, 35 °C

(i) NaClO2 (1.2 equiv) TEMPO (2 mol%) t-BuOH (ii) NaOMe, MeOH heptane 2-MeTHF

H

COONa H

80–87% overall

An application of this reaction to the synthesis of tolterodine is shown in the following.102 Me OH

CO, H2 (100 psi ) [Rh(COD)Cl ] 2 (0.4 mol%) TPPTS (0.9 mol%)

Me O

aq toluene, 100 °C

OH

99% SO3Na

TPPTS =

NaO3S

P

SO3Na

A variant of this reaction couples a reductive amination with the initial hydroformylation to effect the net addition of H—CH2 NR2 across a terminal olefin with high regioselectivity.103 CO, H2 [Rh(COD) 2]B F4 (0.1 mol%) Xantphos (0.4 mol%) Me

aq toluene, 100 °C 92%

Xantphos =

Me

N

98 : 2 regioselectivity

Me

Me

O PPh 2

PPh 2

Hydrocyanation of enones can be achieved via the conjugate addition of Et2 AlCN, as developed by Nagata and Yoshioka.104 The example shown in the following traps the initial enolate with TMSCl and then N-bromosuccinimide

101 102 103 104

Gu, J.; Storz, T.; Vyverberg, F.; Wu, C.; Varsolona, R. J.; Sutherland, K. Organic Process Research & Development 2011, 15, 942–945. Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O. Organic Process Research & Development 2002, 6, 379–383. Ahmed, M.; Seayad, A. M.; Jackstell, R.; Beller, M. Journal of the American Chemical Society 2003, 125, 10311–10318. Nagata, W.; Yoshioka, M. Organic Reactions (New York) 1977, 25, 255–476.

3.5 Hydrogen–Carbon Addition (Hydroalkylation)

(NBS) to provide the α-bromoketone. Replacing NBS with aqueous perchloric acid generates the corresponding ketone (appropriate caution should be exercised when handling perchloric acid).105 O

OTMS

(i) Et 2AlCN toluene, 25 °C (ii) TMSCl, Et3N

H

O

H

H

aq HCl O4

Me Me

Me Me

X CN

NBS, THF, 0 °C or

CN

Me Me NBS (X = Br): 68% (6 : 1 dr) aq HCl O4 (X = H): 53%

An indirect way to effect hydroacylation of an enone is a conjugate reduction and subsequent trapping of the enolate with a suitable acylating reagent. The following example is from Mander and coworkers.106

t-BuOH

O

H

H

Li, NH3 LiO

CNCO2Me O H MeO2C

Et 2O

H

81–84%

The Stetter reaction is formally a hydroacylation of an olefin; it proceeds via a deprotonated cyanohydrin, which functions as an acyl anion equivalent. Conjugate addition of this anion to a Michael acceptor constitutes hydroalkylation of the electron-deficient olefin, as shown in the following example with acrylonitrile.107 O CHO

CN

CN

NaCN (cat ) DMF 64–68%

N

N

A particularly useful variant of the Stetter reaction uses a thiazolium salt in place of the cyanide catalyst, and thus is much safer to operate. Two examples are shown below, the first demonstrating preparation of 2,5,8-nonanetrione,108 and the second providing access to a densely substituted cyclopentenone utilized by Tius in a formal total synthesis of roseophilin.109 Me O

+

Me

CHO

O

Cl– Bn + N S

HO Me

O

O

Me

Et 3N, EtOH

Me O

90% O

Me

BzO i-Pr

+

OHC

Cl– Bn + N S

HO

O

O

BzO i-Pr

Et 3N, 1,4-dioxane 60%

105 106 107 108 109

Ihara, M.; Katsumata, A.; Egashira, M.; Suzuki, S.; Tokunaga, Y.; Fukumoto, K. The Journal of Organic Chemistry 1995, 60, 5560–5566. Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Organic Syntheses 1992, 70, 256–264. Stetter, H.; Kuhlmann, H.; Lorenz, G. Organic Syntheses 1980, 59, 53–58. Sant, M. P.; Smith, W. B. The Journal of Organic Chemistry 1993, 58, 5479–5481. Harrington, P. E.; Tius, M. A. Organic Letters 1999, 1, 649–651.

189

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3 Addition to Carbon–Carbon Multiple Bonds

3.5.7

Nazarov Cyclization

The Nazarov cyclization is an electrocyclic, cationic process which provides a powerful approach to cyclopentenones.110,111 Denmark has developed a silicon-directed Nazarov cyclization that offers improvements in reaction rate and regioselectivity relative to the nondirected reaction. The following example is taken from Stille’s synthesis of Δ9(12) -capnellene, in which he utilized this reaction in both five-membered ring cyclizations.112 Me Me O

Me

BF 3 • Et 2O

Me Me

Toluene 100 °C 70%

TMS

Me Me O

Me

BF 3 • Et 2O TMS

Me

O

Me Me

Toluene 25 °C 80%

H

Me

O

H

The following example was utilized in a synthesis of the hydroazulene core of guanacastepene A.113 O

O BF 3 • Et 2O Me

Me Me

CH2Cl 2 0 °C

Me Me

98%

Me

>95 : 5 regioselectivity

Conia has developed a fragmentation-recombination Nazarov cyclization of α,β-unsaturated esters; the following example was reported by J. D. White and coworkers.114 O

O Me

CO2i-Pr

H3PO4 P2O5 100 °C 65–66%

Me

Me

Me

Me

Scandium and copper catalysts have been reported to effectively catalyze the Nazarov cyclization. Moderate to good asymmetric induction has been observed with chiral bis-oxazoline ligands (61–88% ee with 20–100 mol% catalyst loads).115,116,117 110 111 112 113 114 115 116 117

Habermas, K. L.; Denmark, S. E.; Jones, T. K. Organic Reactions (New York) 1994, 45, 1–158. Pellissier, H. Tetrahedron 2005, 61, 6479–6517. Crisp, G. T.; Scott, W. J.; Stille, J. K. Journal of the American Chemical Society 1984, 106, 7500–7506. Chiu, P.; Li, S. Organic Letters 2004, 6, 613–616. Schwartz, K. D.; White, J. D.; Tosaki, S.-Y.; Shibasaki, M. Organic Syntheses 2006, 83, 49–54. Liang, G.; Gradl, S. N.; Trauner, D. Organic Letters 2003, 5, 4931–4934. Aggarwal, V. K.; Belfield, A. J. Organic Letters 2003, 5, 5075–5078. He, W.; Sun, X.; Frontier, A. J. Journal of the American Chemical Society 2003, 125, 14278–14279.

3.6 Halogen–Halogen Addition

The palladium-catalyzed Nazarov cyclization shown in the following occurs under particularly mild conditions (25 ∘ C, aqueous acetone).118 The reaction retains its conrotatory stereospecificity despite the reduced temperature. OH

O OMe

O

aq acetone 25 °C, 14 h 90%

Me Me

PdCl 2(MeCN)2

Me

Me Me

H

Me OH

O OMe

PdCl 2(MeCN)2

O

aq acetone 25 °C, 48 h

Me Me

H Me

90%

Me

Me Me

Cascade polyene cyclizations induced by an initial Nazarov cyclization have also been reported. These involve a combination of C—H and C—C additions across olefins and are discussed in Section 3.15.8. 3.5.8

Radical-Mediated C—H Addition

Intramolecular radical cyclizations have been utilized effectively in numerous total syntheses. These reactions can be efficient, but their overall attractiveness frequently suffers from the use of toxic organostannane reagents to serve as radical propagators (e.g. Bu3 SnH). The following example shows cyclization of an α-silyl radical and was utilized in a total synthesis of talaromycin A.119 Me O

O

Me Bu 3SnH benzene 80 °C

O

O

30% aq H2O2 Na2CO3 MeOH, THF reflux

Br Me

Me O

O

84% overall Si

O

O Me Si Me

Me

OH OH

In some cases, the quantity of alkyltin reagent can be reduced to catalytic quantities through use of a stoichiometric reducing agent such as a trialkylsilane.120 The following example from the synthesis of (−)-malyngolide uses 10 mol% tributyltin chloride and sodium borohydride as the stoichiometric reductant.121 Not surprisingly, no diastereoselectivity is observed for the newly formed stereocenter. Ph O I

O +

C9H19

MeO2C

Me

Bu 3SnCl (10 mol%) NaBH 4 hν, EtOH 70%

MeO2C

Me O

Ph O

C9H19

3.6 Halogen–Halogen Addition Addition of chlorine or bromine to olefins is generally an efficient reaction; three examples are shown in the following. The first is from the steroid literature.122 The second example is from the preparation of a 118 119 120 121 122

Bee, C.; Leclerc, E.; Tius, M. A. Organic Letters 2003, 5, 4927–4930. Crimmins, M. T.; O’Mahony, R. The Journal of Organic Chemistry 1989, 54, 1157–1161. Hays, D. S.; Scholl, M.; Fu, G. C. The Journal of Organic Chemistry 1996, 61, 6751–6752. Giese, B.; Rupaner, R. Liebigs Annalen der Chemie 1987, 231–233. Fieser, L. F. Organic Syntheses 1955, 35, 43–49.

191

192

3 Addition to Carbon–Carbon Multiple Bonds

pyridinyl-3-azabicyclononene; stereochemistry was not determined but was of no ultimate consequence, as the next step was elimination to a vinyl bromide.123 In the third example, formation of the 5α-bromo-6β-chloro isomer provides access to mixed-dihalides, and also served as proof of the mechanism (i.e. α-bromononium ion formation followed by chloride attack from the β-face at the less-substituted 6-position).124 Me Me

Me Me

Me

84% HO

Br 2 CH2Cl 2 N CO2Et

Me Me

Br 2, NaOAc AcOH Et 2O

Me Me

Me HO

Br

(1)

Br N

Br

Br Br

(2)

KOt-Bu

93%

Me Me

N

N

CO2Et

CO2Et

Me Me

Me

Me Me

HCl CH3CONHBr CHCl 3 72%

Me

Me Me (3)

HO

HO

N Me

Br

Cl

3.7 Hydroxy–Halogen Addition Bromohydrins can be prepared from olefins by bromination in aqueous media. In the following example, NBS in aqueous acetone provided the bromohydrin in 95% yield on 40 g scale.125 OH

Br NBS aq acetone 40 °C

O

O

95%

When performed in an alcohol solvent, a similar reaction delivers the analogous alkyl ether.126 The regioselectivity in this reaction is noteworthy and presumably reflects attack of methanol on the bromonium ion carbon distal from the electron-withdrawing alcohol functionality. OH

NBS MeOH 86%

OH Br OMe

123 Breining, S. R.; Genus, J. F.; Mitchener, J. P.; Cuthbertson, T. J.; Heemstra, R.; Melvin, M. S.; Dull, G. M.; Yohannes, D. Organic Process Research & Development 2013, 17, 413–421. 124 Ziegler, J. B.; Shabica, A. C. Journal of the American Chemical Society 1952, 74, 4891–4894. 125 Larsen, R. D.; Davis, P.; Corley, E. G.; Reider, P. J.; Lamanec, T. R.; Grabowski, E. J. J. The Journal of Organic Chemistry 1990, 55, 299–304. 126 Yang, C. H.; Wu, J. S.; Ho, W. B. Tetrahedron 1990, 46, 4205–4216.

3.7 Hydroxy–Halogen Addition

Intramolecular cyclization of olefins containing oxygen nucleophiles can be similarly effected to form cyclic ethers. Iodine is frequently used as the electrophile in these cyclizations, although other electrophiles have been used (e.g. PhSeBr, Hg(OAc)2 , NBS). With carboxylic acids, the product is a lactone.127 OH

O

OH

I2

HO

Me

aq NaHCO 3 THF, Et 2O

Me

82%

I

O Me

O

Me

96 : 4 diastereoselectivity

With alcohol substrates, the product is a cyclic ether, such as a THF, as shown in the following for a spiro-substituted diol (see also Section 1.2.2.4).128 Levels of diastereoselection in these cyclizations can be quite high with proper choice of substrate.129 Note that with this and the preceding example, diethyl ether is used as a solvent; less volatile and easier handled solvents such as MTBE or 2-methyl-THF are preferred and may very well work in place of Et2 O in these types of reactions. OH

OH

I2 aq NaHCO 3 Et2O 98%

OH

I

O

>95 : 5 diastereoselectivity

Similar cyclization onto a terminal alkyne generates a vinyl halide product; in the following example, this product is hydrolyzed to an α-iodo ketone, which cyclizes to a pyranone. The authors propose that the initial cyclization proceeds via iodination of the terminal alkyne, which is consistent with the observed syn-stereochemistry of the vinyl iodide.130 F

F NHBoc

F

NHBoc

MeOH

OH

F

I2 (or NIS ) KOH F

72%

NaHSO4·H2O aq THF

O I

NHBoc

F

OH

H

Na2CO3 THF 71%

O

F NHBoc

F

O

I

O

Note that a complementary approach (albeit two steps) to preparation of halohydrins is opening of an epoxide with a halide nucleophile. In the following example, the resulting alcohol is trapped as a lactone (note that the C 2 -symmetry of the epoxide removes any regioselectivity issues).131 Ph O

O O

N

N i-Pr Ph

127 128 129 130 131

O

i-Pr O

O O

LiBr Mg(Cl O4)2 THF 85%

O O

O O

O

i-Pr

N i-Pr Br Ph

Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C. Journal of the American Chemical Society 1983, 105, 5819–5825. Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yoshida, Z. The Journal of Organic Chemistry 1987, 52, 4062–4072. Rychnovsky, S. D.; Bartlett, P. A. Journal of the American Chemical Society 1981, 103, 3963–3964. Sun, G.; Wei, M.; Luo, Z.; Liu, Y.; Chen, Z.; Wang, Z. Organic Process Research & Development 2016, 20, 2074–2079. Pan, X.; Xu, S.; Huang, R.; Yu, W.; Liu, F. Organic Process Research & Development 2015, 19, 611–617.

193

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3 Addition to Carbon–Carbon Multiple Bonds

3.8 Amino–Halogen Addition Properly configured amino olefins will cyclize to form heterocycles under conditions leading to bromonium ion intermediates. The following example shows cyclization of an aziridine to form a bicyclic pyrrolidine. The analogous cyclizations of the trans-aziridine and the piperidine homologue are higher yielding, but give a mixture of diastereomers.132 O

H

NBS CH2Cl 2

Ph

68%

NH

H

N Br

Ph

O

Free radical addition of dialkyl-N-chloramines is also known, as shown in the following example with diethylN-chloramine.133 Et 2NCl H2SO4, AcOH hν

Cl

83%

Cl Cl

Et 2N

3.9 Carbon–Halogen Addition 3.9.1

Alkyl–Halogen Addition

Carbohalogenation of olefins is a useful methodology in specific cases. One example is in the halonium-activated cyclization cascade of polyenes, as shown in the following.134 Br S

Me Me

Me

Me

SbCl 5Br Me

Me

CH3NO2

Br

Me MeH

71–72%

A second useful method is atom-transfer radical cyclization, largely developed by Curran et al. One advantage of this method relative to the tin hydride approach (see Section 3.5.8) is that catalytic quantities of hexaalkyldistannane (R3 SnSnR3 ) reagents are frequently adequate to initiate the radical chain. The following examples show additions of alkyl iodides to both olefins135 and acetylenes.136

I

(Bu 3Sn) 2 (10 mol%) hν, PhH 80 °C

CO2Me

MeO2C I

68%

Me

Me 1:1

Me I

(Bu 3Sn) 2 (10 mol%) hν, PhH 80 °C

Me

I

71%

132 133 134 135 136

Chen, G.; Sasaki, M.; Li, X.; Yudin, A. K. The Journal of Organic Chemistry 2006, 71, 6067–6073. Neale, R. S.; Marcus, N. L. The Journal of Organic Chemistry 1967, 32, 3273–3284. Snyder, S. A. T., Daniel, S. Organic Syntheses 2011, 88, 54. Curran, D. P.; Chang, C. T. The Journal of Organic Chemistry 1989, 54, 3140–3157. Curran, D. P.; Chen, M. H.; Kim, D. Journal of the American Chemical Society 1989, 111, 6265–6276.

3.9 Carbon–Halogen Addition

Two other preparatively useful examples are shown in the following. The first is a CuBr-catalyzed addition of a diazonium salt to acrylic acid.137 The second is a free radical addition of chloroform to a terminal olefin.138 NaNO2 HBr

NH2

N2+Br –

MeO

CuBr, HBr

MeO

MeO

61–67%

CHCl 3, FeCl 3 (cat ) Et 2NH2Cl (cat), MeOH benzoin (cat)

C6H13

CO2H

CO2H

Cl

Cl

C6H13

130 °C, sealed tube

Br

Cl

64%

3.9.2

Acyl–Halogen Addition

Addition of an acyl (or aldehyde) group and a halogen atom across an olefin is a synthetically useful type of Friedel–Crafts acylation. The product β-halo carbonyl compound is frequently eliminated to the olefin in a subsequent step, as in the following preparation of ethyl 3,3-diethoxypropanoate.139 O Cl

Cl

EtO CCl 3 0–25 °C

K 2CO3

O

EtO

CCl 3

EtOH

O EtO

CCl 3

87%

92%

Intramolecular variants are also known, as shown in the following example from Paquette’s lab. In this particular case, the anticipated Prins cyclization did not occur, presumably due to stereoelectronic constraints.140 OH

CHO

H

SnCl 4

H

CH2Cl 2 –78 to –10 °C 51%

Cl H

The following examples show the intramolecular cyclization of an enone onto an aldehyde or another enone with placement of an iodide on the β-carbon.141 O CHO

Ph

TiCl 4, Bu 4NI CH2Cl 2 0 °C 85%

O Ph I

>99 : 1 diastereoselectivity O

O O Ph

OH

Ph

TiCl 4, Bu 4NI CH2Cl 2 0 °C 99%

O

Ph

Ph I >99 : 1 diastereoselectivity

137 138 139 140 141

Cleland, G. H. Organic Syntheses 1971, 51, 1–4. Vofsi, D.; Asscher, M. Organic Syntheses 1965, 45, 104–107. Tietze, L. F.; Voss, E.; Hartfiel, U. Organic Syntheses 1990, 69, 238–244. Cheney, D. L.; Paquette, L. A. The Journal of Organic Chemistry 1989, 54, 3334–3347. Yagi, K.; Turitani, T.; Shinokubo, H.; Oshima, K. Organic Letters 2002, 4, 3111–3114.

195

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3 Addition to Carbon–Carbon Multiple Bonds

3.10 Oxygen–Oxygen Addition 3.10.1

Dihydroxylation of Olefins

Dihydroxylation of olefins is an important transformation in organic synthesis, and several methods have been developed to effect this oxidation. Although osmium tetroxide is most frequently used, it suffers from the handling and waste stream issues associated with osmium. Nonetheless, this reagent is particularly useful on laboratory scale for its predictability and tremendously wide scope of substrates. An example using the “Upjohn procedure” (aqueous N-methylmorpholine-N-oxide as the stoichiometric oxidant) is shown in the following.142 For water-soluble product diols, in situ protection with PhB(OH)2 is a useful variation.143,144,145 OsO 4 (0.27 mol%) NMO hydrate

NMO =

OH

aq acetone 25 °C 89–90%

O

OH

+ Me N O–

Although less general than osmium-mediated dihydroxylation, potassium permanganate offers a more practical solution when the substrate allows the use of this reagent.146 This transformation was recently utilized in a large-scale preparation of a nicotine partial agonist; the diol product was then converted to a piperidine via an oxidative cleavage/reductive amination sequence.147 OH F

KMnO 4

F

BnEt 3NCl CH2Cl 2 42–67%

OH F

(i) NaIO4, MeOH aq pH 7 buffer (ii) PhCH2NH2 Na(OAc)3BH CH2Cl 2

F

N

Ph

F F

73%

Catalytic ruthenium represents another alternative to osmium for effecting olefin dihydroxylation. The following example was optimized for a 50 kg pilot plant run.148

O N O

Ph

RuCl 3 (0.8 mol%) NaIO4 EtOAc, CH3CN H2O, 5 °C

HO

O N

HO

Ph

O

73%

One of the most important catalytic asymmetric transformations in organic chemistry is the Sharpless asymmetric dihydroxylation (AD) of olefins. The OsO4 -ligand-salt complex is commercially available (AD-mix-α and β), making this a particularly convenient transformation, although the osmium waste stream and handling issues must still be dealt

142 VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Organic Syntheses 1978, 58, 43–52. 143 Iwasawa, N.; Kato, T.; Narasaka, K. Chemistry Letters 1988, 1721–1724. 144 Gypser, A.; Michel, D.; Nirschl, D. S.; Sharpless, K. B. The Journal of Organic Chemistry 1998, 63, 7322–7327. 145 Sakurai, H.; Iwasawa, N.; Narasaka, K. Bulletin of the Chemical Society of Japan 1996, 69, 2585–2594. 146 Ogino, T.; Mochizuki, K. Chemistry Letters 1979, 443–446. 147 Bashore, C. G.; Vetelino, M. G.; Wirtz, M. C.; Brooks, P. R.; Frost, H. N.; McDermott, R. E.; Whritenour, D. C.; Ragan, J. A.; Rutherford, J. L.; Makowski, T. W.; Brenek, S. J.; Coe, J. W. Organic Letters 2006, 8, 5947–5950. 148 Couturier, M.; Andresen, B. M.; Jorgensen, J. B.; Tucker, J. L.; Busch, F. R.; Brenek, S. J.; Dube, P.; Ende, D. J.; Negri, J. T. Organic Process Research & Development 2002, 6, 42–48.

3.10 Oxygen–Oxygen Addition

with. The following example provides a quantitative yield of product with 84% ee; after recrystallization, a 52–57% yield of 97% ee material is obtained.149,150 O

K 2OsO 2 (cat ) DHQD-PHN (cat )

O

O

K 3Fe(CN)6 aq t-BuOH

O

OH OH

52–57% DHQD-PHN =

Me O N N OMe

An example of a trisubstituted cyclic olefin is shown in the following (>98% ee).151 BnO

O

OsO 4 (DHQD)2PHAL

BnO

BnO

O

HO

CH2Cl 2

OTBDMS

95%

3.10.2

OH O CH2Ph

OTBDMS

Keto-Hydroxylation of Olefins

With proper choice of conditions, olefins can also be converted to α-hydroxy ketones with KMnO4 .151 Note that the outcome of these oxidations is dependent on both solvent and pH. In the example shown, the use of aqueous acetone and a weak acid was credited with controlling the path of oxidation (i.e. diol vs. hydroxy-ketone vs. diketone).

C4H9

OH

KMnO4

C4H9

C4H9

C4H9

73%

O

RuO4 (in this case generated catalytically from RuCl3 and Oxone, 2KHSO5 ⋅ KHSO4 ⋅ K2 SO4 ) effects a similar transformation, with good levels of regioselectivity with certain unsymmetrical disubstituted olefins.152 Styrene derivatives and enones are particularly good substrates for this oxidation. CO2Me

RuCl 3 (1 mol%) Oxone

O CO2Me

NaHCO3 EtOAc, CH3CN, H2O 82%

OAc

RuCl 3 (1 mol%) Oxone NaHCO3 EtOAc, CH3CN, H2O 79%

OH 96 : 4 regioselectivity

OAc OH O >95 : 5 regioselectivity

149 Oi, R.; Sharpless, K. B. Organic Syntheses 1996, 73, 1–12. 150 Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. The Journal of Organic Chemistry 1991, 56, 4585–4588. 151 Luniwal, A.; Khupse, R.; Reese, M.; Liu, J.; El-Dakdouki, M.; Malik, N.; Fang, L.; Erhardt, P. Organic Process Research & Development 2011, 15, 1149–1162. 152 Plietker, B. The Journal of Organic Chemistry 2004, 69, 8287–8296.

197

198

3 Addition to Carbon–Carbon Multiple Bonds

3.10.3

Dihydroxylation of Acetylenes

In a reaction similar to the dihydroxylation of olefins, acetylenes can be oxidized to α-diketones. One of the simplest procedures uses KMnO4 in aqueous acetone (following example).153 H5 IO6 in acetic acid effects the analogous transformation of diphenylacetylene with similar efficiency.154

C7H15

KMnO 4 NaHCO3 MgSO 4

C7H15

O

aq acetone

C7H15

C7H15

O

81%

A variety of other oxidants have been reported to accomplish this transformation, SO3 -dioxane complex provides good results,155 while elevated temperatures (>100 ∘ C) are required for oxidation in DMSO with PdCl2 156 and I2 .157,158 In the following example, an alkoxyacetylene is oxidized to an α-ketoester; since the substrate is generated from addition of LiCCOEt to a ketone, the acetylene anion is serving as an acyl anion equiv.159 OH

CO2Et

aq NaHCO 3 acetone 98%

OEt

3.10.4

OH

KMnO 4

O

Epoxidation

Peracids (RCO3 H) are a useful reagent class for effecting epoxidations, with meta-chloroperbenzoic acid (m-CPBA) and magnesium monoperoxyphthalate (MMPP) being particularly convenient for laboratory scale oxidations. O

O O

CO2– MMPP

OH

Mg ++

Cl

O

OH

2

m-CPBA

It should be noted that high concentrations of nonaqueous m-CPBA have been reported to be explosive160 and are generally not commercially available. Several commercial suppliers sell the reagent at 75–80%, of which the remainder is the benzoic acid derivative and water. This material can be used as received or purified to the crystalline peracid before use.161 Three examples of its use are shown in the following. The first example provides high α-diastereoselectivity for the epoxidation of cholesterol, and in his detailed procedure, Fieser reports that other peracids were less stereoselective.162 The second example also exhibited high diastereoselectivity with m-CPBA (>99 : 1), but 153 154 155 156 157 158 159 160 161 162

Srinivasan, N. S.; Lee Donald, G. The Journal of Organic Chemistry 1979, 44, 1574. Gebeyehu, G.; McNelis, E. The Journal of Organic Chemistry 1980, 45, 4280–4283. Rogatchov, V. O.; Filimonov, V. D.; Yusubov, M. S. Synthesis 2001, 1001–1003. Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov, E. V.; Knight, D. W. Tetrahedron 2002, 58, 1607–1610. Yusybov, M. S.; Filimonov, V. D. Synthesis 1991, 131–132. Yusubov, M. S.; Filimonov, V. D.; Vasilyeva, V. P.; Chi, K.-W. Synthesis 1995, 1234–1236. Tatlock, J. H. The Journal of Organic Chemistry 1995, 60, 6221–6223. Bretherick, L. Bretherick’s Handbook of Reactive Chemical Hazards, 6th Edition; Butterworth-Heinemann Ltd: Oxford, 1999. Schwartz, N. N.; Blumbergs, J. H. The Journal of Organic Chemistry 1964, 29, 1976–1979. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1967.

3.10 Oxygen–Oxygen Addition

little selectivity with MMPP (53 : 47).163 The third example, also highly diastereoselective (>99 : 1), was run on kilogram scale.164 Me Me

Me Me

Me Me

Me

m-CPBA

Me Me

Me

(1)

CH2Cl 2

HO

95%

PMBO

Me

O

OTBS

HO

m-CPBA Na2HPO4

Me

O

PMBO

OTBS

CH2Cl 2

BnO

O OH

BnO

Ph

Ph

O

i-Pr

O

O

N

N i-Pr

O

(2)

Me

89%

OH

Me

O

91%

O

i-Pr N

N

O

CH2Cl 2

O

O

O

m-CPBA

O

i-Pr

O

O

(3)

O

Ph

Ph

An example of an allylic alcohol epoxidation with MMPP is shown below in which there is no diastereoselectivity issue; the example was run on 12 g scale.165 OH

OH

MMPP 9 : 1 MeOH-H2O 25 °C

O

88%

Also convenient for laboratory scale epoxidations are dioxirane reagents, generally derived by the in situ oxidation of ketones with Oxone (larger scale examples are known using the in situ formation method as well). The example shown below uses tetrahydrothiopyran-4-one (the active catalyst is the derived sulfone).166 Numerous examples from the acetone-derived dioxirane (3,3-dimethyldioxirane, DMDO) are also known.167,168,169

®

O

Me Ph

Ph

S Oxone, pH 7–7.5 aq CH 3CN, 25 °C

Me Ph

Ph O

98–99%

163 164 165 166 167 168 169

Marshall, J. A.; Crute, T. D., III; Hsi, J. D. The Journal of Organic Chemistry 1992, 57, 115–123. See Note 131. Krysan, D. J.; Haight, A. R.; Menzia, J. A.; Welch, N. Tetrahedron 1994, 50, 6163–6172. Yang, D.; Yip, Y.-C.; Jiao, G.-S.; Wong, M.-K. Organic Syntheses 2002, 78, 225–233. Roberge, J. Y.; Beebe, X.; Danishefsky, S. J. Journal of the American Chemical Society 1998, 120, 3915–3927. Murray, R. W. Chemical Reviews 1989, 89, 1187–1201. Adam, W.; Rao, P. B.; Degen, H.-G.; Levai, A.; Patonay, T.; Saha-Moeller, C. R. The Journal of Organic Chemistry 2002, 67, 259–264.

199

200

3 Addition to Carbon–Carbon Multiple Bonds

Several groups have reported asymmetric variants of dioxirane-mediated epoxidations.170,171,172 The following example is an improved preparation of one of Shi’s chiral catalysts; the ketone catalyst is prepared in four steps from d-fructose.173 A discussion addendum for this reaction has appeared in Organic Syntheses.174 Me O

O AcO

OH

Ph

Me O

O OAc 10 mol %

Ph

Oxone, aq K 2CO3 CH3CN, DME aq Bu 4NHSO4

OH

O 96% ee

68%

Metal-mediated epoxidations represent one of the first practical examples of catalytic enantioselective transformations and are ubiquitous in epoxidation chemistry. The following example represents a procedure that has undergone significant optimization in the Sharpless lab.175 OH CO2Et

EtO2C

OH Ti(i-PrO)4 OH

Me

Me

t-BuOOH toluene, CH2Cl2

OH

O 97% ee

63–69%

Several large-scale (>100 g) applications of the Sharpless asymmetric epoxidation (AE) have been reported,176,177,178 including the two examples in the following.179,180 OH

Me

OH

Ti(O-i-Pr) 4 D-(–)-DiPT t-BuOOH CH2Cl 2

O Me

OH

F

OH

–25 to –15 °C 81% 96% ee

O F3CO

MeOH

Me

OH OH

43% overall

D-(–)-DIPT

t-BuOOH Ti(O-i-Pr) 4

F3CO K 2CO3

O F

O OH

HO HO

OiPr OiPr

D-(–)-DIPT

O

170 Wu, X.-Y.; She, X.; Shi, Y. Journal of the American Chemical Society 2002, 124, 8792–8793. 171 Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. Journal of the American Chemical Society 1998, 120, 5943–5952. 172 Denmark, S. E.; Wu, Z. Synlett 1999, 847–859. 173 Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A. The Journal of Organic Chemistry 2005, 70, 10143–10146. 174 Ramirez, T. A., Wong, O. A.; Shi, Y. Organic Syntheses 2012, 89, 350. 175 Hill, J. G.; Sharpless, K. B.; Exon, C. M.; Regenye, R. Organic Syntheses 1985, 63, 66–78. 176 Satam, V. S.; Pedada, S. R.; Kamaraj, P.; Antao, N.; Singh, A.; Hindupur, R. M.; Pati, H. N.; Thompson, A. M.; Launay, D.; Martin, D. Organic Process Research & Development 2017, 21, 52–59. 177 Alimardanov, A.; Gontcharov, A.; Nikitenko, A.; Chan, A. W.; Ding, Z.; Ghosh, M.; Levent, M.; Raveendranath, P.; Ren, J.; Zhou, M.; Mahaney, P. E.; McComas, C. C.; Ashcroft, J.; Potoski, J. R. Organic Process Research & Development 2009, 13, 880–887. 178 Henegar, K. E.; Cebula, M. Organic Process Research & Development 2007, 11, 354–358. 179 See Note 177. 180 See Note 176.

3.10 Oxygen–Oxygen Addition

This reaction is also useful for the kinetic resolution of racemic allylic alcohol substrates. The following example is from Roush’s synthesis of (+)-olivose.181 Note that the yield of 27–33% represents 54–66% of theory. A 30% recovery (60% of theory) of optically enriched starting alcohol is also obtained from the reaction (72% ee, (S)-enantiomer). Vanadium-catalyzed epoxidations (and kinetic resolution) of homoallylic alcohols have also been reported.182 OH CO2 i-Pr

i-PrO 2C Me

OH Ti(i-PrO )4

Me O

t-BuOOH CH2Cl 2 27–33%

OH

OH >95% ee

Jacobsen and coworkers have developed a class of Mn-salen catalysts for the enantioselective epoxidation of olefins. This catalyst class offers a wider range of substrate scope than the sharpless epoxidation, as the requirement for an allylic alcohol in the substrate olefin is obviated. The following example was utilized in the synthesis of the HIV protease inhibitor indinavir.183 The catalyst preparation is also described in an earlier Organic Syntheses procedure.184

N t-Bu

O

Mn

Cl

t-Bu

N t-Bu

O t-Bu +

O 84–86% ee

N O–

Ph

NaOCl, CH2Cl 2, 0 °C 71%

Related metal salen catalysts developed by Jacobsen are useful for the hydrolytic kinetic resolution of epoxides.185 As noted earlier for the sharpless kinetic resolution, the 36–37% yield represents 72–74% of theory.

N t-Bu O

N O

t-Bu O

t-Bu

t-Bu

p-TsOH H2O 25 °C 36–37%

OMe

O

O

Co

O

OMe >99% ee

A final class of epoxidations that differs in mechanism from those described previously is the nucleophilic epoxidation of enones. This can be effected with basic hydrogen peroxide and proceeds via a conjugate addition/elimination mechanism.186 O

H2O2 aq NaOH MeOH 0 °C 75–77%

O O

181 Roush, W. R.; Brown, R. J. The Journal of Organic Chemistry 1983, 48, 5093–5101. 182 Zhang, W.; Yamamoto, H. Journal of the American Chemical Society 2007, 129, 286–287. 183 Larrow, J. F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.; Senanayake, C. H.; Reider, P. J.; Jacobsen, E. N. Organic Syntheses 1999, 76, 46–56. 184 Larrow, J. F.; Jacobsen, E. N. Organic Syntheses 1998, 75, 1–11. 185 Stevenson, C. P.; Nielsen, L. P. C.; Jacobsen, E. N.; McKinley, J. D.; White, T. D.; Couturier, M. A.; Ragan, J. Organic Syntheses 2006, 83, 162–169. 186 Felix, D.; Wintner, C.; Eschenmoser, A. Organic Syntheses 1976, 55, 52–56.

201

202

3 Addition to Carbon–Carbon Multiple Bonds

Olefin expoxidation via chlorohydrin formation and cyclization can be a practical alternative to direct epoxidation, as shown in the following kilogram-scale sequence from Bristol-Myers Squibb. The racemic 3,4-epoxyN-benzylpiperidine product can be isolated as the crystalline fumaric acid salt, although it was determined that this salt was a dermal sensitizer. In the published process, the epoxide was processed forward as a solution.187

Cl

(i) NCS aq TFA (ii) aq NaOH

(i) Pyridine NaBH4 EtOH N

(ii) aq MTBE

N

(iiii) aq MeTHF

Ph

3.10.5

O

Ph

58%

•

HO2C

CO2H

Singlet Oxygen Addition to Dienes

Photochemical-mediated addition of singlet oxygen to dienes can be an efficient route to endoperoxides, which can then be reduced to diols or converted to other functional groups. Meso-tetraphenylporphine is frequently used as the photo-sensitizing agent. The following example from Carl Johnson’s group proceeds in 76% yield on 20 g scale.188 In a useful extension of this chemistry, Toste and coworkers have demonstrated the desymmetrization of endoperoxides with chiral quinuclidine bases (Kornblum DeLeMare rearrangement).189 OTBS

O2, hν TPP CH2Cl 2 MeOH 76%

OTBS

OTBS

5 mol% cat O

O

25 °C 83%

HO

O OH

Cat = OAc N

N

3.11 Oxygen–Nitrogen Addition The Sharpless Group has developed the osmium-mediated aminohydroxylation of olefins with chloramines to provide either sulfonamide or carbamate-protected cis-aminoalcohols. For sulfonamides, chloramine-T is used in the presence of 5 mol% phase transfer catalyst.190 TsNClNa • 3H2O OsO4 (1 mol%) BnNEt 3Cl (5 mol%) CHCl 3, H2O

OH NHTs

74–81%

187 Young, I. S.; Ortiz, A.; Sawyer, J. R.; Conlon, D. A.; Buono, F. G.; Leung, S. W.; Burt, J. L.; Sortore, E. W. Organic Process Research & Development 2012, 16, 1558–1565. 188 Johnson, C. R.; Golebiowski, A.; Steensma, D. H. Journal of the American Chemical Society 1992, 114, 9414–9418. 189 Staben, S. T.; Xin, L.; Toste, F. D. Journal of the American Chemical Society 2006, 128, 12658–12659. 190 Herranz, E.; Sharpless, K. B. Organic Syntheses 1983, 61, 85–93.

3.11 Oxygen–Nitrogen Addition

For preparation of carbamates, an N-chloro sodium salt is utilized in the presence of silver nitrate. The N-chloro carbamate salt is prepared by a known method from t-butyl hypochlorite, ethyl carbamate, and base.191

Ph

Ph

EtOCONClNa (1.5 equiv) AgNO3 (1.0 equiv) OsO 4 (1 mol%) CH3CN t-BuOH- H2O 66–69%

NHCO2Et Ph

Ph OH

This method has been utilized as shown below for the preparation of oxazolidinones from styrenes. Regioselectivity for the benzylamine isomer ranges from good to modest (91 : 9 to 50 : 50), but the desired isomer cyclizes more rapidly to the oxazolidinone, which facilitates separation (uncyclized material can be separated by acid extraction). The example shown proceeded in 73% yield and 90–93% ee. An experimental on 2 g scale is provided, and the authors indicate that scale-up to kilograms has been performed.192 H2NCO2Et

F

NaOH

F

F

K 2[OsO 2(OH)4] O Me

Cl N

Me Me

N O Cl aq n-PrOH

Me

Cs 2CO3

HN OH CO2Et

MeOH 73%

Me HN

O O

Merck scientists have utilized an asymmetric epoxidation followed by a Ritter reaction to provide the net syn-aminohydroxylation of olefins. The sequence shown in the following was developed for the synthesis of the protease inhibitor indinavir. The preparation of the starting epoxide is described in the same Organic Syntheses procedure.193 CH3CN H2SO4 (fuming) O

Hexanes 0–5 °C

(i) H2O (ii) L-tartaric acid

O N

Me

(iii) aq NaOH 59%

OH NH2

Copper reagents will effect the coupling of oxaziridines and olefins to generate oxazolines, which constitutes a net aminohydroxylation of the olefin.194 Experimental evidence supports a stepwise, cationic mechanism for this reaction.

Ph

SO2Ph N O (1.5 equiv)

Cu(CF 3CO2)2 (2 mol%) HMPA (10 mol%) CH2Cl 2

H O H N PhO 2S

Ph

77 : 23 diastereoselectivity

81%

191 192 193 194

Herranz, E.; Sharpless, K. B. Organic Syntheses 1983, 61, 93–97. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider, P. J. Organic Letters 2000, 2, 2821–2824. See Note 183. Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. Journal of the American Chemical Society 2007, 129, 1866–1867.

203

204

3 Addition to Carbon–Carbon Multiple Bonds

3.12 Nitrogen–Nitrogen Addition 3.12.1

Aziridination

Rhodium-catalyzed oxidation of olefins with sulfonamides in the presence of a stoichiometric oxidant provides an efficient synthesis of aziridines. The following examples are from Du Bois and coworkers;195 Doyle and coworkers have reported a similar catalyst system for the addition of p-toluenesulfonamide (TsNH2 ) to olefins catalyzed by Rh2 (cap)4 (cap = caprolactam).196 O O S O

Rh 2(oct )4 (2 mol%) PhI(OAc)2

H2N

MgO CH2Cl 2 87%

OTBS

t-BuO 2C

O O S N O

t-BuO 2C H

H

OTBS

20 : 1 diastereoselectivity

Oct = C 7H15COO– Rh 2(NHCOCF3)4 (1–2 mol%) Me PhI(OAc)2

N

SO2OCH2CCl 3 Me

MgO CH2Cl 2 85%

3.12.2

N—N Addition to Olefins

A practical, general method for the diamination of olefins remains elusive. Osmium-mediated diaminations are known, as shown in the following.197 Reactions with fumarate esters showed the diamination to be stereospecific. The practicality of this method is limited by the need for a stoichiometric osmium reagent, the use of LiAlH4 for converting the initial metal complex to the free diamine, and the use of less desirable solvents. t-BuN (t-BuN=) 3Os=O

Ph

CCl 4

t-Bu

N

Os

O

LiAl H4

N t-Bu

Et 2O

Ph

t-Bu

NH

Ph

NH-t-Bu

89%

Palladium-catalyzed diamination of conjugated dienes and trienes is known and utilizes a diaziridinone reagent to generate cyclic ureas. While of more limited substrate scope, this method offers considerable advantages in terms of handling and waste disposal. Detailed procedures for preparation of the diaziridinone reagent198 and use of a chiral phosphorous ligand to induce enantioselectivity199 have also been reported. O t-Bu Et 195 196 197 198 199

N N +

t-Bu

Pd(Ph 3P)4 (10 mol%) (1.0 equiv) benzene-d 6 65 °C (1.2 equiv)

94%

O t-Bu N Et

N

t-Bu

TFA 75 °C 98%

O HN

NH

Et

Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du Bois, J. Tetrahedron 2006, 62, 11331–11342. Catino, A. J.; Nichols, J. M.; Forslund, R. E.; Doyle, M. P. Organic Letters 2005, 7, 2787–2790. Chong, A. O.; Oshima, K.; Sharpless, K. B. Journal of the American Chemical Society 1977, 99, 3420–3426. Du, H.; Zhao, B.; Shi, Y. Journal of the American Chemical Society 2007, 129, 762–763. Zhao, B., Du, H.; Fu, R.; Shi, Y. Organic Syntheses 2010, 87, 263.

3.12 Nitrogen–Nitrogen Addition

A similar Pd(II)-catalyzed diamination of dienes has been reported200 and utilizes ureas as the diamine source. A stoichiometric oxidant is required (O2 or benzoquinone). Palladium-catalyzed intramolecular diaminations to generate N-sulfonyl ureas are known (example below).201 An asymmetric variant has also been reported.202 Intramolecular copper-catalyzed diaminations to generate sulfonylureas are also known.203 Pd(OAc)2 (25 mol%) PhI(OAc)2 (2.2 equiv)

O N H

N H

Tos

O N

CH2Cl 2, 25 °C

N Tos

86%

Vicinal diamines can also be prepared indirectly from diols, via bis-opening of the cyclic sulfate (available in two steps from the corresponding diol). While indirect, this method translates the practicality of Sharpless’ asymmetric dihyroxylation methodology (see Section 3.10.1) into diamines.204 The example shown is for a symmetrical diamine; use of two different amines (the first for formation of the aziridinium ion and the second to open this intermediate) was also reported. O O O S O C8H17

3.12.3

Bn 2NH CH2Cl 2 25 °C

O

SO3–

C8H17

NBn2

Bn 2NH NaOH PhCH 3 105 °C 81%

NBn2 NBn2

C8H17

Triazines from Azide–Olefin Cycloaddition

Cycloaddition of alkylazides with olefins generates triazines and is formally an example of an olefin diamination. The following example provides access to a variety of useful 2-aminoglycosides (via the 1,2-aziridine intermediate).205 Appropriate care should be taken when handling any alkyl azide reagent. OAc

OAc O

AcO OAc

3.12.4

O

PhCH 2N3 (EtO)3CH 120 °C 94%

AcO

Bn N N N

OAc

OAc O

Sc(OTf )3 MeOH 94%

AcO

OMe NHBn

OAc

N—N Addition to Dienes (1,4)

While limited in scope, the following diene-diazodicarboxylate cycloaddition is an example of a preparatively useful 1,4-diamination of a diene; the product is a precursor to bicyclo[2.1.0]pentane. EtO2CN NCO2Et Et 2O 91–95%

200 201 202 203 204 205

N N

CO2Et CO2Et

Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Journal of the American Chemical Society 2005, 127, 7308–7309. Streuff, J.; Hoevelmann, C. H.; Nieger, M.; Muniz, K. Journal of the American Chemical Society 2005, 127, 14586–14587. Muniz, K.; Nieger, M. Synlett 2003, 211–214. Zabawa, T. P.; Kasi, D.; Chemler, S. R. Journal of the American Chemical Society 2005, 127, 11250–11251. Richardson, P. F.; Nelson, L. T. J.; Sharpless, K. B. Tetrahedron Letters 1995, 36, 9241–9244. Dahl, R. S.; Finney, N. S. Journal of the American Chemical Society 2004, 126, 8356–8357.

205

206

3 Addition to Carbon–Carbon Multiple Bonds

3.13 Carbon–Oxygen Addition 3.13.1

Carbon–Oxygen Addition to Olefins (1,2)

3.13.1.1

[2+2] Cycloadditions of Olefins and Carbonyl Compounds

Oxetane Formation (Olefin + Carbonyl) The photochemical reaction of aldehydes and electron-rich olefins (Paterno-

Büchi reaction)206 has been utilized for the synthesis of substituted oxetanes. With proper disposition of substituents, moderate to good levels of diastereo- and regiocontrol can be realized with this reaction, as shown in the following example.207 O O t-Bu

Me Me

H

PhCHO, hν

O

Benzene

OTMS

Ph

70%

t-Bu

O O

Me Me

OTMS

>90 : 10 diastereoselectivity >95 : 5 regioselectivity

Cycloaddition of aldehydes and furans (also known as the photoaldol reaction) has received particular attention in the context of natural product synthesis, as exemplified in the following from a total synthesis of avenaciolide.208 The photocycloaddition is run neat in 10–15 equiv of furan, and the product is carried on without further purification to the crystalline lactol.

+

O

C8H17

H

hν Neat

O

O

C8H17 O

H

(i) H2, Rh/Al 2O3 EtOAc (ii) 0.1 N HCl THF 93%

H

OH C8H17

O

OH

Beta-lactone Formation (Ketene + Carbonyl) Nelson and coworkers have reported the cinchona alkaloid-catalyzed

[2+2] cycloaddition of ketenes and aldehydes, as shown in the following for the synthesis of a cis-α,β-disubstituted β-lactone.209 Note that this is an extension of Wynberg’s 1982 report of the quinidine-catalyzed reaction of ketene and chloral to form the β-lactone in 95% chemical and optical yield.210

O Cl

Me +

R3N =

O

Me

H

Me

TMSO

R3N (10 mol%) LiCl O4 (2 eq) i-Pr 2NEt

O

O Me Et 2O, CH2Cl 2 Me Me –78 °C 72% 95 : 5 diastereoselectivity 99% ee

N N OMe

The following example shows a chiral aluminum amide catalyst that effects the [2+2] cycloaddition of ketenes and aldehydes to form β-lactones with good enantioselectivity. The catalyst is formed in situ by the reaction of Me3 Al 206 207 208 209 210

Buchi, G.; Inman, C. G.; Lipinsky, E. S. Journal of the American Chemical Society 1954, 76, 4327–4331. Bach, T.; Joedicke, K.; Kather, K.; Froehlich, R. Journal of the American Chemical Society 1997, 119, 2437–2445. Schreiber, S. L.; Hoveyda, A. H. Journal of the American Chemical Society 1984, 106, 7200–7202. Zhu, C.; Shen, X.; Nelson, S. G. Journal of the American Chemical Society 2004, 126, 5352–5353. Wynberg, H.; Staring, E. G. J. Journal of the American Chemical Society 1982, 104, 166–168.

3.13 Carbon–Oxygen Addition

and the bis-sulfonamide; the latter reagent is available in two steps from valinol.211 Similarly, C 2 -symmetric Cu(II) complexes catalyze the [2+2] cycloaddition of TMS-ketene with aldehydes.212 Ph N i-Pr N Al N F3CO2S Me SO2CF3

i-Pr

O Me

+ Br

O

(10 mol%)

O H

Ph

O

i-Pr2NEt, CH2Cl2

Ph

–50 °C 80%

92% ee

Romo et al. has developed a SnCl4 -mediated [2+2] cycloaddition route to cis-α,β-disubstituted β-lactones from aldehydes and thiopyridyl ketene acetals.213 The cis-selectivity is in contrast to his ZnCl2 -mediated coupling, which provides predominantly the trans diastereomer (and presumably occurs via a cationic, stepwise mechanism). TESO Me

O

+ S

H

N

O

SnCl 4 CH2Cl 2 –78 °C

Ph

62%

Me

O Ph

>95 : 5 diastereoselectivity

An enantioselective, intramolecular variant has also been described by Romo and coworkers.214 In addition to the cyclization shown in the following, the Organic Syntheses procedure describes the preparation of the substrate, the chloropyridinium reagent, and the silylated quinidine catalyst. CO2H

O

CHO

O

O-TMS QND =

+

O-TMS QND (10 mol%) i-Pr 2NEt

O

CH3CN

O

Cl

N Me

OSO2CF3

OMe TMSO

O O

33–35% recrystallized yield

N H

N

3.13.1.2

Nitrone–Olefin [3+2] Cycloadditions

The [3+2] cycloaddition of nitrones and olefins effects the net addition of carbon and oxygen across an olefin and has seen wide application in synthesis.215 The first example utilizes achiral nitrone and olefin and demonstrates the intrinsic relative facial selectivity (20 : 1 trans:cis) arising from an exo transition state.216 MeO MeO

+

–

+ O

Toluene N

105 °C 93%

MeO MeO

H O N

Highly diastereoselective chiral nitrone cycloadditions with enol ethers have been applied to the preparation of carbohydrates (high diastereoselectivity refers to the absolute facial selectivity of the nitrone; the modest 4 : 1 relative facial 211 212 213 214 215 216

Nelson, S. G.; Mills, P. M.; Ohshima, T.; Shibasaki, M. Organic Syntheses 2005, 82, 170–178. Evans, D. A.; Janey, J. M. Organic Letters 2001, 3, 2125–2128. Wang, Y.; Zhao, C.; Romo, D. Organic Letters 1999, 1, 1197–1199. Nguyen, H.; Oh, S.; Henry-Riyad, H.; Sepulveda, D.; Romo, D. Organic Syntheses 2011, 88, 121–137. Confalone, P. N.; Huie, E. M. Organic Reactions (New York) 1988, 36, 1–173. Iida, H.; Watanabe, Y.; Tanaka, M.; Kibayashi, C. The Journal of Organic Chemistry 1984, 49, 2412–2418.

207

208

3 Addition to Carbon–Carbon Multiple Bonds

selectivity is of no consequence to the downstream chemistry). The following example is taken from the synthesis of daunosamine.217

O

Me Me

O OAc

O

Me

O

Me

72 °C

+ O– N CH2Ph

Me Me H

PhCH 2 N

70%

O

OAc

80 : 20 diastereoselectivity

The following example shows an enantioselective nitrone–olefin cycloaddition using a C 2 -symmetric nickel catalyst.218 The catalyst ligand preparation has been reported in Organic Syntheses.219

Me O

Cat (2 mol%) 4 Å mol sieves

+

N O

Me

PhH 2C + N O–

O OMe

O

O

>99 : 1 diastereoselectivity 99% ee

O N Ni N (H2O)3 Ph Ph

N CH2Ph

OMe

Cat =

O

N O

CH2Cl 2 25 °C 75%

O

O

The [3+2] cycloaddition of an alkyne with a nitrile oxide provides isoxazole products, as shown below.220 On manufacturing scale (20 kg), the nitrile oxide was generated by treatment of 2-methyl-nitropropane with 1,4-phenylenediisocyanate. On smaller scale, the nitrile oxide was formed from isobutyraldehyde by treatment with hydroxylamine, chlorination with NCS, and treatment with triethylamine. NCO i-Pr

NO2 OCN N

Cl N Cl

N

i-Pr

O N

Me

Cl

O

Et 3N i-PrOAc 89% (NMR assay)

N Cl

N

O N

Me O N i-Pr

The Kinugasa reaction involves coupling of a terminal alkyne with a nitrone to form a β-lactam.221 The mechanism involves an initial [3+2] cycloaddition to form a dihydroisoxazole, which then rearranges to the β-lactam product. 217 218 219 220 221

DeShong, P.; Dicken, C. M.; Leginus, J. M.; Whittle, R. R. Journal of the American Chemical Society 1984, 106, 5598–5602. Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. Journal of the American Chemical Society 1998, 120, 12355–12356. Iserloh, U.; Oderaotoshi, Y.; Kanemasa, S.; Curran, D. P. Organic Syntheses 2003, 80, 46–56. Guz, N. R.; Leuser, H.; Goldman, E. Organic Process Research & Development 2013, 17, 1066–1073. Kinugasa, M.; Hashimoto, S. Journal of the Chemical Society, Chemical Communications 1972, 466–467.

3.13 Carbon–Oxygen Addition

Asymmetric variants have been developed. The first example from Fu utilizes a Cu(I)-bis(azaferrocene) catalyst system.222

H

+

Ph

N O + 4-OMe-C6H4

CuCl (1 mol%) Cat (1.1 mol%) Cy 2NMe

–

Me

Cat =

Me

N Fe

Me Me Me

CH3CN –20 °C

N

O

N

4-OMe-C6H4

92% ee

65%

Me

Me Fe

Ph

>95 : 5 diastereoselectivity

Me

Me

Me Me

Me

Tang has developed a Cu(II)-tris(oxazoline) catalyst system as shown in the following.223

Ph

+

Ph

Cat =

Cu(Cl O4)2·6H2O (10 mol%) Cat (12 mol%) Cy 2NH (1 equiv)

H

N O + Ph

–

i-Pr

i-Pr N O

N Me

O

Ph N

Ph

79% ee 93 : 7 diastereoselectivity

O N

O

3.13.1.3

CH3CN Air, 15 °C 63%

Ph

i-Pr

Noncycloaddition Carbon–Oxygen Additions

The free radical oxy-acylation of terminal olefins to provide butyrolactones can be effected by an in situ generated Mn(OAc)3 ⋅H2 O reagent (prepared from Mn(OAc)3 ⋅4H2 O, KMnO4 , and Ac2 O in AcOH). The yield is >95% based on consumed olefin, and 66% based on potassium permanganate.224

C8H17

Mn(OAc) 3·H2O 6 AcOH NaOAc 134 °C

C8H17

O

O

95%

A multistep protocol for addition of carbon to the β-position of an enone with subsequent α-hydroxylation is shown in the following.225 It involves copper-catalyzed addition of MeMgCl to the enone (see Section 3.5.5) followed by enolate 222 223 224 225

Lo, M. M. C.; Fu, G. C. Journal of the American Chemical Society 2002, 124, 4572–4573. Ye, M.-C.; Zhou, J.; Tang, Y. The Journal of Organic Chemistry 2006, 71, 3576–3582. Heiba, E. I.; Dessau, R. M.; Williams, A. L.; Rodewald, P. G. Organic Syntheses 1983, 61, 22–24. Ohta, T.; Zhang, H.; Torihara, Y.; Furukawa, I. Organic Process Research & Development 1997, 1, 420–424.

209

210

3 Addition to Carbon–Carbon Multiple Bonds

trapping with Ac2 O to generate an intermediate enol acetate. Epoxidation with buffered peracetic acid generates the corresponding epoxide, which hydrolyzes to generate the α-hydroxyketone in 95% yield. Me Me

MeMgCl, CuCl

H

Me H AcO

Me Me

O

H

H

Me

Ac 2O

H AcO

H

OAc Me

H

H NaOAc MeCO3H

Me Me Me

NaOH

Me

H

H AcO

Me Me

O OH

H

3.13.2.1

H

H AcO

95% overall

H

3.13.2

Me

MeOH

OAc O Me

H

H

Carbon–Oxygen Addition to Dienes (1,4) Hetero Diels–Alder Cycloaddition

The [4+2] cycloaddition of an aldehyde and diene (hetero Diels–Alder reaction) constitutes the 1,4 addition of carbon and oxygen across a diene. Danishefsky et al. was an early pioneer of this methodology,226 as shown in the following two examples.227,228 Me

OTMS Me

Me + H O

MeO

TMSO

Me

OBn

Et

+ H

OTMS

Me

TiCl 4

OBn O

Me

O

CH2Cl 2 –78 °C 80%

O

Me

OBn

>95 : 5 diastereoselectivity

H

O

MgBr 2

Me

O

THF 0 °C

OBn

Me

78%

>95 : 5 diastereoselectivity

Jacobsen and coworkers have developed a chromium catalyst for effecting hetero Diels–Alder reactions with high levels of enantioselectivity.229 Me

N O

+ MeO

226 227 228 229

H

OTBS

O

Cr

O Cl (1.5 mol%)

4 Å mol sieves neat 90%

MeO

O

OTBS

>99% ee

Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59–69. Danishefsky, S. J.; Myles, D. C.; Harvey, D. F. Journal of the American Chemical Society 1987, 109, 862–867. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. Journal of the American Chemical Society 1985, 107, 1256–1268. Chavez, D. E.; Jacobsen, E. N.; Grabowski, E. J. J.; Kubryk, M. Organic Syntheses 2005, 82, 34–42.

3.14 Carbon–Nitrogen Addition

3.14 Carbon–Nitrogen Addition 3.14.1

Carbon–Nitrogen Addition to Olefins

Ketenes and imines undergo a formal [2+2] cycloaddition to form β-lactams (Staudinger reaction). The relative diastereofacial selectivity can be quite high for these reactions, as shown in the following example230 (a single diastereomer was detected, suggesting >95 : 5 diastereoselectivity). Et 3N, CH2Cl 2 –78 to 25 °C

OTBS

BnO

Me

+ O

Cl

Bn

Me N

OTBS Me Me N Bn

BnO

85%

O

Chiral auxiliary-mediated Staudinger reactions have also been utilized in the synthesis of carbacephem intermediates, as shown in the following. In this example, the product crystallizes from 2-propanol in 75% yield on 140 g scale.231 Ph O O

N

+

O

Bn

Cl

Ph

Et 3N, CH2Cl 2 –70 to –10 °C

O

O

75%

N

O

O

N O

N

Bn

Variants using chiral catalysts have also been developed, as shown in the following for the chiral bifunctional catalysis system developed by Lectka and coworkers.232

N

Ts

Cl

BQ (10 mol%) In(OTf )3 (10 mol%) proton sponge

O

+

Toluene, –78 to 25 °C 95%

Ph

EtO2C BQ =

Ts

N

EtO2C

O Ph

98% ee

N

N

OBz

An alternative approach is to perform a racemic cycloaddition, then couple it with an enzymatic resolution to provide a single enantiomer of the bicyclic amino amide product shown in the following. Although limited by the resolution to a maximum yield of 50%, this sequence was otherwise efficient and performed well on multikilogram scale.233

O

ClSO 2NCO CH2Cl 2

N

S O O Cl

Racemic

aq Na 2SO3 NaHCO3 Na2CO3 CH2Cl 2 76%

O NH

(i) C. antarctica MTBE (ii) aq NH3 (iii) TFA, CH2Cl2

CONH2 NH2 •TFA

230 Palomo, C.; Aizpurua, J. M.; Garcia, J. M.; Galarza, R.; Legido, M.; Urchegui, R.; Roman, P.; Luque, A.; Server-Carrio, J.; Linden, A. The Journal of Organic Chemistry 1997, 62, 2070–2079. 231 Kumar, Y.; Tewari, N.; Nizar, H.; Rai, B. P.; Singh, S. K. Organic Process Research & Development 2003, 7, 933–935. 232 France, S.; Wack, H.; Hafez, A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. Organic Letters 2002, 4, 1603–1605. 233 Allwein, S. P.; Roemmele, R. C.; Haley, J. J.; Mowrey, D. R.; Petrillo, D. E.; Reif, J. J.; Gingrich, D. E.; Bakale, R. P. Organic Process Research & Development 2012, 16, 148–155.

211

212

3 Addition to Carbon–Carbon Multiple Bonds

3.14.2

Carbon–Nitrogen Addition to Alkynes

Ellman and coworker have reported Rh-catalyzed C—H functionalization of unsaturated imines, which effects the net C—N addition to alkynes to form tetrahydropyridine products on decagram scale.234

Bn

N

Me

Me Me

+

Et

Et

(1.5 equiv)

(i) [RhCl(cod)]2 4-Me2N-C6H4-PEt 2 toluene, 80 °C (ii) NaBH(OAc)2 AcOH, EtOH 0 °C 93% (1 mol% Rh, bench)

Et Bn

Et

N

Me

Me Me

95% (0.25 mol% Rh, glovebox)

3.14.3

Carbon–Nitrogen Addition to Dienes

The [4+2] cycloaddition of dienes and imines falls into this reaction class and is a form of a hetero-Diels–Alder reaction. The following example utilizes the N-benzylimine derived from benzylamine and formaldehyde.235

PhCH 2NH2 • HCl aq H2C=O H2O 25 °C 91–92%

N CH2Ph

3.15 Carbon–Carbon Addition The addition of a carbon atom to each end of an olefin encompasses a wide variety of cycloaddition reactions and represents one of the most important classes of bond-forming methods in organic chemistry. The wide variety of cycloaddition reactions makes it difficult to be comprehensive in this section, but several of the most important classes will be exemplified. 3.15.1

[4+2] Cycloaddition: Diels–Alder Reaction

The Diels–Alder reaction, a cycloaddition of a conjugated diene with an olefin (dienophile) to provide a cyclohexene product, is one of the highest profile C—C bond-forming reactions in organic synthesis.236 Its utility arises in large part from the regioselectivity, stereospecificity, and relative (facial) stereoselectivity exhibited in the reaction. In this section, examples are subdivided into several categories based on the structural elements of each reaction component. 3.15.1.1

Intermolecular, Nonsubstituted

The following example comes from a preparation of 2-cyclohexene-1,4-dione. The initial cycloadduct (shown in the following) is selectively reduced with Zn/AcOH, then heated to effect a retro-Diels–Alder, which generates 234 Mesganaw, T.; Ellman, J. A. Organic Process Research & Development 2014, 18, 1105–1109. 235 Grieco, P. A.; Larsen, S. D. Organic Syntheses 1990, 68, 206–209. 236 Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis, Vol. 5, Chapters 4.1–4.5; Pergamon Press: New York, 1991.

3.15 Carbon–Carbon Addition

2-cyclohexene-1,4-dione (not shown). Cyclopentadiene is a particularly reactive diene (due to its constraint to the s-cis conformation), and the cycloaddition thus occurs under particularly mild conditions.237 O

O

CH2Cl 2 0 °C

+

94–97% O

O

H

H

An intramolecular example in which an anthracene moiety serves as the diene is provided in the following238 (see Section 3.15.1.9 for intramolecular examples in which relative stereochemistry is explored). H N

O

H

p-xylene

NH O

138 °C 97%

3.15.1.2

Intermolecular, Heteroatom-substituted Dienophile

Diels–Alder cycloadditions are accelerated through the combination of electron-deficient dienophiles and electron-rich dienes (the opposite combination applies to inverse electron demand Diels–Alder reactions). As such, dienophiles conjugated to an electron-withdrawing group (e.g. CO2 R, COR, CN, NO2 ) have seen wide application. In addition to providing rate acceleration, they offer the possibility of post-cycloaddition manipulation. In the following example from Paquette, the sulfone-substituent on the dienophile provides a handle for post-cycloaddition manipulations such as alkylation and/or reductive cleavage.239 Note that the direct cycloaddition of this diene to an unactivated olefin (e.g. cyclopentene) is not an efficient process.

SO2Ph

3.15.1.3

+

MeO OTMS

(i) xylenes 125 °C

H

(ii) aq HCl THF 44–49%

SO2Ph

O

Zn/AcOH

H

O

25 o C 65–71%

Intermolecular, Heteroatomsubstituted Diene

Oxygen substitution on the diene component accelerates the rate of cycloaddition, is a useful regiochemistry control element, and provides a handle for subsequent synthetic manipulations. The following example from Danishefsky et al. is representative.240 An improved preparation of a more highly substituted 1,3-dioxydiene has also been reported.241 (i) Neat, 0–25 °C OMe

O

Me

TMSCl ZnCl 2 Et 3N benzene 46–56%

237 238 239 240 241

OMe

TMSO

MeO O

O

O

(ii) aq HCl, THF 90%

O

H

O O

H

O

Oda, M.; Kawase, T.; Okada, T.; Enomoto, T. Organic Syntheses 1996, 73, 253–261. Ciganek, E. The Journal of Organic Chemistry 1980, 45, 1497–1505. Lin, H. S.; Paquette, L. A. Organic Syntheses 1989, 67, 163–169. Danishefsky, S.; Kitahara, T.; Schuda, P. F. Organic Syntheses 1983, 61, 147–151. Myles, D. C.; Bigham, M. H. Organic Syntheses 1992, 70, 231–239.

213

214

3 Addition to Carbon–Carbon Multiple Bonds

Amino-substituted dienes can be even more reactive, as shown in the following example from Rawal and coworkers.242 The preparation of the diene is also reported in the same volume of Organic Syntheses.243

NMe2

CO2Me

Et 2O 20 °C

TBSO

NMe2 CO2Me

Et 2O 5 °C 91%

TBSO

98%

3.15.1.4

NMe2

LiAl H4

OH TBSO

HF

OH O

THF 20 °C 84%

Intermolecular, Aqueous Media

Dramatic rate acceleration of Diels–Alder cycloadditions in water has been noted by several labs244,245,246 and was utilized in the synthesis of vernolepin in the following example.247

BnO

3.15.1.5

CHO

Cat. BHT

+ CO2Na

BnO

BnO

(i) NaBH 4 OHC

H2O 50 °C

CO2Na

(ii) aq H2SO4

H

O

91%

O

Intermolecular, Aromatic Product

With heteroatom-substituted dienes and/or dienophiles, the Diels–Alder product may eliminate the elements of HX (X = heteroatom), and the resulting dihydroaromatic species may undergo further oxidation to provide the fully aromatic product. The following example utilizes an enamine dienophile to provide a mixture of hexahydroisoquinolines, which upon treatment with Pd/C undergoes further two-electron oxidation to the tetrahydroisoquinoline as a single regioisomer.248 Note that the use of an electron-rich dienophile with an electron-deficient diene constitutes a reversal of the normal electronics of the reaction and is referred to as an inverse electron demand Diels–Alder reaction (see Section 3.15.1.7). CO2Me CO2Me N Me

N

CO2Me Pd/C

Benzene reflux 94%

Me

N

Mixture of stereo/regioisomers

MeOH 93%

Me

N

Danheiser has developed a cycloaddition of vinylketenes with electron-rich acetylenes in which the former species is generated by electrocyclic opening of cyclobutenones. The initial cyclobutanone [2+2] adduct undergoes a cascade of two electrocyclic openings and closures to generate a highly substituted phenol product. Because the initial cycloaddition is [2+2], it could arguably be included in Section 3.15.2. But as the final product is formally the product of a [4+2] 242 243 244 245 246 247 248

Kozmin, S. A.; He, S.; Rawal, V. H. Organic Syntheses 2002, 78, 160–168. Kozmin, S. A.; He, S.; Rawal, V. H. Organic Syntheses 2002, 78, 152–159. Hopff, H.; Rautenstrauch, C. W. Addition products of butadiene with vinyl methyl ketone, maleic acid, etc US1941 Rideout, D. C.; Breslow, R. Journal of the American Chemical Society 1980, 102, 7816–7817. Braun, R.; Schuster, F.; Sauer, J. Tetrahedron Letters 1986, 27, 1285–1288. Yoshida, K.; Grieco, P. A. The Journal of Organic Chemistry 1984, 49, 5257–5260. Danishefsky, S.; Cavanaugh, R. The Journal of Organic Chemistry 1968, 33, 2959–2962.

3.15 Carbon–Carbon Addition

cycloaddition, it is included in this section. The following example is taken from the synthesis of mycophenolic acid and proceeds in 73% yield on 1 g scale.249 TBSO

TBSO

O

Me

Me

+ OMe

O

Me

OH

Sealed tube

OMe

Benzene 120 °C 73%

MeO

Me

O

OMe

O Me

O

TBSO(CH 2)3

OMOM

MeO Me

OMOM

Me TBSO(CH 2)3

Me

O

O

TBSO(CH 2)3 MeO

3.15.1.6

MeO

OMOM

OMOM

Intermolecular, Lewis Acid–Catalyzed

Lewis acids can serve as effective catalysts for Diels–Alder cycloadditions through coordination with the carbonyl oxygen and lowering of the dienophile’s lowest unoccupied molecular orbital (LUMO). Two examples from the pharmaceutical industry are shown in the following. The first was utilized in the asymmetric synthesis of an NMDA receptor antagonist.250

Me

Me O

O

O

TiCl 4 CH2Cl 2

+

O

–20 °C

O

O

O

75%

Me Me

O

97 : 3 diastereoselectivity

The second example involves a cyclopropylidene dienophile.251 O O

O

O N

+

Me2AlCl CH2Cl 2

O

O N

–75 °C 95% 36 : 1 endo-exo selectivity

249 Danheiser, R. L.; Gee, S. K.; Perez, J. J. Journal of the American Chemical Society 1986, 108, 806–810. 250 Hansen, M. M.; Bertsch, C. F.; Harkness, A. R.; Huff, B. E.; Hutchison, D. R.; Khau, V. V.; LeTourneau, M. E.; Martinelli, M. J.; Misner, J. W.; Peterson, B. C.; Rieck, J. A.; Sullivan, K. A.; Wright, I. G. The Journal of Organic Chemistry 1998, 63, 775–785. 251 Kuethe, J. T.; Zhao, D.; Humphrey, G. R.; Journet, M.; McKeown, A. E. The Journal of Organic Chemistry 2006, 71, 2192–2195.

215

216

3 Addition to Carbon–Carbon Multiple Bonds

An interesting variant on this approach is to use an electron-rich dienophile and a catalyst that forms a radical cation of the olefin, such as the ruthenium photocatalyst shown in the following.252 The Organic Syntheses procedure referenced includes the preparation of the catalyst, as well as the indicated cycloaddition. Ru(bpz)3(BArF)2 (0.1 mol%)

MeO +

hν Air, CH2Cl 2

Me

Me

MeO

Me

Me

91–93% N F3C N

N

N

N Ru 2+ N N

N

N N

CF3

F3C

CF3 B

N

F3C

CF3 F3C

CF3

N Ru(bpz) 32+

3.15.1.7

(BArF) –

Intermolecular, Inverse-electron Demand

The normal electronic configuration in a Diels–Alder reaction is an electron-rich diene and an electron-deficient dienophile. This distribution can be inverted to an electron-deficient diene and electron-rich dienophile as shown in the following two examples from Boger’s lab. In each case, a subsequent extrusion occurs to generate an aromatic product (CO2 253 or N2 followed by elimination of pyrrolidinone).254 OMe O

O CO2Me

OMe Toluene

OMe

110 °C

CO2Me

Sealed tube 84% O N

EtO2C

N

EtO2C

N

CO2Et N

CHCl 3 60 °C

EtO2C

N

CO2Et

EtO2C

68–92%

252 Lies, S. Organic Syntheses 2016, 93, 178–199. 253 Boger, D. L.; Mullican, M. D. Organic Syntheses 1987, 65, 98–107. 254 Boger, D. L.; Panek, J. S.; Yasuda, M. Organic Syntheses 1988, 66, 142–150.

3.15 Carbon–Carbon Addition

3.15.1.8

Intermolecular, Benzyne as Dienophile

Benzyne can serve as the dienophile in a Diels–Alder reaction when generated in situ, as in the following example.255 As in the Boger example cited previously, a CO2 extrusion occurs after the initial cycloaddition. Me CO2H

ONO

Me

CO2–

NH2

N 2+ –CO2, –N2 Br

Br O O

DME

CO2Me

CO2Me

85 °C 79%

3.15.1.9

Intramolecular Examples

Intramolecular Diels–Alder (IMDA) cycloadditions have been studied extensively, particularly in the context of complex natural product total synthesis.256,257 The following example is from an early series of studies in the Roush lab directed at the synthesis of the nargenicins.258 Note that the cis-ring fusion is undesired relative to the target structures, and extensive studies were pursued by both Roush and Boeckman to alter the stereochemical outcome with bromo259 or trimethylsilyl substituents260 on the diene moiety. Me O TBDPSO MeO2C O

Me

Me

H O

110 °C

O

Toluene

Me

78%

TBDPSO MeO2C

H

O

Me O Me

The following example is from Boeckman’s synthesis of the cyclohexene subunit of (+)-tetronolide.261,262 CO2-t-Bu

O

O Br

CO2Et

CO2-t-Bu

CO2-t-Bu

SrCO 3 cat. BHT

H

Xylenes 155 °C

O

H O

CO2Et

+

O

O

CO2Et

Br

Br 48%

15%

255 Ashworth, I. W.; Bowden, M. C.; Dembofsky, B.; Levin, D.; Moss, W.; Robinson, E.; Szczur, N.; Virica, J. Organic Process Research & Development 2003, 7, 74–81. 256 Takao, K.; Munakata, R.; Tadano, K. Chemical Reviews 2005, 105, 4779–4807. 257 Ciganek, E. Organic Reactions (New York) 1984, 32, 1–374. 258 Coe, J. W.; Roush, W. R. The Journal of Organic Chemistry 1989, 54, 915–930. 259 Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B. B.; Warmus, J. S.; Moriarty, K. J. The Journal of Organic Chemistry 1991, 56, 1192–1210. 260 Boeckman, R. K., Jr.; Barta, T. E. The Journal of Organic Chemistry 1985, 50, 3421–3423. 261 Boeckman, R. K., Jr.; Wrobleski, S. T. The Journal of Organic Chemistry 1996, 61, 7238–7239. 262 Boeckman, R. K., Jr.; Estep, K. G.; Nelson, S. G.; Walters, M. A. Tetrahedron Letters 1991, 32, 4095–4098.

217

218

3 Addition to Carbon–Carbon Multiple Bonds

Overman and coworkers utilized a silyl-tethered IMDA cyclization in their synthesis of (+)-aloperine. The Diels-Alder cyclization is quite efficient, as the 76% overall yield encompasses six individual transformations (BOC removal, N-silylation, cycloaddition, N-desilylation, lactam formation, and oxidation of the C-Si bond).263 HH

(i) TMSI, 2,6-lutidine CH2Cl 2

N Boc

(ii) RSiMe2OTf Et 3N, CH2Cl 2

N Ts

(i) HF • pyr, rt concentrate

H

(ii) mesitylene reflux (rearrangement)

N

[4+2]

N Me Si Me CO2Me SiMe 2F

0–25 °C

N Ts

N

MeOH, THF reflux 76% overall

O

N H Ts CO2Me

OH

H

KF, H 2O2 KHCO 3

N H Ts

N Me Si Me H

N H Ts O

5 : 1 diastereoselectivity

Deslongchamps and coworkers have published extensive stereochemical studies and synthetic applications of the transannular Diels–Alder cyclization. The example shown below is taken from his studies on the synthesis of kempane diterepenes.264 HO

HO

Et 3N toluene

Me Me CO2Me CO2Me

Me

3.15.1.10

Sealed tube 180 °C

CO2Me CO2Me

Me

Me

H

93%

Me

H

Asymmetric Examples

Asymmetric Diels–Alder cycloadditions have been effected with both chiral auxiliary and chiral catalyst methods. The following two examples show chiral auxiliary methods. The first example is from the Evans lab.265 O

O

Me

+

N

O

Et 2AlCl CH2Cl 2

Me

N

–30 °C

Me

100% crude, 77% after crystallization

Ph

O

O

Me

O Ph

95 : 5 diastereoselectivity

The second example is from Oppolzer and was utilized in his enantiospecific total synthesis of loganin.266 The high crystallinity of the sultam auxiliary is an attractive feature of this methodology. Me

+

O

Me N O2 S

263 264 265 266

Me

TiCl 4 CH2Cl 2 –78 °C 87%

Me Me O

Me

N O2S

97 : 3 diastereoselectivity

Brosius, A. D.; Overman, L. E.; Schwink, L. Journal of the American Chemical Society 1999, 121, 700–709. Caussanel, F.; Wang, K.; Ramachandran, S. A.; Deslongchamps, P. The Journal of Organic Chemistry 2006, 71, 7370–7377. Evans, D. A.; Chapman, K. T.; Bisaha, J. Journal of the American Chemical Society 1988, 110, 1238–1256. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron 1986, 42, 4035–4043.

3.15 Carbon–Carbon Addition

Asymmetric catalysts have also been developed for effecting enantioselective Diels–Alder cycloadditions. The first example is from Corey et al. one of the early pioneers in asymmetric Diels–Alder reactions.267,268 The in situ catalyst synthesis from the bis-sulfonamide (prepared in one step from the diamine) and a 10 g Diels–Alder cycloaddition have been reported.269 The same authors also provide a synthesis of the chiral diamine in two steps from (PhCO)2 (benzil) and ammonium acetate via resolution with tartaric acid.270 The diamine is commercially available. NHSO2CF3

Me3Al

Ph

NHSO2CF3

ClCH 2CH2Cl heptane-CH2Cl 2 crystallization

O

+

SO2CF3 N Al Me N SO2CF3

Ph

Ph

Ph

O N

O

CH2Cl 2 O

–78 °C 89%

O

N

O

89% ee

Yamamoto and coworkers have reported a boron-based catalyst for effecting enantioselective Diels–Alder cycloadditions. The reference for the following example includes the preparation of the diacid precatalyst, available in two steps from tartaric acid.271 MeO

OH

O O OMe

BH 3 • THF

CO2H

Me

+

Me

BLn*

CH2Cl2 0 °C

OH

Me

BLn* (10 mol%) CH2Cl 2

Me

–78 °C

Me

CHO

86%

3.15.2

CHO Me 95% ee

[2+2] Cycloaddition

Olefins can undergo photochemically mediated [2+2] cycloadditions. One of the olefin partners is frequently electron deficient, such as an enone. The following intramolecular example was utilized in the synthesis of isocomene272,273 and is preparatively useful (76% yield on 6 g scale, albeit using a large volume of solvent: 500 mL/g). O

O

Me Me Me

267 268 269 270 271 272 273

Me

hν Hexane 25 °C 76–77%

Me Me

Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. Journal of the American Chemical Society 1989, 111, 5493–5495. Corey, E. J.; Ensley, H. E. Journal of the American Chemical Society 1975, 97, 6908–6909. Pikul, S.; Corey, E. J. Organic Syntheses 1993, 71, 30–38. Pikul, S.; Corey, E. J. Organic Syntheses 1993, 71, 22–29. Furuta, K.; Gao, Q.-Z.; Yamamoto, H. Organic Syntheses 1995, 72, 86–94. Pirrung, M. C. Journal of the American Chemical Society 1981, 103, 82–87. Pirrung, M. C. Journal of the American Chemical Society 1979, 101, 7130–7131.

219

220

3 Addition to Carbon–Carbon Multiple Bonds

Allenes will also add to enones in a photocycloaddition to give exo-methylene-substituted cyclobutanes.274 H

O

Me

Me

Me

H

CO2Me

H2C=C=CH2 hν

Me

CH2Cl 2, –78 °C

Me

O

H

H

80%

Me

CO2Me

Cyclobutenes are also available by photochemical [2+2] cycloadditions between an acetylene and an electron-deficient olefin. The following is from a synthesis of xanthocidin and proceeds in 57% yield on 5 g scale.275 O

Et +

O

i-Pr

O

hν , Ph 2CO

O

Et

O

CH3CN

i-Pr

57%

O

Cyclobutanones can also be formed by [2+2] cycloaddition between olefins and ketenes (also known as the Staudinger ketene cycloaddition). Intramolecular variants are particularly useful for formation of bicyclic ring systems, as exemplified in the following.276 The substrate was designed to test the kinetic preference for five- vs. six-membered tether length; complete regioselectivity for the five-membered ring was observed.

Et 3N

COCl

O

Toluene reflux

O

82%

Lewis acid catalysis has also been used to effect intermolecular ketene-olefin cycloadditions.277 O Ph

Et 3N EtAlCl2

+

Cl Ph

CH2Cl 2 64%

H

O Ph Ph

H

Intermolecular examples are also known, frequently with dichloroketene, as exemplified below from the synthesis of homogynolide B.278

Me

Me Me

Me O O

Cl 3CCOCl Zn(Cu) POCl 3 Et 2O, 20 °C 81%

Cl Cl O

Me Me

Me Me O O H

274 Tobe, Y.; Yamashita, D.; Takahashi, T.; Inata, M.; Sato, J.; Kakiuchi, K.; Kobiro, K.; Odaira, Y. Journal of the American Chemical Society 1990, 112, 775–779. 275 Smith, A. B., III; Boschelli, D. The Journal of Organic Chemistry 1983, 48, 1217–1226. 276 Belanger, G.; Levesque, F.; Paquet, J.; Barbe, G. The Journal of Organic Chemistry 2005, 70, 291–296. 277 Rasik, C. Organic Syntheses 2016, 93, 401–412. 278 Brocksom, T. J.; Coelho, F.; Depres, J.-P.; Greene, A. E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang, Y. Journal of the American Chemical Society 2002, 124, 15313–15325.

3.15 Carbon–Carbon Addition

Alkyne–alkene [2+2] cycloadditions with gold catalysis are also useful, as shown in the gram-scale reaction in the following.279 Me Au cat (3 mol%)

+

CH2Cl2 24 °C, 14 h Au cat = t-Bu

Me

98%

t-Bu Au NCMe i-Pr i-Pr i-Pr

Silver-catalyzed cycloadditions of silyloxy alkynes and activated olefins have also been described.280 CO2Me (i) t-BuOOH LiHMDS THF

H

OSi(i-Pr)3

(ii) TIPSOTf

Me

Me AgNTf 2 (5 mol%)

CO2Me Me

CH2Cl 2

Me

87%

3.15.3

(i-Pr) 3SiO

Me

77–80%

[3+2] Cycloaddition

Several methods for effecting [3+2] annulations have been developed. The order of presentation below is arbitrary; the preferred method for a given application will largely depend on the specific functionality present in the target. Danheiser et al. has developed a [3+2] annulation reaction between electron-deficient olefins and trimethylsilylallenes; the example shown in the following proceeds in 71% yield on 5 g scale.281 O

TMS

+

Me

O

TiCl 4 CH2Cl 2 –78 °C

Me

Me

Me

TMS

71%

Trost has developed a [3+2] cycloaddition utilizing a Pd-mediated coupling of electron-deficient olefins with allylsilane/allylic acetate nucleophiles.282 The example shown below is from Paquette’s lab.283 Me

Me TMS

MeO2C

Me

Me

OAc

Pd(OAc) 2, P(OEt)3 THF, reflux

O

98%

Me MeO2C

Me

O

279 de Orbe, M. E. Organic Syntheses 2016, 93, 115–126. 280 Shubinets, V. S., Michael P.; Kozmin, S. A. Organic Syntheses 2010, 87, 253. 281 Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A. Tetrahedron 1983, 39, 935–947. 282 Trost, B. M. Angewandte Chemie International Edition in English 1986, 98, 1–20. 283 Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.; Blackwell, C. M.; Anderson, L. G. Journal of the American Chemical Society 1992, 114, 7375–7387.

221

222

3 Addition to Carbon–Carbon Multiple Bonds

A similar example is shown in the following.284 TMS O

OAc

Pd(OAc) 2, P(O-i-Pr) 3

N O

O

Toluene, reflux

Ph

N O

80%

Ph

The Pauson–Khand cyclization involves a [2+2+1] cycloaddition of an olefin, an acetylene, and carbon monoxide; the latter two components arise from a cobalt complex of the acetylene, generated either in situ or as an isolated intermediate.285,286 The following example comes from the synthesis of methyl deoxynorpentalenolactone H.287 OTBS

Me Me

85 °C hexane sealed tube 64%

MOMO

OTBS

Co 2(CO)8 CO

Me Me MOMO

O H

A second example shown in the following is from Schreiber’s synthesis of epoxydictymene.288,289 It utilizes a cobalt-stabilized propargylic cation cyclization to generate the eight-membered carbocycle, followed by a Pauson–Khand cyclization of the isolated cobalt complex. The olefin component of the Pauson–Khand cyclization was present in the propargylic cation precursor (identification of conditions to provide regiocontrol in the acetal ionization required considerable optimization). Me

(i) Co 2(CO)8 Et 2O

Me O Me OEt

Me

(CO)3 Co Co(CO) 3

H

(ii) TMSOTf Et 2O, –78 °C

TMS

O

H

Me

O Air

Me

CH3CN reflux 85%

Me

89%

H

H O

Me Me

H

Brummond has developed a Pauson–Khand cyclization of allenes, as shown in two examples below. The first cyclization product constitutes the carbon skeleton of guanacastepene A.290 The second example is an Organic Syntheses procedure performed on 5 g scale,291 including an associated procedure for preparation of a key allene intermediate.292 OTBS OTBS

PhMe 2Si

Toluene 80 °C 65%

Me

i-Pr

Ts

N

[Rh(CO) 2Cl] 2 (10 mol%) CO (1 atm )

Me OTBDPS

OTBS OTBS

O

(1)

i-Pr

(i) [Rh(CO) 2Cl] 2 (1 mol%) CO (1 atm )

Me

Ts

Me N

O

(ii) Ph3P-polymer bound 88%

284 285 286 287 288 289 290 291 292

PhMe 2Si

(2)

OTBDPS

Jao, E.; Bogen, S.; Saksena, A. K.; Girijavallabhan, V. Tetrahedron Letters 2003, 44, 5033–5035. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263–3283. Schore, N. E. Organic Reactions (New York) 1991, 40, 1–90. Magnus, P.; Slater, M. J.; Principe, L. M. The Journal of Organic Chemistry 1989, 54, 5148–5153. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Journal of the American Chemical Society 1997, 119, 4353–4363. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Journal of the American Chemical Society 1994, 116, 5505–5506. Brummond, K. M.; Gao, D. Organic Letters 2003, 5, 3491–3494. Burchick, J. Organic Syntheses 2017, 94, 123–135. Burchick, J. Organic Syntheses 2017, 94, 109–122.

3.15 Carbon–Carbon Addition

Trialkylphosphines can mediate a [3+2] cycloaddition of allenic esters with electron-deficient olefins, as shown in the following examples.293 The reaction proceeds with high diastereospecificity with respect to the olefin geometry. CO2Et

+ EtO2C

CO2Et

CO2Et

PPh 3 (10 mol%)

CO2Et

Benzene, 25 °C CO2Et

67%

+

CO2Et

CO2Et EtO2C

CO2Et

PPh 3 (10 mol%)

CO2Et

Benzene, 25 °C CO2Et

46%

Krische and coworkers have extended this approach to the intramolecular [3+2] annulation of ynones with enones mediated by trialkylphosphines. The reaction requires reasonably electrophilic olefins (enones and thioesters cyclize efficiently, whereas esters do not).294

MeO2C

O

Ph

O PBu 3 (10 mol%)

MeO2C

EtOAc, 110 °C sealed tube

Ph H

H

76%

Azomethine ylides can be utilized to generate pyrrolidines from addition to electron-deficient olefins. The first example below utilizes N-methylglycine and paraformaldehyde to generate an azomethine ylide which undergoes a [3+2] cycloaddition to generate an N-methylpyrrolidine with 4 : 1 diastereoselectivity.295 In the second example, a similar cycloaddition is then coupled with a chiral resolution to deliver a single diastereomeric salt in ∼40% overall yield for the sequence (∼80% of theoretical).296 Me Me MeNHCH2COOH

Me Me Boc N i-Pr

O

Boc N

(HCHO)n CO2Me

4 Å sieves Benzene, 80 °C

O

H

i-Pr

CO2Me

(1)

N Me

96%

Br MeNHCH2CO2H (HCHO)n ditolyl-D-tartaric acid

Br CO2Et

293 294 295 296

98%

42%

CO2Et O p-Tol

CO2H O

O HO2C

p-Tol O

(2) N Me

Zhang, C.; Lu, X. The Journal of Organic Chemistry 1995, 60, 2906–2908. Wang, J.-C.; Ng, S.-S.; Krische, M. J. Journal of the American Chemical Society 2003, 125, 3682–3683. See Note 86. Chen, J.; Chen, T.; Hu, Q.; Püntener, K.; Ren, Y.; She, J.; Du, Z.; Scalone, M. Organic Process Research & Development 2014, 18, 1702–1713.

223

224

3 Addition to Carbon–Carbon Multiple Bonds

Copper and BINAP catalysis has been utilized to prepare a highly substituted pyrrolidine in high yield and 94 : 6 er by chemists at Hoffman-La Roche.297 This reaction has been successfully scaled to 100 kg, maintaining the high yield and enantioselectivity (78% and 93 : 7, respectively).298 CO2Me Cl

Cl

F

FO

OMe CO2H

NH

CN Cl

NH

Cu(OAc) 2 (1.3 mol%) (R)-BINAP (1.4 mol%) i-Pr 2NEt

F + CO2Me

CN F

Cl

Cl

t-Bu

FO

THF aq NaOH

exo (80%)

MeTHF

CO2Me

O

FO NH

NH

OMe

Cl

94 : 6 er 84% yield

OMe

OMe

NH

i-PrOH (crystn)

Cl

NH

CN F

t-Bu

NH

N t-Bu

CN F

Cl

t-Bu

endo (8%)

Azomethine ylides have also been used to introduce trifluoromethyl functionality, as shown in the Organic Syntheses procedure from Steve Ley’s group in the following.299 OMe TMS

N

CF3

+

TMSOTf CH2Cl 2

CO2Et

O

EtO

Ph

CF3

N

34–47%

Ph

Azomethine ylides can also be generated by high temperature thermolysis of aziridines. The following example was executed on 500 g scale and utilized the unusual solvent DW-therm, a mixture of triethoxyalkylsilanes (DW-therm is a heat transfer fluid available from Huber Corporation of Germany, www.huber-online.com).300

O Ph

Ph

O N

Me N

240 °C DW-therm 61%

R

O N

N

Me –

N+

Me H

N

H

Ar

+ Ph

O N

Me H

N

H 1 : 1 diastereoselectivity 297 Shu, L.; Gu, C.; Fishlock, D.; Li, Z. Organic Process Research & Development 2016, 20, 2050–2056. 298 Rimmler, G.; Alker, A.; Bosco, M.; Diodone, R.; Fishlock, D.; Hildbrand, S.; Kuhn, B.; Moessner, C.; Peters, C.; Rege, P. D.; Schantz, M. Organic Process Research & Development 2016, 20, 2057–2066. 299 Allwood, D. M.; Browne, D. L.; Ley, S. V. Organic Syntheses 2014, 91, 162–174. 300 Shieh, W.-C.; Chen, G.-P.; Xue, S.; McKenna, J.; Jiang, X.; Prasad, K.; Repic, O.; Straub, C.; Sharma, S. K. Organic Process Research & Development 2007, 11, 711–715.

3.15 Carbon–Carbon Addition

3.15.4

Carbene Addition (Cyclopropanation)

The Simmons–Smith reaction is an efficient route to cyclopropanes. It involves the Zn-mediated addition of a dihalomethane to an olefin. The following example was executed on 60 g scale and proceeded in 84% yield.301 Some nitrile reduction to the aldehyde was observed (c. 8%), which was minimized by optimization of reaction conditions. Et 2Zn Cl 3CO2H CH2I2 Toluene DCE 84%

OMe O

CN

OMe O

CN

An example from Merck executed a Simmons–Smith on a vinyl boronate, which was then converted to a cyclopropyl alcohol via peroxide oxidation. The yields below are from a >30 kg pilot plant campaign; the lab scale yields described in the experimental are slightly lower (79% and 69%, respectively).302

B O

Cl

Et 2Zn, TFA CH2I2

Me

O

Me

CH2Cl 2

Me Me

B O

Cl

96%

O

Me Me

H2O2 (30 wt% aq) NaOH

OH

MeOH

Me Me

Cl

83%

Several enantioselective cyclopropanation methods are known. The transition metal-mediated coupling of diazoesters with olefins can be highly selective. Substrate scope is limited to α-diazo carbonyl reagents, however, which means that only carbonyl-substituted cyclopropanes are available via this route. The example shown below proceeds in 91% yield on 35 g scale with a catalyst load of just 0.12 mol%.303 Me Me O

O N

N

t-Bu Me

t-Bu

Me

0.12 mol %

Me

EtO2C

CO2Et

Me

N2

CuOTf, CHCl3 91%

>99% ee

Intramolecular variants of the transition metal-catalyzed cyclopropanation can be useful for preparation of bicyclic cyclopropanes. The preparation of Doyle’s chiral dirhodium catalyst used in the following example is described in an Organic Syntheses procedure.304 It is also commercially available in smaller quantities (CAS 131796-58-2). H3COCHN Me Me

O

Me

(i) CH3CN, 25 °C

O

O

SO2N3

Me

Me

(ii) LiOH, H 2O, 25 °C

O O N2

81% Rh 2(5R-MEPY)4(CH3CN)2(i-PrOH) (0.23 mol%) CH2Cl 2 Slow addition, 24 h 84–88%

H Me

O

Me O

H

92–93% ee

O 5R-MEPY =

HN

MeO2C

301 Frey, L. F.; Marcantonio, K. M.; Chen, C.-Y.; Wallace, D. J.; Murry, J. A.; Tan, L.; Chen, W.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron 2003, 59, 6363–6373. 302 Bassan, E. M.; Baxter, C. A.; Beutner, G. L.; Emerson, K. M.; Fleitz, F. J.; Johnson, S.; Keen, S.; Kim, M. M.; Kuethe, J. T.; Leonard, W. R.; Mullens, P. R.; Muzzio, D. J.; Roberge, C.; Yasuda, N. Organic Process Research & Development 2011, 16, 87–95. 303 Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. Journal of the American Chemical Society 1991, 113, 726–728. 304 Doyle, M. P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L. J. Organic Syntheses 1996, 73, 13–24.

225

226

3 Addition to Carbon–Carbon Multiple Bonds

Efficient catalysts for the cyclopropanation of allylic alcohols have been developed which avoid the use of diazo esters (and thus allow unsubstituted cyclopropanes to be prepared). The following two examples are from Charette et al.305 and Denmark and O’Connor,306 respectively. Me

Me

O

O

Ph Ph

O

i-PrO Ph

Ti

O

Ph Ph

O-i-Pr (25 mol%) Ph

Zn(CH 2I)2

OH

4 Å mol sieves, CH2Cl2, 0 °C

OH

92% ee

85% Me Me O

O N

N t-Bu (10 mol%)

t-Bu Ph

Et 2Zn, ZnI 2, Zn(CH 2I)2

OH

CH2Cl 2, 0 °C

Ph

OH 89% ee

88%

A stoichiometric boronate ligand developed by Charette et al.307 has also received broad application for the enantioselective cyclopropanation of allylic alcohols.308,309,310 Me O

Me

O

O

B

Me

O

Me

O

n-Bu

OH Me

CON(Me)2

(Me)2NOC Me

OH

Zn(CH 2I2)2, CH2Cl 2 0 to 25 ° C

H Me

Me O

H Me

Me

97%, >95 : 5 dr CON(Me)2

(Me)2NOC O

Me HO O

O

N Ts

HO

Me O

ZnEt 2, CH2I2 0 to rt 88%, 18 : 1 dr

O

Me OTBS

CON(Me)2

(Me)2NOC

NC

O

n-Bu

Me OTBS

OH

B

O B (1.2 equiv) n-Bu

O

Zn(CH 2I)2, DME CH2Cl 2,/PhMe 0 °C 83%, 88% ee

NC

H

H

OH

N Ts

305 Charette, A. B.; Molinaro, C.; Brochu, C. Journal of the American Chemical Society 2001, 123, 12168–12175. 306 Denmark, S. E.; O’Connor, S. P. The Journal of Organic Chemistry 1997, 62, 584–594. 307 Charette, A. B.; Prescott, S.; Brochu, C. The Journal of Organic Chemistry 1995, 60, 1081–1083. 308 Dake, G. R.; Fenster, E. E.; Patrick, B. O. The Journal of Organic Chemistry 2008, 73, 6711–6715. 309 Schiess, R.; Gertsch, J.; Schweizer, W. B.; Altmann, K.-H. Organic Letters 2011, 13, 1436–1439. 310 Anthes, R.; Benoit, S.; Chen, C.-K.; Corbett, E. A.; Corbett, R. M.; DelMonte, A. J.; Gingras, S.; Livingston, R. C.; Pendri, Y.; Sausker, J.; Soumeillant, M. Organic Process Research & Development 2008, 12, 178–182.

3.15 Carbon–Carbon Addition

Chemists at Infinity Pharmaceuticals, in consultation with Charette and coworkers, provided a detailed report of their optimization and scale-up of the cyclopropanation/cationic ring-expansion sequence shown in the following. Yields of 55–80% were realized on 33 kg scale.311 Me H Me O Me O BnO

H

N

Me

CH2Cl 2

H

O

Me O

H Cbz Et 2Zn, CH2I2 Me (Ar*O )2P(O)OH

H

H

Me

O BnO

Ar* = 2,6-dimethylphenyl

H Me

H

H

N

H

O

Cbz

MeSO3H CH2Cl 2 55–80% BnO

H O

Me Me O

H

H H

Me

Me N H Cbz

O

An iodonium ylide derived from dimethyl malonate has been used to cyclopropanate styrenes in high yield.312 Rh 2(esp)2 (0.02 mol%)

O

O

OMe

MeO I

Ph

+

CO2Me

CH2Cl 2

Ph

Ph

CO2Me

92–95% esp = HO2C Me

Me Me

CO2H Me

Dihalocarbenes will also add to olefins, and generally do not require metal catalysis. The following example prepares a crystalline bis-cyclopropane tetrabromide from dibromocarbene addition to 1,4-cyclohexadiene and was utilized as an intermediate in Danheiser’s synthesis of anatoxin a.313 CHBr3, aq NaOH

Br

Br

n-Bu 3N, CH2Cl 2 45 °C

Br

Br

77%

Corey has developed the synthesis of epoxides from carbonyl compounds (and cyclopropanation of electron deficient olefins) with the anion of DMSO. The reaction proceeds by an addition/elimination mechanism, although the net effect is that of carbene addition to the olefin. Heathcock and coworker utilized this cyclopropanation in a synthesis of isovelleral; the reaction shown was run on a 3 g scale.314 O– K +

Me Me Me

3.15.5

CO2Me O

Me

S

CH2

THF 65%

Me Me Me

CO2Me O

[4+3] Cycloadditions

Although not formally a C—C bis-addition to an olefin, [4+3] cycloadditions will be briefly discussed, given their analogy to other cycloadditions described in this section. Cycloadditions in which the four-carbon component is a heterocycle (e.g. furan or pyrrole) are well known, and include the oxyallyl cation/furan cycloaddition to form 311 Austad, B. C.; Hague, A. B.; White, P.; Peluso, S.; Nair, S. J.; Depew, K. M.; Grogan, M. J.; Charette, A. B.; Yu, L.-C.; Lory, C. D.; Grenier, L.; Lescarbeau, A.; Lane, B. S.; Lombardy, R.; Behnke, M. L.; Koney, N.; Porter, J. R.; Campbell, M. J.; Shaffer, J.; Xiong, J.; Helble, J. C.; Foley, M. A.; Adams, J.; Castro, A. C.; Tremblay, M. R. Organic Process Research & Development 2016, 20, 786–798. 312 Goudreau, S. R., Marcoux, D.; Charette, A. B. Organic Syntheses 2010, 87, 115. 313 Danheiser, R. L.; Morin, J. M., Jr.; Salaski, E. J. Journal of the American Chemical Society 1985, 107, 8066–8073. 314 Thompson, S. K.; Heathcock, C. H. The Journal of Organic Chemistry 1992, 57, 5979–5989.

227

228

3 Addition to Carbon–Carbon Multiple Bonds

oxabicyclo[3.2.1]octenes.315,316 The interested reader is directed to these reviews. The examples in this section are limited to cycloadditions that generate products in which only carbon atoms comprise the bicyclic core. The example below generates an α-bromoketone tricyclic adduct through the cycloaddition of an oxyallylcation and cyclopentadiene.317 O Br

Et 3N CF3CH2OH, Et 2O

+

Br

Br

–78 to 25 °C

O

70%

West has reported an intramolecular [4+3] cycloaddition in which a diene traps a Nazarov cationic intermediate to form tricyclic products such as that shown in the following.318 O Me

Me

BF 3 • Et 2O (10 mol%)

Me

+ Me

Me O

ClCH 2CH2Cl 40 °C

Me H

67%

The following example is an apparent [4+3] cycloaddition, which actually entails a sequence of anionic additions/rearrangements.319 The stereospecificity is attributed to the intermediacy of a divinylcyclopropane, which undergoes anion-accelerated Cope rearrangement to generate the seven-membered carbocycle. The cyclopropane arises from initial 1,2-addition to the acylsilane followed by Brook rearrangement/cyclopropanation. Takeda and Sasaki have provided a Discussion Addendum to his initial report.320 O

O

O TBS

LDA, THF

+ Me

TBSO

–78 to –30 °C

TMS

79–82%

3.15.6

TMS

Conjugate Addition-Alkylation

As discussed in Section 3.5.5, cuprate reagents are effective for the 1,4-addition of alkyl groups to activated olefins. If the resulting enolate is trapped with an alkylating agent, then the net addition of two carbon atoms across the olefins is achieved. The following example couples a cuprate addition to an enone with a conjugate addition to a second enone, followed by an aldol reaction (net Robinson annulation).321 The α-silyl MVK (methyl vinyl ketone) reagent was developed specifically for this type of reaction sequence. TMS Me

Me2CuLi

O

Et 2O, –78 °C

Me Me

HO 315 316 317 318 319 320 321

O

Me

O

TMS Me

Me

Me

O–

KOH

Me Me

aq MeOH 43–57%

O

Hosomi, A.; Tominaga, Y. Comprehensive Organic Synthesis, Vol. 5, Chapter 5.1 1991, Pergamon Press, Oxford, 593. Noyori, R.; Hayakawa, Y. Organic Reactions (New York) 1983, 29, 163–344. Harmata, M.; Wacharasindhu, S. Organic Letters 2005, 7, 2563–2565. Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Organic Letters 2003, 5, 2747–2750. Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E. Organic Syntheses 1999, 76, 199–213. Takeda, K.; Sasaki, M. Organic Syntheses 2012, 89, 267–273. Boeckman, R. K., Jr.; Blum, D. M.; Ganem, B. Organic Syntheses 1978, 58, 158–163.

3.15 Carbon–Carbon Addition

The following example shows a similar sequence but with enolate trapping with an alkyl triflate.322 For details on the generation of the vinyl cuprate reagent and the enolate transmetalation, see Chapter 12. (i) THF, –78 °C Me(NC)–Cu O

Li +

C5H11

LiMe 2ZnO

BnO

(ii) Me3 Zn – Li +

TBSO

3.15.7

O

TfO C5H11

TBSO

TMS THF, –78 °C

BnO

74%

TBSO

TMS C5H11 BnO

Bis-Alkoxycarbonylation

Bis-carbonylation of olefins can be effected with CuCl2 and Pd/C in methanol, as shown in the following example.323 OMe

OMe

CO, CuCl 2 NaOAc, Pd/ C

CO2Me

MeOH, 25 °C OMe

3.15.8

CO2Me OMe

70%

Cascade Cyclizations

Although limited in scope to olefin substrates possessing the requisite arrangement of initiator and terminator, cationic cascade cyclizations of polyenes as pioneered by W. S. Johnson et al. represent a powerful strategy for construction of steroids and steroid-like carbon skeletons. In the following example, a fluorine atom is installed on one of the olefins to serve as a cation-stabilizing group, a strategy that improves the efficiency of the cascade cyclization.324 This remarkable transformation forms four C—C sigma bonds in a single synthetic operation; the 70% yield translates to an average yield of 91.5% per bond forming event! Me Me F Me

Me Me

Me Me

CF3CO2H CH2Cl 2 –78 °C TMS

Me

F Me

70%

H

HO Me

Me

H

CH2

Me

Me

The following example was executed on a 5 g scale. The initial cation is formed by addition of the terminal olefin to a Pummerer-type intermediate generated from phenyl methyl sulfoxide and trifluoroacetic anhydride, which leads to sulfur incorporation into the cyclized product.325 PhS(=O)Me (CF3CO)2O

Me

Me

322 323 324 325

Me

CN

Pyridine CH2Cl 2 25 °C 62%

Me PhS

H Me Me

CN

Lipshutz, B. H.; Wood, M. R. Journal of the American Chemical Society 1994, 116, 11689–11702. Jolliffe, K.; Paddon-Row, M. N. Tetrahedron 1995, 51, 2689–2698. Johnson, W. S.; Plummer, M. S.; Reddy, S. P.; Bartlett, W. R. Journal of the American Chemical Society 1993, 115, 515–521. Burnell, R. H.; Caron, S. Canadian Journal of Chemistry 1992, 70, 1446–1454.

229

230

3 Addition to Carbon–Carbon Multiple Bonds

Cascade radical cyclizations have also been used to dramatic effect in natural product syntheses in which multiple C—C bonds are formed in a tandem series of radical cyclizations. The following example from Snider utilizes a Mn(III) oxidation of a β-ketoester to generate the initial radical, which then undergoes two sequential radical cyclizations to generate the bicyclic product.326 O CO2Me

Mn(OAc)3 Cu(OAc)2 AcOH

E

O

73% E = CO2Me

Lanthanide catalysts can serve to enhance the selectivity and efficiency of a similar cascade cyclization, as shown in the following.327 Yb(OTf)3 Mn(OAc)3 CF3CH2OH

OMe i-Pr Me

O

OMe i-Pr H

69%

CO2Et

Me

EtO2C

O

The following example shows a rather extreme extension of this strategy. Although of modest efficiency (35% yield), the formation of four C—C bonds in a single reaction is impressive.328 Me

O

Me

Me

Me

Mn(OAc)3 Cu(OAc)2

Me H

MeOH 25 °C, 3 h 35%

CO2Et

O

H Me CO2Et

The following cascade radical cyclization was utilized as the final step in Curran’s synthesis of hirsutene. The isolated yield (65%) suffers somewhat from the volatility of the product hydrocarbon; the crude yield was estimated to be c. 80%.329 I

Bu 3SnH AIBN

Me

Me Me

H Me

Me Me

Benzene 85 °C, 1 h

H

H

65%

Cascade polyene cyclizations initiated by a Nazarov cyclization have been reported, as exemplified in the following.330 H Me

TiCl 4 Me

Me O

CH2Cl 2, –78 °C

H Me

Me Me O

99%

326 327 328 329 330

Snider, B. B.; Dombroski, M. A. The Journal of Organic Chemistry 1987, 52, 5487–5489. Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Cheung, K.-K. Journal of the American Chemical Society 2000, 122, 1658–1663. Snider, B. B.; Kiselgof, J. Y.; Foxman, B. M. The Journal of Organic Chemistry 1998, 63, 7945–7952. Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943–3958. Bender, J. A.; Arif, A. M.; West, F. G. Journal of the American Chemical Society 1999, 121, 7443–7444.

231

4 Nucleophilic Aromatic Substitution Stéphane Caron and Emma McInturff Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 231 Oxygen Nucleophiles, 232 Sulfur Nucleophiles, 234 Nitrogen Nucleophiles, 236 Halogen Nucleophiles, 241 Carbon Nucleophiles, 243 ortho-Arynes, 245

4.1 Introduction Nucleophilic aromatic substitution (SN Ar), which can operate through several different reaction mechanisms, is considered one of the preferred methods to derivatize arenes. As such, there are numerous examples of simple functionalization and complex fragment union. Despite great advances in transition metal-catalyzed arene functionalization, SN Ar remains an attractive option due to simplicity, low cost, and avoidance of metal contamination of the product. The scope of this reaction is guided by three basic principles: electron deficiency at the reactive carbon on the aromatic system, nature of the leaving group to be displaced, and reactivity of the nucleophile.1 In general, more electron-deficient arenes will undergo more facile aromatic nucleophilic substitution in an addition/elimination sequence. Aryl halides, specifically fluorides, and diazonium compounds have proven to be the most successful substrates for this reaction. While the typical order of reactivity for an aliphatic nucleophilic substitution follows I− > Br− > Cl− ≫ F− , this trend is generally reversed for the nucleophilic aromatic substitution. The electron withdrawing nature of an aryl fluoride enhances the propensity for nucleophilic attack at the fluorine-bearing carbon. Primary and secondary amines, as well as alkoxides, are usually excellent nucleophiles for the reaction. A few types of carbon nucleophiles, including cyanide and malonate derivatives, are also commonly used. The preparation of ortho-arynes will also be briefly discussed in this chapter. In this case, the elimination of a leaving group obviously precedes the addition of a nucleophile in what is formally a nucleophilic aromatic substitution. This methodology is not as common as the SN Ar reaction because of the very high reactivity and instability of the aryne generated. However, it has been used in cycloaddition reactions to access relatively complex polycycles. The chapter is organized by the type of nucleophile and nature of the product generated. This account should not be considered a comprehensive review in this area, but rather a highlight of the diversity of SN Ar reactions that have been performed on scale. Furthermore, transition metal promoted couplings are discussed separately in Chapter 6.

1 Buncel, E.; Dust, J. M.; Terrier, F. Chemical Reviews 1995, 95, 2261–2280. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

232

4 Nucleophilic Aromatic Substitution

4.2 Oxygen Nucleophiles 4.2.1

Preparation of Phenols

Phenols can be synthesized via nucleophilic aromatic substitutions from several starting materials with either hydroxide or water as the nucleophile. For examples, aryl fluorides can be displaced by hydroxide under fairly mild conditions.2 Other activated aryl halides, such as 2-pyridinyl chlorides, are also easily displaced.3 Me Me Me

NO2

N . O

~96%

N

F 3C

N . O

NO2 OH

I

Cl NaOH, tBuOH 75 °C

Cl O

Me Me

82%

F I

Cl

Me

50% NaOH dioxane

OH O

N

F3C

In cases where aryl sulfonic acids prove to be an inexpensive and readily available starting materials, their conversion to phenols can be accomplished using hydroxide at high temperature.4 Finally, the substitution of a diazonium salt provides another alternative in the case where the starting aniline is readily accessible. In the example provided, water from aqueous sulfuric acid acts as the nucleophile.5 It is always preferable to generate the diazonium in situ rather than attempt its isolation due to their known instability and potential shock sensitivity. CO2H CO2H

N

CO2H

77%

SO3H H N

CO2H

KOH, 215 °C then, H+ OH H N

O Br

NaNO2 H2SO4 (aq)

N

O Br

91% NH2

4.2.2

OH

Preparation of Aryl Ethers

Aryl ethers are an important class of compounds and are often prepared using copper-catalyzed Ullman couplings (see Section 6.12). These compounds can also be accessed via nucleophilic aromatic substitutions, which usually require elevated reaction temperatures unless the arene starting material is very electron deficient. Displacement of an aryl fluoride with an alkoxide is well precedented. The example shown below demonstrates the selectivity of fluoride displacement over bromide or chloride. Additionally, electron withdrawing groups ortho or para to the leaving group facilitate the reaction.6 Another example, in which SN Ar was used to replace a Mitsunobu reaction, demonstrates 2 Hankovszky, H. O.; Hideg, K.; Lovas, M. J.; Jerkovich, G.; Rockenbauer, A.; Gyor, M.; Sohar, P. Canadian Journal of Chemistry 1989, 67, 1392–1400. 3 Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk, K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. Organic Process Research & Development 2016, 20, 1476–1481. 4 Campayo, L.; Jimenez, B.; Manzano, T.; Navarro, P. Synthesis 1985, 197–200. 5 Singh, B.; Bacon, E. R.; Lesher, G. Y.; Robinson, S.; Pennock, P. O.; Bode, D. C.; Pagani, E. D.; Bentley, R. G.; Connell, M. J.; Hamel, L. T.; Silver, P. J. Journal of Medicinal Chemistry 1995, 38, 2546–2550. 6 Song, Z. J.; Tellers, D. M.; Dormer, P. G.; Zewge, D.; Janey, J. M.; Nolting, A.; Steinhuebel, D.; Oliver, S.; Devine, P. N.; Tschaen, D. M. Organic Process Research & Development 2014, 18, 423–430.

4.2 Oxygen Nucleophiles

halogen selectivity and influence of an ortho electron withdrawing group. In this case, displacement of the fluorine with an ortho bromide is preferred, although the fluorine with the para bromide does react, producing 2-4% of the undesired regioisomer.7 F

MeONa MeOH, 80 °C

I

90%

Br Br OH

Br Br

KOtBu, THF 67 °C

F

HN

92%

I

MeO

Br F

O +

HN

F

F

O NH

(2–4%)

A more complex example was demonstrated in the manufacture of AZD0530, which features a series of SN Ar reactions to construct the active pharmaceutical ingredient (API). Regioselectivity in the first ether formation is controlled by the electron character of the di-fluoroanilide core (also assembled by SN Ar), and more forcing conditions were required for the second ether formation.8 Me

OH O

Cl F

HN N

F

O

Na t-amylate, NMP 55 °C, 5 h O

N

Cl

O O

HN

80%

N

N

N

F

O

O

OH

NaOH, PhMe 105 °C, 10 h 87%

N

Cl

O O Me

HN

N

N N

O

O

N

O

AZD0530

Aryl bromides can also participate in this reaction although the substrate scope is not as broad.9 Chloropyridines are generally excellent substrates for this reaction, especially with chlorine at the 2-, 4-, or 6-position. Conversely, 3- or 5-substituted pyridines are poorly reactive. The example presented demonstrates once again that monosubstitution is possible since the ether generated renders the product more electron-rich, and therefore less reactive.10 Me Me Me Br

N O

Me

OH NaH, DMF 50 °C 87%

Me

Me

Me Me Me

O

N

Me

O

7 Girardin, M.; Dolman, S. J.; Lauzon, S.; Ouellet, S. G.; Hughes, G.; Fernandez, P.; Zhou, G.; O’Shea, P. D. Organic Process Research & Development 2011, 15, 1073–1080. 8 Ford, J. G.; O’Kearney-McMullan, A.; Pointon, S. M.; Powell, L.; Siedlecki, P. S.; Purdie, M.; Withnall, J.; Frances Wood, P. O. K. Organic Process Research & Development 2010, 14, 1088–1093; Raw, S. A.; Taylor, B. A.; Tomasi, S. Organic Process Research & Development 2011, 15, 688–692. 9 Wilson, J. M.; Cram, D. J. The Journal of Organic Chemistry 1984, 49, 4930–4943. 10 Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu, R.-L. The Journal of Organic Chemistry 1997, 62, 6588–6597.

233

234

4 Nucleophilic Aromatic Substitution

O O

O

MeONa, MeOH 65 °C

Me

Me

O

93% Cl

4.2.3

N

Cl

Cl

N

OMe

Preparation of Diaryl Ethers

Diaryl ethers can be accessed by nucleophilic aromatic substitution. As a rule of thumb, it is preferable to have the most electron-deficient arene contain the leaving group, while the “phenol” provides the electron-rich partner. Many times, the reaction can be conducted with a mild inorganic base in a polar parotic solvent with heat. This synthetic method is complemented by the metal-catalyzed cross-coupling of aryl halides (see Section 6.12). Activated bromides,11 chlorides,12 and fluorides13 generally provide high-yielding reactions. In the final example in the following scheme, chemoselectivity of the aryl fluoride over pyridinyl chloride is likely due to the ortho electron withdrawing substituent.14 Br

K2CO3, NMP 135–155 °C

HO

+

MeO2S

OCF3

O N

CN

HO

N

+ N

OMe

OHC

F +

89%

N

F 3C OH

K2CO3, NMP 60 °C 92%

CN

N

N

N

O

O OMe

OHC I

Cl I

O

Cs2CO3, NMP 125 °C

K2CO3, DMP reflux

HO +

Cl

OCF3

MeO2S

90%

Cl

F

95%

O

Cl Cl O

N

F3C

4.3 Sulfur Nucleophiles 4.3.1

Preparation of Aryl Thioethers

Thiols are suitable nucleophiles in aromatic substitutions and are generally more reactive than the corresponding alcohols, allowing for a lower reaction temperature. It is convenient to utilize the thiolate directly if it is commercially available to avoid potential disulfide formation and minimize the odor associated with free thiols.15 11 Chang, S.-J.; Fernando, D.; Fickes, M.; Gupta, A. K.; Hill, D. R.; McDermott, T.; Parekh, S.; Tian, Z.; Wittenberger, S. J. Organic Process Research & Development 2002, 6, 329–335. 12 Pippel, D. J.; Mills, J. E.; Pandit, C. R.; Young, L. K.; Zhong, H. M.; Villani, F. J.; Mani, N. S. Organic Process Research & Development 2011, 15, 638–648. 13 Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63–68. 14 See Note 3. 15 Lipton, M. F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor, D. W.; Newby, J. J.; Appell, R. B.; Daugs, E. D. Organic Process Research & Development 2003, 7, 385–392.

4.3 Sulfur Nucleophiles

Br

MeSNa, NMP 65 °C

Br

Br

SMe

>72%

When necessary, the thiol can be used in the presence of a mild base. Because of its comparatively lower pK a and greater nucleophilicity, the reaction can be conducted in an alcohol solvent.16 Furthermore, introduction of a hindered tert-butyl thiolate moiety is feasible,17 and it has been shown that a nitro moiety is a sufficient leaving group to participate is this reaction.18 MeO

Br

MeO

NO2

N

N

MeSH, K2CO3 EtOH, rt 79%

SMe

MeO

NO2

N

t-BuSNa, DMF 70 °C

F

84%

F

97%

O2N

N

t-BuS

St-Bu

C12H25SH Cs2CO3 DMSO

CHO

4.3.2

MeO

CHO C12H25S

Preparation of Diaryl Thioethers

Arylthiols are effective partners in the formation of diaryl thioethers by nucleophilic aromatic substitutions. As with alkylthiols, arylthiols are excellent nucleophiles, leading to faster reactions compared to the corresponding phenols. As shown in the following scheme, displacement of an aryl fluoride19 with thiophenol can occur under fairly mild conditions. In another interesting example, thiol participates in the reaction in the absence of base, and instead the HCl produced as a by-product is removed by distillation. When base is used, disubstitution occurs.20 Boc N EtO2C

F

91%

S O O

Boc N

PhSH, K2CO3 DMF, rt EtO2C

S

S O O F

Cl F

S CO2Et

F

N F

HS

F

DCM, reflux 91%

F

CO2Et

F

N F

16 Dillard, R. D.; Yen, T. T.; Stark, P.; Pavey, D. E. Journal of Medicinal Chemistry 1980, 23, 717–722. 17 Wheelhouse, R. T.; Jennings, S. A.; Phillips, V. A.; Pletsas, D.; Murphy, P. M.; Garbett, N. C.; Chaires, J. B.; Jenkins, T. C. Journal of Medicinal Chemistry 2006, 49, 5187–5198. 18 Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 2357–2360. 19 Becker, D. P.; Villamil, C. I.; Barta, T. E.; Bedell, L. J.; Boehm, T. L.; DeCrescenzo, G. A.; Freskos, J. N.; Getman, D. P.; Hockerman, S.; Heintz, R.; Howard, S. C.; Li, M. H.; McDonald, J. J.; Carron, C. P.; Funckes-Shippy, C. L.; Mehta, P. P.; Munie, G. E.; Swearingen, C. A. Journal of Medicinal Chemistry 2005, 48, 6713–6730. 20 Hao, Q.; Pan, J.; Li, Y.; Cai, Z.; Zhou, W. Organic Process Research & Development 2013, 17, 921–926.

235

236

4 Nucleophilic Aromatic Substitution

4.3.3

Other Sulfur Nucleophiles

Other sulfur-substituted arenes have been prepared by nucleophilic aromatic substitutions. For example, sulfones can be accessed by nucleophilic attack of the sulfur center of a sulfinate anion, in contrast to traditional approaches to sulfones via thioether oxidation.21 Pyridinyl halides have also been shown to react readily with sulfinates, and this process has been demonstrated on scale.22,23 Sodium sulfide can react with electron-deficient arene to generate sodium thiolates directly, albeit in moderate yields. The regioselectivity observed reflects the activating nature of a nitro moiety at the ortho position.24 RSO2Na, DMSO 100 °C

F

R = Me, 85% R = Ph, 88%

OHC

Cl

OHC

MeSO2Na H2O, AcOH 110 °C 80%

N

Me

SO2R

SO2Me N

Me O

O

Cl

NO2

Na2S, H2O reflux

Cl

NO2

50%

Cl

SNa

4.4 Nitrogen Nucleophiles Substituted anilines are commonly seen in pharmaceutical agents, agrochemicals, dyes, and many other useful materials. Their preparation by nucleophilic aromatic substitution of an amine onto an electron-deficient arene containing a leaving group is well precedented and a very common strategy for fragment union. This class of compounds has attracted much attention and led to the development of new synthetic methods such as palladium and copper-mediated aryl aminations. (see Section 6.11). Additionally, alkylation or reductive amination of anilines, often obtained from a previous nitration, remains an attractive synthetic approach. The availability of the prerequisite starting materials and ability to purge residual metal catalysts often dictates which strategy might be preferred. 4.4.1

Preparation of Anilines

Nucleophilic substitution of an aryl halide with ammonia is an alternative to nitration and reduction that is typically required to access anilines. Due to the high temperature required for this process and low boiling point of ammonia, these reactions must be performed in a vessel suitable for pressure reactions, or in flow. The examples shown in the following scheme demonstrate the atom-economic amination on activated aryl halides.25,26 Cl NO2 N

Cl

aq NH3 91 °C 94%

NH2 NO2 N

NH2

21 Ulman, A.; Urankar, E. The Journal of Organic Chemistry 1989, 54, 4691–4692. 22 Maloney, K. M.; Kuethe, J. T.; Linn, K. Organic Letters 2011, 13, 102–105. 23 Reeves, J. T.; Tan, Z.; Reeves, D. C.; Song, J. J.; Han, Z. S.; Xu, Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; Mahaney, P. E.; Lee, H.; Busacca, C. A.; Senanayake, C. H. Organic Process Research & Development 2014, 18, 904–911. 24 Gupta, R. R.; Kumar, R.; Gautam, R. K. Journal of Heterocyclic Chemistry 1984, 21, 1713–1715. 25 Cleator, E.; Scott, J. P.; Avalle, P.; Bio, M. M.; Brewer, S. E.; Davies, A. J.; Gibb, A. D.; Sheen, F. J.; Stewart, G. W.; Wallace, D. J.; Wilson, R. D. Organic Process Research & Development 2013, 17, 1561–1567. 26 Le, P. T.; Richardson, P. F.; Sach, N. W.; Xin, S.; Ren, S.; Xiao, J.; Xue, L. Organic Process Research & Development 2015, 19, 639–645.

4.4 Nitrogen Nucleophiles

Cl N N

OMe

N

67%

Cl

4.4.2

Cl

aq NH3, n-BuOH 90 °C

OMe

N

NH2

Preparation of Aryl Amines

Primary and secondary amines react readily with appropriately functionalized electron-deficient arenes to provide the desired anilines. An excess of the starting amine is often utilized if it is an inexpensive commodity, since they are stronger bases than the products and hence can effectively scavenge the acid generated. In cases where the amine is more valuable, an additional non-nucleophilic base, such as a carbonate or a tertiary amine can be employed to neutralize the acid generated in the process. For primary amines, disubstitution is avoided as the resulting product is a less nucleophilic aniline.27,28 When a substrate contains multiple leaving groups, introduction of the first amine renders the product more electron-rich, thereby slowing down the second nucleophilic substitution. In the example shown, control of temperature inhibits the second substitution.29 OMe

i-Pr2NEt, DMSO 60 °C

H2N

OMe

100%

F

NH2

K2CO3, THF reflux

NO2 F

+

+ Br

NO2

Me CN N

Cl

O

O

OMe

N H

OMe

H N

telescoped forward 92% yield over 4 steps

NH

+

NO2

Br

O

NO2

Me

MeOH, rt

CN

>78% N

Cl

N

Cl

O

In the case of the trichloropyrimidine shown below, the first two substitutions were accomplished readily using SN Ar, but the introduction of a third amine required the generation of a lithium amide in order to avoid harsh reaction conditions.30 The second example shows the addition of a pyrrolidine that proceeded in very high yield where tetramethylguanidine was used as the base in a fairly complex system.31 O Cl N Cl

+ N

Cl

H N

N

Na2CO3 heptane, water 60 °C 91%

H2N n-BuLi, heptane 82 °C

N N N

N

Cl

95%

N

O N

N N

N

N H

27 Beaulieu, P. L.; Hache, B.; Von Moos, E. Synthesis 2003, 1683–1692. 28 Kuroda, K.; Tsuyumine, S.; Kodama, T. Organic Process Research & Development 2016, 20, 1053–1058. 29 Remarchuk, T.; St-Jean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.; Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Organic Process Research & Development 2014, 18, 1652–1666. 30 Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.; Parlett; Vrieze, D. Organic Process Research & Development 2007, 11, 441–449. 31 Mauragis, M. A.; Veley, M. F.; Lipton, M. F. Organic Process Research & Development 1997, 1, 39–44.

237

238

4 Nucleophilic Aromatic Substitution

O

O F

NH2

N

F

N

O

+

TMG, DMSO 80 °C

BocHN H NH

Me

BocHN

93%

Me

F H

N

N

N

NH2 O

Me

Me TMG = tetramethylguanidine

Other functionalized arenes will also participate in amine substitution via SN Ar reaction, including sulfones and triflates.32,33

Me

O S

O O CO2Et S + Me

S I

NC

1: 1 mixture Me

N

NH S

NC

OSO2CF3

CO2Et

HNEt2 DMSO, 40 °C

S

N

THF, rt >98%

I

CN CO2Et

4.4.3

O

O

NC

Me

N

CO2Et I

NEt2

CN CO2Et

>99%

Preparation of Diaryl Amines

Because they are not as nucleophilic as alkylamines, aryl amines require more forcing conditions to participate in a nucleophilic aromatic substitution.34,35 F

K2CO3, DMF reflux

+

N H

NO2

N

88% NO2 O

O N N N Me

+

N N

Cl

i-Pr

N N H

K3PO4, NMP 160 °C 78%

N N N Me

N N i-Pr

N N

One method to circumvent this problem is to deprotonate the amine using a strong base.36 In the first example, a mixture of both substrates is added to a suspension of the lithium amide, and deprotonation occurs more rapidly than addition of the lithium amide. In contrast, in the second example shown, pretreatment of the aryl amine was required to minimize exposure of the pyridazinone to strongly basic conditions to avoid decomposition.37 32 Huang, Q.; Richardson, P. F.; Sach, N. W.; Zhu, J.; Liu, K. K. C.; Smith, G. L.; Bowles, D. M. Organic Process Research & Development 2011, 15, 556–564. 33 Schmidt, G.; Reber, S.; Bolli, M. H.; Abele, S. Organic Process Research & Development 2012, 16, 595–604. 34 Jian, H.; Tour, J. M. The Journal of Organic Chemistry 2003, 68, 5091–5103. 35 Carrera, D. E.; Sheng, P.; Safina, B. S.; Li, J.; Angelaud, R. Organic Process Research & Development 2013, 17, 138–144. 36 Davis, E. M.; Nanninga, T. N.; Tjiong, H. I.; Winkle, D. D. Organic Process Research & Development 2005, 9, 843–846. 37 Shu, L.; Wang, P.; Gu, C.; Garofalo, L.; Alabanza, L. M.; Dong, Y. Organic Process Research & Development 2012, 16, 1870–1873.

4.4 Nitrogen Nucleophiles

Cl

CO2H F

NH2

+

90%

I

F

Cl

LiNH2, THF 35 °C

CO2H

H N

I

F F

F O

H2N

+

N N

Me

N Me

Br

N N

O

Na t-pentoxide THF

Me

H N

N N

87% Cl

N N

N Me

Cl

A detailed account of reaction condition and base optimization for SN Ar coupling of an aminopyridine and chloropyrimidine was disclosed in Pfizer’s synthesis of palbociclib, in which a Grignard-mediated reaction was most effective at controlling impurity formation.38 Me

NH2 N

N

N

Cl

N

Me Br

CyMgCl, THF 20 °C

O

85%

Br

N N

HN

N

O

N N Boc

N N Boc

Sulfones can also be used as leaving groups. In this example, sulfone displacement was achieved, requiring strong base to improve the nucleophilicity of the aminopyrazole.39 N

N Me

N Me O

S

O

O

N

Cl

N

F

NH2

LiHMDS 2-MeTHF, THF −25 °C

N

N

N Me

N H

O

N

Cl

N

F

96% conversion

OTBS

OTBS

In some instances where the product of the nucleophilic aromatic substitution is a better base then the starting aniline, it is possible to conduct the reaction under acidic conditions.40 t-Bu Cl N

t-Bu

+ H2N

HCl, n-BuOH 79%

HN N

38 Duan, S.; Place, D.; Perfect, H. H.; Ide, N. D.; Maloney, M.; Sutherland, K.; Price Wiglesworth, K. E.; Wang, K.; Olivier, M.; Kong, F.; Leeman, K.; Blunt, J.; Draper, J.; McAuliffe, M.; O’Sullivan, M.; Lynch, D. Organic Process Research & Development 2016, 20, 1191–1202. 39 Linghu, X.; Wong, N.; Iding, H.; Jost, V.; Zhang, H.; Koenig, S. G.; Sowell, C. G.; Gosselin, F. Organic Process Research & Development 2017, 21, 387–398. 40 Denni-Dischert, D.; Marterer, W.; Baenziger, M.; Yusuff, N.; Batt, D.; Ramsey, T.; Geng, P.; Michael, W.; Wang, R.-M. B.; Taplin, F., Jr.; Versace, R.; Cesarz, D.; Perez, L. B. Organic Process Research & Development 2006, 10, 70–77.

239

240

4 Nucleophilic Aromatic Substitution

4.4.4

Other Nitrogen Nucleophiles

Several other nitrogen nucleophiles can participate in nucleophilic aromatic substitution. For example, a pyrimidone or pyrazole will react with an activated aryl halides.41,42 Hydrazine is also an excellent nucleophile and can be introduced under relatively mild conditions.43 O2N

O N

HN

O2 N F

N

N

92%

O

N

N

K2CO3, DMF 80 °C

N

N

+

O

O

OAc

OAc

AcO

AcO Me

Cl

O

N

Me OEt

+

O O S

N

CHO K2CO3, KI, DMF 100 °C 72%

N H

H2N NH2

+

CHO

N

N

O

N

OEt

O O S

DMSO 58 °C 92%

F

N H

NH2

Hydrazones will undergo intramolecular cyclization to 1H-indazoles when a leaving group is present at the ortho position. It has been demonstrated that a fluoride44 requires less forcing conditions than a mesylate45 to promote cyclization. Finally, an elegant sequence involving two nucleophilic aromatic substitutions was developed at Abbott for the preparation of a quinolone antibiotic. The first substitution generated the quinolone by cyclization of a vinylogous amide on an aryl fluoride. This was followed by introduction of an azetidine sidechain in a second substitution reaction.46 Et Et O F

H2N

+

H N

N

• MsOH

F

F

O F

CO2Et DBU, LiCl, NMP, 35 °C

NH

F

CO2Et

F

N

F

N H2N

F

N H2N

F

H N 98%

F

NH • HCl DBU, 23 °C

N

F

HO

O

F F

Et

NaOAc, toluene reflux

then, (i-PrCO)2O 35 °C 93%

N

O F

CO2Et

N

N

i-PrCO2

F

N H2N

F

F

41 De Napoli, L.; Messere, A.; Montesarchio, D.; Piccialli, G. The Journal of Organic Chemistry 1995, 60, 2251–2253. 42 DeBaillie, A. C.; Jones, C. D.; Magnus, N. A.; Mateos, C.; Torrado, A.; Wepsiec, J. P.; Tokala, R.; Raje, P. Organic Process Research & Development 2015, 19, 1568–1575. 43 Fleck, T. J.; Chen, J. J.; Lu, C. V.; Hanson, K. J. Organic Process Research & Development 2006, 10, 334–338. 44 Caron, S.; Vazquez, E. Organic Process Research & Development 2001, 5, 587–592. 45 Caron, S.; Vazquez, E. Synthesis 1999, 588–592. 46 Barnes, D. M.; Christesen, A. C.; Engstrom, K. M.; Haight, A. R.; Hsu, M. C.; Lee, E. C.; Peterson, M. J.; Plata, D. J.; Raje, P. S.; Stoner, E. J.; Tedrow, J. S.; Wagaw, S. Organic Process Research & Development 2006, 10, 803–807.

4.5 Halogen Nucleophiles

4.5 Halogen Nucleophiles 4.5.1

Reaction of Diazonium Salts

Introduction of a halogen atom onto an aromatic ring by nucleophilic aromatic substitution is complementary to halogenation of arenes through electrophilic aromatic substitution discussed in Section 5.4. One of the most common methods is the Sandmeyer reaction, in which an aniline is diazotized and displaced by a halide. The diazonium salt is obtained by treatment of the sodium nitrite under acidic conditions or with an alkyl nitrite. While the salt can be isolated, due to the energetic nature of the diazonium salt, it is frequently preferable to keep this reactive intermediate in solution and to carry it through the next step. This chemistry may also be amenable to continuous processing, so not to build up large quantities of diazonium salts. When setting up this reaction, it is prudent to have sufficient venting and a large headspace, as a large amount of gas evolves over the course of the reaction. In general, formation of fluoroarenes are lower yielding than other aryl halides and at times requires isolation of the diazonium salt.47 Many times, the Balz–Schiemann reaction is used, in which the intermediate diazonium fluoroborate is isolated, and then heated to transfer fluorine to the substrate and liberate N2 gas. In the second example shown, an alternative method was developed, using a one-pot process and hydrofluoric acid (HF) as fluorine source. Extreme care must be taken when using HF, both on laboratory scale and upon scale-up.48 NH2 N

HBF4, EtOH then, i-amylONO −5 °C

Cl

N2+ N

BF3-OEt2 t-BuONO, THF −20 °C

Cl

• BF4−

N

MeO

N N

MeO

NH2

Heptane reflux 70%

N2

heptane 85 °C

HBF3

81% MeO

NaNO2, HF −40 to 65 °C

N

F N

Cl

N

F N

90%

For the formation of chlorides, copper(II) chloride is often used as the halide source.49 As part of a methodology evaluation, the Sandmeyer reaction has been conducted on 7-amino-1-indanone and 8-amino-tetralone with several halide sources. The preparation of 8-bromo-1-tetralone is exemplified.50 H2N

Me

O2N

NO2

O

NH2

t-BuONO, CuCl2 MeCN, 65 °C 92%

Me

Cl O2N

HBr, EtOH, NaNO2, H2O then, CuBr, HBr 95 °C

NO2

O

Br

70%

For the preparation of aryl iodides, potassium iodide is generally the reagent selected.51,52 Amine diazotization and displacement can also be used in combination with oxygen- and nitrogen-based nucleophiles. 47 Munson, P. M.; Thompson, W. J. Synthetic Communications 2004, 34, 759–766. 48 Abele, S.; Schmidt, G.; Fleming, M. J.; Steiner, H. Organic Process Research & Development 2014, 18, 993–1001. 49 Knapp, S.; Ziv, J.; Rosen, J. D. Tetrahedron 1989, 45, 1293–1298. 50 Nguyen, P.; Corpuz, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M. E. The Journal of Organic Chemistry 2003, 68, 10195–10198. 51 Satyanarayana, K.; Srinivas, K.; Himabindu, V.; Reddy, G. M. Organic Process Research & Development 2007, 11, 842–845. 52 Singh, J.; Kim, O. K.; Kissick, T. P.; Natalie, K. J.; Zhang, B.; Crispino, G. A.; Springer, D. M.; Wichtowski, J. A.; Zhang, Y.; Goodrich, J.; Ueda, Y.; Luh, B. Y.; Burke, B. D.; Brown, M.; Dutka, A. P.; Zheng, B.; Hsieh, D.-M.; Humora, M. J.; North, J. T.; Pullockaran, A. J.; Livshits, J.; Swaminathan, S.; Gao, Z.; Schierling, P.; Ermann, P.; Perrone, R. K.; Lai, M. C.; Gougoutas, J. Z.; DiMarco, J. D.; Bronson, J. J.; Heikes, J. E.; Grosso, J. A.; Kronenthal, D. R.; Denzel, T. W.; Mueller, R. H. Organic Process Research & Development 2000, 4, 488–497.

241

242

4 Nucleophilic Aromatic Substitution

H2N

CF3

NaNO2, aq HCl, 5 °C then, KI, H2O, 60–70 °C

F3C

Cl

Cl

Cl

4.5.2

CF3

F3C

95%

H 2N

I

AcOH, HCl, NaNO2 35–40 °C then, KI, H2O 15–20 °C 75%

I

Cl

Cl

Cl

Preparation of 2-Halopyridines and Derivatives

Another type of halogenation through nucleophilic substitution is the conversion of a pyrone-type structure to a halopyridine. The oxygen atom generally reacts with either a phosphorous or sulfur reagent, to provide an activated ester which is displaced by a halide. For the preparation of chlorides, phosphorous oxychloride53 , or thionyl chloride are most commonly used.54 When phosphorous oxychloride is used, proper precautions should be taken in the workup (see Section 19.4.1.4). Many times, the halogenated product is telescoped directly into another SN Ar reaction without isolation. H N

MeO

POCl3, CH3CN reflux

MeO

87%

MeO

NH

MeO Me

MeO N

O

O

OH

SOCl2, DMF 80 °C

N

Cl

N

MeO

54%

O

Cl N

Me

O

N

N

N

Cl N

O

O

In some cases, base is also required in the chlorination step, and additives such as 1,4-diazabicyclo[2.2.2]octane (DABCO) have been found to accelerate the reaction.55 In the following example shown, studies identified that DABCO was also capable of participating in the SN Ar reaction, resulting in a nonproductive pathway. Optimization was undertaken to minimize this, while still accelerating the chlorination. Cl N OH

EtO2C

N N

N

POCl3, i-Pr2NEt DABCO, toluene 95 °C >99% conversion

Cl

EtO2C

N

EtO2C N

N

N

N N

N

DABCO related impurity

Phosphorous oxybromide can be utilized for the preparation of bromides but is generally not as efficient as phosphorous oxychloride for the synthesis of chlorides.56 Another common method is the in situ generation of phosphorous pentabromide, although this method might be less practical on small scale due to the challenges with handling bromine.57 53 Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.; Zhu, J. Organic Process Research & Development 2006, 10, 391–397. 54 Plé, P. A.; Green, T. P.; Hennequin, L. F.; Curwen, J.; Fennell, M.; Allen, J.; Lambert-van der Brempt, C.; Costello, G. Journal of Medicinal Chemistry 2004, 47, 871–887. 55 Zheng, B.; Conlon, D. A.; Corbett, R. M.; Chau, M.; Hsieh, D.-M.; Yeboah, A.; Hsieh, D.; Müslehiddino˘glu, J.; Gallagher, W. P.; Simon, J. N.; Burt, J. Organic Process Research & Development 2012, 16, 1846–1853. 56 Ricci, G.; Ruzziconi, R.; Giorgio, E. The Journal of Organic Chemistry 2005, 70, 1011–1018. 57 Ager, D. J.; Erickson, R. A.; Froen, D. E.; Prakash, I.; Zhi, B. Organic Process Research & Development 2004, 8, 62–71.

4.6 Carbon Nucleophiles

N

N

OH POBr , 100 °C 3

Br

45%

PBr3, Br2, DCE reflux

O2N N

O2N

70%

OH

N

Br

An attractive method for this transformation utilizes phosphorous pentoxide in the presence of a bromide source. This procedure offers some advantage in the workup as the product resides in the toluene layer, while the phosphoric acid generated can easily be removed via an aqueous wash.58

Me

N

CN

P2O5, n-Bu4NBr toluene, 100 °C

OH

75%

CN Me

N

Br

Preparation of aryl fluorides or iodides by these methods is rather uncommon.

4.6 Carbon Nucleophiles 4.6.1

Cyanide as a Nucleophile

Cyanide is an excellent nucleophile and can participate in nucleophilic aromatic substitutions. This method is complementary, but often inferior to the metal-mediated couplings that typically utilize zinc cyanide (see Section 6.15). For substrates that are highly activated, sodium cyanide can be employed.59 Copper (I) cyanide can also be used in this reaction, as shown in the following scheme. This cyanation is proposed to operate via a different mechanism, in which CuCN serves both as cyanide source and Cu catalyst.60 This may explain the observed selectivity for iodine over chlorine in the substrate shown.61 F

O

NaCN, DMSO 120 °C

Me

NC

O

Me

77% Me

Me

Cl

I OH O

N

Me

CuCN, NMP 110 °C 87%

F3C

4.6.2

Cl

Me

CN OH O

N

F3 C

Malonates as Nucleophiles

Malonate derivatives have been utilized in nucleophilic aromatic substitutions of electron-deficient arenes. In some cases, the salt of the malonate is available and can be used directly.62 In most cases, a strong base such as sodium 58 59 60 61 62

Kato, Y.; Okada, S.; Tomimoto, K.; Mase, T. Tetrahedron Letters 2001, 42, 4849–4851. Cheung, E.; Rademacher, K.; Scheffer, J. R.; Trotter, J. Tetrahedron 2000, 56, 6739–6751. Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.; Wang, Y. Tetrahedron Letters 2014, 55, 1271–1280. See Note 3. Gurjar, M. K.; Murugaiah, A. M. S.; Reddy, D. S.; Chorghade, M. S. Organic Process Research & Development 2003, 7, 309–312.

243

244

4 Nucleophilic Aromatic Substitution

hydride or KOt-Bu is utilized to generate the enolate at lower temperatures in tetrahydrofuran, and the temperature is increased for the substitution to proceed.63 F

CO2Et

F

ONa

+ EtO C 2

Cl

N

Cl N

F

+

Me

CO2Et Cl

NO2

EtO2C CO2Et N Me

NaH, THF −10 °C

CO2Et

EtO2C

CO2Et

EtO2C

94%

OEt

NO2

Cl

DMF, 100 °C

98%

Cl N

F

Methyl cyanoacetate is also an effective nucleophile and can allow for the preparation of benzylic nitriles after decarboxylation.64 A similar SN Ar/decarboxylation pathway is shown in the following example, using ethylacetoacetate as carbon nucleophile to generate a 1-aryl propanone.65

CO2Me

NC

+

NO2

O Me

EtO

+

F

F F

MeO2C

79%

O2 N

O

CN

NaH, THF 0 °C to reflux

F

O2N

NO2 KOtBu THF

CO2Et

F F

O

Me

H2SO4, HOAc 70 °C 80–85% 2 steps

NO2 F F

O

Me

Functionalizated malonates can also be introduced via SN Ar and telescoped to perform downstream chemistry. In the following example, the substitution reaction is performed under mild conditions, using an inorganic base. The SN Ar product is then cyclized by a Cu-catalyzed C—O bond formation to generate a benzofuran.66 O Ar

O

OH O

NHMe Ar = C6H4F Br

O2 N

4.6.3

+

F

K3PO4 DMAc, H2O

Ar

NHMe Br

Br

Br

NO2

CuI 69% 2 steps

Br

O

O2N O

Ar NHMe

Other Carbon Nucleophiles

While less common, other carbon nucleophiles can participate in nucleophilic aromatic substitution. One such example is the preparation of indoles through intramolecular cyclization, which is believed to proceed through a benzyne mechanism.67 63 Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Organic Process Research & Development 2001, 5, 28–36. 64 Selvakumar, N.; Rajulu, G. G. The Journal of Organic Chemistry 2004, 69, 4429–4432. 65 Pesti, J. A.; LaPorte, T.; Thornton, J. E.; Spangler, L.; Buono, F.; Crispino, G.; Gibson, F.; Lobben, P.; Papaioannou, C. G. Organic Process Research & Development 2014, 18, 89–102. 66 Song, Z. J.; Tan, L.; Liu, G.; Ye, H.; Dong, J. Organic Process Research & Development 2016, 20, 1088–1092. 67 Kudzma, L. V. Synthesis 2003, 1661–1666.

4.7 ortho-Arynes

F

N

Bn N

LDA, THF −78 °C

Bn

N

97%

N H

Sulfone anions can also act as nucleophiles, as shown in the following example.68

F

F

(i) t-BuOK, DMF 30–35 °C

O O S Ph

Cl

(ii) F3 C

Ph S O O CN

CN F3C

60 °C 85%

Furthermore, the reaction of secondary nitrile anions with aryl fluorides has been demonstrated, even with electron-rich arenes.69,70 Et N

F

Et

N

KHMDS, toluene CN 100 °C

+

77%

NC

CN

N

N

NC

4.7 ortho-Arynes Arynes are extremely active intermediates that react rapidly with a number of reagents, most notably alkenes and alkynes in dipolar cycloadditions. The chemistry for the preparation of arynes and their reactivity has been extensively reviewed.71,72 Two major methods exist for the preparation of arynes. The first method consists of generation of an anion ortho to a leaving group. Typically, this is accomplished by ortho-metalation73 or halogen-metal exchange.74 OMe MeO + O Br

NaNH2, THF MeO 50 °C

O

76%

OMe

OMe

Br + Br

68 69 70 71 72 73 74

OMe

n-BuLi, toluene 0 °C to rt 89%

Sommer, M. B.; Begtrup, M.; Boegesoe, K. P. The Journal of Organic Chemistry 1990, 55, 4817–4821. See Note 44. Caron, S.; Wojcik, J. M.; Vazquez, E. Organic Syntheses 2003, 79, 209–215. Dyke, A. M.; Hester, A. J.; Lloyd-Jones, G. C. Synthesis 2006, 4093–4112. Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701–730. Sutherland, H. S.; Higgs, K. C.; Taylor, N. J.; Rodrigo, R. Tetrahedron 2001, 57, 309–317. Coe, J. W.; Wirtz, M. C.; Bashore, C. G.; Candler, J. Organic Letters 2004, 6, 1589–1592.

245

246

4 Nucleophilic Aromatic Substitution

While diazotization and decomposition of anthranilic acid derivatives has historically been an important method for the generation of arynes, it is now less commonly used due its impracticality and potential safety hazard associated with the large volume of gas generated.75 NH2 + CO2H

O O

Ph

t-amylONO, THF 70 °C 67%

H Ph

O O

75 Pu, L.; Grubbs, R. H. The Journal of Organic Chemistry 1994, 59, 1351–1353.

H H

247

5 Electrophilic Aromatic Substitution Stéphane Caron and Emma McInturff Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 247 Nitrogen Electrophiles, 247 Sulfur Electrophiles, 250 Halogenation, 253 Carbon Electrophiles, 257

5.1 Introduction Electrophilic aromatic substitution reactions are the most commonly used methods to derivatize simple aromatic substrates.1 The parameters that control the outcome of these reactions are generally well understood. Electron-rich arenes will often undergo facile reactions, while electron-poor arenes require more forcing conditions or will not react at all. The factors that control the regiochemical outcome of the reaction on substituted arenes follow the general rule that electron-rich substituents direct primarily to the para-position and to a lesser extent, the ortho-position, while electron withdrawing groups will favor meta substitution. Halogens are also ortho/para directors but reduce the rate of substitution relative to more electron-rich substituents. For aromatic rings with multiple substituents, the most electron-rich functional group usually has the dominant effect. Most of the reactions presented in this chapter proceed at room temperature or above and many require the presence of a protic or Lewis acid in stoichiometric amount. The most commonly utilized Lewis acid is AlCl3 , but many others are acceptable as well. This chapter is organized based on the nature of the electrophile and then subdivided by the type of products obtained from the substitution. Many reactions with little practical use have been omitted.

5.2 Nitrogen Electrophiles 5.2.1

Nitration

Nitration is the most utilized reaction for incorporation of a nitrogen substituent on an aromatic ring. A desirable feature of this reaction is that it directly functionalizes an arene C—H bond, and the reagent used, nitric acid, is inexpensive. Another advantage of the nitration reaction is that the active nitrating species, the nitronium ion (NO2 + ), is very reactive, and the reaction typically stops after a single nitration due to the deactivating effect of a nitro substituent. The most common and practical way to perform a nitration is to dissolve the substrate in sulfuric acid (often an exothermic process) followed by slow addition of concentrated HNO3 or a cold mixture of H2 SO4 and HNO3 . When the reaction is performed in this manner, the nitronium ion is generated in the presence of the substrate and is rapidly

1 Olah, G. A. Interscience Monographs on Organic Chemistry: Friedel-Crafts Chemistry; Wiley-Interscience: New York, N. Y., 1973. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

248

5 Electrophilic Aromatic Substitution

consumed, thus minimizing safety concerns. Nitrations are highly exothermic and the exotherm can be controlled by the rate of addition of HNO3 .2,3 H2SO4 HNO3

CO2Et N H

O

CO2Et N H

89%

Me

N Cl

82%

N

O

Me

H2SO4 HNO3

N Cl

O2 N

N NO2

In cases where the arene is highly electron rich, dinitration is possible under standard conditions using 70% nitric acid. In this case, a 7 : 1 mixture of regioisomers formed and the 2,5-isomer purged downstream.4 OMe

OMe

OMe

OMe

HNO3 (70%)

NO2

94% 7: 1 ratio

NO2

O2N +

NO2

OMe

OMe

A modification of the aforementioned procedure is to incorporate acetic anhydride as a water scavenger. The reaction can be performed using Ac2 O as either the solvent without H2 SO4 5 or as an additive. In the second case below (115 kg scale), the yield dropped significantly when the reaction was conducted only in acetic acid without acetic anhydride.6 OMe

NO2

Ac2O HNO3

OMe

43%

NHAc MeO

AcOH, Ac2O H2SO4 , HNO3

O2N

>70%

MeO

NHAc

Not isolated from a previous step

Another modification was reported, in which the substrate and potassium nitrate were treated with trifluoroacetic acid (TFA), then slowly warmed to control the exotherm of the nitration.7 Cl O OMe

Cl

KNO3 TFA 91%

O O2N OMe

2 Hutt, M. P.; MacKellar, F. A. Journal of Heterocyclic Chemistry 1984, 21, 349–352. 3 Marterer, W.; Prikoszovich, W.; Wiss, J.; Prashad, M. Organic Process Research & Development 2003, 7, 318–323. 4 Funel, J.-A.; Brodbeck, S.; Guggisberg, Y.; Litjens, R.; Seidel, T.; Struijk, M.; Abele, S. Organic Process Research & Development 2014, 18, 1674–1685. 5 Maehr, H.; Smallheer, J. Journal of the American Chemical Society 1985, 107, 2943–2945. 6 Giles, M. E.; Thomson, C.; Eyley, S. C.; Cole, A. J.; Goodwin, C. J.; Hurved, P. A.; Morlin, A. J. G.; Tornos, J.; Atkinson, S.; Just, C.; Dean, J. C.; Singleton, J. T.; Longton, A. J.; Woodland, I.; Teasdale, A.; Gregertsen, B.; Else, H.; Athwal, M. S.; Tatterton, S.; Knott, J. M.; Thompson, N.; Smith, S. J. Organic Process Research & Development 2004, 8, 628–642. 7 Allwein, S. P.; Roemmele, R. C.; Haley, J. J.; Mowrey, D. R.; Petrillo, D. E.; Reif, J. J.; Gingrich, D. E.; Bakale, R. P. Organic Process Research & Development 2012, 16, 148–155.

5.2 Nitrogen Electrophiles

Nitronium triflate is a superior nitrating agent for less reactive substrates and can be generated with tetraalkylammonium nitrate and triflic anhydride8 or triflic acid in the presence of fuming nitric acid.9 Because of the nature of these reactants, solvent choice is critical, and dichloromethane (DCM) is often selected. The product is then isolated through an extractive workup. Me4NNO3 Tf2O CH2Cl2

OMe CN

CN

100%

OMe

N R

OMe O2N

OMe

HNO3 TfOH CH2Cl2 77%

R = COCF3

O2N N R O2N

An interesting process for nitration of substituted pyrroles was developed by Bristol-Myers Squibb, using sodium nitrate and SO3 -pyridine to form an insoluble nitronium sulfate species as the nitrating agent. Detailed studies of the mechanism and safety of this process provide an interesting option to the aforementioned methods using corrosive acids.10 O

NaNO3 (4 equiv) SO3-pyridine (2 equiv) NaHSO4 (2 equiv) ACN

H N

EtO

70% yield

O

H N

NO2

EtO

Br

5.2.2

Br

Nitrosation

The most common method for the preparation of a nitroso derivative is by slow addition of aqueous sodium nitrite to an arene dissolved in a carboxylic acid. One advantage of carrying out the reaction in this manner is that if the product is a solid, it will often crystallize from the reaction mixture and can be easily isolated by filtration. The three examples shown are representatives of this reaction. In the first example, the reaction proceeded at 0 ∘ C,11 in the second, at room temperature,12 and the third example required 90 ∘ C, due to the lack of reactivity of the substrate.13 aq NaNO2 CH3CH2CO2H MeO

OH

66% aq NaNO2 AcOH

N H

97% Br

NO MeO

OH NO N H

Br

8 Shackelford, S. A.; Anderson, M. B.; Christie, L. C.; Goetzen, T.; Guzman, M. C.; Hananel, M. A.; Kornreich, W. D.; Li, H.; Pathak, V. P.; Rabinovich, A. K.; Rajapakse, R. J.; Truesdale, L. K.; Tsank, S. M.; Vazir, H. N. The Journal of Organic Chemistry 2003, 68, 267–275. 9 Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E. P.; Huang, J.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.; Shrikhande, A.; Heym, J. H.; Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.; Schulz, D. W.; Tingley, F. D., III; O’Neill, B. T. Journal of Medicinal Chemistry 2005, 48, 3474–3477. 10 Beutner, G. L.; Desai, L.; Fanfair, D.; Lobben, P.; Anderson, E.; Leung, S. W.; Eastgate, M. D. Organic Process Research & Development 2014, 18, 1812–1820. 11 Maleski, R. J. Synthetic Communications 1993, 23, 343–348. 12 Liu, Y.; McWhorter, W. W., Jr. Journal of the American Chemical Society 2003, 125, 4240–4252. 13 Erickson, R. H.; Hiner, R. N.; Feeney, S. W.; Blake, P. R.; Rzeszotarski, W. J.; Hicks, R. P.; Costello, D. G.; Abreu, M. E. Journal of Medicinal Chemistry 1991, 34, 1431–1435.

249

250

5 Electrophilic Aromatic Substitution

O Pr

N

O

O

aq NaNO2 AcOH

N Me

Pr

83%

NH2

NO

N

O

N Me

NH2

Alkyl nitrites are an alternative class of reagent that is particularly useful if the starting material is not soluble in a carboxylic acid. The most common alkyl nitrites are n-butyl and i-amyl nitrite.14 An extractive workup is usually required for isolation of the desired product when these conditions are utilized. OMe

OMe

i-AmONO DMSO, rt

N

ON

75%

MeO

N

5.2.3

Diazonium Coupling

NH2

MeO

N N

NH2

The reaction between a diazonium salt and an arene, known as a diazonium coupling, is not a very common reaction although the products from this reaction often lead to materials with interesting optical properties. When performing this reaction, it is recommended that proper safety precautions are used in handling the diazonium salts, since they are known to be very energetic and can decompose easily.15 O2N •

BF 4−

N2

PhNMe2 aq AcOH

+

O2N N

N

62%

NMe2

5.3 Sulfur Electrophiles 5.3.1

Sulfonation

While the sulfonation reaction is not utilized as often as the chlorosulfonation, this transformation allows for the direct formation of a sulfonic acid. Sulfonation is conducted in fuming sulfuric acid (oleum), a highly corrosive reagent. On a reactive substrate, the reaction is generally carried out around 0 ∘ C. Ideally, the product is precipitated by pouring the reaction mixture into cold water and isolated by filtration.16 Alternatively, the reaction can be quenched, and the crude sulfonic acid can be isolated and purified by generation of the sodium salt.17 N

Oleum 65–70 °C

SO3H N

54%

F3C

Oleum, − 5 °C then, NaOH

N S

78%

F3C

SO3Na

N S

14 Marchal, A.; Melguizo, M.; Nogueras, M.; Sanchez, A.; Low, J. N. Synlett 2002, 255–258. 15 Ulman, A.; Willand, C. S.; Kohler, W.; Robello, D. R.; Williams, D. J.; Handley, L. Journal of the American Chemical Society 1990, 112, 7083–7090. 16 Dorogov, M. V.; Filimonov, S. I.; Kobylinsky, D. B.; Ivanovsky, S. A.; Korikov, P. V.; Soloviev, M. Y.; Khahina, M. Y.; Shalygina, E. E.; Kravchenko, D. V.; Ivachtchenko, A. V. Synthesis 2004, 2999–3004. 17 Ikemoto, N.; Liu, J.; Brands, K. M. J.; McNamara, J. M.; Reider, P. J. Tetrahedron 2003, 59, 1317–1325.

5.3 Sulfur Electrophiles

Another method to access the sulfonic acid is similar to a halosulfonation (Section 5.3.2) reaction, but the sulfonic acid is obtained by not employing a large excess of the halosulfonic acid.18 EtO2C

EtO2C

ClSO3H >80%

O

SO3H

O

Not isolated

5.3.2

Halosulfonation

The halosulfonation reaction is probably the most commonly employed method for introduction of a sulfur substituent onto an arene. The substrate is normally added directly to the halosulfonic acid, the mixture is heated until reaction completion, then quenched into cold water. The initial product of the reaction is the sulfonic acid that is converted to the sulfonyl chloride by reaction with the excess halosulfonic acid.19,20 Proper precautions must be taken when using chlorosulfonic acid, which is highly toxic. ClSO3H (5 equiv) 0–70 °C

Br N CONHMe Cl Cl

86%

Br

ClSO3H (5 equiv) 30–50 °C

Cl

N CONHMe

ClO2S Cl Cl

Cl

60%

5.3.3

SO2Cl

Sulfurization

The sulfurization reaction is not commonly employed. It can be performed with a variety of sulfur sources such as SCl2 , S2 Cl2 , or even elemental sulfur. In some cases, a Lewis acid is employed, but it is not always necessary with activated substrates. This method has been used in an efficient synthesis of a benzothiophene.21 Disulfides can also be generated in a single step by treatment with sulfur monochloride in the presence of TiCl4 .22 MeO

SCl2 CHCl3 0 °C to rt

OMe

MeO

OMe

t-Bu

t-Bu

47%

OMe

MeO

90%

S2Cl2, TiCl4 toluene, −6 °C

HO

MeO

OMe S

t-Bu HO t-Bu

S

t-Bu S

OH t-Bu

A variation on the sulfurization is the Herz reaction, in which an aniline reacts with SCl2 to generate a thiazothionium halide (Herz compound).23 One positive aspect of the Herz compounds is that they can be further derivatized. For 18 Urban, F. J.; Jasys, V. J.; Raggon, J. W.; Buzon, R. A.; Hill, P. D.; Eggler, J. F.; Weaver, J. D. Synthetic Communications 2003, 33, 2029–2043. 19 Borror, A. L.; Chinoporos, E.; Filosa, M. P.; Herchen, S. R.; Petersen, C. P.; Stern, C. A.; Onan, K. D. The Journal of Organic Chemistry 1988, 53, 2047–2052. 20 Moore, R. M., Jr. Organic Process Research & Development 2003, 7, 921–924. 21 Engman, L. Journal of Heterocyclic Chemistry 1984, 21, 413–416. 22 Pastor, S. D. The Journal of Organic Chemistry 1984, 49, 5260–5262. 23 Belica, P. S.; Manchand, P. S. Synthesis 1990, 539–540; Girard, G. R.; Bondinell, W. E.; Hillegass, L. M.; Holden, K. G.; Pendleton, R. G.; Uzinskas, I. Journal of Medicinal Chemistry 1989, 32, 1566–1571.

251

252

5 Electrophilic Aromatic Substitution

instance, they will react with sodium hydroxide to generate the ortho-thioaniline, which makes the two-step sequence very attractive for the preparation of such products. Cl

100%

N NH2

S2Cl2 AcOH 100%

AcHN

5.3.4

Cl

Cl

S2Cl2 AcOH

NaNO2 N

S S N Cl

S N N

N S S Cl

N

H2N SH

Sulfinylation

There are only a few reports on the sulfinylation of arenes, and they generally lead to the symmetrical diaryl sulfoxide. The reaction is executed by treating an aromatic compound with thionyl chloride in the presence of a Lewis acid. The example shown proved to be fairly general, especially for electron-rich systems.24

MeO

SOCl2 Sc(OTf)3 CH2Cl2

MeO

92%

MeO

MeO

5.3.5

O S

OMe OMe

Sulfonylation

The sulfonylation reaction is similar to the sulfinylation reaction. A key advantage is that it is straightforward to synthesize asymmetrical sulfones, since the reaction can be performed using an alkyl or aryl sulfonyl chloride and an arene.25 It has also been shown that Lewis acids with triflate counterions are superior to the corresponding chlorides for catalysis of the reaction.26 The reaction usually requires high temperature and is not suitable for sensitive substrates. Me

PhSO2Cl Sn(OTf)2 120 °C

Me SO2Ph

99% Me

5.3.6

Me

Thiocyanation

The thiocyanation reaction is another method for the introduction of sulfur to an arene. The reaction is typically performed with a thiocyanate source in the presence of an oxidizing agent. For example, ammonium thiocyanate is used in conjunction with bromine.27 An alternative method, which might be more practical on a small scale, generates the reactive intermediate from sodium thiocyanate and N-bromosuccinimide.28 The resulting product can easily be hydrolyzed to the thiol for further functionalization.

24 25 26 27 28

Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Kumar, S. P.; Nagaiah, K. Synlett 2002, 784–786. Singh, R. P.; Kamble, R. M.; Chandra, K. L.; Saravanan, P.; Singh, V. K. Tetrahedron 2001, 57, 241–247. Repichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J.; Desmurs, J.-R. The Journal of Organic Chemistry 1999, 64, 6479–6482. Hirokawa, Y.; Harada, H.; Yoshikawa, T.; Yoshida, N.; Kato, S. Chemical & Pharmaceutical Bulletin 2002, 50, 941–959. Toste, F. D.; De Stefano, V.; Still, I. W. J. Synthetic Communications 1995, 25, 1277–1286.

5.4 Halogenation

NH4SCN CO2Me Br2, MeOH 0 °C OMe

MeHN

NaSCN NBS, AcOH rt

MeO

OMe

MeHN

74%

OMe

CO2Me

NCS

OMe MeO

89%

SCN NHBoc

NHBoc

5.4 Halogenation 5.4.1

Fluorination

Electrophilic fluorination of arenes is not a very common reaction. Several of the reagents used for electrophilic fluorination are not practical or present safety concerns for scaling.29 Furthermore, the regioselectivity observed in electrophilic fluorination is usually very poor. For instance, the fluorination of anisole using N-fluoro pentachloropyridinium triflate gives a 1 : 1 ratio of the ortho and para regioisomers.30 Aryl fluorides are more likely to be accessed through a Balz–Schiemann reaction using a nucleophilic fluoride source (Section 4.5.1). Cl Cl

Cl

Cl

+

MeO

N Cl F TfO−

F

MeO

MeO

CH2Cl2 rt 74%

5.4.2

F :

1

1

Chlorination

The electrophilic chlorination of arenes is not as straightforward as the corresponding bromination or iodination because the regioselectivity observed is not always as high and that the simplest chlorinating reagent, Cl2 , is a gas. Nonetheless, chlorination of anilines and other electron rich arenes has been reported using N-chlorosuccinimide.31 NH2

NH2

NCS CH3CN, 60°C

Cl

89% CO2Me

CO2Me

OH Me O Me

95% 97 : 3

Cl

Cl

NCS DCM, rt

OH Me O Me

+

OH Me O Me

29 Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. The Journal of Organic Chemistry 1999, 64, 7048–7054. 30 Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. Journal of the American Chemical Society 1990, 112, 8563–8575. 31 Nickson, T. E.; Roche-Dolson, C. A. Synthesis 1985, 669–670; Wang, P.; Briggs, A. J. Organic Process Research & Development 2014, 18, 656–661.

253

254

5 Electrophilic Aromatic Substitution

Sulfuryl chloride has been utilized as a chlorinating agent, though it is a better option when regioselectivity is not of concern.32 It has been reported that catalytic amounts of diphenylsulfide in the presence of AlCl3 improve the regioselectivity of the reaction.33 Another interesting approach to chlorination of anilines is shown in the second example below, using HCl and hydrogen peroxide to effect the bis-chlorination.34 SO2Cl2 CH2Cl2/MeOH rt

OH

OH Cl

95% t-Bu

t-Bu

NH2

HCl in Et2O (4 equiv) 30% H2O2 (2.1 equiv) Cl DMF

NH2

Cl

93% OCHF2

OCHF2

5.4.3

Bromination

The bromination of arenes is the most common aromatic electrophilic halogenation. Aryl bromides are synthetically useful since they are readily converted to organomagnesium or organolithium species (see Chapter 12) as well as being excellent substrates for a number of metal-catalyzed processes (see Chapter 6). There are many methods available for the preparation of aryl bromides. The two reagents that are most practical and easily scalable are 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, also named dibromantin) and N-bromosuccinimide (NBS). DBDMH is an effective reagent with both electron deficient35 and electron rich36 arenes. In some cases, NBS proved to be a superior reagent to bromine in the bromination of ortho-nitroanilines.37 Commonly, these reactions are sensitive to pH, and typically acidic conditions promote the bromination. CF3

94%

F3C Me MeO MeO

H2N O2N

DBDMH AcOH/H2SO4 10–45 °C

DBDMH EtOAc 45 °C 96% NBS AcOH 91% or Br2 AcONa/AcOH 78%

CF3

Br

F 3C

DBDMH =

Me MeO

Br

Me Me Br

O N Br N

O

MeO

H2N O2N

Br

Bromine, while impractical on small scale because of its low boiling point, is a very useful brominating agent on large scale because of its low cost and the generation of HBr as the sole by-product. The bromination is usually carried out 32 Masilamani, D.; Rogic, M. M. The Journal of Organic Chemistry 1981, 46, 4486–4489. 33 Watson, W. D. The Journal of Organic Chemistry 1985, 50, 2145–2148. 34 Li, J.; Smith, D.; Krishnananthan, S.; Hartz, R. A.; Dasgupta, B.; Ahuja, V.; Schmitz, W. D.; Bronson, J. J.; Mathur, A.; Barrish, J. C.; Chen, B.-C. Organic Process Research & Development 2012, 16, 156–159. 35 Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery, T.; Bachert, D. The Journal of Organic Chemistry 2003, 68, 3695–3698. 36 Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.; Zhu, J. Organic Process Research & Development 2004, 8, 624–627. 37 Manley, P. W.; Acemoglu, M.; Marterer, W.; Pachinger, W. Organic Process Research & Development 2003, 7, 436–445.

5.4 Halogenation

in acetic acid at room temperature.38 In another example, bromine is used as a solution in methanol, buffered with aqueous CaCO3 .39 Bromine can also be used in the presence of a Lewis acid, in this case, AlCl3 .40 Me

Br2 AcOH 15 °C

O

Me

N

N H

R

Me

O Br

Me

89%

N H

Me

R

Br

87%

NH2

N H

N H

Br2, MeOH CaCO3, H2O

Me

N

NH2

F

F

Me F

Br2, AlCl3 DCM, 5–10 °C

F

85%

Me Br

F F

Another reagent proven to be superior to bromine on a very electron-poor arene is sodium bromate.41 Unfortunately, the strongly acidic conditions required for this reaction do not make it practical for substrates with sensitive functionality. Pyridine tribromide (Pyr-HBr3 ) and tertbutylammonium tribromide (TBATB) can also be used for bromination.42,43 NaBrO3 H2SO4,K2SO4 40–50 °C

O2N

Br

O2N

86%

CO2Me

TBATB, MeOH 30–35 °C

F

5.4.4

CO2Me

88%

OH O

Br

H N

OH

Pyr-HBr3 THF, DCM 0–5 °C N H

83%

O

F

H N

N H

Br

Iodination

The iodination reaction is not as common as bromination. Since iodide is not as electronegative, and therefore deactivating as other halogens, diiodination can be observed on very reactive substrates.44

38 Tilley, J. W.; Coffen, D. L.; Schaer, B. H.; Lind, J. The Journal of Organic Chemistry 1987, 52, 2469–2474. 39 Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-Y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Organic Process Research & Development 2012, 16, 1832–1845. 40 Naganathan, S.; Andersen, D. L.; Andersen, N. G.; Lau, S.; Lohse, A.; Sørensen, M. D. Organic Process Research & Development 2015, 19, 721–734. 41 Groweiss, A. Organic Process Research & Development 2000, 4, 30–33. 42 Williams, M. J.; Chen, Q.; Codan, L.; Dermenjian, R. K.; Dreher, S.; Gibson, A. W.; He, X.; Jin, Y.; Keen, S. P.; Lee, A. Y.; Lieberman, D. R.; Lin, W.; Liu, G.; McLaughlin, M.; Reibarkh, M.; Scott, J. P.; Strickfuss, S.; Tan, L.; Varsolona, R. J.; Wen, F. Organic Process Research & Development 2016, 20, 1227–1238. 43 Gillmore, A. T.; Badland, M.; Crook, C. L.; Castro, N. M.; Critcher, D. J.; Fussell, S. J.; Jones, K. J.; Jones, M. C.; Kougoulos, E.; Mathew, J. S.; McMillan, L.; Pearce, J. E.; Rawlinson, F. L.; Sherlock, A. E.; Walton, R. Organic Process Research & Development 2012, 16, 1897–1904. 44 Wariishi, K.; Morishima, S.; Inagaki, Y. Organic Process Research & Development 2003, 7, 98–100.

255

256

5 Electrophilic Aromatic Substitution

OMe

ICl, MeOH 15 °C to reflux

I

85%

MeO

OMe I

MeO

Iodine is commonly used for these reactions, and several modifications have been developed.45 On a similar substrate, iodine and hydrogen peroxide were used to access the 3-iodopyrazole in an efficient process using water as solvent.46 I

I2, K2CO3, DMF

O2 N

N H

N

O2N

90% 0.55 eq I2 0.6 eq H2O2 H2O

Me N N Me

Me

N H

N

I N N Me

91%

Aryl iodides can also be accessed using iodopyridinium chloride, which is easier to handle from a handling perspective than iodine.47 Finally, another proven alternative is the use of iodine in the presence of iodic acid.48 A similar example, using sodium periodate, was specifically developed for unactivated arenes.49 N

I NaOH, CH2Cl2 10 °C

Me N O N H Me

Cl−

+

CO2H

Telescoped 75%

CO2Et

HIO3, I2 AcOH, H2SO4 80 °C

N

Me

I

N O N H Me

I

N H

NaIO4, I2, H2SO4 AcOH, Ac2O

CO2H AcO

CO2Et N

59%

N H

CO2H

I

CO2H

AcO

90%

In a similar mode of reactivity, an oxidative iodination using NaBO3 and potassium iodide effectively iodinated the aniline shown in the following example.50 Me H2N

F

KI, NaBO3 AcOH/H2O 90%

Me H2N

F I

45 Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. J. Organic Process Research & Development 2014, 18, 266–274. 46 Ruck, R. T.; Huffman, M. A.; Stewart, G. W.; Cleator, E.; Kandur, W. V.; Kim, M. M.; Zhao, D. Organic Process Research & Development 2012, 16, 1329–1337. 47 Atkins, R. J.; Banks, A.; Bellingham, R. K.; Breen, G. F.; Carey, J. S.; Etridge, S. K.; Hayes, J. F.; Hussain, N.; Morgan, D. O.; Oxley, P.; Passey, S. C.; Walsgrove, T. C.; Wells, A. S. Organic Process Research & Development 2003, 7, 663–675. 48 Huth, A.; Beetz, I.; Schumann, I.; Thielert, K. Tetrahedron 1987, 43, 1071–1074. 49 Yang, X.-D.; Pan, Z.-X.; Li, D.-J.; Wang, G.; Liu, M.; Wu, R.-G.; Wu, Y.-H.; Gao, Y.-C. Organic Process Research & Development 2016, 20, 1821–1827. 50 Wang, X.-J.; Zhang, L.; Sun, X.; Lee, H.; Krishnamurthy, D.; O’Meara, J. A.; Landry, S.; Yoakim, C.; Simoneau, B.; Yee, N. K.; Senanayake, C. H. Organic Process Research & Development 2012, 16, 561–566.

5.5 Carbon Electrophiles

N-Iodosuccinimide (NIS) is another iodination reagent that has been scaled successfully, though cost of reagent may be of concern.51 An interesting procedure for the iodination of an arene is the use of N-chlorosuccinimide (NCS) in the presence of hydroiodic acid and potassium iodide.52 This procedure has the advantage that the cost of NCS is significantly lower than NIS. NIS, TFA MeCN, 0–5 °C

CO2Et NPMB2

N

EtO2C

93%

N

F

N H

CO2i-Bu

CO2Et N

EtO2C

N

I

NCS, KI, HI CH2Cl2, H2O 32 °C

I

79%

F

N H

NPMB2

CO2i-Bu

5.5 Carbon Electrophiles 5.5.1

Friedel–Crafts Alkylation

The reaction of an alkyl halide or alkene with an arene in the presence of an acid is usually referred to as a Friedel–Crafts alkylation. Overall, this reaction is not as useful as its acylation counterpart, mainly because of the lower reactivity of the alkylating agent and the harsher conditions often necessary for the electrophilic substitution to proceed. While much of the older literature will cite the use of carbon disulfide or deactivated arenes such as nitrobenzene as solvents, these solvents are now generally avoided because of the safety hazards associated with them and have often been replaced by DCM or by the arene itself if it is a commodity. In the following example, a benzylic cation is formed by treating the α-chiral benzyl alcohol with strong acid. The nosyl-indole reacts with carbocation to furnish the desired product. Optimization of indole protecting groups and Lewis and Bronsted acids enabled good diastereoselectivity, and the off-diastereomer was purged by crystallization.53 CO2H CO2H

Cl Me

Cl

MsOH, TFA

+ OH

Pr

F

22 °C N 83%, >99:1 dr Ns

Pr

Me

F

N Ns

The Friedel–Crafts alkylation proceeds best when performed in an intramolecular fashion as exemplified in the preparation of a fluoroindanone in sulfuric acid at elevated temperature.54 In another example, an excess of toluene is used in the presence of a dichloride freshly prepared from the diol to effect intermolecular alkylation followed by intramolecular cyclization in 91% yield.55

51 Mullens, P.; Cleator, E.; McLaughlin, M.; Bishop, B.; Edwards, J.; Goodyear, A.; Andreani, T.; Jin, Y.; Kong, J.; Li, H.; Williams, M.; Zacuto, M. Organic Process Research & Development 2016, 20, 1075–1087. 52 Herrinton, P. M.; Owen, C. E.; Gage, J. R. Organic Process Research & Development 2001, 5, 80–83. 53 Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-Y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Organic Process Research & Development 2012, 16, 1832–1845. 54 Sircar, I.; Duell, B. L.; Cain, M. H.; Burke, S. E.; Bristol, J. A. Journal of Medicinal Chemistry 1986, 29, 2142–2148. 55 Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. The Journal of Organic Chemistry 2001, 66, 5772–5782.

257

258

5 Electrophilic Aromatic Substitution

O

O

H2SO4 140 °C

Cl

55%

F

PhMe CH2Cl2 AlCl3, rt

Me Me Cl Cl

F

Me Me

91%

Me Me

Me

Me Me

Another method by which to perform the Friedel–Crafts alkylation is to utilize an alkene as the electrophilic reagent. This method is often utilized to prepare tert-butyl arenes using isobutylene.56 An inconvenience with this procedure is the necessity for a reaction vessel which can be pressurized, since isobutylene is a gas. Me OH OH

t-Bu

Me

AcOH/H2SO4 70 °C

OH OH

>85% t-Bu

Once again, this reaction is more general in the intramolecular sense. Benzomorphane57 and benzazepine58 derivatives could be prepared by initial protonation of an olefin with a strong acid followed by nucleophilic attack of the arene at the more stable tertiary carbocation. CHO

OMe

N

OMe

MeSO3H 100 °C

N Me

96%

Me

CHO

Me Me

Me Me

H2SO4 0–45 °C N

79%

H

N

Me

Me

H

Another interesting example is shown in the following scheme, in which an iminium cation serves as the activated species for the Friedel–Crafts alkylation. Due to the propensity of the phenolic starting material to dehydrate to generate quinone methide species, Brønsted and Lewis acids were unsuitable for this reaction.59 OH

OH

MeN NMe

O

O

PhMe, reflux then, HCl OH

Ph

Ph

57% OH

56 Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.; Hoveyda, A. H.; Schrock, R. R. Angewandte Chemie, International Edition 2001, 40, 1452–1456. 57 Grauert, M.; Bechtel, W. D.; Weiser, T.; Stransky, W.; Nar, H.; Carter, A. J. Journal of Medicinal Chemistry 2002, 45, 3755–3764. 58 Varlamov, A.; Kouznetsov, V.; Zubkov, F.; Chernyshev, A.; Alexandrov, G.; Palma, A.; Vargas, L.; Salas, S. Synthesis 2001, 849–854. 59 Dirat, O.; Bibb, A. J.; Burns, C. M.; Checksfield, G. D.; Dillon, B. R.; Field, S. E.; Fussell, S. J.; Green, S. P.; Mason, C.; Mathew, J.; Mathew, S.; Moses, I. B.; Nikiforov, P. I.; Pettman, A. J.; Susanne, F. Organic Process Research & Development 2011, 15, 1010–1017.

5.5 Carbon Electrophiles

5.5.2

Friedel–Crafts Arylation

The Friedel–Crafts arylation, also known as the Scholl reaction, involves the generation of a doubly benzylic carbocation followed by intramolecular formation of the diphenyl bond. The carbocation is usually generated from an alcohol precursor upon treatment with a protic or Lewis acid. Often, the starting material is dissolved in acetic acid followed by addition of sulfuric acid which induces the cation formation and cyclization.60 CO2Et

HO CO2Et

Cl

AcOH/H2SO4 rt 68%

Cl

Cl

Cl

A spectacular example of a cascade Friedel–Crafts alkylation and arylation is shown below. Starting from hexaphenylbenzene, six alkylations and arylations are performed in a single operation in excellent yield.61 t-Bu t-BuCl FeCl3 CH2Cl2 MeNO2

t-Bu

t-Bu

t-Bu

t-Bu

92%

t-Bu

5.5.3

Claisen Rearrangement

The aryl Claisen rearrangement generally requires much harsher conditions than the alkyl variant (Section 7.3.2.4) since aromaticity is lost in the transition state. The following are three representative examples highlighting the high temperature usually required for this transformation and the occasional low regioselectivity which can result.62 It is interesting that in the third example, modification from a methyl ester to a diethyl amide changed the product distribution from a ratio of 87 : 13 to 96 : 4.63 The predominant regioisomer arises from two sequential [3.3] sigmatropic rearrangements, first a Claisen, followed by a Cope rearrangement. Me

Me

O

Me

OH CO2Na

CO2Na 170 °C

Me O

H+

CO2H

75% Cl

Cl O

215 °C xylenes

Me HO

Cl O

O

>77%

Me HO

OH

60 Levy, A.; Rakowitz, A.; Mills, N. S. The Journal of Organic Chemistry 2003, 68, 3990–3998. 61 Rathore, R.; Burns, C. L. The Journal of Organic Chemistry 2003, 68, 4071–4074. 62 Burks, J. E., Jr.; Espinosa, L.; LaBell, E. S.; McGill, J. M.; Ritter, A. R.; Speakman, J. L.; Williams, M.; Bradley, D. A.; Haehl, M. G.; Schmid, C. R. Organic Process Research & Development 1997, 1, 198–210; Manchand, P. S.; Micheli, R. A.; Saposnik, S. J. Tetrahedron 1992, 48, 9391–9398. 63 Patterson, J. W. The Journal of Organic Chemistry 1995, 60, 4542–4548.

259

260

5 Electrophilic Aromatic Substitution

OH

O CONEt2 205 °C 90%

MeO

OH

CONEt2

CONEt2

+

MeO

MeO 96 : 4

5.5.4

Formylation

The formylation of arenes is a particularly useful electrophilic aromatic substitution because of the synthetic utility of the resulting aldehyde. A large number of procedures are available to effect this transformation including the reaction of a disubstituted formamide in the presence of an activating agent such as phosphorous oxychloride or oxalyl chloride (Vilsmeier–Haack reaction), reaction with hexamethylenetetramine (HMT) in the presence of an acid (Duff reaction), reaction of a 1,1-dichloroether in the presence of a Lewis acid, reaction of zinc cyanide in the presence of HCl (Gatterman reaction), reaction of carbon monoxide and HCl in the presence of AlCl3 and CuCl (Gatterman–Koch reaction), and the reaction with a dichlorocarbene, generated by treatment of chloroform with sodium hydroxide (Reimer–Tiemann reaction). One of the most frequently utilized procedures for the formylation reaction is the Vilsmeier–Haack reaction. Dimethylformamide (DMF) is usually used as the formamide and is activated with POCl3 .64 In the formylation of resorcinol, POCl3 was shown to be slightly superior to oxalyl chloride.65 Another convenient way to carry out the formylation is to utilize the Vilsmeier reagent, which is a commercially available solid. The final example shows the preparation of an iminium chloride which was further reacted with a nucleophile.66 While there are many reports on the use of 1,1-dichloroethers in the presence of a Lewis acid to generate benzaldehyde derivatives,67 the toxicity of the starting dichloroether makes this procedure less preferable. OMe Ph Ph

N H

MeO

82%

OH

O Me

NH N H

Me

NEt2

N CHO H

MeO

POCl3, DMF MeCN, −15 °C then, H2O 75% or (COCl)2, DMF MeCN, −15 °C then, H2O 70%

HO

OMe Ph

POCl3, DMF, 0 °C then, NaOH

OH CHO HO

O

Me H Cl− N Me + Cl MeCN >74%

Ph

Me Cl−

NH

H

Me +N

Me

N H

NEt2

Me

One of the most practical formylation procedures is the Duff reaction where HMT is used as the formaldehyde surrogate to generate an iminium species in the presence of acid. A nice feature of the Duff reaction is that it is not as 64 65 66 67

Black, D. S. C.; Kumar, N.; Wong, L. C. H. Synthesis 1986, 474–476. Mendelson, W. L.; Hayden, S. Synthetic Communications 1996, 26, 603–610. Manley, J. M.; Kalman, M. J.; Conway, B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan, R. The Journal of Organic Chemistry 2003, 68, 6447–6450. Boswell, G. E.; Licause, J. F. The Journal of Organic Chemistry 1995, 60, 6592–6594.

5.5 Carbon Electrophiles

exothermic as the Vilsmeier–Haack and often necessitates higher temperatures in order to proceed. This can be an advantage from a process safety standpoint.68,69 OH

HMT AcOH, H2O i-Pr reflux

OH i-Pr

i-Pr

i-Pr

81%

CHO

The Reimer–Tiemann reaction allows for introduction of an aldehyde ortho to a phenol. The reaction proceeds through the generation of dichlorocarbene by deprotonation of chloroform followed by α-elimination. The initially formed dichloride hydrolyzes to the aldehyde. Generally, the reaction is low yielding, and precautions must be taken when adding the chloroform to the strongly basic reaction mixture.70 OH

CHCl3 40% NaOH 70–80 °C

OH

CHO

48%

OMe

OMe

5.5.5

Hydroxyalkylation

Aldehydes and derivatives thereof can also be cyclized under Friedel–Crafts conditions. In the first example below, an aldehyde is cyclized to a benzylic alcohol by treatment with a Lewis acid.71 A dimethyl acetal can be cyclized using methane sulfonic acid, and the resulting ether reduced using BH3 ⋅t-BuNH2 .72 In the last example, formation of an oxocarbenium ion from a dimethylacetal in the presence of an alcohol resulted in the desired isochromane after cyclization.73 MeO

Me

O O

SnCl4 CH2Cl2

Me Me

MeO

Me

O O

85%

CHO OMe

Me Me

OMe OH

Cl

Cl

MeO

OMe OMe N

Me

MeSO3H, CH2Cl2 −15 to 40 °C t-BuNH2 • BH3

MeO H

N

72%

Me

MeO

O

NHCHO OMe TMSOTf, MeCN

O OH

85%

O

O O NHCHO

68 Roth, B.; Baccanari, D. P.; Sigel, C. W.; Hubbell, J. P.; Eaddy, J.; Kao, J. C.; Grace, M. E.; Rauckman, B. S. Journal of Medicinal Chemistry 1988, 31, 122–129. 69 Lindoy, L. F.; Meehan, G. V.; Svenstrup, N. Synthesis 1998, 1029–1032. 70 Baker, R.; Castro, J. L. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1990, 47–65. 71 Achmatowicz, O.; Szechner, B. The Journal of Organic Chemistry 2003, 68, 2398–2404. 72 Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Vater, E. J. Organic Process Research & Development 1998, 2, 186–193. 73 DeNinno, M. P.; Perner, R. J.; Morton, H. E.; DiDomenico, S., Jr. The Journal of Organic Chemistry 1992, 57, 7115–7118.

261

262

5 Electrophilic Aromatic Substitution

5.5.6

Haloalkylation

Haloalkylation is the outcome of a hydroxyalkylation of an arene followed by in situ conversion of the resulting benzylic alcohol to a halide. Benzylic chlorides have been obtained in very high yield using this method.74 Trioxane has also been used as carbon source.75 F

F

MeO

37% CH2O AcOH, HCl

MeO

MeO

95%

MeO

O

O

O H2SO4 SOCl2

CF3

Cl

CF3

80%

5.5.7

Cl

Aminoalkylation

The aminoalkylation of an arene through electrophilic aromatic substitution is possible by generation of an iminium ion. The reaction proceeds with both acyl76 and alkyl77 iminium ions. Me +

Me

Me

(CH2O)n H2SO4

O NH2

O N H

75%

NO2

Me

NO2 OH

(CH2O)n Et2NH EtOH

AcHN

69%

OH NEt2 AcHN

A powerful version of this reaction is an intermolecular aminoalkylation known as the Pictet–Spengler reaction. A β-amino arene is treated with an aldehyde to generate an imine that is protonated and undergoes the electrophilic aromatic substitution as shown in the following example.78 A variation of the reaction which leads directly to a N-formyl tetrahydroisoquinoline has also been reported.79 HO

CO2H NH2

CH2O aq HCl 70%

HO

CO2H NH

Amides have also been shown to participate in a similar fashion, to access a bicyclic lactam product.80 The example below uses Eaton’s reagent (7.7% w/w of P2 O5 in MsOH) for the transformation. 74 Ladd, D. L.; Weinstock, J. The Journal of Organic Chemistry 1981, 46, 203–206. 75 Sengupta, D.; Gharbaoui, T.; Krishnan, A.; Buzard, D. J.; Jones, R. M.; Ma, Y.-A.; Burda, R.; Garrido Montalban, A.; Semple, G. Organic Process Research & Development 2015, 19, 618–623. 76 Maulding, D. R.; Lotts, K. D.; Robinson, S. A. The Journal of Organic Chemistry 1983, 48, 2938–2939. 77 O’Neill, P. M.; Mukhtar, A.; Stocks, P. A.; Randle, L. E.; Hindley, S.; Ward, S. A.; Storr, R. C.; Bickley, J. F.; O’Neil, I. A.; Maggs, J. L.; Hughes, R. H.; Winstanley, P. A.; Bray, P. G.; Park, B. K. Journal of Medicinal Chemistry 2003, 46, 4933–4945. 78 Ornstein, P. L.; Arnold, M. B.; Augenstein, N. K.; Paschal, J. W. The Journal of Organic Chemistry 1991, 56, 4388–4392. 79 Maryanoff, B. E.; Rebarchak, M. C. Synthesis 1992, 1245–1248. 80 Yang, Q.; Ulysse, L. G.; McLaws, M. D.; Keefe, D. K.; Haney, B. P.; Zha, C.; Guzzo, P. R.; Liu, S. Organic Process Research & Development 2012, 16, 499–506.

5.5 Carbon Electrophiles

(CH2O)n Eaton’s reagent 80 °C

O HN

O2N

98%

Me

O N

O2N

Me

Another variation of the aminoalkylation is the Bischler–Napieralski reaction wherein an amide is converted to an imidoyl chloride, which undergoes electrophilic aromatic substitution followed by elimination to provide a cyclic imine (dihydroisoquinoline).81 MeO HN

MeO

O

F3COCHN

5.5.8

POCl3 MeCN

MeO

94%

MeO

N NHCOCF3

Thioalkylation

The thioalkylation of arenes through electrophilic aromatic substitution is not a very common reaction. The reaction usually utilizes a sulfoxide as a starting material which is activated to generate the oxosulfenium ion and ultimately a sulfenium ion which will react with the arene.82 Sometimes, the reaction is also observed as a side product from Moffatt-type oxidations (see Section 10.4.1.2).83 CO2Me

O S

CO2Me

Me TFAA, SnCl4

SMe

74%

5.5.9

Friedel–Crafts Acylation

The most utilized Friedel–Crafts reaction is the Friedel–Crafts acylation. Some of the aspects that render this reaction practical are the fact that a number of acid chlorides are commercially available or easily prepared (Section 2.26). The reaction will usually stop after monoacylation since the newly introduced carbonyl is highly deactivating and that the activated intermediate, either an acyl cation or a complex of a Lewis acid with the carbonyl, is sufficiently reactive such that the reaction can be carried out at a reasonable temperature and with acceptable reaction rates. Furthermore, the product of the reaction is an aryl ketone, which can easily be further derivatized in a number of ways. Several Lewis acids can be employed. Two of the most frequently utilized reagents are AlCl3 and TiCl4 , and the selection is often a personal preference between the addition of a solid (AlCl3 ) or a liquid (TiCl4 ). On smaller scale, TiCl4 is often preferred since it is available as a solution in DCM. Generally, AlCl3 is mixed with the acid chloride in DCM followed by addition of the arene. In the case of an electron-rich arene,84 the reaction might require cooling in order to control the exotherm. For less reactive substrates, the reaction can be performed at higher temperatures.85 For unreactive substrates, where DCM does not provide the appropriate temperature range, dichloroethane can serve as a substitute since the Friedel–Crafts alkylation is much slower than the acylation. However, DCM is a preferable solvent from a safety standpoint. O

MeCOCl AlCl3, CH2Cl2 5–10 °C 83%

81 82 83 84 85

O Me O

von Nussbaum, F.; Schumann, S.; Steglich, W. Tetrahedron 2001, 57, 2331–2335. Veeraraghavan, S.; Jostmeyer, S.; Myers, J. N.; Wiley, J. C., Jr. The Journal of Organic Chemistry 1987, 52, 1355–1357. Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal, K. T. Tetrahedron Letters 1999, 40, 4593–4596. Alabaster, R. J.; Cottrell, I. F.; Marley, H.; Wright, S. H. B. Synthesis 1988, 950–952. Tang, P. W.; Maggiulli, C. A. The Journal of Organic Chemistry 1981, 46, 3429–3432.

263

264

5 Electrophilic Aromatic Substitution

O

AlCl3, CH2Cl2 reflux

O + Cl

76%

Me

Me

84:16 ratio of regioisomers

The choice of Lewis acid and acylating agent can have an effect on the regioselectivity of the acylation. For instance, in the following example, much higher regioselectivity was observed using AlBr3 than with AlCl3 .86 Me

O

MeCOBr AlBr3, CH2Cl2 0–15 °C

OH

OAc

94%

OMe

OMe

The Friedel–Crafts acylation can also proceed from other activated carboxylic acid derivatives. For instance, P2 O5 or Eaton’s reagent can allow for the direct condensation of arene and carboxylic acid.87 This is particularly effective in intramolecular cases.88 HO2C

Cl O

O

n-Bu

PhthN

CO2H

80%

N H

O

Cl

P2 O5 H3PO4 90–100 °C Cl

n-Bu

Cl

PhthN

75%

Cl

Cl

O

P2O5 (15 wt%) in MsOH 35 °C

O

O

N H

Anhydrides can also be used for the acylation. In the first example below, dichlorobenzene was used in excess (3 equivalents) such that no additional solvent is needed.89 In cases where it might not be desirable to use the arene as a solvent, a mixture of DCM and nitromethane has proven to be an efficient combination although the use of nitromethane is usually not recommended.90 AlCl3 60 °C

Cl + Cl

Cl MeO

86 87 88 89 90

O

O

O

NHCO2Me

+ O

O

O

92% AlCl3 CH2Cl2, MeNO2 reflux 94%

O Cl Cl

CO2H O

Cl

NHCO2Me CO2H

Cl

Caron, S.; Do, N. M.; Arpin, P.; Larivee, A. Synthesis 2003, 1693–1698. Hivarekar, R. R.; Deshmukh, S. S.; Tripathy, N. K. Organic Process Research & Development 2012, 16, 677–681. Chandrasekhar, B.; Prasad, A. S. R.; Eswaraiah, S.; Venkateswaralu, A. Organic Process Research & Development 2002, 6, 242–245. Quallich, G. J.; Williams, M. T.; Friedmann, R. C. The Journal of Organic Chemistry 1990, 55, 4971–4973. Melillo, D. G.; Larsen, R. D.; Mathre, D. J.; Shukis, W. F.; Wood, A. W.; Colleluori, J. R. The Journal of Organic Chemistry 1987, 52, 5143–5150.

5.5 Carbon Electrophiles

Another formal acylation is the Hoesch reaction, wherein a nitrile is used as the electrophile. This reaction is seldom used since nitriles are not very reactive. The reaction can be achieved when performed in an intramolecular fashion.91 For intermolecular cases, precomplexation of a phenol is allowed for the reaction to proceed.92 S MeO

CF3SO3H, DCM then, H2O

NC

60%

Cl

OH

S MeO O

ClCH2CN BCl3, AlCl3 DCE

OH Cl

86%

5.5.10

Cl

O

Fries Rearrangement

The Fries rearrangement is one of the most useful electrophilic aromatic substitution reactions since it regioselectively introduces an acyl group ortho to a phenol. An acylated phenol is treated with a Lewis acid under conditions similar to the Friedel–Crafts reaction to induce the rearrangement, which usually proceeds in high yield as shown in the following examples.93,94 O Me

O

OH O

BF3•OEt2 120 °C

Me

96% OMe Me

O

OMe O

AlCl3, PhMe 90 °C

Me

Me

OH Me

95% O

The acylation and rearrangement can easily be accomplished in a single operation. The acylation proceeds at low temperature, and once disappearance of the phenol is confirmed, the reaction mixture can be heated to induce the rearrangement.95 EtCOCl AlCl3 ClCH2CH2Cl rt to reflux

OH

Br

5.5.11

79%

OH O Et Br

Carboxylation

The carboxylation of an arene through electrophilic aromatic substitution is seldom employed, and the desired product is usually obtained through a halogenation followed by generation of an organometallic species which is reacted with 91 Achmatowicz, O.; Szechner, B. The Journal of Organic Chemistry 2003, 68, 2398–2404. 92 Toyoda, T.; Sasakura, K.; Sugasawa, T. The Journal of Organic Chemistry 1981, 46, 189–191. 93 Nguyen Van, T.; Kesteleyn, B.; De Kimpe, N. Tetrahedron 2001, 57, 4213–4219. 94 Ouellet, S. G.; Gauvreau, D.; Cameron, M.; Dolman, S.; Campeau, L.-C.; Hughes, G.; O’Shea, P. D.; Davies, I. W. Organic Process Research & Development 2012, 16, 214–219. 95 Caron, S.; Vazquez, E. Synthesis 1999, 588–592.

265

266

5 Electrophilic Aromatic Substitution

an electrophile such as CO2 . The Kolbe–Schmitt reaction is an example of an electrophilic carboxylation which is specific for the introduction of a carboxylic acid at the ortho position of a phenol. The reaction suffers from the fact that it requires elevated temperature and CO2 under high pressure, making it inconvenient for general application. This reaction was recently demonstrated in a microreactor.96 CO2H OH

22%

OH

5.5.12

OH

K2CO3 (aq) 160 °C 40 bar

OH

Amidation

Formation of an amide through electrophilic aromatic substitution is not straightforward. The reaction of phenoxides with isocyanates has been reported to proceed in low yield with high regioselectivity in the presence of AlCl3 .97 It has also been reported that BCl3 is a superior alternative to AlCl3 for this transformation.98 OLi

OH O

PhNCO AlCl3

N H

36% OH

OH O

BuNCO BCl3

N H

89%

5.5.13

Ph

Bu

Thioamidation and Thioesterification

Electron-rich arenes can react under Friedel–Crafts conditions with isothiocyanates to provide a thioamide. It has been shown that for phenol derivatives, the reaction does not proceed through an acylation-rearrangment mechanism (like a Fries rearrangement) and that a polar solvent is required for the electrophilic substitution to proceed. In DCM, acylation of the phenol was observed.99 An alternative to AlCl3 in MeNO2 is the commercially available AcOH complex of BF3 . This method has proven to be advantageous in some cases and works with alkyl isothiocyanates.100 O OH

EtO

N

C

S

OH

AlCl3 MeNO2 82%

HO

OH

S C Ph N BF3 • 2 AcOH 97%

S

HO

N H

CO2Et

OH H N

Bn

S

Methyl thioesters can be prepared by reaction of an arene with CS2 and MeI in the presence of AlCl3 . Interestingly, the reaction is far superior when using an alkyl ether rather than a phenol as the starting material.101 The reaction proceeds with high selectivity for the para regioisomer. 96 Hessel, V.; Hofmann, C.; Loeb, P.; Loehndorf, J.; Loewe, H.; Ziogas, A. Organic Process Research & Development 2005, 9, 479–489. 97 Balduzzi, G.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Synthesis 1982, 879–881. 98 Piccolo, O.; Filippini, L.; Tinucci, L.; Valoti, E.; Citterio, A. Tetrahedron 1986, 42, 885–891. 99 Jagodzinski, T. Organic Preparations and Procedures International 1990, 22, 755–760. 100 Sosnicki, J.; Jagodzinski, T.; Krolikowska, M. Journal of Heterocyclic Chemistry 1999, 36, 1033–1041. 101 Dieter, R. K.; Lugade, A. G. Synthesis 1988, 303–306.

5.5 Carbon Electrophiles

OMe

OMe

CS2, MeI AlCl3 73% S

5.5.14

S

Me

Cyanation

Preparation of cyanoarenes through electrophilic aromatic substitution is not commonly utilized. This transformation has been reported for ortho-substitution of anilines with trichloroacetonitrile in the presence of one equivalent of BCl3 . Interestingly, the reaction can also be accomplished with an alkylthiocyanate. Depending on the method utilized for the quench of the reaction, the nitrile or thioester can be obtained. The methodology also works with phenols as starting materials.102 Less direct methods such as the elimination of oxime derivatives (Section 8.6.2) or cross-coupling reactions of aryl halides with cyanide are usually preferred (see Section 6.15). NHPh

Cl3CCN BCl3 toluene

NHPh CN

87%

NHBn

MeSCN BCl3 toluene

NaOH

H2O

NHBn CN

NHBn COSMe

102 Adachi, M.; Sugasawa, T. Synthetic Communications 1990, 20, 71–84.

267

269

6 Selected Catalytic Reactions Sebastien Monfette 1 , Adam R. Brown 1 , Pascal Dubé 2 , Nathan D. Ide 3 , Chad A. Lewis 1 , Jared L. Piper 1 , Shashank Shekhar 3 , and Shu Yu 1 1 Pfizer Worldwide R&D, Groton, CT, USA 2 3

Matsys Inc., Sterling, VA, USA Abbvie Inc., North Chicago, IL, USA

CHAPTER MENU Introduction, 269 Organoboron Reagents: The Suzuki–Miyaura Coupling, 270 Organomagnesium Reagents: Kumada–Corriu Coupling, 282 Organozinc Reagents: Negishi Coupling, 287 Cross-Electrophile Coupling, 291 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction), 292 Cross-Coupling Reactions with Organosilicon Compounds, 295 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling), 296 Metal-Catalyzed Coupling of Alkenes (Heck Coupling), 298 Enolate Arylations, 303 Pd- and Cu-Catalyzed Aryl C—N Bond Formation, 306 Pd- and Cu-Catalyzed Aryl C—O Bond Formation, 320 Pd- and Cu-Catalyzed Aryl C—S Bond Formation, 322 Aryl C—B Bond Formation, 324 Pd-Catalyzed Aryl C—CN Bond Formation, 327 Metal-Catalyzed Allylic Substitution, 329 Catalytic Metal-Mediated Methods for Fluorination, 337 Selected Metal-Mediated C—H Functionalization, 347 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies, 357 Alkene and Alkyne Metathesis Reactions, 362 Organocatalysis, 369

6.1 Introduction In the past few decades, significant improvements have been achieved in metal-mediated processes, often utilizing catalytic quantities of a transition metal. Such advances were made possible, in part, through extensive mechanistic studies that have been carried out in several cases. A plethora of novel synthetic methodologies have emerged from research in both academic and industrial laboratories. In pharmaceutical companies, processes ensuing from these advances are now widely utilized for the synthesis of new drug candidates in medicinal chemistry as well as for the preparation of active pharmaceutical ingredients (APIs) on small and up to commercial scale. While the full coverage of all catalytic methodologies falls outside the scope of this chapter, it seeks to provide a comprehensive overview of catalytic methodologies that are most frequently employed in the synthesis of complex organic molecules. We also showcase reactions that have been carried on multigram or preferably multikilogram scale where possible.

Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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6 Selected Catalytic Reactions

For reactions that are less developed but show significant promise (e.g. C—H functionalization, fluorination, etc.), current protocols are documented despite the fact that few or none of these reactions have been carried out on the aforementioned scale. While some of the reactions covered in this chapter have the potential to be enantioselective, such reactions will not be explicitly covered in this chapter (barring exceptions) but instead will be discussed in Chapter 14. Given its fundamental importance in organic synthesis, the first portion of this chapter will cover cross-coupling reactions catalyzed by palladium in most cases. Given the importance of cost considerations, environmental impact as well as long-term sustainability, significant advances in nonprecious metal catalysis have now enabled the development of effective protocols that circumvent the use of Pd as catalyst. Thus, examples of Ni, Fe as well as Cu-catalyzed coupling reactions are also discussed where available. In all cases, particular attention was given to identify reliable reaction conditions with an emphasis on heterocyclic substrates. In this edition, we expanded the coverage of cross-coupling reactions to form carbon-heteroatoms such as C—N, C—O, C—S, and C—B bond formation. We also included a new section on the α-arylation of various enolizable carbon nucleophiles. In addition to cross-coupling reactions, other reactions discussed will include allylic alkylation, selected C—H bond functionalization, hydrogene borrowing, as well as metathesis reactions. In line with the increasing number of fluorinated API disclosed in the literature, various catalytic fluorination methods are now included in this Chapter, thus complementing the already established stoichiometric methods. Lastly, the final section of this chapter will examine nonmetal-mediated catalytic reactions such as organocatalysis and phase transfer catalysis, among others. Biocatalysis using enzymes is discussed in Chapter 15.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling The palladium-catalyzed cross-coupling reaction between organoborane derivatives and an electrophile, known as the Suzuki–Miyaura reaction,1,2,3 is one of the most widely explored cross-coupling reactions. The Suzuki–Miyaura reaction has received special attention since its relatively mild reaction conditions make it amenable to a broad scope of substrates. The base required in this reaction serves multiple purposes including generating the key metal-hydroxo intermediate that undergoes transmetalation with the nucleophile4,5,6 and neutralizing the acid generated in the reaction.7 The by-products are often easily removed by an aqueous wash in the workup. In addition, the by-product boric acid is much more environmentally friendly than the tin by-product from Stille couplings. The reaction tolerates a wide range of solvents and works in homogeneous or biphasic conditions. Predicting the efficiency of these reactions can be difficult since yields can vary based on the electronic and steric nature of the substrates, the choice of ligands, catalyst, and other additives. While electron-withdrawing groups facilitate nucleophilic aromatic substitution and to some extent the ability of an arene to undergo oxidative addition with a metal, the nature of the halogen or pseudohalide is more important in this type of cross-coupling reaction. The reactivity of the halide toward oxidative addition follows the following order: I > Br > Cl ≫ F. This trend for metal insertion is generally based on the increasing C—X bond strength, and a number of reviews have been published in recent years that cover different aspects of these processes.8 The examples below were chosen to highlight effective reaction conditions that maximize the usefulness of this reaction. Proposed reaction mechanisms have also been included where sufficient data are available.

1 2 3 4 5 6 7 8

Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Letters 1979, 3437–3440. Martin, R.; Buchwald, S. L. Accounts of Chemical Research 2008, 41, 1461–1473. Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–2440. Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329–332. Carrow, B. P.; Hartwig, J. F. Journal of the American Chemical Society 2011, 133, 2116–2119. Amatore, C.; Jutand, A.; Le Duc, G. Chemistry - A European Journal 2011, 17, 2492–2503. Matos, K.; Soderquist, J. A. The Journal of Organic Chemistry 1998, 63, 461–470. Corbet, J.-P.; Mignani, G. Chemical Reviews 2006, 106, 2651–2710.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

The most common coupling partners are aryl and alkenyl boronic acids, which are easily prepared by various stoichiometric or catalytic methods (see Sections 6.14 and 6.18.3.1). These are usually crystalline, air, and moisture stable solids that can be stored indefinitely. Borate complexes generated in situ have also been used. For boronic acid that are less stable and tend to decompose, formation of the boronic ester (e.g. pinacol ester) or trifluoroborate salt is a good way to stabilize the fragile boronic acids. It will be noted that the boronic ester and trifluoroborate will need to undergo hydrolysis to participate in the Suzuki–Miyaura coupling, and thus, water is required for the reaction to proceed.9 In some cases, boronic acids have been derivatized as a diethanolamine complex10 or a N-methyliminodiacetic acid (MIDA) boronate11 for additional stability. Organoborons have been prepared with all states of carbon hybridization (sp, sp2 , and sp3 ) and have been employed successfully in Suzuki–Miyaura cross-coupling. While sp-hybridized acetylenic boronic acid derivatives are prepared in situ due to poor stability, the alkyl derivatives are much less reactive and often require electron-rich organoboranes (e.g. 9-borabicyclo(3.3.1)nonane (BBN) derivatives) and/or electron-rich ligands (e.g. PCy3 ) to participate in the reaction.12 6.2.1

Preparation of Biaryls

Generation of biaryls is the predominant use for the Suzuki–Miyaura reaction. Aryl iodides and bromides are known to be the most reactive organic halides, but for large-scale synthesis, aryl chlorides13 are often preferred because they are cheaper. New catalyst systems allow for mild reaction conditions and low catalyst loadings.14,15 The early literature on the reaction usually utilized Pd(PPh3 )4 as the catalyst of choice, but a more stable palladium (II) source, such as Pd(OAc)2 in the presence of a phosphine ligand, is generally preferred. While aryl iodides are often unstable and fairly expensive, they are very good partners in the Suzuki–Miyaura coupling. A convergent route to LY 451395, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) potentiator for the treatment of cognitive deficits associated with Alzheimer’s disease, was developed by Eli Lilly.16 A large-scale Suzuki–Miyaura coupling was used in the final step to produce the desired biaryl using palladium black as the catalyst. Rigorous exclusion of dissolved oxygen and introduction of potassium formate as a mild reducing agent to minimize the concentration of Pd(II) efficiently suppressed formation of the undesired homocoupled product. Me

O O S Me N H

B(OH) 2

H N

Me

i-Pr S O O

I

1 mol% Pd black 0.5 equiv KCO2H 1.6 equiv K2CO3

O O S N H

H N

i-Pr S O O

Me

n-PrOH:H2O 1 : 1 90 °C 93%

9 Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones, G. C.; Murray, P. M. Angewandte Chemie International Edition 2010, 49, 5156–5160. 10 Caron, S.; Hawkins, J. M. The Journal of Organic Chemistry 1998, 63, 2054–2055. 11 Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17–27. 12 Littke, A. F.; Dai, C.; Fu, G. C. Journal of the American Chemical Society 2000, 122, 4020–4028. 13 Littke, A. F.; Fu, G. C. Angewandte Chemie, International Edition 2002, 41, 4176–4211. 14 Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. Journal of the American Chemical Society 2005, 127, 4685–4696. 15 Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. Journal of the American Chemical Society 2006, 128, 4101–4111. 16 Miller, W. D.; Fray, A. H.; Quatroche, J. T.; Sturgill, C. D. Organic Process Research & Development 2007, 11, 359–364.

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6 Selected Catalytic Reactions

The faster rate of oxidative addition of an aryl iodide relative to that of aryl bromide can lead to selectivity problems in Suzuki–Miyaura coupling. This strategy was successfully employed to prepare an intermediate on route to the synthesis if IKK2 inhibitor. Accordingly, the mediation of a Suzuki–Miyaura coupling at the iodide atom in the presence of a bromide allowed functionalization of the heterocyclic substrate.17 Me N O

Boc N

O

Bpin

Boc N

Me Br

Br

Me

2-MeTHF, H2O Pd(PPh 3)4 Na2CO3, 50–70 °C

I

O

N O

80%

Me

The synthesis of various PI3K inhibitors was carried out with a Suzuki coupling as a key step. Although initial efforts lead to large amount of des-iodo impurity, high-throughput experimentation revealed key conditions allowing for a reproducible Suzuki reaction, which was successfully scaled to 250 g.18 These results are also quite remarkable given the known instability of aryl boronic acid bearing an adjacent fluorine atom.19,20 F O

N

O

S

O

N

(HO)2B

OEt

NC

CN

O OEt

NC

Dioxane, toluene

F

1.5 mol% Pd[P(t-Bu)3] 2 aq CsF, reflux

I

S

CN

90%

Aryl bromides are extremely common electrophilic starting materials in Suzuki–Miyaura cross-coupling. An intermediate in the synthesis of a p38 mitogen-activated protein (MAP) kinase inhibitor was prepared by a Suzuki coupling of heterocyclic aryl bromide with tolerance of a carboxylic acid functionality on the nucleophile.21 The air- and moisture-stable PdCl2 (A-Phos) precatalyst proved to be highly effective to mediate this transformation as Pd loading of only 0.1 mol% allowed for a high yield of 93% on a 2 kg scale. Br N F

N F

N Me

O

Me

Me (HO)2B

CO2H

0.1 mol% PdCl2(A-Phos)2 aq K 3PO4 i-PrOH, H 2O, 85 °C

N F

CO2H N F

N Me

O

tBu

P

tBu

A-Phos = NMe2

93%

An intermediate in the synthesis of Losartan, an angiotensin II receptor antagonist developed by DuPont and Merck,22 was prepared by a cross-coupling that was tolerant of spectator aryl halide and primary alcohol functionalities. 17 Murugan, A.; Bachu, S.; Manjunatha, S. G.; Ramakrishnan, R.; Kadambar, V. K.; Reddy, C.; Torlikonda, V. R.; George, S.; Ramasubramanian, S.; Nambiar, S. Organic Process Research & Development 2014, 18, 646–651. 18 Huang, Q.; Richardson, P. F.; Sach, N. W.; Zhu, J.; Liu, K. K. C.; Smith, G. L.; Bowles, D. M. Organic Process Research & Development 2011, 15, 556–564. 19 Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.; Lloyd-Jones, G. C. Journal of the American Chemical Society 2017, 139, 13156–13165. 20 Chen, L.; Francis, H.; Carrow, B. P. ACS Catalysis 2018, 8, 2989–2994. 21 Milburn, R. R.; Thiel, O. R.; Achmatowicz, M.; Wang, X.; Zigterman, J.; Bernard, C.; Colyer, J. T.; DiVirgilio, E.; Crockett, R.; Correll, T. L.; Nagapudi, K.; Ranganathan, K.; Hedley, S. J.; Allgeier, A.; Larsen, R. D. Organic Process Research & Development 2011, 15, 31–43. 22 Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Rossano, L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F. The Journal of Organic Chemistry 1994, 59, 6391–6394.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

The second example showed below also demonstrates the mild nature of the reaction, where a sulfonyl urea is not hydrolyzed nor is the aldehyde decomposed to the Cannizarro by-products under the cross-coupling conditions.23 Tr N N N N Cl

N n-Bu

N

(HO)2B

n-Bu

OH

N

Br

Cl Tr N N N N

OH

N

1 mol% Pd(OAc)2 4 mol% PPh3 aq K 2CO3 DME, THF 95%

O2 S

H N

Br

H N

OHC

OHC

n-Pr

O2S

B(OH) 2

O

H N

H N

n-Pr

O

4 mol% Pd(OAc)2 12 mol% PPh 3 aq Cs 2CO3 EtOH, toluene, 70 °C 75%

For the multikilogram synthesis of a pharmaceutical intermediate at Abbott, a biphenyl subunit was assembled from 4-trifluoromethoxy phenylboronic acid and bromofluorobenzonitrile using a Suzuki reaction.24 Complete conversion could be achieved in 15 hours using 0.025 mol% of (Ph3 P)2 PdCl2 . With 0.06 mol% of catalyst, the reaction was complete (98% yield) within six hours using sodium bicarbonate as the base in a biphasic toluene and water. This process was well designed and optimized to achieve high turnover numbers because of the nature of the coupling partners. The electron withdrawing groups of the aryl halide greatly facilitates oxidative insertion, and the electron rich nature of the boronic acid facilitates the transmetalation as well. OCF3 CN F

(HO)2B

CN F

PdCl 2(PPh 3)2

Br

aq NaHCO3, H2O 98%

OCF3

Electron-rich phosphine ligands, often t-Bu3 P or Cy3 P, generally provide enhanced catalytic activity. The Merck process group has utilized such a catalytic system in a reaction where the boronic acid is activated with a fluoride source.25 Cl

B(OH) 2

CN

Cl

F

Br

CN

0.3 mol% Pd[P(t-Bu 3)] 2 F

THF, KF, 0–20 °C 92%

F

F

23 Heitsch, H.; Wagner, A.; Yadav-Bhatnagar, N.; Griffoul-Marteau, C. Synthesis 1996, 1325–1330. 24 Rozema, M. J.; Kruger, A. W.; Rohde, B. D.; Shelat, B.; Bhagavatula, L.; Tien, J. J.; Zhang, W.; Henry, R. F. Tetrahedron 2005, 61, 4419–4425. 25 Cameron, M.; Foster, B. S.; Lynch, J. E.; Shi, Y.-J.; Dolling, U.-H. Organic Process Research & Development 2006, 10, 398–402.

273

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6 Selected Catalytic Reactions

Control of the palladium levels in the isolated product can be problematic, especially when the resulting product can serve as a ligand for the metal. The Abbott group developed an efficient four-step process for the synthesis of multikilogram quantities of a COX-2 inhibitor that involved a high- yielding Suzuki coupling in the penultimate step.26 To alleviate the high level of Pd contamination, the coupled product was treated with a Deloxan resin that reduced Pd levels from 200 ppm to 20–40 ppm in this process. We note that a plethora of different Pd (and other metal) scavengers are readily available on a very large scale, and screening various scavengers is often needed to ensure optimum removal of Pd for a given process.

®

Me Me

B(OH) 2

F

OH

F

O

O

MeS

OH O

F

K 3PO4 i-PrOH, H 2O 84%

F

O N N

Pd(OAc)2, PPh 3

N N

Br

Me Me

MeS

Dialkyl aryl boranes participate efficiently in the Suzuki–Miyaura reaction. In the example shown below, the initial conditions for the preparation of the biaryl involved a cross-coupling reaction between 3-bromophenylsulfone and 3-pyridyldiethyl borane, which reproducibly delivered the free base or hydrochloride salt in 80% yield. The catalyst loading was significantly reduced by changing the solvent from tetrahydrofuran (THF) to toluene and the base from sodium hydroxide to potassium carbonate. The coupled product was reproducibly isolated as the methanesulfonic acid salt in 92–94% yield on 200-kg scale.27 SO2Me +

(i) Pd(PPh 3)4, aq K 2CO3

Et 2B

toluene, 84 °C N

Br

SO2Me • CH3SO3H

(ii) MeSO3H N

92%

Cyclic boronic acid can also serve as effective nucleophiles in preparation of biphenyl. In the synthesis of Mavatrep, a Suzuki coupling between a brominated benzimidazole and a cyclic boronic acid was highly effective and provided the desired product in 89% yield.28 The tert-butyl phosphino ferrocene ligand was instrumental in providing high yields. In sharp contrast, the less bulky diphenyl phosphino ferrocene ligand lead to much lower yield (32%) even when employed in 20 mol% loading. It is also worth noting that the use of an aryl iodide in place of the bromide did not provide any benefits. Me Me Br

N

O B OH

HCl

N H

CF3

P(tBu)2 dtbpf =

Fe

P(tBu)2

PdCl 2(dtbpf) aq Na2CO3 DME 79 °C

Me OH Me N N H

CF3

89%

Aryl chlorides are less reactive toward the oxidative addition of the metal and usually require electron-rich ligands in order to proceed. The significant advances in ligands design by the group of Buchwald and others have led to highly effective examples of Suzuki coupling employing aryl chlorides as electrophiles. For example, in the synthesis of hepatitis C virus (HCV) inhibitor MK-8876, researchers at Merck employed the second generation SPhos palladacycle to 26 Kerdesky, F. A. J.; Leanna, M. R.; Zhang, J.; Li, W.; Lallaman, J. E.; Ji, J.; Morton, H. E. Organic Process Research & Development 2006, 10, 512–517. 27 Lipton, M. F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor, D. W.; Newby, J. J.; Appell, R. B.; Daugs, E. D. Organic Process Research & Development 2003, 7, 385–392. 28 Wells, K. M.; Mehrman, S. J.; Abdel-Magid, A. F.; Ferraro, C.; Scott, L.; Zhong, H. M.; Teleha, C. A.; Ballentine, S.; Li, X.; Russell, R. K.; Spink, J. M.; Diamond, C.; Youells, S.; Zhang, Y.; Tsay, F.-R.; Cesco-Cancia, S.; Manzo, S. M.; Beauchamp, D. A. Organic Process Research & Development 2015, 19, 1774–1783.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

effectively mediate the Suzuki coupling on a 25 kg scale to afford the desired product in 86% isolated yield with 18 ppm residual Pd.29 CO2NHMe

(HO)2B Ms

O N N

Ms

F

0.25 mol% [Pd] aq Na2CO3

Cl

F

F

O

N Me

O

N

Me

N CO2NHMe

N O

THF, H2O, 70–80 °C 86%

[Pd] =

F

L=

Pd NH2 L

PCy 2 OMe

MeO

Cl

Electron-rich ferrocene type ligand such as 1,1′ -bis(di-tert-butylphosphino)ferrocene can be also quite effective at promoting Suzuki coupling of aryl chloride. In the following example, a catalyst loading of just 0.2 mol% was needed to carry out reaction, and the product could be isolated in 90% yield.30

Me O F F N Me

N H

N N N

MeSO3H

BPin

O

O

Cl

Me O F F N Me

N H

0.2 mol% PdCl2(dtbpf) K 3PO4

O N N O

N

DMAc, H 2O, 75 °C

N H

90%

N H

In the following example, the reaction originally required the use of 2–2.5 equiv of boronic acid to completely consume the chloroarene. The efficiency of the process was improved by using the boronic ester produced in situ from isopropyl borate, which resulted in faster reactions requiring less of the expensive boronic acid reagent. The rate acceleration was attributed to the presence of a trace amount of isopropyl alcohol in the reaction mixture. Subsequently, the reaction conditions were further modified to incorporate isopropyl alcohol as solvent and used only 1.1 equiv of the boronic acid to yield the coupled product.31 An N-heterocyclic carbene ligand also proved to be efficient for this reaction.32 B(OH) 2 F Cl O

Cl O

Cl N

Cl N Cl

Cl N

Cl

F

N

Pd(OAc)2, 80 °C >95% PPh 3, Na2CO3

IMes =

Me N

Me F

Me

Me

N Me

Me

i-PrOH, 12 h IMes.HCl, K 3PO4 >94% DMF, 2 h

F

29 Williams, M. J.; Chen, Q.; Codan, L.; Dermenjian, R. K.; Dreher, S.; Gibson, A. W.; He, X.; Jin, Y.; Keen, S. P.; Lee, A. Y.; Lieberman, D. R.; Lin, W.; Liu, G.; McLaughlin, M.; Reibarkh, M.; Scott, J. P.; Strickfuss, S.; Tan, L.; Varsolona, R. J.; Wen, F. Organic Process Research & Development 2016, 20, 1227–1238. 30 Hicks, F.; Hou, Y.; Langston, M.; McCarron, A.; O’Brien, E.; Ito, T.; Ma, C.; Matthews, C.; O’Bryan, C.; Provencal, D.; Zhao, Y.; Huang, J.; Yang, Q.; Heyang, L.; Johnson, M.; Sitang, Y.; Yuqiang, L. Organic Process Research & Development 2013, 17, 829–837. 31 Chung, J. Y. L.; Cvetovich, R. J.; McLaughlin, M.; Amato, J.; Tsay, F.-R.; Jensen, M.; Weissman, S.; Zewge, D. The Journal of Organic Chemistry 2006, 71, 8602–8609. 32 Chung, J. Y. L.; Cai, C.; McWilliams, J. C.; Reamer, R. A.; Dormer, P. G.; Cvetovich, R. J. The Journal of Organic Chemistry 2005, 70, 10342–10347.

275

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6 Selected Catalytic Reactions

Dialkylbiarylphosphine ligands have shown enhanced reactivity in the Suzuki–Miyaura couplings of highly functionalized aryl chlorides or heterocyclic chlorides/bromides. The Buchwald group has relied on the increased reactivity and stability of metal catalysts using these ligands. Thus, cross-coupling reactions of aryl- and heteroaryl chlorides with potassium aryl- and heteroaryltrifluoroborates have been accomplished with the supporting ligand 2-(2′ ,6′ -dimethoxybiphenyl)-dicyclohexylphosphine (S-Phos) in good to excellent yield.33 Substrates that are sterically demanding and contain a variety of functional groups can be prepared following this protocol. Couplings of several trifluoroborate salts with aryl- and heteroaryl chlorides proceed in good yields.34 MeO Cl

MeO

tBu

KF 3B

tBu

Pd(OAc)2, SPhos

MeO

PCy 2 OMe

MeO

MeO

K 2CO3, MeOH

S-Phos

93%

Electrophiles containing free amine groups can be problematic substrates. One strategy to deal with this issue is to temporarily protect the amine in situ, as demonstrated by researchers at Pfizer. A protocol where the benzaldehyde imine was generated in situ allowed the Suzuki coupling to proceed efficiently. The imine of the product was hydrolyzed as part of the reaction work-up.35 (i) PhB(OH)2, PhCHO PdCl2(PPh3)2 (0.4 mol%) aq Na2CO3, toluene

NH2

(ii) H3O+

Cl

N

NH2 Ph

N

99%

While the majority of Suzuki couplings utilize an aryl halide as a starting material, aryl triflates also participate in the reaction. Scientists at Johnson & Johnson have successfully accomplished the coupling of a challenging substrate using PdCl2 (dppf ) as the catalyst. The addition of an excess of the dppf ligand improved the yield as well as the substrate scope. A dppf/Pd ratio of 1.5 in conjunction with PdCl2 (dppf ) as the palladium source was crucial for broader applicability to a diverse range of substrates.36 Me N N

(HO)2B OTf

Me

OMe N

1.2 mol% PdCl2(dppf) 1.8 mol% dppf K 3PO4 1,4-dioxane, 100 °C

Me N

OMe

Me

90%

Difficulty in scavenging the residual palladium requiring expensive thio-silica or florisil treatment as well as large volumes of solvents can render palladium-mediated processes inoperable. As an example, a large-scale nickel-catalyzed Suzuki cross-coupling was preferable to palladium owing to the ease of removing residual Ni from the organic product. A simple ammonia wash sequestered the nickel and provided the target in 79% yield (54 kg scale). The authors also note the better performance of the boronic acid over the pinacol esters.37 O

HO

N S N Ms

N

O

OH

N N THP

N N

B

S

N Cl

Ni(NO3)2•6H2O, PPh 3 K 3PO4, MeCN, 60 °C 79%

N Ms

N N

THP N N

N

33 See Note 2. 34 Barder, T. E.; Buchwald, S. L. Organic Letters 2004, 6, 2649–2652. 35 Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.; Braish, T. F. Organic Process Research & Development 2001, 5, 254–256. 36 Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. The Journal of Organic Chemistry 2005, 70, 4188–4190. 37 Tian, Q.; Cheng, Z.; Yajima, H. M.; Savage, S. J.; Green, K. L.; Humphries, T.; Reynolds, M. E.; Babu, S.; Gosselin, F.; Askin, D.; Kurimoto, I.; Hirata, N.; Iwasaki, M.; Shimasaki, Y.; Miki, T. Organic Process Research & Development 2013, 17, 97–107.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

Copper is an attractive metal for catalysis owing to its low cost, increased earth abundance, and tolerance of hetereocyclic cross-partners. Despite of these obvious advantages, examples of copper-mediated Suzuki–Miyaura reactions are considerably rarer relative to Pd and even Ni owing to the difficulty with which Cu undergoes oxidative additions. Thus, reported examples are typically restricted to aryl iodides, and the reaction conditions are generally quite harsh, as shown in the following.38

Ar R

B

O

Me

O

Me

Ligand = NMe2

R

2 mol% CuI 2 mol% ligand 1.5 equiv CsF DMF, dioxane 120 °C, 48 h

I

Ar

P(tBu)2

While the triflate readily undergoes oxidative addition and thus represent an effective electrophilic coupling partner, its relative instability along with the difficulties associated with working with triflic anhydride as a reagent for its preparation constitute significant disadvantages. In the preparation of a pharmaceutical intermediate, several alternatives to a triflate were investigated, namely the mesylate, tosylate, phosphate, benzenesulfonate, 4-fluorobenzenesulfonate, and 4-chlorobenzenesulfonate esters. Among them, the 4-fluorobenzenesulfonate ester was found to be the most suitable substitute for the triflate group in the Suzuki reaction. Of the catalyst systems studied, PdCl2 (PPh3 )2 in the presence of triphenylphosphine turned out to be the most reliable and robust.39 Imidazoylsulfonates have also proven to be suitable coupling partners.40

O

O F3C MeO2C

N

Et

O S O

PdCl 2(PPh 3)2 PPh 3, Na2CO3

O S O O

F3 C MeO2C

B(OH) 2

THF

F

N

O S O

O O Et

87% Me N O

N S O O

Me

(HO)2B PdCl 2(dppf ) K 2CO3 DMAc, H 2O, 60 °C 89%

Although the majority of Suzuki reactions employ isolated boron nucleophiles, there are several examples of Suzuki reaction mediated with boronic acid generated in situ. In the following example, the AstraZeneca crew chose to prepare and use the boronic acid without isolation after experiencing challenges in its isolation due to decomposition.41 38 Gurung, S. K.; Thapa, S.; Kafle, A.; Dickie, D. A.; Giri, R. Organic Letters 2014, 16, 1264–1267. 39 Jacks, T. E.; Belmont, D. T.; Briggs, C. A.; Horne, N. M.; Kanter, G. D.; Karrick, G. L.; Krikke, J. J.; McCabe, R. J.; Mustakis, J. G.; Nanninga, T. N.; Risedorph, G. S.; Seamans, R. E.; Skeean, R.; Winkle, D. D.; Zennie, T. M. Organic Process Research & Development 2004, 8, 201–212. 40 Albaneze-Walker, J.; Raju, R.; Vance, J. A.; Goodman, A. J.; Reeder, M. R.; Liao, J.; Maust, M. T.; Irish, P. A.; Espino, P.; Andrews, D. R. Organic Letters 2009, 11, 1463–1466. 41 See Note 17.

277

278

6 Selected Catalytic Reactions

Following treatment of the boronic ester with dilute aqueous HCl and subsequent extraction, the organic layer was treated with the bromo thiophene unit, base and then the palladium catalyst. The Suzuki product was readily isolated in high yield. O Boc N

O Br

Me

Boc N

(i) n-HexLi –78°C, THF

Me

(ii) B(O-iPr)3

N O

O

N O

(iii) 1M HCl Me

OH B OH

Br

NH2 NH

S

O

O Boc N

S

Me

2-MeTHF / Water

N O

PdCl 2(dtbpf )

Me

O

NH2

K 2CO3, 35 °C

NH2 NH O

NH2

Me

90%

Given the similarity between the reaction conditions employed in the Miyaura borylation and the Suzuki–Miyaura cross-coupling, it is not surprising to find examples where both steps are telescoped. This is what the researchers at Bristol-Myers Squibb (BMS) did during the synthesis of (+)-BMS-820836.42 Accordingly, an aryl triflate was readily converted into the corresponding boronic ester using PdCl2 (dppf ), which was reacted with the chloropyridazine. Although this is a nice example of a telescoped phenol activation, borylation, and then Suzuki coupling, it is not clear why the authors chose to telescope this process. It is also worth noting that although Suzuki couplings are often tolerant of unprotected amines, the bis-Boc protected pyridazine greatly increased solubility, which lead to a reproducible reactions and greatly facilitated purification of the products in this case. Me Me

Me

Me

O O

B B

O O

Me Me Boc 2N

Me Me

PdCl 2(dppf ) N

TfO

KOAc, DMSO Me

85 °C

Bpin

N

Me

N N

Cl

DMSO, Water PdCl 2(dtbpf) Cs 2CO3, 85 °C 47% over 2 steps

N Boc 2N

N

Me

N

It is also worth noting that other electrophile such as acid chlorides43 as well as diazonium salts have also been successfully employed in Suzuki cross-coupling reactions.44 6.2.2

Preparation of Alkynyl-Substituted Arenes

Coupling of alkynes using the Suzuki–Miyaura coupling is very rare, as this overall reaction is usually achieved by a Sonogashira coupling (see Section 6.8). The Molander group has demonstrated that tetrafluoroborate salts can lead to productive cross-couplings as shown in the following example.45 n-Bu Br

n-Bu

BF3K

PdCl 2(dppf ) • CH2Cl 2 Cs 2CO3 THF, H2O 87%

42 Lobben, P. C.; Amin, R.; Chen, B.-C.; Cui, W.; Hu, M.; Isherwood, M.; Liu, S.; Nacro, K.; Miles, B.; Mobele, B.; Olson, R. E.; Wang, B.; Yang, Y.-L.; Zhao, R. Organic Process Research & Development 2016, 20, 44–50. 43 Wang, Y.; Przyuski, K.; Roemmele, R. C.; Hudkins, R. L.; Bakale, R. P. Organic Process Research & Development 2013, 17, 846–853. 44 Colleville, A. P.; Horan, R. A. J.; Tomkinson, N. C. O. Organic Process Research & Development 2014, 18, 1128–1136. 45 Molander, G. A.; Katona, B. W.; Machrouhi, F. The Journal of Organic Chemistry 2002, 67, 8416–8423.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

6.2.3

Preparation of Vinyl-Substituted Arenes

Researchers at Boehringer Ingelheim developed a practical approach for the synthesis of 1,1-diarylsubstituted alkenes with a Suzuki–Miyaura reaction. A variety of boronic acids and substituted acrylonitriles were used to define the scope of the reaction.46 In their work, they elected to use the tetrafluoroborate salt of tri-tert-butyl phosphine47 as a more stable and easily handled form of the phosphine ligand. The authors reported complete retention of the alkene geometry. OH Cl

HO

CN

CN

(HO)2B Pd 2(dba) 3 [(t-Bu)3PH]BF4

F

KF, THF, 45 °C

F

89%

The strategy of using a vinylboronic acid, usually prepared by hydroboration of an alkyne, is also an effective approach to styrene derivatives. The Suzuki–Miyaura coupling reactions of aryl and heteroaryl halides with vinylboronic acids was found to proceed in good to excellent yield using S-Phos as a ligand. This ligand allows reactions to be performed at low catalyst levels, even in the preparation of hindered aryl halides.48 Me Br Me

Me

Me

Ph

(HO)2B

1 mol% Pd(OAc)2 2 mol% S-Phos

Ph Me

Me

K 3PO4, THF 99%

Vinyl boronic ester can also be used. In this specific case, the boronic ester was prepared from the vinyl triflate and used in the Suzuki coupling after purification by chromatography on silica gel.49 BPin O OEt Cl

MeO

N

N

N Boc 1 mol% Pd(OAc)2 2 mol% XPhos 2-MeTHF, H2O K 3PO4, 67 °C

OMe O OEt

N Boc

46 Taylor, S. J.; Netherton, M. R. The Journal of Organic Chemistry 2006, 71, 397–400. 47 Netherton, M. R.; Fu, G. C. Organic Letters 2001, 3, 4295–4298. 48 See Note 14. 49 Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.; Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Organic Process Research & Development 2011, 15, 1138–1148.

279

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6 Selected Catalytic Reactions

One of the most impressive examples of the Suzuki–Miyaura cross-coupling has been in the synthesis of carbapenem derivatives, which are known to be highly sensitive to reaction conditions. In the following example, a vinyltriflate was coupled with a complex boronic acid to afford the fully elaborated carbapenem in excellent yield.50 (i) Pd(dba)2, LiCO3. DMF, CH2Cl2 CONH2 Br– O TESO H H Me O

Me

+ N TfO–

(HO)2B

OTf

N

N

+

CO2PNB

TESO

H H

Me O

(ii) NaOTf 93%

H2NOC

Me

N+

O + N

N CO2pNB

• 2 TfO–

The vinyl triflate does not necessarily need to be isolated. In the following examples, the triflate was used without isolation in the Suzuki coupling.51 (i) LiCl Me Me

Ph

N O

Me

N Li

Ph

Me

(HO)2B

N OTf

(ii) Ph-N(SO2CF3)2 THF, n-hexane –70 °C

6.2.4

Me

S

N

0.33 mol% Pd(PPh3)4 K 3PO4, LiC l THF, H2O, reflux

S

70%

Preparation of Dienes

1,3-Dienes can be prepared via the Suzuki–Miyaura reaction. An impressive example was demonstrated in the synthesis of a pharmaceutical intermediate where two vinylic coupling partners were joined to provide a sensitive product.52 B(Oi-Pr)2

Cl Cl

6.2.5

NH2

OMe Br

CO2Me

CsF, Pd 2(dba)3

CO2Me Cl Cl

OMe NH2

>59%

Preparation of Alkyl-Substituted Arenes

Following its work in palladium-catalyzed cross-coupling,53 the Fu group has demonstrated the Suzuki cross-coupling of a series of unactivated primary and secondary alkyl halides through the use of nickel catalysts aided by an amino 50 Yasuda, N.; Huffman, M. A.; Ho, G.-J.; Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M. H.; Rieger, D. L.; Karady, S.; Sohar, P.; Abramson, N. L.; DeCamp, A. E.; Mathre, D. J.; Douglas, A. W.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. The Journal of Organic Chemistry 1998, 63, 5438–5446. 51 Malmgren, H.; Cotton, H.; Frostrup, B.; Jones, D. S.; Loke, M.-L.; Peters, D.; Schultz, S.; Soelver, E.; Thomsen, T.; Wennerberg, J. Organic Process Research & Development 2011, 15, 408–412. 52 Yu, M. S.; Lopez De Leon, L.; McGguire, M. A.; Botha, G. Tetrahedron Letters 1998, 39, 9347–9350. 53 Netherton, M. R.; Fu, G. C. Topics in Organometallic Chemistry 2005, 14, 85–108.

6.2 Organoboron Reagents: The Suzuki–Miyaura Coupling

alcohol ligand. This catalyst/ligand combination has circumvented the notorious problem with β-hydride elimination that was usually seen with this class of substrates.54

Br Ph

O

O

NiI2, NaHMDS trans-2-aminocyclohexanol

+

O

O

i-PrOH, 60 o C

Me B(OH) 2

73%

Me

Ph

With proper tuning of the amino alcohol ligand, the reaction can be successfully carried out using unactivated secondary alkyl chlorides. NiCl 2 • glyme (6 mol%) prolinol (12 mol%) KHMDS (2 equiv)

Cl + O

i-PrOH, 60 °C

B(OH) 2

84%

O

Iron-catalyzed Suzuki reactions remain rare.55 Preactivated pinacolate esters with (e.g.) alkyl lithium was found to be critical for the cross-coupling but also limits the substrate scope of the reaction. A series of sp3 chlorides, bromides, and iodides were competent in the cross-coupling with diverse aryl boronates under mild conditions. Improvements to ligands and reagents will proliferate the use of iron-catalyzed Suzuki reactions in the future. Catalyst =

Cl

Bu Ph

B

Me Me Li Me Me

R

3 mol% catalyst 20 mol% MgBr2 25 °C, 4 h

Ph

(91–93%)

R

R R

P

P Fe Cl Cl

(1.4 equiv)

R

R R R

R = t-Bu or TMS

6.2.6

Preparation of Alkyl-Substituted Alkenes

Elaboration of an alkene is possible via the Suzuki coupling. Often, the alkyl borane utilized is the 9-BBN derivative that arises from hydroboration of the corresponding alkene. An impressive application of this methodology came from the Shionogi laboratory in the preparation of carbapanem derivatives.56 TESO Me O

H H N

9-BBN

Me

NHCO2PMB PdCl 2(dppf )

OTf CO2PMB

THF, aq. NaOH, 60 °C 66%

TESO

H H

Me O

N

Me

H N CO2PMB

CO2PMB

54 Gonzalez-Bobes, F.; Fu, G. C. Journal of the American Chemical Society 2006, 128, 5360–5361. 55 Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. Journal of the American Chemical Society 2010, 132, 10674–10676. 56 Narukawa, Y.; Nishi, K.; Onoue, H. Tetrahedron 1997, 53, 539–556.

281

282

6 Selected Catalytic Reactions

6.2.7

Preparation of Alkanes

The coupling of sp3 to sp3 carbons by the Suzuki–Miyaura coupling is very rare. Slow oxidative addition of the alkyl–halogen bond coupled with the propensity of the oxidative addition product to undergo β-H elimination has slowed progress in this area. Nevertheless, Fu and coworkers have shown that electron rich and bulky phosphines such as tricyclohexyl phosphine (PCy3 ) enables the coupling between alkyl bromide and 9-BBN functionalized alkanes.57 (9-BBN)

n-Dodec-Br 4 mol% Pd(OAc)2

Me2N

Me 13

Me2N

8 mol% PCy3 1.2 equiv K 3PO4•H2O THF, rt. 78%

Furthermore, the same group has developed a nickel-mediated Suzuki–Miyaura reaction catalyzed by chiral 1,2-diamines that enables the coupling of racemic secondary bromides with 9-BBN adducts to afford branched alkanes with good yield and enantioselectivity that is controlled by the ligand making it such that all the racemic starting material is consumed.58 The sensitivity of Ni(cod)2 toward air and moisture is worth noting. Me

Ph

Ph

9-BBN

Me

Ph

Ph

Ni(cod) 2 (10 mol%)

Br

ligand (12 mol%)

+/–

Ligand =

F 3C

CF3 MeHN

90% ee

NHMe

t-BuOK i-BuOH, i-Pr2O 78%

Given the enhanced sp2 character conferred by the rigidity of the cyclopropane ring, iodo-cyclopropane can participate in Suzuki coupling under conditions typical of aryl electrophiles. The following example shows the formation of contiguous cyclopropanes using this strategy.59 O B O

BnO I

OBn

Pd(OAc)2, PPh3

BnO

OBn

KOtBu, DME, 80 °C 71%

6.3 Organomagnesium Reagents: Kumada–Corriu Coupling The transition metal-catalyzed reaction of an organomagnesium reagent with a vinyl or aryl halide, published by Kumada and Corriu in 1972, was one of the first reported examples of a cross-coupling reaction.60,61 The reaction, generally utilizing nickel or palladium catalysis, has found many industrial applications.62 One of the major limitations of the Kumada reaction is the use of highly reactive Grignard reagents. Due to their high nucleophilicity and basicity, the scope of this reaction is often limited to less functionalized or relatively less reactive substrates. However, 57 58 59 60 61 62

Lou, S.; Fu, G. C. Organic Syntheses 2010, 87, 299–309. Saito, B.; Fu, G. C. Journal of the American Chemical Society 2008, 130, 6694–6695. Charette, A. B.; De Freitas-Gil, R. P. Tetrahedron Letters 1997, 38, 2809–2812. Kumada, M. Pure and Applied Chemistry 1980, 52, 669–679. Corriu, R. J. P.; Masse, J. P. Journal of the Chemical Society, Chemical Communications 1972, 144. Banno, T.; Hayakawa, Y.; Umeno, M. Journal of Organometallic Chemistry 2002, 653, 288–291.

6.3 Organomagnesium Reagents: Kumada–Corriu Coupling

the reaction benefits from the fact that many organomagnesium reagents are commercially available. This is particularly relevant in the case where the related boron reagent might not be available on larger scale or is prohibitively expensive.63 Where the Grignard reagent is not readily available and must be synthesized, two main options exist: use of magnesium turnings or use of a Grignard transfer reagent such as isopropyl magnesium chloride (with and without LiCl) popularized by Knochel. Both reagents are readily available on large scale. While magnesium turnings typically react with both electron rich and poor aryl halides to make the corresponding Grignard, the rate of reaction can be irreproducible. Thus, careful monitoring of the reaction is required particularly on large scale given the significant exotherm associated with this reaction. Various additives (e.g. I2 , 1,2-dibromoethane, TMSCl) are also commonly added to those reaction. In contrast, isopropyl magnesium chloride or its variants generally react quite fast, and the rate of reaction can be controlled by varying the rate of addition of the reagent. One drawback of this reagent is that reaction with electron-rich electrophiles can be slow. 6.3.1

Preparation of Biaryls

In cases where an aryl Grignard is easily accessible, the Kumada coupling presents an attractive option for the preparation of biaryls. In the following example, the cross-coupling proceeded in high efficiency using the organomagnesium reagent derived from bromoanisole.64 OMe Br

BrMg 5 mol% Pd(PPh3)4

MeO

OMe

THF, reflux

MeO

97%

Linghu et al. reported an excellent application of the isopropyl magnesium chloride lithium chloride adduct to generate a Grignard reagent of interest along with a subsequent Pd-mediated Kumada coupling.65 Using a simple plug-flow reactor setup (for additional details on flow chemistry, see Chapter 17), the Grignard was readily synthesized by combining streams of the aryl iodide and iPrMgCl⋅LiCl at a temperature between −5 and −10 ∘ C for eight minutes. The resulting Grignard was then mixed with another stream containing the chloropyrimidine and the Pd catalyst at a temperature of 60–65 ∘ C for 16 minutes. The development of the flow process was motivated by the low thermal stability of the Grignard, which lead to a diminished yield of the Kumada coupling as the scale of the reaction increased from 2 to 30 kg in batch mode.

N

·

I

F i-PrMgCl LiCl N

6.3.2

THF –5 to –10 °C 8 min res. time

XMg

F N

MeS

N

Cl

1.2 mol% PEPPSI-iPr THF, 60–65 °C 16 min res. time 82%

PEPPSI-iPr =

N MeS

F

N N

i-Pr N

i-Pr N

i-Pr i-Pr Cl

Pd

Cl

N Cl

Preparation of Vinyl-Substituted Arenes

Vinyl-substituted arene derivatives have been prepared using the Kumada coupling. As stated previously, despite the high reactivity of Grignard reagents, they sometimes benefit from a greater availability and a lower cost compared to the corresponding organoboron reagents. This is what lead a team at Merck to employ vinyl Grignard in their synthesis 63 Smejkal, T.; Gopalsamuthiram, V.; Ghorai, S. K.; Jawalekar, A. M.; Pagar, D.; Sawant, K.; Subramanian, S.; Dallimore, J.; Willetts, N.; Scutt, J. N.; Whalley, L.; Hotson, M.; Hogan, A.-M.; Hodges, G. Organic Process Research & Development 2017, 21, 1625–1632. 64 Mewshaw, R. E.; Edsall, R. J., Jr.; Yang, C.; Manas, E. S.; Xu, Z. B.; Henderson, R. A.; Keith, J. C., Jr.; Harris, H. A. Journal of Medicinal Chemistry 2005, 48, 3953–3979. 65 Linghu, X.; Wong, N.; Jost, V.; Fantasia, S.; Sowell, C. G.; Gosselin, F. Organic Process Research & Development 2017, 21, 1320–1325.

283

284

6 Selected Catalytic Reactions

of a pyrimidyl tetrazole as a key intermediate of an ongoing clinical program.66 Given that such Kumada reactions are typically exothermic, slow addition of one reagent is usually performed. In this example, the vinyl Grignard was added over the course of 105 minutes to maintain a reaction temperature between 80 and 85 ∘ C. It is worth noting that the 53% yield of product is not due to an inefficient reaction but was due to a suspected polymerization of the product during isolation. Cl

N

NPMB2 N

MgCl

N

Toluene PdCl2(dppf)

NPMB2 N

80 °C 53%

Nickel and iron catalysts have also been used in Kumada–Corriu coupling. In the following example, a dibromobenzofuran was regioselectively functionalized using a nickel catalyst.67

Br

Br

Me

OMe OTBS

O

MgBr

NiCl 2(dppe) (10 mol%)

Br

Me

THF, rt

O

OMe OTBS

89%

Iron represents a very attractive metal catalyst to employ given its low cost and lower toxicity relative to other transition metals and its application in Kumada coupling is gaining momentum. As such, a new large-scale synthesis of Cinacalcet was carried out using an iron-catalyzed Kumada coupling as a key step.68 The Grignard was prepared in situ using magnesium turnings and was added to a solution of vinyl chloride, Fe(acac)3 in a THF-NMP solvent mixture while maintaining the reaction temperature below 0 ∘ C. Addition of NMP as a co-solvent, as was first demonstrated by Cahiez and Avedissian,69 serves to improve the chemoselectivity of the coupling. Although the authors did not specify the stoichiometry between the vinyl chloride and the Grignard reagent, we note that in the presence of a protic group, as in the following case, the Grignard must be used in excess to compensate for the reaction with the protic group.

F3 C

Br Mg

Cl

H N

F3 C Me

MgBr Fe(acac) 3 THF, NMP –5–0 °C

F 3C

H N Me

61%

Aryl or alkenyl pivalates have been shown by Shi and coworkers to undergo Kumada coupling mediated by iron salts in conjunction with an N-heterocyclic carbene ligand.70 The additional of LiCl to the Grignard allowed the reaction to be carried out in the absence of ligand. The authors note that aryl pivalates were less reactive than alkenyl pivalate. The scope of Grignard reagents is also limited: only primary Grignard reacted (except for methyl Grignard), while 66 Mullens, P.; Cleator, E.; McLaughlin, M.; Bishop, B.; Edwards, J.; Goodyear, A.; Andreani, T.; Jin, Y.; Kong, J.; Li, H.; Williams, M.; Zacuto, M. Organic Process Research & Development 2016, 20, 1075–1087. 67 Bach, T.; Bartels, M. Synthesis 2003, 925–939. 68 Tewari, N.; Maheshwari, N.; Medhane, R.; Nizar, H.; Prasad, M. Organic Process Research & Development 2012, 16, 1566–1568. 69 Cahiez, G.; Avedissian, H. Synthesis 1998, 1199–1205. 70 Li, B.-J.; Zhang, X.-S.; Shi, Z.-J. Organic Syntheses 2014, 91, 83–92.

6.3 Organomagnesium Reagents: Kumada–Corriu Coupling

secondary and tertiary Grignard proved to be ineffective. The authors did not comment on the possible addition of the Grignard nucleophile to the ester in the following example, but the high yield could suggest that this side reaction does not readily occur in this case. OPiv CO2Et

n-hexyl CO2Et

n-hexylMgCl 1 mol% FeCl 2 2 mol% H2IMes • HCl THF, 0 °C 93%

6.3.3

Preparation of Aryl—Alkyl Bonds

Aryl halides can be converted to the corresponding alkyl derivatives by treatment with a Grignard reagent and a catalyst, usually palladium, nickel, or even iron. Preparation of 4-allylisoindoline was prepared via a Pd-catalyzed Kumada coupling with allyl Grignard.71 Three equivalents of allyl Grignard were used for this reaction: one equivalent to break the HCl salt, the second to deprotonate the amine, and the third to functionalize the aryl bromide. It is interesting to note that despite the authors desire to limit cost, cheap nonprecious metals such as Ni or Fe were not discussed.

NH • HCl Br

MgCl

NH

1 mol% Pd(OAc)2 2 mol% (Np)tbu2PHBF4 THF, toluene 92%

In the preparation of a key precursor used in the synthesis of a thymidylate synthase inhibitor, an iodoarene was methylated with methylmagnesium bromide under palladium catalysis. While the crude yield was excellent, recrystallization resulted in a 58% yield.72a I

Me MeMgBr (2.2 equiv) N

O

1 mol% PdCl 2(PPh 3)2 THF, toluene 58% After recrystallization

H

N

O

H

The installation of a cyclopropyl moiety through a Fe-catalyzed Kumada coupling was reported by Risatti et al. at Bristol-Myers Squibb.72b The authors mention that the choice for a Kumada coupling was prompted by the cost and stability of the cyclopropyl boronic acid. The Grignard reagent was added slowly while keeping the reaction temperature below 12 ∘ C with active cooling, presumably to control the exotherm that is generally observed during Kumada coupling. Me

CF3

MgBr 5–7 mol% Fe(acac)3

N Cl

Me

CF3 N

THF, NMP 0–5 °C 94–96%

71 Zacuto, M. J.; Shultz, C. S.; Journet, M. Organic Process Research & Development 2011, 15, 158–161. 72 (a) Marzoni, G.; Varney, M. D. Organic Process Research & Development 1997, 1, 81–84. (b) Risatti, C.; Natalie, K. J.; Shi, Z.; Conlon, D. A. Organic Process Research & Development 2013, 17, 257–264.

285

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6 Selected Catalytic Reactions

A very efficient Kumada cross-coupling was demonstrated during the development of an environmentally benign scalable process for the synthesis of the asymmetric phase-transfer catalyst (R)-3,5-dihydro-4H-dinaphth[2,1-c:1’2’-e] azepine.73

MeMgI (3 equiv) OTf OTf

NiCl2(dppp) (0.5 mol%)

Me Me

MTBE, reflux 96%

A manganese-copper catalyzed cross-coupling was developed to replace an inefficient Pd-mediated coupling.74 The palladium was suspected to suffer due to steric hindrance in a model system. Protolysis of the halide remains a challenge in the Mn/Cu coupling, but the overall reaction was successful in providing a good yield and efficient purge of the by-products. (i) MeMgBr (3.1 equiv) MnCl2 (20 mol%) CuCl (10 mol%), THF

Br HO

N

n-Bu

Me

(ii) HCI (aq)

O

HO

80%

6.3.4

Preparation of Vinyl—Alkyl Bonds

A vinyl halide is an effective coupling partner in the Kumada reaction. During the synthesis of Aliskiren, an iron catalyzed Kumada coupling was envisioned as a key bond-forming reaction.75 The authors performed an extensive study aimed at ensuring a safe and reproducible synthesis of the alkyl Grignard as well as a reproducible Kumada reaction.

MeO MeO

O

Mg, MeMgCl 1,2-dibromoethane

iPr Cl

THF 60–65°C

MeO MeO

Cl iPr

MeO

MgCl

O O

MeO

iPr

2 mol% Fe(acac)3 THF, NMP, 0–5 °C 82%

NMe2

iPr

O

O

NMe2 iPr

73 Ikunaka, M.; Maruoka, K.; Okuda, Y.; Ooi, T. Organic Process Research & Development 2003, 7, 644–648. 74 See Note 63. 75 Gangula, S.; Neelam, U. K.; Baddam, S. R.; Dahanukar, V. H.; Bandichhor, R. Organic Process Research & Development 2015, 19, 470–475.

6.4 Organozinc Reagents: Negishi Coupling

Iron was also shown to successfully engage nonhalide carbon electrophiles such as various sulfonates (trifluoro, tosyl, nosyl, etc.).76 Esters are rarely used due to their sensitivity to carbon nucleophiles and inefficient C—O oxidative addition. In contrast, pivalates are simple to prepare and have been shown to participate in iron-catalyzed Kumada coupling.

OPiv

+

Ligand =

FeCl 2 (1 mol%) ligand (2 mol%)

n-HexylMgCl (2.0 equiv)

THF, 0–5 °C, 2.5 h

N Me

95%

Me

Me

n-Hexyl

Me

N

Cl

H Me

Me

6.4 Organozinc Reagents: Negishi Coupling During the late 1970s, the Negishi group first reported the systematic screening of various alkynylmetals as nucleophiles in cross-couplings and identified Zn, B, and Sn as three superior metals. These are the three most widely used metals today, associated with the Negishi, Suzuki–Miyaura, and Stille couplings, respectively. Carbon nucleophiles derived from organozinc reagents have long been known. They are much less reactive than organolithium and organomagnesium reagents, and the modest nucleophilicity of organozinc reagents has been exploited to achieve excellent chemoselectivity in coupling reactions.77 One of the challenges with the Negishi coupling is that the required organozinc reagents are typically more difficult to prepare than the corresponding boronic acids and organostannanes utilized in the Suzuki–Miyaura and Stille reactions (see Sections 6.2 and 6.6, respectively). 6.4.1

Preparation of Biaryls

Synthesis of biaryls using the Negishi coupling has been the most prominent use of this reaction and proceeds with aryl iodides, bromides, triflates and even some chlorides. Cross-coupling between the in situ prepared 2-pyridylzinc chloride and 5-iodo-2-chloropyrimidine catalyzed by Pd(PPh3 )4 was used during the synthesis of 2-chloro-5-(pyridin-2-yl)pyrimidine, an intermediate in the synthesis of a selective phosphodiesterase (PDE)-V inhibitor developed by Johnson & Johnson. In this case, the yield increased from 55% with the bromide to >80% with the iodide.78

I (i) n-HexLi THF, –60 °C N

Br

(ii) ZnCl2, THF

N

ZnX

N N

Cl

Pd(PPh 3)4 (2 mol%) THF, rt

N

N N

Cl

>80%

Eli Lilly scientists reported the preparation of a potent 5-HT1a agonist using a Negishi cross-coupling strategy.79 It was unnecessary to protect the indole nitrogen of the starting material. In this case, the organozinc 76 See Note 70. 77 Negishi, E.-I.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In Metal-Catalyzed Cross-Coupling Reactions; 2nd ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004; Vol. 2, 815–889. 78 Perez-Balado, C.; Willemsens, A.; Ormerod, D.; Aelterman, W.; Mertens, N. Organic Process Research & Development 2007, 11, 237–240. 79 Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. The Journal of Organic Chemistry 1997, 62, 8634–8639.

287

288

6 Selected Catalytic Reactions

reagent was prepared by deprotonation/trans-metalation with 2 equiv of n-butyllithium, and the catalyst was generated from a stable palladium(II) source reduced in situ with catalytic n-butyllithium. (i) n-BuLi, THF, –70 °C I

Pr N

N

O

O

N

Pr N

(ii) ZnCl2

Pr

(iii) PdCl2(PPh3)2 (4.8 mol%) H

n-BuLi

N

54%

H

Pr

N

Novartis scientists investigated different synthetic routes to a selective inhibitor of the phosphodiesterase PDE4 D isoenzyme. An important refinement of the key Negishi aryl–aryl coupling involved premixing of the arylbromide and the catalyst, which was then added to the arylzinc intermediate. The work-up of this reaction was also thoroughly optimized to minimize the levels of residual metals in the final product.80 Br

N

N O N

N

Pd(PPh 3)4 (0.8 mol%)

MeO

THF

MeO ZnCl

79%

N O N

When catalytic amounts of Zn or Cd salts are present, the Ni- or Pd-catalyzed coupling of aryl halides (X = Cl, Br, I) with aryl Grignard reagents can provide unsymmetrical biaryls.81 This double metal-catalyzed synthesis of biaryls avoids the stoichiometric preparation of arylzinc reagents. It is noteworthy that addition to the nitrile can be avoided by slow addition of the organomagnesium reagent. MgCl Br

CN

PdCl 2(dppf) (2 mol%) ZnCl2 (5 mol%)

+

CN

THF, 55–60 °C

N

N

92%

An efficient process for the preparation of adapalene is shown in the following. The key step employs a palladium-zinc double metal-catalyzed coupling, which avoids the use of stoichiometric zinc and greatly improves the purification process.82 CO2Me Br MgBr MeO

PdCl 2(PPh 3)2 (2 mol%) ZnCl 2 (5 mol%)

CO2Me

THF, 55 o C 86%

MeO

Readily available aryl chlorides have been used as substrates in Negishi-type cross-coupling reactions with arylzinc reagents via either Ni- or Pd-catalysis to produce unsymmetrical biaryls in an efficient manner. Since a wide range 80 Manley, P. W.; Acemoglu, M.; Marterer, W.; Pachinger, W. Organic Process Research & Development 2003, 7, 436–445. 81 Miller, J. A.; Farrell, R. P. Tetrahedron Letters 1998, 39, 6441–6444. 82 Liu, Z.; Xiang, J. Organic Process Research & Development 2006, 10, 285–288.

6.4 Organozinc Reagents: Negishi Coupling

of functional groups (e.g. nitrile, ketone, ester) tolerate arylzinc compounds, this methodology results in the direct synthesis of biaryls from aryl chlorides containing those functionalities. In the following example, the Ni(0) catalyst is prepared in situ and mixed with the organozinc reagent prior to introduction of the aryl chloride, which affords the biphenyl product in high yield.83 (i) Ni(acac)2 (5 mol%) PPh 3 (20 mol%) H2O (10 mol%) Vitride (5 mol%)

O

Cl

Me

(ii) ZnCl2,THF, 0 °C ClMg

O

Me

Me

Me 85%

Vitride = Red-Al = bis(2-methoxyethoxy) aluminum hydride

Aryl triflates can also be utilized in the Negishi coupling. In the following example, a chemoselective halogen-metal exchange followed by transmetalation provides the organozinc reagent which is then coupled with the aryl triflate.84 Cl

Cl

(i) n-BuLi, ZnBr2 THF, –70 °C

N

N

(ii) Pd(PPh3)4 (1.4 mol% ) THF, 25 °C TfO

Br

N N

79%

The cross-coupling of a pyridyl zinc reagent and a pyridyl triflate under Negishi conditions can be used for the efficient and high yielding synthesis of 4-, 5-, and 6-methyl-2,2′ -bipyridines.85 Br

Me

(i) t-BuLi, THF (ii) ZnCl2 (iii) LiCl, Pd(PPh3)4

N

Me TfO

N N

N 94%

6.4.2

Preparation of Aryl—Alkyl Bonds

Because of the availability of benzylic halides and their straightforward conversion to benzylic organozinc reagents, the Negishi reaction has been utilized for their coupling to aryl halides. The example below shows the introduction of a benzyl group to the 2-position of a pyridine that proceeded in excellent yield.86 Br Ph

ZnBr

+

Pd(PPh3)4 (0.8 mol%) N

Me

THF

Ph N

Me

99% 83 See Note 81. 84 Denni-Dischert, D.; Marterer, W.; Baenziger, M.; Yusuff, N.; Batt, D.; Ramsey, T.; Geng, P.; Michael, W.; Wang, R.-M. B.; Taplin, F., Jr.; Versace, R.; Cesarz, D.; Perez, L. B. Organic Process Research & Development 2006, 10, 70–77. 85 Smith, A. P.; Savage, S. A.; Love, J. C.; Fraser, C. L. Organic Syntheses 2002, 78, 51–62. 86 Khatib, S.; Tal, S.; Godsi, O.; Peskin, U.; Eichen, Y. Tetrahedron 2000, 56, 6753–6761.

289

290

6 Selected Catalytic Reactions

This method has also been employed starting from the methylthioether, although an electron-deficient arene is required for the reaction to proceed.87 PhCH 2ZnBr Pd(PPh 3)4 (1mol%) N

THF, 55 °C

SMe

Ph

N

80%

6.4.3

Preparation of Alkanes

The interest in chiral alkyl boronate esters, spurred by Aggerwal, Matteson, and others, has generated enormous interesting possibilities for chiral Suzuki–Miyuara reactions.88 The availability and diversity of chiral boronate esters remains small, however. Fu and coworkers developed a method to provide chiral boronate esters using nickel catalysis. Addition of alkyl zinc reagents to α-chloro boronate esters with chiral diamine nickel complexes results in highly enantioenriched secondary boronate esters. The use of racemic and diastereomerically mixed populations of isomers converges to an enriched stereoisomer.

Ph

BPin Cl racemic

R-ZnBr (1.8 equiv.) 10 mol% NiBr2 • diglyme 13 mol% ligand THF, DMA, 0 °C

ligand = BPin

Ph

56–82% yield 82–95% ee

R

o-tol

o-tol

MeHN

NHMe

Chiral centers that are remote from functional groups can be difficult to generate in high enantiopurity by means other than asymmetric hydrogenation of the prochiral olefin. In a particularly elegant example by Fu and coworkers, two different chiral centers were set using a Ni-catalyzed Negishi cross-coupling between an alkyl zinc and an allylic chloride.89 Highest regioselectivity for this reaction is obtained when the substituents at the end of the allyl group have a substantial difference in steric demand. Cl Me

Me

CO2Et 5 mol% NiCl2 • glyme

Zn, I2 O O

ZnX

Ligand =

O

Ph

O O

Me

CO2Et >98% ee >15 : 1 dr

O

N N

6.4.4

5.5 mol% ligand 4 equiv NaCl DMF:DMA (1 : 1) –10 °C 82%

O

O

Br

Me

Me

N Ph

Preparation of 1,3-Dienes

The Negishi coupling can be used for the preparation of 1,3-dienes. In the following example, dibromostyrene undergoes a selective coupling to provide the bromodiene in high yield.90 Br Ph BrMg

ZnCl 2 THF

ClZn

Br

Pd(PPh 3)4 (1.6 mol%)

Br Ph

THF, 0 °C 84%

87 88 89 90

Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 905–907. Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Science 2016, 354, 1265–1269. Lou, S.; Fu, G. C. Organic Syntheses 2010, 87, 317–329. Ogasawara, M.; Ikeda, H.; Hayashi, T. Angewandte Chemie, International Edition 2000, 39, 1042–1044.

6.5 Cross-Electrophile Coupling

The vinylzinc reagent can also be accessed through in situ transmetalation of an organoaluminum reagent as shown in the following reaction of the vinyl iodide.91

C8H17

6.4.5

AlMe2

+

I

ZnCl 2 Pd(PPh 3)4 (1 mol%)

C 4H 9

C4H9 C8H17

THF >66%

Preparation of Ketones

The Negishi coupling provides a mild alternative for the preparation of benzylic ketones. In the following example, the benzylic bromide is coupled with the acid chloride in the presence of zinc and a palladium(0) catalyst.92 Cl

Cl +

O

Cl

Cl

Zn (2 equiv) Pd(PPh 3)4 (10 mol%)

Cl

O

DME 0 °C to rt

Br

78%

6.5 Cross-Electrophile Coupling The avoidance of carbon nucleophiles for metal-mediated cross-couplings remains a challenge.93,94 The preparation, isolation, and degradation of carbon nucleophiles renders these processes less efficient than the direct use of a carbon electrophiles. The coupling of two carbon electrophiles, i.e. cross-electrophile coupling, alleviates the requirement for a carbon nucleophile but introduces additional challenges. The activation of one of the carbon electrophile and subsequent engagement of the transition metal requires optimization to avoid nonproductive pathways such as reduction or homocoupling. Using zinc as the reductant, a nickel mediated cross-electrophile coupling was achieved with heterocyclic amidine-based ligands.

+

X N

NiX2(dme) (5 mol%) ligand (5 mol %) NaI (25 mol%)

X Ph

Ph

Zn (2 equiv), TFA (10 mol%) DMAC, 60 °C N N

Ligand = R1

R2 NH2

R2 H2N

R1 = H, OMe R2 = H, CN

N

N N

N

R2 NH2

R1

Engaging benzylic radicals has proven fertile ground for non-precious metal catalysis.95 The asymmetric reductive cross-coupling uses bioxazoline ligands with nickel to provide chiral diaryl alkanes. Racemic benzylic chlorides 91 Negishi, E.; Takahashi, T.; Baba, S. Organic Syntheses 1988, 66, 60–66. 92 Brandt, T. A.; Caron, S.; Damon, D. B.; Di Brino, J.; Ghosh, A.; Griffith, D. A.; Kedia, S.; Ragan, J. A.; Rose, P. R.; Vanderplas, B. C.; Wei, L. Tetrahedron 2009, 65, 3292–3304. 93 Hansen, E. C.; Li, C.; Yang, S.; Pedro, D.; Weix, D. J. The Journal of Organic Chemistry 2017, 82, 7085–7092. 94 Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. Nature Chemistry 2016, 8, 1126–1130. 95 Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E. Journal of the American Chemical Society 2017, 139, 5684–5687.

291

292

6 Selected Catalytic Reactions

cleanly cross-coupled with heteroarenes using Mn as the reductant. The selectivity of the reaction for aryl iodides was demonstrated by cross-coupling of a dichloroiodobenzene which retained both chlorides and proceeded in good yield.

Et

NiBr 2(diglyme) (10 mol%) ligand (20 mol%) Mn (3 equiv) TMSCl (0.75 equiv)

I

Ar Cl racemic 1.2 equiv

+

Het

1,4-dioxane, rt, 18 h

Et

R

O

O

R

R

N

N

R

Ligand =

Ar

Het

R = 4-heptyl

81–92% ee NiBr2(diglyme) (10 mol%) ligand (20 mol%) Mn (3 equiv) Cl TMSCl (0.75 equiv)

I Cl +

Cl

Cl

1,4-dioxane, rt, 48 h 70% yield 84% ee

Cl

6.6 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction) The Stille coupling, also known as Migita-Stille reaction, was independently reported in the late 1970s96,97 and has been the subject of many reviews.98,99 It has mainly been utilized for the coupling of sp and sp2 carbon electrophiles where an alkyl, vinyl, or aryl halide is reacted with an organotin reagent in the presence of a palladium catalyst. Due to the use of toxic organostannanes and the poor atom economy of the tin reagents, this reaction is not ideal from a “green” or process chemistry perspective. However, the highly covalent nature of the Sn—C bond compared to other organometallic reagents (e.g. Li-, Mg-, Al-, Zn-) makes this reagent less nucleophilic, more stable, and very tolerant of a variety of different functional groups. While the Suzuki-Miyaura coupling has arguably become more prominent than the Stille coupling, the latter can still be extremely valuable for small laboratory scale reaction where a boronic acid nucleophile may be too unstable for reaction. Residual tin by-products are often a problem with this method. Addition of a fluoride source100 as part of the reaction quench and extractive work-up has been used, although the efficiency of the tin removal is usually specific to the nature of the product. More often than not, the Stille coupling requires difficult chromatographic purification in order to eliminate unwanted tin derivatives in the product. 6.6.1

Preparation of Biaryls

The Stille coupling is an efficient method for the preparation of biaryls, although it is not as practical as the Suzuki–Miyaura reaction. In the following example shown, an activated aryl chloride is coupled with an arylstannane to afford the desired biphenyl in high yield. As part of the work-up, an aqueous solution of KF was utilized to reduce the levels of alkyltin by-products.101 Me

Me

Cl + O2N

SnBu3

O

OBn

PdCl 2(PPh 3)2 1,4-dioxane 89%

O2 N

O

OBn

96 Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chemistry Letters 1977, 301–302. 97 Stille, J. K.; Lau, K. S. Y. Accounts of Chemical Research 1977, 10, 434–442. 98 Stille, J. K. Angewandte Chemie, International Edition 1986, 98, 504–519. 99 Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions; Wiley: New York, 1997; Vol. 50, 1–652. 100 Hoshino, M.; Degenkolb, P.; Curran, D. P. The Journal of Organic Chemistry 1997, 62, 8341–8349. 101 Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi, H.; Hosaka, T.; Kawase, Y.; Yasuda, K.; Kikkawa, K.; Yamauchi-Kohno, R.; Yamada, K. Journal of Medicinal Chemistry 2001, 44, 3355–3368.

6.6 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction)

Another example of a Stille coupling of an iodide was reported by the Pfizer process group. While several other cross-coupling methods were investigated, the organostannane was the only reagent that reliably provided the desired product. A number of different work-ups were investigated to control the residual tin levels.102 Me N N

Cl +

SnBu3

S

I

Pd(PPh 3)4

S

N

DMF, 95 °C

N

Cl

Me N

N

67%

The Stille coupling can also proceed starting from the aryl triflate103 or 4-fluorophenylsulfonate,104 which are easily accessed from the corresponding phenol. OTf

SnBu3

PdCl 2(PPh 3)2 LiCl, 100 °C

+ NO2

NO2

48%

OMe

F

PhSnBu3 LiCl, dppp Pd(OAc) 2 (5 mol%)

O S O O

Me O

6.6.2

MeO

DMF

Ph Me

DMF O

85%

Preparation of Vinyl-Substituted Arenes

Vinyl stannanes will undergo efficient cross-couplings with aryl and heteroaryl halides. In the example shown in the following, the Stille coupling proceeded at room temperature and in high yield on a sensitive substrate.105 S

Me3Sn O

N

PhI Pd 2(dba) 3

OAc

O

DMF, rt

CO2Bn

S

Ph

>92%

N

OAc CO2Bn

Tributylvinyl tin is frequently used for vinylation of aryl halides and triflates. Lithium chloride is often added as an additive to the reaction to facilitate the transmetalation step by exchanging a Pd—O bond for a more active Pd—Cl bond. The two cases shown below exemplify the level of tolerance for other functional groups in this cross-coupling.106,107 SnBu 3 CO2Me TfO

CO2Me

Pd(PPh 3)4 (2 mol%) BHT (cat.) LiCl, 1,4-dioxane

NC

NC

91%

NHBoc TfO

O

N H

Me

SnBu3 PdCl 2(PPh 3)2 (1 mol%) LiCl, DMF 82%

NHBoc O

Me

N H

102 Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Organic Process Research & Development 2003, 7, 676–683. 103 Stille, J. K.; Echavarren, A. M.; Williams, R. M.; Hendrix, J. A. Organic Syntheses 1993, 71, 97–106. 104 Badone, D.; Cecchi, R.; Guzzi, U. The Journal of Organic Chemistry 1992, 57, 6321–6323. 105 Buynak, J. D.; Doppalapudi, V. R.; Frotan, M.; Kumar, R.; Chambers, A. Tetrahedron 2000, 56, 5709–5718. 106 Albert, J. S.; Ohnmacht, C.; Bernstein, P. R.; Rumsey, W. L.; Aharony, D.; Alelyunas, Y.; Russell, D. J.; Potts, W.; Sherwood, S. A.; Shen, L.; Dedinas, R. F.; Palmer, W. E.; Russell, K. Journal of Medicinal Chemistry 2004, 47, 519–529. 107 Larsen, S. D.; Barf, T.; Liljebris, C.; May, P. D.; Ogg, D.; O’Sullivan, T. J.; Palazuk, B. J.; Schostarez, H. J.; Stevens, F. C.; Bleasdale, J. E. Journal of Medicinal Chemistry 2002, 45, 598–622.

293

294

6 Selected Catalytic Reactions

When a simple phenyl group needs to be introduced, phenyltributyltin can be utilized. Enol tosylates have been utilized in a few cases and have the advantage of being more stable than the corresponding vinyl triflates.108 PhSnBu3 Pd(PPh 3)4 (5 mol%)

CO2Et NHBoc

TsO

CO2Et NHBoc

Ph

KF, THF 89%

6.6.3

Preparation of 1,3-Dienes

1,3-Dienes have been prepared via Stille coupling between the vinyl triflate derived from the corresponding ketone and commercially available vinyltributyl tin. In the first example below, triphenylarsine was utilized as a ligand,109 while the second example shows the use of Pd(PPh3 )4 as the palladium source.110 SnBu3 Pd 2(dba)3

OTf

AsPh3 NMP 70%

CO2Et

CO2Et

SnBu3 Pd(PPh 3)4

OTf

LiCl THF t-Bu

t-Bu

78–79%

While the use of stannanes is usually not preferred at large scale, the Stille coupling has been used extensively in the preparation of complex and sensitive β-lactams. One of the first examples was reported by Bristol-Myers Squibb chemists for their orally active antibiotic, cis-cefprozil.111 A Stille coupling was used to avoid the limitations of the earlier synthesis, which utilized a Wittig reaction. The requisite Z-alkene was obtained by coupling a stable cis-vinylstannane reagent with 3-trifloxycephem.112 Later, the same group reported the use of fluorosulfonate as a triflate replacement and NMP as the solvent to perform the Stille coupling under ligandless conditions, producing a variety of semi-synthetic β-lactam products.113,114

H H H S N

PhO O

108 109 110 111 112 113 114

O

N

OSO2F CO2CHPh 2

Me

SnBu3

Pd(OAc)2 NMP, rt 89%

H H H S N

PhO O

O

Me

N CO2CHPh 2

Steinhuebel, D.; Baxter, J. M.; Palucki, M.; Davies, I. W. The Journal of Organic Chemistry 2005, 70, 10124–10127. Pal, K. Synthesis 1995, 1485–1487. Scott, W. J.; Crisp, G. T.; Stille, J. K. Organic Syntheses 1990, 68, 116–129. Naito, T.; Hoshi, H.; Aburaki, S.; Abe, Y.; Okumura, J.; Tomatsu, K.; Kawaguchi, H. Journal of Antibiotics 1987, 40, 991–1005. Farina, V.; Baker, S. R.; Sapino, C., Jr. Tetrahedron Letters 1988, 29, 6043–6046. Baker, S. R.; Roth, G. P.; Sapino, C. Synthetic Communications 1990, 20, 2185–2189. Roth, G. P.; Sapino, C. Tetrahedron Letters 1991, 32, 4073–4076.

6.7 Cross-Coupling Reactions with Organosilicon Compounds

6.6.4

Preparation of Alkyl-Substituted Alkenes

The Stille coupling has also been utilized in the preparation of alkyl-substituted carbapenems. Merck utilized this approach for the conversion of a vinyl triflate to the corresponding hydroxymethyl analog.115 +

TESO H H Me O

N

Me OTf

N

Sn

O O S N

N

TESO

Me

H H

Me

Pd2(dba)3• CHCl3 P(2-furyl)3 DIPEA, NMP 98%

CO2PNB

N

R

CONH2 N

S O O

N

O

+

• 2TfO–

CO2PNB

A shorter and superior synthesis of the same carbapenem was accomplished using the cross-coupling of the enol triflate with the fully elaborated sidechain, utilizing a stannatrane as the heteroalkyl transfer reagent.116 It is worth mentioning that the toxic hexamethylphosphoramide (HMPA) was replaced by Hunig’s base and NMP as the solvent.

TESO

H H

Me O

N

Me OTf

N

Sn

O O S N

+ N

R

N TESO H H Me

Pd 2(dba) 3 • CHCl3 P(2-furyl)3 DIPEA, NMP

CO2PNB

Me

CONH2 N

S O O

N

O

+

• 2 TfO

–

CO2PNB

98%

An allyl chloride has been used as the coupling partner in the preparation of a cephalosporin. Trifurylphosphine was selected as the preferred ligand for this transformation.117 BocNH

HO

H N O

O

SnBu 3 Pd 2(dba) 3 (2 mol%)

S N

BocNH

H N

P(2-furyl)3 Cl

CO2CHPh 2

THF 82%

HO

O

O

S N CO2CHPh 2

6.7 Cross-Coupling Reactions with Organosilicon Compounds While much of cross-coupling chemistry, both in academia and in industry, is dominated by the Stille and Suzuki–Miyaura reactions, couplings that utilize organosilicon compounds have advanced to the point that they are a viable alternative to these well-established methods. In addition to being efficient reactions, cross-coupling reactions with organosilicon compounds can offer advantages in terms of waste disposal and atom-economy.118,119 The utility 115 Yasuda, N.; Yang, C.; Wells, K. M.; Jensen, M. S.; Hughes, D. L. Tetrahedron Letters 1999, 40, 427–430. 116 Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K. M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Organic Letters 2000, 2, 1081–1084. 117 Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C., Jr. The Journal of Organic Chemistry 1990, 55, 5833–5847. 118 Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling Reactions; 2nd ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004; Vol. 1, 163–216. 119 Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Current Organic Synthesis 2004, 1, 211–226.

295

296

6 Selected Catalytic Reactions

of this approach was shown by Denmark and Yang during their synthesis of (+)-brasilenyne.120 In this case, the cyclic silyl ether was activated by fluoride, transmetalated with palladium, and coupled to the pendant iodide to form the nine-membered ring in 61% yield. I Me2Si

[allylPdCl]2 TBAF

O

O PMBO

HO O

61%

Me

Me

OPMB

During their total synthesis of herboxidiene/GEX 1A, Panek and Zhang utilized a similar method for the synthesis of the diene functionality.121 In this case, the yields were variable (50–71%), but the conditions provided the diene exclusively as the (E,E) isomer. Me I

Me NC H

O

Me

+

H SiMe 2Bn

NC Me

OMe Me TBDPSO

[allylPdCl]2 TBAF

H

50–71% Me

Me

O

Me H Me

OMe Me TBDPSO

Me

Me

6.8 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling) Nearly a decade after the first cross-coupling between an sp and an sp2 carbon was reported by Stephens and Castro using stoichiometric copper (I) acetylide, Cassar and Heck independently demonstrated the cross-coupling of aryl and vinyl halides with terminal acetylenes via palladium catalysis. Mechanistically, this procedure could be considered as a Heck reaction on an alkyne substrate. A major improvement on this protocol was reported by Sonogashira and Hagihara, who found that the presence of CuI as a co-catalyst and an amine base allowed the reaction to proceed under very mild conditions. The operational simplicity and functional group tolerance of this procedure has resulted in it becoming the most common method for cross-coupling between a vinyl or aryl halide/triflate and a terminal acetylene.122,123 6.8.1

Reaction with Aryl Halides

The following example shows the robust preparation of a disubstituted alkyne using 2-bromopyridine and a terminal alkyne, which was prepared by alkylation with propargyl bromide and used without purification.124 N

H

CN

Br

CuI (2 mol%) PdCl 2(PPh 3)2 (2 mol%) Et 3N, THF, 60 °C

N CN

80% 120 121 122 123 124

Denmark, S. E.; Yang, S.-M. Journal of the American Chemical Society 2002, 124, 15196–15197. Zhang, Y.; Panek, J. S. Organic Letters 2007, 9, 3141–3143. Chinchilla, R.; Najera, C. Chemical Reviews 2007, 107, 874–922. Plenio, H. Angewandte Chemie, International Edition 2008, 47, 6954–6956. Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L. Organic Process Research & Development 2007, 11, 246–250.

6.8 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling)

The functional group tolerance of the Sonogashira reaction is exemplified in the following examples with a terminal alkyne.125,126 Note that the addition of CuI was not necessary in the first example.

Me Me

• Cy2NH H N

O

MeO

MeO

CO2H

N

O N

Br

O

•HCl

O

Me Me

[Pd(allyl)Cl] 2 (1.7 mol%)

CO2Et

P(tBu)3 HBF4 (6.8 mol%)

N CO2Bn

H N

O

CO2H

CO2Et N CO2Bn

O

NH(iPr)2 (5.6 equiv) MeCN, 50 °C 90% OH

O

O N

•TsOH Me

Br

N

Me

O

OH

Bn Me

O

N

N

PdCl 2(PPh 3)2 (1 mol%) CuI (1 mol%)

O

Bn

Me

NEt 3 (3 equiv)

O

toluene, 35–50 °C

When a terminal alkyne is the desired product, the reaction is not conducted with acetylene but rather with a protected derivative of acetylene, typically the trimethylsilyl derivative127 or 2-methyl-3-butyn-2-ol, an inexpensive alternative that can be deprotected under basic conditions.128 In general, electron-rich alkynes tend to work well in the trans-metalation step while electron-poor substrates often fail to react. TMS Br

H TMS Pd(PPh 3)2Cl 2 (2 mol%)

O

O

CuI (2 mol%) EtOAc, E t 3N

O

Cl

N Me

Me

N

CO2Et

Cl

N Me

Me H

HO

Cl

O

87%

PPh 3 (4 mol%) CuI (4 mol%) 10% Pd/C (2 mol%) aq. K 2CO3, DME

Me

Me

HO

CO2Et N

83% 125 Song, Z. J.; Tellers, D. M.; Dormer, P. G.; Zewge, D.; Janey, J. M.; Nolting, A.; Steinhuebel, D.; Oliver, S.; Devine, P. N.; Tschaen, D. M. Organic Process Research & Development 2014, 18, 423–430. 126 Singer, R. A.; Ragan, J. A.; Bowles, P.; Chisowa, E.; Conway, B. G.; Cordi, E. M.; Leeman, K. R.; Letendre, L. J.; Sieser, J. E.; Sluggett, G. W.; Stanchina, C. L.; Strohmeyer, H.; Blunt, J.; Taylor, S.; Byrne, C.; Lynch, D.; Mullane, S.; O’Sullivan, M. M.; Whelan, M. Organic Process Research & Development 2014, 18, 26–35. 127 Andresen, B. M.; Couturier, M.; Cronin, B.; D’Occhio, M.; Ewing, M. D.; Guinn, M.; Hawkins, J. M.; Jasys, V. J.; LaGreca, S. D.; Lyssikatos, J. P.; Moraski, G.; Ng, K.; Raggon, J. W.; Stewart, A. M.; Tickner, D. L.; Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. Organic Process Research & Development 2004, 8, 643–650. 128 Frigoli, S.; Fuganti, C.; Malpezzi, L.; Serra, S. Organic Process Research & Development 2005, 9, 646–650.

297

298

6 Selected Catalytic Reactions

In the following example, two successive Sonogashira couplings were conducted in a single pot. Upon completion of the first coupling, the alkyne was deprotected and coupled with a second aryl bromide.129

MeO Br OMe

+

Me

(i) i-Pr2NH Pd(PPh 3)2Cl 2 (1 mol%) PPh3 (2 mol%) CuI (1 mol%) toluene, 78 °C

Me H

HO

MeO N

(ii) n-Bu4NBr

OMe

toluene, aq NaOH

Et

N

N

Br Et

N

75%

When a 2-amino aryl halide is used as a substrate, an indole product can sometimes be obtained directly as first shown by Larock and Yum.130 Although the majority of Larock-type indole syntheses employ an aryl iodide as the substrate, examples of aryl bromides and chlorides have been reported, as shown below.131 Given the relatively low boiling point of trimethylsilyl acetylene (53 ∘ C), the reaction was performed under pressure to prevent evaporation of the alkyne substrate. TMS [Pd(allyl)Cl]2 (2.3 mol%) Me

Br NH2 F

6.8.2

DPEphos (4.6 mol%)

Me

NMe(Cy) 2 (2.2 equiv) toluene-heptane, 72–75 °C

F

N H

TMS

98%

Preparation of Enynes

Enynes can be accessed through the coupling of a vinyl halide with a terminal alkyne under Sonogashira conditions. In the following example, a vinyl chloride was reacted under very mild conditions, which was necessary due to the known instability of the product.132 H

C5H11

Cl

C5H11

PdCl 2(PhCN) 2 (2.5 mol%) CuI (5 mol%) Piperidine, rt

C5H11

C5H11

91%

6.9 Metal-Catalyzed Coupling of Alkenes (Heck Coupling) The Heck reaction is one of the most versatile methods for adding carbon nucleophiles to alkenes, and many reviews have been written addressing various aspects of it.133,134,135,136 All oxidation states of carbon have been shown to add to the alkene under palladium catalysis, but the best reaction is achieved with sp2 nucleophiles, such as aryl halides, 129 Koenigsberger, K.; Chen, G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 2003, 7, 733–742. 130 Larock, R. C.; Yum, E. K. Journal of the American Chemical Society 1991, 113, 6689–6690. 131 Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-Y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Organic Process Research & Development 2012, 16, 1832–1845. 132 Alami, M.; Crousse, B.; Ferri, F. Journal of Organometallic Chemistry 2001, 624, 114–123. 133 Heck, R. F. Accounts of Chemical Research 1979, 12, 146–151. 134 Beletskaya, I. P.; Cheprakov, A. V. Chemical Reviews 2000, 100, 3009–3066. 135 See Note 13. 136 Crisp, G. T. Chemical Society Reviews 1998, 27, 427–436.

6.9 Metal-Catalyzed Coupling of Alkenes (Heck Coupling)

and will be the only type covered herein. Almost any functionality is tolerated in the nucleophilic partner from a reactivity sense, although substituents can alter the regioselectivity. Substitution on the alkene partner is more limiting. Monosubstituted alkenes have the highest reactivity; increasing the substitution can greatly reduce the rate of reaction. Neutral, cationic, and anionic mechanisms have been proposed for the reaction; reaction conditions dictate which is thought to be operational, and the substrates, especially the alkene, dictate which is preferred. As with almost all metal-mediated processes, the optimal conditions (catalyst source, ligand, base, solvent) need to be identified by screening although recommended “first-pass” protocols have been published.137 For Heck reactions, it can be generalized that if both partners are reactive, such as aryl halides and electron-deficient alkenes, coupling occurs under the mildest conditions with monodentate ligands. Reactions of less reactive substrates, such as electron-rich alkenes or vinyl halides may work better under halide-free conditions or with polydentate ligands. The selection of the base can also have a profound effect on the rate and product distribution. The stereochemical outcome of the reaction is generally predicted by consideration of the intermediate: the palladium nucleophile adds in a syn fashion to the alkene, generating a σ-palladium species that must rotate for the required syn Pd–H elimination. Substrates in which there is no strong conformational or electronic preference for the elimination can give regiochemical mixtures of isomers. Cyclic substrates containing bonds that cannot rotate to achieve the required conformation for syn elimination give products of β′ -hydride elimination, often as mixtures of regioisomers and stereoisomers. 6.9.1

Formation of Aryl Alkenes

The coupling of aryl halides or sulfonates, such as triflates, with alkenes is the most commonly reported variation of the Heck reaction. The order of reactivity of the aryl halide partner is I > Br ≫ Cl. Aryl bromides are most frequently used because of their availability and reactivity. A wide array of functional groups is tolerated on the aryl group, and many different alkene partners have been successfully employed. The following example, utilizing an electron-deficient alkene, demonstrates the selectivity of the palladium insertion for the aryl bromide over the chloride.138 Br + Cl

CO2Et

NO2

CO2Et

Pd(OAc)2, PPh 3 TEA, DMF 95%

Cl

NO2

Aryl chlorides are attractive partners for coupling because of their generally lower cost than the corresponding bromides, but their lower reactivity precluded their use in Heck reactions for many years. More reactive catalysts have been developed that will couple even unactivated aryl chlorides, as shown in the following. Bulky, electron-rich ligands such as P(t-Bu)3 form very reactive catalysts, especially when combined with methyldicyclohexylamine as the base.139 Cl

Pd 2(dba)3 P(t-Bu)3

CO2Me

+

Me

CO2Me

Cy 2NMe dioxane, 100 °C

Me

84%

The regioselectivity of the addition is often driven by steric considerations. In the example below, the nature of the protecting groups on the allyl amine had a strong influence on the regioisomeric purity of the product.140 The bis(Boc) derivative was found to be optimal, and the reaction was run under ligand-free conditions. Me O HN I

N Me

N N

(i) Pd 2(dba)3, TEA 2-PrOH, 78 °C Boc 2N (ii) Conc. HCl, 40 °C

Me NH2

O

• 2 HCl HN

N Me

N

79–84% N

137 Murray, P. M.; Bower, J. F.; Cox, D. K.; Galbraith, E. K.; Parker, J. S.; Sweeney, J. B. Organic Process Research & Development 2013, 17, 397–405. 138 Caron, S.; Vazquez, E.; Stevens, R. W.; Nakao, K.; Koike, H.; Murata, Y. The Journal of Organic Chemistry 2003, 68, 4104–4107. 139 Littke, A. F.; Fu, G. C. Journal of the American Chemical Society 2001, 123, 6989–7000. 140 Ripin, D. H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M., III; Vetelino, M. G.; Wei, L. Organic Process Research & Development 2005, 9, 440–450.

299

300

6 Selected Catalytic Reactions

In the synthesis of Axitinib, acyl protection of the indazole nitrogen atom served a dual purpose: prevented Michael addition of the indazole group on the vinyl pyridine and accelerated oxidative addition of the C—I bond.141 The large chelating ligand Xantphos was identified as optimal for this transformation. N O

Me N

O

Me N

4 mol% Pd(OAc)2 4 mol% Xantphos

S

N

O H N

Me

S

3 equiv DIPEA

I

NMP, 90°C

N

74–77%

The electronic nature of substituents on the alkene can enhance or conflict with the inherent steric bias. In the first example above, the ester substituent complemented the regioselectivity of addition based on sterics, resulting in a coupling that occurred at room temperature. Electron-rich alkenes were at one-time problematic substrates because the electronics favor addition at the α rather than the β carbon, resulting in slow reaction rates and mixtures of regioisomers. The regioselectivity can be controlled by the appropriate choice of ligand and additives, however. In the second of the two examples below, DPEphos was crucial in obtaining reaction at the α carbon of the vinyl moiety.142 When using 1,1′ -Bis(diphenylphosphino)ferrocene (DPPF) as the ligand, addition of LiOTf was required to improve the high level of regioselectivity, but the undesired isomer still formed in small amount and was difficult to purge. Both examples also employ a chelating ligand to direct the addition to the α carbon.143 In the first example, the aryl ketone is isolated, resulting from hydrolysis of the initially formed enol ether. MeO2C

MeO2C F

Me Me

O

N

Me Me

F

Me Me N

Pd(OAc) 2

Br

N Et

Me dppp

Me Me

Cs 2CO3

O

N Et

Me

DMF, water BocN

Me N

Br

N N

N H

O

BocN

Me

N

N

O

N

2.5 mol% DPEphos 2.4 equiv DIPEA

OBu

N

O

N

2 mol% Pd(OAc)2 N

Me

N H

N

n-butanol, 95° C 85%

Intramolecular Heck reactions have been used to assemble very complex substrates with tertiary or quaternary centers that would otherwise be quite challenging to manufacture.144 Br

Br N F

O

Pd(OAc)2, DMF K 2CO3, H2O 80%

H

Br

H

H

N F

O

141 Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. J. Organic Process Research & Development 2014, 18, 266–274. 142 Maloney, M. T.; Jones, B. P.; Olivier, M. A.; Magano, J.; Wang, K.; Ide, N. D.; Palm, A. S.; Bill, D. R.; Leeman, K. R.; Sutherland, K.; Draper, J.; Daly, A. M.; Keane, J.; Lynch, D.; O’Brien, M.; Tuohy, J. Organic Process Research & Development 2016, 20, 1203–1216. 143 Jiang, X.; Lee, G. T.; Prasad, K.; Repic, O. Organic Process Research & Development 2008, 12, 1137–1141. 144 Campos, K. R.; Journet, M.; Lee, S.; Grabowski, E. J. J.; Tillyer, R. D. The Journal of Organic Chemistry 2005, 70, 268–274.

6.9 Metal-Catalyzed Coupling of Alkenes (Heck Coupling)

For substrates in which the inherent regioselectivity of the β-H elimination is poor, introduction of a temporary biasing agent, such as a silane, can be used to help control the outcome. In the following example, a trimethylsilyl group was used to control elimination away from the ring. A mixture of vinyl silanes was obtained but was of no consequence after protodesilylation. In the absence of the silyl group, a mixture of regioisomers was obtained, and the trisubstituted olefin was also a mixture of stereoisomers.145 Pd(OAc)2, TEA PPh 3, toluene

OTf

75 °C 90% TMS

TMS Pd(OAc) 2, TEA PPh 3, toluene

OTf

+

70 °C Me 47–45%

Me 33–36%

Asymmetric induction can be achieved with the use of chiral ligands.146 The enantioselectivity achieved is generally modest,147 but for some substrate and catalyst combinations, it can be quite high.148 O Me OTf

O

Pd(OAc)2, ligand proton sponge

Ph

Me

DMF, 100 °C Ph

90%

94% ee Me

Ligand = MeO MeO

PAr 2 PAr 2

Ar = Me

6.9.2

Formation of Dienes

The second most common nucleophilic partner in the Heck reaction is a vinyl halide, which gives a diene as the product. The reaction is less robust than the aryl version, and mixtures of olefin isomers may be obtained. However, there are several examples of remarkable selectivity, especially considering the ability of the palladium to isomerize alkenes. In the following example, the stereochemistry of the olefins in the alkene was not perturbed, and no products of π-allyl formation were observed.149 Me

Me Me

OH

+ Me I

OEt OEt

Pd(OAc) 2 Ag 2CO3, DMF 70%

Me Me

Me OH

Me

OEt OEt

E/Z = 45/55

E/Z = 40/60

145 Tietze, L. F.; Modi, A. European Journal of Organic Chemistry 2000, 1959–1964. 146 Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371–7395. 147 Busacca, C. A.; Grossbach, D.; Campbell, S. J.; Dong, Y.; Eriksson, M. C.; Harris, R. E.; Jones, P.-J.; Kim, J.-Y.; Lorenz, J. C.; McKellop, K. B.; O’Brien, E. M.; Qiu, F.; Simpson, R. D.; Smith, L.; So, R. C.; Spinelli, E. M.; Vitous, J.; Zavattaro, C. The Journal of Organic Chemistry 2004, 69, 5187–5195. 148 Minatti, A.; Zheng, X.; Buchwald, S. L. The Journal of Organic Chemistry 2007, 72, 9253–9258. 149 Bienayme, H.; Yezeguelian, C. Tetrahedron 1994, 50, 3389–3396.

301

302

6 Selected Catalytic Reactions

In other cases, special ligands have been developed to promote the reaction.150 [Pd( η3-C3H5)Cl] 2 Ph

Br +

CO2n-Bu

Me

DMF, 100 °C 95%

Ph

CO2n-Bu

Me

N

Br +

Me

Tedicyp, K 2CO3

92%

Me

N

Me Me

PPh 2

Tedicyp = Ph 2P Ph 2P

PPh 2

Catalytic systems can also be tuned to give the expected product of insertion β to the activating group of the electrophilic partner or the product of 1,2-migration of the alkenyl palladium(II) species, resulting in an apparent α insertion.151 6.9.3

Reductive Heck

In most Heck reactions, the product of the reaction is a substituted alkene. However, if a reducing agent is present in the reaction, the alkene can be reduced. Formic acid or formate salts are the most commonly used reducing agents.152 Pd(OAc)2, DMF NaOAc/HCO 2Na Et 4NCl•H 2O

Br O

Me

85–95 °C 91%

Me Me

O

The reduction can also be carried out as a separate step. Note that in the following example, the aryl triflate was used instead of the aryl bromide.153 Triflates may require the use of chelating ligands in order to work well. Me

Me

Me

Me Me

Oi-Pr Oi-Pr OTf

(1) Pd(OAc)2, dppp K 2CO3, DMF 100 °C (2) RhCl(PPh3)2 H2, benzene

i-Pr O Me

Oi-Pr

Me Me

Me Me

85%

150 Lemhadri, M.; Battace, A.; Berthiol, F.; Zair, T.; Doucet, H.; Santelli, M. Synthesis 2008, 1142–1152. 151 Ebran, J.-P.; Hansen, A. L.; Gogsig, T. M.; Skrydstrup, T. Journal of the American Chemical Society 2007, 129, 6931–6942. 152 Liu, P.; Huang, L.; Lu, Y.; Dilmeghani, M.; Baum, J.; Xiang, T.; Adams, J.; Tasker, A.; Larsen, R.; Faul, M. M. Tetrahedron Letters 2007, 48, 2307–2310. 153 Planas, L.; Mogi, M.; Takita, H.; Kajimoto, T.; Node, M. The Journal of Organic Chemistry 2006, 71, 2896–2898.

6.10 Enolate Arylations

Example of enantioselective reductive Heck has been reported. Although an appreciable level of enantioselectivity was obtained in the following example, high level of debromination prohibited further development of this reaction.154 Me O

MeO2C

[Pd(OMs)(2-N H2Ph)] 2 (5 mol%)

N

Br N

Me O

MeO2C

N

SL-W005-1 (10.5 mol%)

CF3 N N

OMe

CsOC(O)H DMF, 60 °C

N

N

F

N

F

6.9.4

CF3 OMe

86% ee

Oxidative Heck

Reaction between a boronic acid (in place of a, e.g. aryl halide) and an olefin is termed an oxidative Heck coupling since the reaction requires a terminal oxidant for the catalyst to turn over.155 The oxidative Heck usually proceeds at milder temperature relative to standard Heck coupling and does not require base. As with many reactions requiring an added oxidant, applications on larger scale are scarce. Molecular oxygen is frequently employed for such a reaction, as shown below,156 but the use of benzoquinone or Cu(OAc)2 as the terminal oxidant has also been reported.157 More recently, tube-in-tube continuous-flow reactors with gas-permeable membranes have been utilized to carry out oxidative Heck coupling using O2 as the terminal oxidant.158

PhB(OH)2 10 mol% Pd(OAc) 2 O

O

15 mol% phen-NO2 O2, DMF, 80°C

phen-NO2 =

Ph

O

O

NO2

N N

97%

6.10 Enolate Arylations α-Arylated carbonyl are commonly encountered in biologically active compounds and are thus of keen interest to the pharmaceutical industry. Conventional synthetic methods to prepare such functionalities include direct SN Ar reaction, which is limited to highly activated aryl rings. Other methods make use of stoichiometric amounts of toxic reagents such as aryl lead compounds159 or chromium reagents160 and are therefore unattractive. Alternative methods for the synthesis of α-arylated compound were therefore needed. Although one of the earliest example of an α-arylation

154 Humphrey, G. R.; Dalby, S. M.; Andreani, T.; Xiang, B.; Luzung, M. R.; Song, Z. J.; Shevlin, M.; Christensen, M.; Belyk, K. M.; Tschaen, D. M. Organic Process Research & Development 2016, 20, 1097–1103. 155 Lee, A. L. Organic & Biomolecular Chemistry 2016, 14, 5357–5366. 156 Li, Y.; Qi, Z.; Wang, H.; Fu, X.; Duan, C. The Journal of Organic Chemistry 2012, 77, 2053–2057. 157 See Note 155. 158 Park, J. H.; Park, C. Y.; Kim, M. J.; Kim, M. U.; Kim, Y. J.; Kim, G.-H.; Park, C. P. Organic Process Research & Development 2015, 19, 812–818. 159 Morgan, J.; Pinhey, J. T.; Rowe, B. A. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 1997, 1005–1008. 160 Mino, T.; Matsuda, T.; Maruhashi, K.; Yamashita, M. Organometallics 1997, 16, 3241–3242.

303

304

6 Selected Catalytic Reactions

reaction was reported by Semmelhack et al. in 1973,161 the groups of Hartwig and coworkers,162 Buchwald and coworkers,163 and Miura and coworkers164 reported the Pd-catalyzed version of this reaction in 1997. This topic has received a lot of attention and has been reviewed.165 Typical reaction conditions make use of a base, often K3 PO4 or NaOtBu, with either Pd(0) and Pd(II) precatalysts at temperature typically ranging from 60 to 100 ∘ C. Although asymmetric version of this reaction have been reported,166 these will not be discussed here. 6.10.1

𝛂-Arylation of Ketones

Chung et al. at Merck carried out the α-arylation of a ketone during the synthesis of a glucagon receptor antagonist.167 Given the higher reactivity of aryl-Br over aryl-Cl, the oxidative addition occurs selectively at the former. Despite the popularity of the (±)-2,2′ -Bis(diphenylphosphino)-1,1′ -binaphthalene (BINAP) ligand in α-arylation reaction, the authors found better reactivity using DPEphos as the ligand and were able to reduce the loading to 0.5 mol%, leading to a cost reduction of 10-fold. O Me O

Cl OtBu

0.5 mol% Pd(OAc)2

O

Cl

0.5 mol% DPEphos NaOtBu, THF, 60 °C 86%

Br

Me

O

OtBu

In the previous example, the authors did not mention whether they have observed reaction at the Cl atom or whether impurity arising from overarylation was observed, which can be a problem given the higher acidity of the newly formed α-arylated C—H bond. Such problems can be kept in check by careful control of the reagents stoichiometry and/or catalyst choice, however. Nevertheless, other strategies to avoid multiple arylation include the synthesis of silyl-enol ethers,168 or using enamine catalysis.169 6.10.2

𝛂-Arylation of Esters

Esters can also be effective coupling partners in the α-arylation reaction as demonstrated by Risatti and Natalie at Bristol-Myers Squibb in the synthesis of dual SK1/Serotonin receptor antagonist.170 In this example, formation of the lithium enolate was first carried out followed by addition of the aryl bromide, the Pd source, and the ligand. O

OEt

N Boc

Cy 2NH n-BuLi

LiO

F

OEt

F

O

Br N Boc

OEt

Pd 2(dba)3•CHCl3 P(t-Bu)3•HBF 4 toluene, 20–30 °C

N Boc

76%

Although the majority of reports of α-arylation employ a Pd or Ni catalyst, Cu catalyst can also perform this reaction if a suitable aryl group, typically an aryl-iodide, is used. In the following example, when the cyclization was examined using Pd as the metal catalyst, high degree of debromination was observed, and Cu was selected given the reduced 161 162 163 164 165 166 167 168 169 170

Semmelhack, M. F.; Stauffer, R. D.; Rogerson, T. D. Tetrahedron Letters 1973, 4519–4522. Hamann, B. C.; Hartwig, J. F. Journal of the American Chemical Society 1997, 119, 12382–12383. Palucki, M.; Buchwald, S. L. Journal of the American Chemical Society 1997, 119, 11108–11109. Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angewandte Chemie International Edition 1997, 36, 1740–1742. Bellina, F.; Rossi, R. Chemical Reviews 2010, 110, 1082–1146. Johansson, C. C. C.; Colacot, T. J. Angewandte Chemie International Edition 2010, 49, 676–707. See Note 131. See Note 165. Xu, Y.; Su, T.; Huang, Z.; Dong, G. Angewandte Chemie International Edition 2016, 55, 2559–2563. Risatti, C.; Natalie, K. J.; Shi, Z.; Conlon, D. A. Organic Process Research & Development 2013, 17, 257–264.

6.10 Enolate Arylations

amount of this impurity.171 Consistent with the lower reactivity of Cu with aryl bromide, low conversion was observed with the bromo pyrimidine. However, after screening of various ligands, picolinic acid showed the most promise and was selected for further development. Ultimately, near quantitative formation of the cyclized product was observed, albeit with a relatively high loading of CuI and ligand (25 mol% each). CuI picolinic acid

CO2Et EtO2C

N

toluene, THF, DMA 60 °C >99%

N

I

6.10.3

NPMB 2

N

EtO2C

NPMB 2

N CO2Et

𝛂-Arylation of Amides

Yang and et al. at Albany Molecular Research Inc. (AMRI) reported the synthesis of a triple reuptake inhibitor for the treatment of major depressive disorder.172 The reaction conditions are quite typical but, interestingly, the authors noted a significant exotherm aside from the expected exotherm associated with addition of sodium tert-butoxide when the reaction reached a temperature of 60 ∘ C. Although slow addition of 5-bromobenzothiophene can mitigate this exotherm, this lead to a dramatic increase in the number of impurities formed. S

Br O N

N

Me

S 5 mol% Pd(OAc)2

O

O

5 mol% BINAP NaOtBu dioxane, 80 °C

N

N

Me

O

66%

6.10.4

𝛂-Arylation of Nitrile

Although nitriles are less acidic than ketones α-arylation on nitrile containing substrates has been documented. Interesting mechanistic studies by the Hartwig group has shown the multitude of binding modes that are possible for the nitrile anion and provided insight as to ligand design for an efficient reaction.173 As previously stated, nitriles are usually less acidic than (e.g.) ketones and stronger bases are normally required to promote the reaction. The group of Knoechel described the α-arylation of aliphatic nitrile using tetramethylpiperidine zinc chloride lithium chloride (TMPZnCl⋅LiCl) as the base.174 Once formed, the nitrile anion underwent smooth coupling using Pd(OAc)2 and Sphos as the ligand. An unprotected aniline substrate was also reportedly tolerated under those conditions. The tetramethyl piperidine co-product of this reaction was also reported not to slow down the progress of Pd-catalyzed reaction as do other less hindered amines.175 This method has the advantage of not having to prepare the α-silyl nitrile to avoid problem with multiple arylation.176 OMe CN

TMPZnCl·LiCl THF 25 °C

ZnCl·LiCl CN

Br

OMe

2 mol% Pd(OAc)2 4 mol% SPhos THF, 50 °C

CN

92% 171 See Note 66. 172 Yang, Q.; Ulysse, L. G.; McLaws, M. D.; Keefe, D. K.; Haney, B. P.; Zha, C.; Guzzo, P. R.; Liu, S. Organic Process Research & Development 2012, 16, 499–506. 173 Culkin, D. A.; Hartwig, J. F. Journal of the American Chemical Society 2002, 124, 9330–9331. 174 Duez, S.; Bernhardt, S.; Heppekausen, J.; Fleming, F. F.; Knochel, P. Organic Letters 2011, 13, 1690–1693. 175 Manolikakes, G.; Schade, M. A.; Munoz Hernandez, C.; Mayr, H.; Knochel, P. Organic Letters 2008, 10, 2765–2768. 176 Wu, L.; Hartwig, J. F. Journal of the American Chemical Society 2005, 127, 15824–15832.

305

306

6 Selected Catalytic Reactions

A very interesting extension of this methodology was reported by Dunn at Merck for the α-arylation of cyclopropyl nitriles, which are even less acidic than unstrained alkyl nitriles.177 In this example, the authors had to use the strong base LiHMDS to promote the reaction, which limited the substrate scope. The authors also noted the importance of preligation of the BINAP ligand with the Pd source prior to addition of the coupling partners and the base. CN Br BnO

5 mol% Pd(OAc)2 10 mol% BINAP LiHMDS CPME, 80 °C 75%

CN BnO

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation Nitrogen heterocycles are key constituents of many natural products and pharmaceuticals. Synthesis of these compounds frequently starts from the appropriately functionalized aniline derivatives involving multiple chemical manipulations. In special cases where the corresponding aryl halides are highly activated, direct SN Ar substitutions have been reported (e.g. reaction of n-butylamine with 2,4-dinitrochlorobenzene proceeds in 83% yield in chloroform at ambient temperature in the presence of a phase-transfer catalyst).178 Copper-catalyzed reactions are well established, and recent advances have been reviewed.179 Although Pd-catalyzed aminations have received more recent attention,180 the Cu-catalyzed couplings can in many cases be competitive and potentially more economical. The first preparation of aryl amines from an aryl bromide using Bu3 SnNEt2 in the presence of PdCl2 [P(o-tol)3 ]2 was reported by Kosugi and Migita in 1983.181 A severe limitation of this process was the use of an alkyltin reagent that made it less attractive for industrial purposes. However, significant improvements have been reported that make this strategy more synthetically useful.182,183,184,185 Buchwald and Hartwig independently demonstrated that under optimized conditions and with the appropriate choice of base (e.g, NaOt-Bu or Cs2 CO3 ) and ligand (e.g. BINAP), tin-free aminations of aryl iodides and bromides can be performed under relatively mild conditions.186,187 Since then, several improvements on palladium- and copper-catalyzed N-arylation have been reported from numerous laboratories and, in some cases, less expensive and more widely available aryl chlorides have been successfully employed.188 Numerous catalysts and conditions have been reported for these couplings, and selection of the optimal system will in most cases be substrate dependent and will involve some degree of optimization. A “user’s guide” has been published to help select reaction conditions.189 The examples shown below are organized by the type of amine nucleophile used. 177 178 179 180 181 182 183 184 185 186 187 188 189

McCabe Dunn, J. M.; Kuethe, J. T.; Orr, R. K.; Tudge, M.; Campeau, L.-C. Organic Letters 2014, 16, 6314–6317. Ross, S. D. Tetrahedron 1969, 25, 4427–4436. Ley, S. V.; Thomas, A. W. Angewandte Chemie, International Edition 2003, 42, 5400–5449. Ruiz-Castillo, P.; Buchwald, S. L. Chemical Reviews 2016, 116, 12564–12649. Kosugi, M.; Kameyama, M.; Migita, T. Chemistry Letters 1983, 927–928. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Accounts of Chemical Research 1998, 31, 805–818. Hartwig, J. F. Accounts of Chemical Research 1998, 31, 852–860. Hartwig, J. F. Pure and Applied Chemistry 1999, 71, 1417–1423. Surry, D. S.; Buchwald, S. L. Angewandte Chemie International Edition 2008, 47, 6338–6361. Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. Journal of the American Chemical Society 1996, 118, 7215–7216. Driver, M. S.; Hartwig, J. F. Journal of the American Chemical Society 1996, 118, 7217–7218. See Note 13. Surry, D. S.; Buchwald, S. L. Chemical Science 2011, 2, 27–50.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

6.11.1

Alkyl Amine as Nucleophile

In the synthesis of AMG-3969, Bourbeau and coworkers employed the first generation Ruphos palladacycle precatalyst developed by the Buchwald lab190 to obtain the desired product in quantitative yield.191 CF3 OH CF3

Br Bn N

NH

First gen Ruphos palladacycle (4 mol%) t-BuONa(2.5 equiv) dioxane, 100 °C

Me

Bn N

CF3 OH CF3

N

Me

Although SN Ar is a very attractive method for the introduction of amine functionalities onto properly functionalized electrophiles, selectivity can sometimes be challenging when SN Ar is possible at more than one location. In such a case, the metal-catalyzed amination may yield a much-improved selectivity. This is illustrated by the following example from Kuethe at Merck.192 Introduction of the amine through SN Ar in a variety of solvents gave the desired product as the major isomer, but the selectivity for the desired product was ∼3 : 1 at best. It was then found that the Pd-catalyzed amination gave a much-improved selectivity for the desired product using LiHMDS as the base, while other bases lead to a lower selectivity. The Pd catalyst used in the C—N bond formation was carried over from a previous Suzuki reaction. F

Me Me

F

Cl

N

Cl

[Pd] =

N

Br N

NH

Me

1.5 mol% [Pd] 1.1 equiv LiHMDS THF, –10 to –5 °C 85%

Me

N

N N

Cl

Ph 3P Cl

Cl N Pd

N PPh 3

Cl

N

Br

97 : 3 regioselectivity

High selectivity can sometimes be obtained even in the presence of an unhindered primary alcohol, as shown in the following from Sperry et al.193 Me Br N CN

H 2N

H N

OH

2.5 mol% Pd(dba)2 2.5 mol% rac-Binap Cs2CO3, THF, 65 °C 80%

Me OH

N CN

The following chloroarene primary amine coupling was developed for the synthesis of torcetrapib.194 Phenylboronic acid is used to activate the catalyst, and the phosphine ligand (first reported by Buchwald and coworkers)195 was 190 Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. Journal of the American Chemical Society 2008, 130, 6686–6687. 191 Bourbeau, M. P.; Ashton, K. S.; Yan, J.; St. Jean, D. J. The Journal of Organic Chemistry 2014, 79, 3684–3687. 192 Kuethe, J. T.; Journet, M.; Peng, Z.; Zhao, D.; McKeown, A.; Humphrey, G. R. Organic Process Research & Development 2016, 20, 227–232. 193 Sperry, J. B.; Price Wiglesworth, K. E.; Edmonds, I.; Fiore, P.; Boyles, D. C.; Damon, D. B.; Dorow, R. L.; Piatnitski Chekler, E. L.; Langille, J.; Coe, J. W. Organic Process Research & Development 2014, 18, 1752–1758. 194 Damon, D. B.; Dugger, R. W.; Hubbs, S. E.; Scott, J. M.; Scott, R. W. Organic Process Research & Development 2006, 10, 472–480. 195 Old, D. W.; Wolfe, J. P.; Buchwald, S. L. Journal of the American Chemical Society 1998, 120, 9722–9723.

307

308

6 Selected Catalytic Reactions

selected from an extensive screen of both monodentate and chelating ligands. Buchwald and coworkers have described the benefits of these biarylphosphine ligands,196 which are also useful in heterocyclic cross-couplings.197,198

F3C

NH2 Me

(i) Pd(OAc)2 ligand PhB(OH)2 Cs 2CO3

+

CN

Cl

O F3C

NH2

(ii) aq H2SO4

N H

75–79% overall

Et

Ligand = Me2N PCy2

Pd-catalyzed amination of a 3-chlorobenzimidazole was utilized in a synthesis of Norastemizole, a potent, nonsedating histamine H1 -receptor antagonist, as reported by Senanayake at Sepracor.199 N N

Cl

+

NH • 2HCl

H2N

Pd 2(dba)3 BINAP NaOt-Bu toluene 85 °C

NH N N

NH

84%

F

F 18:1 regioselectivity

Interestingly, while the Pd-catalyzed conditions preferentially provided the product of primary amine coupling, base-catalyzed displacement (K2 CO3 , glycol, 140 ∘ C) furnished the tertiary amine by preferential attack of the more nucleophilic secondary amine. Hartwig and coworkers have reported remarkable catalytic efficiency with Josiphos ligands with primary amine couplings.200 With primary amines, chelating ligands are particularly important to avoid binding of multiple amines to palladium to give a stable, catalytically inactive species.201 Singer et al. have developed a nonproprietary bis-pyrazole phosphine ligand, bippyphos,202 which is commercially available. Utilization of this ligand in a coupling with 3-chloropyridine is shown in the following.203 Ureas204 and hydroxylamines205 have also been effectively N-arylated using bippyphos as ligand. Cl

NH2

+ N Bippyphos =

tert-amyl alcohol Ph

N N

N N

196 197 198 199 200 201 202 203 204 205

KOH (1.5 equiv) Pd2(dba)3 (0.5 mol%) Bippyphos (2 mol%)

Ph

H N N

94%

Ph P(t-Bu)2

See Note 185. Charles, M., D.; Schultz, P.; Buchwald Stephen, L. Organic Letters 2005, 7, 3965–3968. Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angewandte Chemie International Edition 2006, 45, 6523–6527. Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.; Bakale, R. P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Letters 1997, 38, 5607–5610. Shen, Q.; Ogata, T.; Hartwig, J. F. Journal of the American Chemical Society 2008, 130, 6586–6596. Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15, 3534–3542. Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner, M. A. Tetrahedron Letters 2006, 47, 3727–3731. Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Organic Process Research & Development 2008, 12, 480–489. Kotecki, B. J.; Fernando, D. P.; Haight, A. R.; Lukin, K. A. Organic Letters 2009, 11, 947–950. Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Organic Letters 2009, 11, 233–236.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

Bromoarenes have been widely utilized in Pd-catalyzed aminations and frequently lead to more robust couplings than the corresponding (and less expensive) chloroarenes. The following two examples from Organic Syntheses employ a chelating diphosphine ligand (rac-BINAP)206 as well as a monodentate biphenyl ligand (Cy2 P-2-biphenyl).207

Me Br

+

H2N

Me

MeO

Me

Br +

[Pd2(dba)3] NaO-t-Bu ligand

Me Me Me

Me

Toluene 80 °C 94% H N

Me

Toluene 80 °C 86%

NH2

Me

Pd2(dba)3 BINAP NaO-t-Bu

H N

n-C6H13

MeO

Me Me Me

Ligand =

PCy 2

Me

Several copper catalysts have been developed for formation of C(aryl)—N bonds, and this area has been reviewed.208 As previously discussed, copper-mediated aminations tend to be less general than the Pd-catalyzed aminations but offers significant advantages in terms of cost, toxicity, and environmental impact. Selected examples employing copper as catalyst are shown in the following examples. Amino acids can be effectively N-arylated, as shown below in the examples from Yang and coworkers,209 as well as from Ma et al. in their synthesis of martinellic acid.210 It is worth pointing out that in the Ma example, the amino acid coupling partner is proposed to also act as a ligand for Cu. This is particularly advantageous as no additional ligand is required to promote the reaction thus simplifying the reaction setup and likely product isolation.

NH O N

Br

O

O

10 mol% CuI

Me

60 mol% L-proline K 2CO3, DMSO

N

N

Me

O

85 °C 68% CO2H H2 N

I I

206 207 208 209 210

OH 10 mol% CuI

K 2CO3, aq DMF 100 °C >72%

I

CO2H N H

OH

Wolfe, J. P.; Buchwald, S. L. Organic Syntheses 2002, 78, 23–35. Zhang, W.; Lu, Y.; Moore, J. S. Organic Syntheses 2007, 84, 163–176. See Note 179. See Note 172. Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. The Journal of Organic Chemistry 2003, 68, 442–451.

309

310

6 Selected Catalytic Reactions

Buchwald reported the efficient coupling of aryl- and heteroarylbromides with primary amines catalyzed by copper iodide and diethylsalicylamide as a ligand.211 5 mol% CuI 20 mol% ligand

Me + Br

+ N

K 3PO4, DMF 90 °C 95%

H2N

O

N H Ligand =

5 mol% CuI 20 mol% ligand

H2N

Br

Me

N

K 3PO4, DMF 90 °C 91%

N H

OH

O

Et 2N

O

Recent improvements to this method that use β-diketones212 and β-keto-esters213 as ligands have been reported. Copper-catalyzed N-arylations have also been reported with β-amino acids214 and 1,1′ -Bi-2-naphthol (BINOL)215 as ligands. Buchwald has demonstrated both N- and O-arylation of 1,2-aminoalcohols.216 In the first example, N-selective arylation is realized with strong base (NaOH) in aqueous dimethyl sulfoxide (DMSO); the presence of water was found to enhance the N- vs. O-selectivity. In the second example, use of a milder base (Cs2 CO3 ) and a secondary amine provided O-selective arylation. Me + Me

H2N

Cl

Me Me

OH NHMe Me

Me

CuI NaOH

OH

OH

aq DMSO 90 °C 88%

Me

CuI Cs 2CO3 PhI

N H

Me Me

OPh NHMe

Butyronitrile 125 °C 74%

Me

Subsequently the Buchwald group described that choice of ligand could provide nearly complete control of N- vs. O-regioselectivity with iodoarenes.217

I

Br

H2N + HO

H2N Br

I

+ HO

211 212 213 214 215 216 217

Br CuI, L 1 Cs 2CO3

Toluene, 90 °C 86%

O

O i-Pr

NH

DMF, 25 °C 97%

CuI, L2 Cs 2CO3 3A MS

L1

HO H2N

Me

L2

Me N N

Br O

Me Me

Kwong, F. Y.; Buchwald, S. L. Organic Letters 2003, 5, 793–796. Shafir, A.; Buchwald, S. L. Journal of the American Chemical Society 2006, 128, 8742–8743. Lv, X.; Bao, W. The Journal of Organic Chemistry 2007, 72, 3863–3867. Ma, D.; Cai, Q.; Zhang, H. Organic Letters 2003, 5, 2453–2455. Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. The Journal of Organic Chemistry 2007, 72, 672–674. Job, G. E.; Buchwald, S. L. Organic Letters 2002, 4, 3703–3706. Shafir, A.; Lichtor, P. A.; Buchwald, S. L. Journal of the American Chemical Society 2007, 129, 3490–3491.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

6.11.2

Aryl Amine as Nucleophile

Given the lower nucleophilicity of aryl amine vs. alkyl amines, the metal catalyzed C—N bond formation is quite attractive in cases where the SN Ar is not possible or is low yielding. Primary aryl amines are generally great coupling partner in the metal-catalyzed C—N bond formation given that competing β-hydride elimination is not possible. Care must be taken, however, as over-arylation of the product can occur. Significant improvements in ligand design have provided reaction conditions selective for the monoarylation product.218,219 N-alkyl anilines have the opposite advantages and inconveniences: β-hydride elimination is possible for these nucleophiles but given that the product of the reaction will be a tertiary amine, over arylation is not possible in this case. Heterocyclic anilines have been successfully employed as nucleophile. The best conditions for such substrate vary widely depending on the position of the heteroatom(s) with respect to the amine functionalities. Gallagher et al. at Bristol-Myers Squibbs employed a Cu-catalyzed C—N bond formation in the synthesis of HIV inhibitor BMS-663068.220 As discussed in the previous section, the driving force for the development of this reaction was the higher regioselectivity with respect to the thermal SN Ar. High-throughput experimentation identified key reaction parameters for this reaction. It was also shown that the presence of water in the reaction improves catalyst lifetime and the regioselectivity in favor of the desired isomer. A very detailed analysis of the factor influencing the conversion, regioselectivity, and overall impurity profile of the reaction was discussed. HN N

OMe O

O

N

N

N H

N

30 mol% CuI

N

Br

OMe O

Me

N Ph

O

80 mol% DMCHDA 1.9 equiv KOH EtOH, H 2O, 80 °C 67%

DMCHDA =

OMe O

O N

N N

N

N K

N O

Me

N

Li I

Ph

MeCN H2O

N

N N

O

N

Me

N Li

N O

Ph

NHMe NHMe

Caille and coworkers at Amgen reported the synthesis of AMG 925, which features a Pd-catalyzed C—N coupling.221 Consistent with the low nucleophilicity of 2-aminopyrimidines, formation of the C—N bond without the intermediacy of transition metal catalysis proved to be low-yielding. While both tert-amyl alcohol and isopropanol afforded similar yield, reactions carried out in isopropanol performed well at a much lower temperature (60 ∘ C vs. 100 ∘ C). This may be attributed to the easier reduction of the Pd(II) precatalyst to Pd(0) through β-hydride elimination from isopropanol, which is not possible with tert-amyl alcohol. NBoc N H 2N

N N

N

Me

Cl

N HN

N

1 mol% Pd(OAc)2 1.2 mol% BrettPhos 1.2 equiv NaOtBu i-PrOH, 60 °C 91%

N

N Boc

N

N

N

Me

Copper-catalyzed C—N bond formation can sometimes be carried out in the absence of added ligand. This usually proceeds when the amine coupling partner may act as a ligand for the metal. Graham et al. took advantage of the 218 See Note 189. 219 See Note 180. 220 Gallagher, W. P.; Soumeillant, M.; Chen, K.; Fox, R. J.; Hsiao, Y.; Mack, B.; Iyer, V.; Fan, J.; Zhu, J.; Beutner, G.; Silverman, S. M.; Fanfair, D. D.; Glace, A. W.; Freitag, A.; Sweeney, J.; Ji, Y.; Blackmond, D. G.; Eastgate, M. D.; Conlon, D. A. Organic Process Research & Development 2017, 21, 1156–1165. 221 Affouard, C.; Crockett, R. D.; Diker, K.; Farrell, R. P.; Gorins, G.; Huckins, J. R.; Caille, S. Organic Process Research & Development 2015, 19, 476–485.

311

312

6 Selected Catalytic Reactions

fact that 4-methyl imidazole may act as both the ligand and coupling partner in the synthesis of a glycine transporter inhibitor.222 Br

NH

Me

Me

N

15 mol% CuI

O HN

N

N

O

2.1 equiv K 2CO3

N

DMSO, 130 °C

HN

N

54%

When tautomerization is possible within the substrate, regioselectiviy may be a problem. Nevertheless it may be possible to obtain a highly regioselective reaction through appropriate choice of reaction conditions and coupling partner. Chung et al. at Merck reported a very interesting example during the synthesis of Niraparib.223 A series of indazoles in which the substituent at the 7-position was varied showed that the selectivity for N-2 vs. N-1 varied from 1 : 1 to >50 : 1. Furthermore, it was shown that the selectivity is not purely due to sterics and that both steric and electronic effect play a role in determining the regioselectivity of the coupling.

N H

Boc N

Br

O

N

NHt-Bu

5 mol% CuBr 10 mol% 8-hydroxyquinoline 3 equiv K2CO3 DMAc, 110 °C

N O

Boc N

N

NHt-Bu

94%

6.11.3

Amides as Nucleophile

The lower nucleophilicity of amides compared to amines makes amides a more difficult coupling partner. A ligand capable of inhibiting or tampering with a K2 interaction of the amide nucleophile with the metal catalyst helps in promoting high yield of the coupling product. This is in part why several example of Pd-catalyzed C—N bond formation involving amides make use of very bulky ligands. Copper catalysts can also effectively mediate C—N bond formation between amides and an electrophile and are quite popular in process chemistry. Typical reaction conditions for both Pd- and Cu-catalyzed coupling of amides use phosphate or carbonate bases in a solvent at >80 ∘ C. Both primary and secondary amides can be employed. Although many different phosphines can serve as effective ligand for the Pd-catalyzed N-arylation of amides, the biphenyl family of ligand from the Buchwald lab are quite effective at promoting this reaction. A variety of electrophile including aryl chlorides can be used, as shown in the following example.224

Cl + OMe

O NH2

Me

Pd 2(dba)3 ligand K 3PO4

Me

t-BuOH 99%

Me

Ligand =

H N O

Me i-Pr

P(t-Bu)2 i-Pr

OMe i-Pr

222 Graham, J. P.; Langlade, N.; Northall, J. M.; Roberts, A. J.; Whitehead, A. J. Organic Process Research & Development 2011, 15, 44–48. 223 Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.; Emerson, K. M. Organic Process Research & Development 2014, 18, 215–227. 224 Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Journal of the American Chemical Society 2007, 129, 13001–13007.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

Amides such as oxazolidinones can also serve as coupling partners with bromoarenes, as shown in the following example. The coupling was utilized in a synthesis of DuP-721 developed by workers at Abbott.225 Analogous couplings of oxazolidinones with aryl chlorides have also been reported.226 Pd2(dba)3 BINAP Cs2CO3

O

Br HN

+

O

F

O

O

OHC N

Toluene 100 °C 77%

N

CHO

F

O

O

O N O

Buchwald and coworkers first reported that diamines serve as effective ligands in Cu-catalyzed N-arylation of amides as shown in the following example.227,228

Br + N

CuI diamine K 3PO4

O HN

O N

Dioxane 110 °C 98%

Me Ligand =

N

N H

H N

Me

Kallemeyn et al. at AbbVie employed a Cu-catalyzed coupling with an amide nucleophile in the synthesis of a histamine-3 antagonist.229 Consistent with the low nucleophilicity of the amide, competing coupling between the aryl bromide and the ligand 8-hydroxyquinoline was observed. Fortunately, using dimethylethylenediamine (DMEDA) as the ligand gave a clean reaction profile. O Br

S

OMe

N

OMe

NH N

N N

15 mol% CuCl 30 mol% DMEDA 2 equiv K2CO3 pyridine, 100 °C 84%

O

S

OMe

N

OMe

As discussed in the previous section, “ligand-free” coupling can sometimes be carried out with Cu as the metal. Typically such reactions use of the nucleophilic coupling partner and/or a polar aprotic solvent as a potential ligand for Cu. In the following example, the coupling reaction was performed in toluene, suggesting that the amide itself acts as the ligand for Cu in this reaction.230 O O Br

OEt NHBz

30 mol% CuCl 1.5 equiv Cs2CO3 Toluene, reflux 76%

O

O N Bz

OEt

225 Madar, D. J.; Kopecka, H.; Pireh, D.; Pease, J.; Pliushchev, M.; Sciotti, R. J.; Wiedeman, P. E.; Djuric, S. W. Tetrahedron Letters 2001, 42, 3681–3684. 226 Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Organic Letters 2003, 5, 2207–2210. 227 Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. Journal of the American Chemical Society 2001, 123, 7727–7729. 228 Klapars, A.; Huang, X.; Buchwald, S. L. Journal of the American Chemical Society 2002, 124, 7421–7428. 229 Kallemeyn, J. M.; Ku, Y.-Y.; Mulhern, M. M.; Bishop, R.; Pal, A.; Jacob, L. Organic Process Research & Development 2014, 18, 191–197. 230 Zhao, H.; Koenig, S. G.; Dankwardt, J. W.; Singh, S. P. Organic Process Research & Development 2014, 18, 198–204.

313

314

6 Selected Catalytic Reactions

A copper-catalyzed N-arylation of an oxazolidinone was utilized in a synthesis of the κ-agonist CJ-15,161.231,232 Br

O +

HN n-Pr

HN

O

CuI (10 mol%) 1,2-diaminocyclohexane (10 mol%) K 2CO3 (2 equiv)

O

O

n-Pr N H

N

O

Dioxane 100 °C 97%

O

3-Bromofuran was utilized in the following example from Padwa et al. for his synthesis of 3-amidofurans, a useful class of dienes for Diels–Alder methodologies developed in his lab.233

Br

PhCONH 2 CuI (10 mol%) (MeNHCH2)2 (10 mol%) K 2CO3

O

O HN

1,4-dioxane 110 °C 98%

6.11.4

Ph

O

Other Amine as Nucleophile

A variety of other amine-type nucleophiles have been used to form C—N bonds. This section will feature selected examples of sulfonamide, urea, carbamate, amidine, and hydrazone nucleophiles. Coupling with sulfonamide may be advantageous over the traditional reaction between an amine and sulfonyl chloride given the genotoxicity of the latter. Multiple examples of sulfonamide couplings have appeared in the literature.234,235,236,237 Typical reaction conditions employ bulky monodentate or bidentate ligand238 along with an inorganic base (e.g. K3 PO4 or Cs2 CO3 ) in an organic solvent such as toluene, tert-amyl alcohol, or (less preferably) dioxane at 80–100 ∘ C. Various electrophilic partners are also compatible.

H2N O

Cl N

Br

O

S

Me N

O

O

O

6.6 mol% Pd 2(dba) 3 15 mol% Xantphos

O

Cl

H N O

S

Me N

O O

O

N

1.6 equiv Cs2 CO3 THF, 60°C 69%

Copper can also mediate the coupling of sulfonamides, as shown in the following example.239 Although a relatively high loading of CuI and ligand was employed, the authors noted limited success in the use of Pd catalyst to mediate 231 Ghosh, A.; Sieser, J. E.; Caron, S.; Couturier, M.; Dupont-Gaudet, K.; Girardin, M. The Journal of Organic Chemistry 2006, 71, 1258–1261. 232 Ghosh, A.; Sieser, J. E.; Caron, S.; Watson, T. J. N. Chemical Communications 2002, 1644–1645. 233 Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. The Journal of Organic Chemistry 2003, 68, 2609–2617. 234 Shekhar, S.; Dunn Travis, B.; Kotecki Brian, J.; Montavon Donna, K.; Cullen Steven, C. The Journal of Organic Chemistry 2011, 76, 4552–4563. 235 Sun, X.; Tu, X.; Dai, C.; Zhang, X.; Zhang, B.; Zeng, Q. The Journal of Organic Chemistry 2012, 77, 4454–4459. 236 Alcaraz, L.; Bennion, C.; Morris, J.; Meghani, P.; Thom, S. M. Organic Letters 2004, 6, 2705–2708. 237 Muniz, K.; Nieger, M. Synlett 2005, 149–151. 238 Stewart, G. W.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.; Davies, A. J.; Edwards, J. S.; Gibson, A. W.; Hamilton, S. E.; Katz, J. D.; Keen, S. P.; Mullens, P. R.; Scott, J. P.; Wallace, D. J.; Wise, C. S. Organic Process Research & Development 2010, 14, 849–858. 239 Lin, J.; Houpis, I. N.; Liu, R.; Wang, Y.; Zhang, J. Organic Process Research & Development 2014, 18, 205–214.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

this transformation. It is also interesting to note that the coupling occurred preferentially at the sulfonamide position over an amide and a carbamate.

Me OH O N

NHBoc

O

H N O

S

N H

O

OH O N

1 equiv CuI

OEt N

N

1 equiv bipyridine 4 equiv K 2CO3 DMF, 70–80 °C

Br

OEt

F Me

N O

S

NHBoc

O HN

O

F

68%

Selectivity can be an issue when the urea contains two different primary or secondary amines, although selectivity for the less bulky amine is usually observed, as in the following example.240 tBu

O Cl

H2N N N Me

tBu

O

N H

CF3

HN

1 mol% Pd 2(dba)3 4 mol% Bippyphos 1.5 equiv K 2CO3

N H N

CF3

N

Me

DME, 80°C 84%

Example where both sides of the urea undergo coupling have also been reported.241,242 Coupling with carbamate have also been reported. The most common carbamate used in N-arylation reaction is tert-butyl carbamate (NH2 Boc), which can serve as an effective ammonia surrogate. As with amides common ligands for the Pd-catalyzed coupling with carbamate include Xantphos or Buchwald biaryl ligands,243 as illustrated in the following.244 Other bulky ligands such as P(t-Bu)3 have also been employed.245 It is worth noting that coupling with NH2 Boc has been successfully carried out at room temperature in certain cases.246 Br O

Cl OMe Me Me

O H2N

Ot-Bu

2.5 mol% Pd 2(dba)3 13 mol% tBuXPhos 1.2 equiv NaOtBu toluene, 80 °C

BocHN O

Cl OMe Me Me

77%

Although challenging for reasons listed in the below, amidine have nevertheless been successfully employed as nucleophile in N-arylation reactions, as shown in the following example from Li et al.247 Amidines are difficult coupling partner given that they usually form strong coordination complexes, which can lead to catalyst deactivation.248 To limit the extent of complexation with the metal catalyst, amidines are typically added to the reaction mixture as salts, which 240 241 242 243 244 245 246 247 248

Yu, S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill, D. R. The Journal of Organic Chemistry 2009, 74, 9539–9542. Ernst, J. B.; Tay, N. E. S.; Jui, N. T.; Buchwald, S. L. Organic Letters 2014, 16, 3844–3846. Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L. Organic Letters 2006, 8, 5089–5091. Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger, K. R. The Journal of Organic Chemistry 2009, 74, 4634–4637. Wang, P.; Briggs, A. J. Organic Process Research & Development 2014, 18, 656–661. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. The Journal of Organic Chemistry 1999, 64, 5575–5580. See Note 243. Li, B.; Samp, L.; Sagal, J.; Hayward, C. M.; Yang, C.; Zhang, Z. The Journal of Organic Chemistry 2013, 78, 1273–1277. Rauws, T. R. M.; Maes, B. U. W. Chemical Society Reviews 2012, 41, 2463–2497.

315

316

6 Selected Catalytic Reactions

lowers their solubility in non-polar organic solvents. Lastly, the stability of certain amidines under the reaction conditions can be questionable. Me Ph

HN HCl HN CF3 O N

CF3 O N

MeO OH

I

2 mol% Pd 2(dba)3

N

3 mol% Xantphos

N H OMe

3.4 equiv Cs 2CO3 tert amyl alcohol

Me

CF3 O

OH

HBTU

Me

N

N

Ph

N

Ph

MeO

104°C 77%

Coupling with hydrazones can be a convenient way to prepare indazoles. Two representative examples are shown below. Goodyear, Linghu and coworkers at Merck used benzophenone hydrazone as a safer and more easily handled reagent relative to hydrazine hydrate.249 Commonly used ligands for C—N bond formation also lead to functionalization of the C—Cl bond. Fortunately, the dppf ligand was more selective and was used for this reaction. CN CN

Cl

N O

OMe

Cl

OMe Br

Ph

NH2 Ph

Cl

O

OMe

Cl

OMe

PdCl 2(dppf)

NH N

K 3PO3 toluene, reflux 79%

Ph

Ph

In the second from Kallman at Eli Lilly,250 N-methyl hydrazone was employed, and the cyclization was performed using Cu as the metal catalyst. Interestingly, the cyclization was reported to have failed under multiple different Pd-mediated conditions. F

NO2

O

F 10 mol% CuCl

Br

1.5 equiv K 2CO3

NO2

O Br

DMF, 100 °C Br

6.11.5

N

NHMe

60%

MeN N

Coupling with Ammonia Surrogate

Primary anilines are extremely common functional group found in a plethora of natural product or API, and thus their synthesis is of high importance. Although direct coupling with ammonia has been reported,251 handling of ammonia as a gas or as a solution in another solvent can be problematic. Moreover, direct coupling with ammonia can lead to polyarylated compounds, which can be difficult to control. Given these difficulties, other reagents have been developed to provide a safer and cleaner reaction and still provide (hetero)anilines after a simple deprotection. 249 Goodyear, A.; Linghu, X.; Bishop, B.; Chen, C.; Cleator, E.; McLaughlin, M.; Sheen, F. J.; Stewart, G. W.; Xu, Y.; Yin, J. Organic Process Research & Development 2012, 16, 605–611. 250 Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Organic Process Research & Development 2014, 18, 501–510. 251 Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angewandte Chemie International Edition 2010, 49, 4071–4074.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

In addition to BocNH2 discussed previously in Section 6.11.4, other commonly encountered ammonia surrogates include benzophenone imine as well as lithium hexamethyl disalizide (LiHMDS). A variety of different electrophiles including aryl bromide, chloride, and triflates have been employed as coupling partner with benzophenone imine. Leahy et al. reported the reaction between a 2-Cl-pyridine with benzophenone imine en route to a calcitonin gene-related peptide (CGRP) receptor antagonist.252 Coupling with LiHMDS or ammonia proved inefficient, and only poor conversion of the starting 2-chloro-pyridine was observed along with various impurities. Following reaction completion and a quick work-up, the oily residue was treated with aqueous citric acid to liberate the desired amine. Boc N

Ph

Ph NH N

Cl

Boc N

Boc N

NH

Citric acid

2 mol% Pd(OAc)2 3 mol% rac-BINAP 2 equiv Cs3CO3 toluene, 95–100 °C 80% overall

NH

NH N

Ph

N

NH2

N

Ph

In a second example from Banyu and Merck, a coupling with benzophenone imine was used in the synthesis of a muscarinic receptor antagonist following Buchwald and Hartwig’s protocol.253,254,255 Tri-n-butylphosphine was used to irreversibly coordinate the residual palladium and allow removal from the product, which was pulled into aqueous acid. Workers at Pfizer have described a screening method for identifying effective palladium purges by recrystallization or reslurry in the presence of various diamine ligands.256

N Boc

N

Br

Ph 2C=NH Pd(OAc) 2 dppf

N Boc

NaOt-Bu toluene, 80 °C

N H

N H

N

N

Ph Ph

n-PBu3 citric acid 86% overall

N Boc

N

NH2

N H

The use of LiHMDS as an ammonia surrogate was reported by Briggs and coworkers in the synthesis of a Bruton’s tyrosine kinase (BTK) inhibitor.257 A simple catalyst system comprising of Pd2 (dba)3 and a Buchwald biphenyl ligand was employed in this reaction. No base is typically needed when using LiHMDS as an ammonia surrogate. The authors noted the importance of a slow addition of LiHMDS to avoid problem with the reaction stalling on scale larger than 0.1 g. Interestingly, the authors mention that the use of BocNH2 was not successful but did not discuss the use of benzophenone imine. Cl

LiHMDS in THF

N

N

1 mol% Pd2(dba)3 3 mol% CyJohnPhos

O Me

NH2

Me

N

toluene, 63 °C 86%

O Me

Me

N

Other examples of the use of LiHMDS as an ammonia surrogate have been reported.258,259 252 Leahy, D. K.; Desai, L. V.; Deshpande, R. P.; Mariadass, A. V.; Rangaswamy, S.; Rajagopal, S. K.; Madhavan, L.; Illendula, S. Organic Process Research & Development 2012, 16, 244–249. 253 Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. The Journal of Organic Chemistry 2001, 66, 6775–6786. 254 Mann, G.; Hartwig, J. F.; Driver, F. M. S.; Fernandez-Rivas, C. Journal of the American Chemical Society 1998, 120, 827–828. 255 Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Letters 1997, 38, 6367–6370. 256 Flahive, E. J.; Ewanicki, B. L.; Sach, N. W.; O’Neill-Slawecki, S. A.; Stankovic, N. S.; Yu, S.; Guinness, S. M.; Dunn, J. Organic Process Research & Development 2008, 12, 637–645. 257 Alabanza, L. M.; Dong, Y.; Wang, P.; Wright, J. A.; Zhang, Y.; Briggs, A. J. Organic Process Research & Development 2013, 17, 876–880. 258 Huang, X.; Buchwald, S. L. Organic Letters 2001, 3, 3417–3419. 259 Lee, S.; Jorgensen, M.; Hartwig, J. F. Organic Letters 2001, 3, 2729–2732.

317

318

6 Selected Catalytic Reactions

A fluorous-tagged BOC-protected amine (C8 F17 CH2 CH2 C(Me2 )OCONH2 ) has also been used as an ammonia surrogate. The fluorous reagent allows for solid–liquid or liquid–liquid fluorous extraction techniques to be utilized prior to cleavage of the protecting group.260 6.11.6

Oxidative Coupling

Copper-mediated couplings of amines and arylboronic acids represent an alternative to haloarene couplings, although the need for a stoichiometric oxidant or stoichiometric amount of “catalyst” can be a major drawback. More recently, there has been renewed interest in this reaction owing to the high-cost of palladium and associated ligands. Intense scrutiny of the oxidation state of copper in the catalytic cycle and the coordination sphere of the metal has generated numerous studies. A notorious deep investigation into a Chan-Lam coupling was conducted by Watson at the University of Strathclyde in collaboration with GlaxoSmithKline (GSK) and used experimental, electron paramagnetic resonance (EPR), UV-Vis, X-ray diffraction, and computational analysis to provide a general Chan-Lam amination reaction.261 These researchers proposed the complex mechanistic picture shown in the following. Me

2

Me

O O O O AcO Cu Cu OAc ·2 R R N O O O O H2 Me

Me Me

O

Me Me

O

Cu

O O

Me Me

AcOH R2NH

2

[Cu(OAc) 2] 2·2H2O AcO

O2 + AcOH·Et 3N R2NH Ar-H Ar-OH

ArB(OR)2

Me

Me Pinacol

Me Me

Me

MeCN HO

O

AcOH·NEt 3

Cu II

R2HN Cu O

O

O Cu NHR 2 O

Me

OAc

ArB(OR)2

NHR2

L n Cu IOAc

R2HN O O NHR2 O Cu Cu OAc O O H H O O Cu R2HN AcO O Me O O NHR 2 Me

Me

MeCN OAc H Cu II O NHR2

Ar-NR 2

RO B Ar RO

Ar2O MeCN Ar

Cu III

OAc NHR2 MeCN

L n Cu IX

Ar L n Cu IIX2

Cu

II

OAc

HOB(OR) 2

NHR2

Buchwald and coworker have reported copper-catalyzed couplings in the presence of myristic acid (n-C14 H29 COOH); couplings with anilines are generally higher yielding (70–90%), but the system does tolerate alkylamines, as shown in 260 Trabanco, A. A.; Vega, J. A.; Fernandez, M. A. The Journal of Organic Chemistry 2007, 72, 8146–8148. 261 Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. Journal of the American Chemical Society 2017, 139, 4769–4779.

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation

the following example.262 Chan has reported similar couplings with a wide variety of amine nucleophiles, including amides, imides, carbamates, and sulfonamides, using triethylamine or pyridine as an additive.263 Cu(OAc) 2 (10 mol%) C14H29COOH (20 mol%)

Me + B(OH)2

H 2N

Me N H

Air, 2,6-lutidine 55%

N-arylation of imidazoles with arylboronic acids has been developed by Collman. These couplings are catalytic in copper and utilize tetramethylethylenediamine (TMEDA) as ligand.264 The couplings also work in water, as shown in the second example below.265

Me

N

+ HN

Ph

B(OH)2

Me +

[Cu(OH)·TMEDA] 2Cl 2 (10 mol%) O2

HN

N

Me N

N

CH2Cl 2 77%

Ph

[Cu(OH)·TMEDA] 2Cl 2 (10 mol%) O2

Me N

H2O 63%

B(OH)2

N

A kilogram scale coupling between an aryl boronic acid and a dihydropyridazinone was reported by Yoshida et al. and is shown in the following.266 It is unclear whether the related coupling with an aryl halide or pseudohalide instead of boronic acid would also be successful. (HO)2B O

H N

N

O

Me 15 mol% Cu(OAc)2 O

O F

4 equiv pyridine DM, air. 25 °C

Me N

N

Me HCl

O

O

88%

F

O

N

N

O

F

Alternative reactivity patterns can arise when applying non-precious metals toward cross-coupling reactions.267 For example, in the presence of a copper catalyst in air, aryl silanes smoothly undergo cross-coupling with primary amines to afford alkyl anilines. A majority of the aryl silanes are dichlorinated and do not demonstrate chloride insertion under these reaction conditions. Although the reaction requires stoichiometric copper, the transformation provides a starting point for future improvements.

HNRRʹ + R (2.0 equiv)

Me OTMS Si OTMS

Cu(OAc)2 (3.0 equiv) Na2CO3 (2.0 equiv) NaF (2.0 equiv) Air, DMSO, 80 °C

NRRʹ R

262 Antilla, J. C.; Buchwald, S. L. Organic Letters 2001, 3, 2077–2079. 263 Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Letters 1998, 39, 2933–2936. 264 Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. The Journal of Organic Chemistry 2001, 66, 7892–7897. 265 Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. The Journal of Organic Chemistry 2001, 66, 1528–1531. 266 Yoshida, S.; Hayashi, Y.; Obitsu, K.; Nakamura, A.; Kikuchi, T.; Sawada, T.; Kimura, T.; Takahashi, T.; Mukuta, T. Organic Process Research & Development 2012, 16, 1818–1826. 267 Morstein, J.; Kalkman, E. D.; Cheng, C.; Hartwig, J. F. Organic Letters 2016, 18, 5244–5247.

319

320

6 Selected Catalytic Reactions

6.12 Pd- and Cu-Catalyzed Aryl C—O Bond Formation In general, metal-catalyzed C(aryl)—O bond formation is less well-developed than the analogous C—N bond forming reactions, particularly with primary or secondary alcohols, which are prone to β-hydride elimination of the PdAr(OR)Ln intermediate. Buchwald has developed a useful class of ligands for effecting these transformations, even with electron-neutral aryl chlorides, a particularly challenging class of substrates.268 The bulky phosphine ligand serves to suppress β-hydride elimination while promoting reductive elimination.

Me Me

Cl

n-BuOH Pd(OAc)2 (2 mol%) Ligand (2.5 mol%) Cs 2CO3 Toluene, 70 °C 89%

Ligand =

Me Me

O

NMe2 P(t-Bu)2

Me

Secondary alcohols are particularly demanding in these types of couplings (being more easily oxidized), as are aryl halides lacking ortho substitution. For these challenging substrates, a more hindered ligand was developed, as shown in the following.269

Cl Me

s-BuOH Pd(OAc) 2 (2 mol%) Ligand (2.4 mol%) Cs 2CO3

Ligand = O

t-Bu

Me Me

Me

P(t-Bu)2

Me

Bu 3N, 100 °C 70%

Me

Me Me

Couplings of tertiary alcohols have also been demonstrated on large scale. In the following example, racemic BINAP was used as the ligand outperforming various bulky monodentate phosphine ligands.270 O N Br Ph

NaOtBu 1 mol% Pd(OAc)2

Me Me CN

O

1.5 mol% rac-BINAP toluene, 95–100 °C

N t-BuO

Me Me CN

Ph

Phenols can be directly prepared from aryl halides with potassium hydroxide and a catalyst derived from Pd2 (dba)3 and a hindered biphenyl phosphine ligand.271 This transformation can also be done indirectly, by arylation of alcohols such as t-BuOH or PhCH2 OH and subsequent dealkylation.

Cl N

Ligand = Me

KOH Pd2dba3 (0.5 –2 mol%) Ligand (2–6 mol%) aq dioxane 100 °C 97%

OH N

Me Me P(t-Bu)2 i-Pr

Me i-Pr

i-Pr

Copper-catalyzed variants of C(aryl)—O bond-forming reactions can also be useful, although they are generally narrower in scope. The classic Ullman diaryl ether formation is catalyzed by copper and involves rather harsh conditions 268 269 270 271

Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. Journal of the American Chemical Society 2001, 123, 10770–10771. Vorogushin, A. V.; Huang, X.; Buchwald, S. L. Journal of the American Chemical Society 2005, 127, 8146–8149. Sera, M.; Yamashita, M.; Ono, Y.; Tabata, T.; Muto, E.; Ouchi, T.; Tawada, H. Organic Process Research & Development 2014, 18, 446–453. Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. Journal of the American Chemical Society 2006, 128, 10694–10695.

6.12 Pd- and Cu-Catalyzed Aryl C—O Bond Formation

in its traditional variants (high temperatures, pyridine solvent). Song and coworkers at Merck have developed a particularly useful variant that uses CuCl and an inexpensive 1,3-diketone ligand.272 Cs 2CO3, CuCl O

HO

Br

O

+

OMe

OMe

O

t-Bu

t-Bu

O Me

NMP 120 °C 78%

OMe

Beller and coworkers have reported N-methylimidazole as an effective ligand for Cu-catalyzed O-arylation of phenols.273 i-Pr H2N

Br

i-Pr

HO

CuCl, K2CO3 N-Me-imidazole

Me

Toluene, 140 °C

+

i-Pr H2N

95%

O

Me

i-Pr

Primary and secondary alcohols can be coupled with iodoarenes with a catalyst derived from CuI and 1,10phenanthroline.274 i-PrOH (neat) CuI (10 mol%) 1,10-phenanthroline (20 mol%)

I N

O

Me

N

Cs 2CO3, 110 °C 92%

Me

In aniline-containing substrates, protection of the aniline as the 2,5-dimethylpyrrole gives more successful coupling.275 Deprotection to the aniline is achieved by treatment with hydroxylamine hydrochloride and triethylamine in aqueous ethanol. Me

I

F N

NaOMe CuCl (15 mol%)

Me

OMe

N

MeOH-DMF 80 °C

Me

F

Me

75%

Heterocyclic electrophiles can be successfully coupled with benzyl alcohol, as shown in the following example.276 BnOH CuI (10 mol%) Br 1,10-phenanthroline (20 mol%) Me

Cs2CO3, toluene, 110 °C

N

OBn Me

74%

N

Stoichiometric copper-promoted coupling of boronic acids and phenols has been developed by Evans et al. as an effective route to the vancomycin class of antibiotics.277

H

Boc N CO2Me

272 273 274 275 276 277

OH + HO

Cu(OAc) 2 (1.0 equiv) Et 3N, 3A MS

OH B OMe

CH2Cl 2 76%

H

Boc N

N CO2Me

O OMe

Buck, E.; Song, Z. J.; Denmark, S. E.; Baird, J. D. Organic Syntheses 2005, 82, 69–74. Schareina, T.; Zapf, A.; Cotte, A.; Mueller, N.; Beller, M. Organic Process Research & Development 2008, 12, 537–539. Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Organic Letters 2002, 4, 973–976. Ragan, J. A.; Jones, B. P.; Castaldi, M. J.; Hill, P. D.; Makowski, T. W. Organic Syntheses 2002, 78, 63–72. Nara, S. J.; Jha, M.; Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. The Journal of Organic Chemistry 2008, 73, 9326–9333. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Letters 1998, 39, 2937–2940.

321

322

6 Selected Catalytic Reactions

Aryl trifluoroborates can also be effectively coupled with alcohols.278 This is a particularly convenient method if the trifluoroborate is readily available, as these compounds are frequently well-behaved, crystalline solids.

H N

BnO

C6H5BF3K (2 equiv) Cu(OAc) 2·H2O (10 mol%) DMAP (20 mol%) 3A MS, O 2

OH

O

H N

BnO

O

O

CH2Cl 2, 25 °C 85%

6.13 Pd- and Cu-Catalyzed Aryl C—S Bond Formation The Pd-catalyzed cross-coupling of thiols and aryl halides has been known since 1980,279 and later work has shown that several classes of ligands deliver catalysts with good activity and substrate scope. Copper-catalyzed couplings are also known but are limited to aryl iodides.280,281,282 The examples below all utilize commercially available ligands and allow for couplings with aryl bromides and/or chlorides. Yu and coworkers have demonstrated an elegant example of a telescoped process featuring two C—S bond formation.283 In the first C—S bond formation, isooctyl-3-mercaptopropionate was used as a convenient and cheap alternative to the common triisopropylsilanethiol (TIPS-SH). Treatment of the product with sodium tertamylate liberates the aryl thiolate which was then used in the second C—S bond formation. O O

HS

H2N

Br

O

C8H17

1 mol% Pd 2(dba) 3

O H2N

2 mol% Xantphos

O

O S

toluene, reflux

N N Me

H2N

S

NaOt-Amyl n-PrOH, toluene 80 °C

N N Me

Br 0.5 mol% Pd 2(dba) 3 1 mol% Xantphos 2.2 equiv NaO-t-Amyl n-PrOH, 80 °C 72% over 3 steps

O

C8H17

O

2 equiv DIPEA

O

O

O H2N

SNa O

Buchwald and coworker have reported the use of DiPPF as a ligand for the Pd-catalyzed coupling of thiols and aryl bromides and chlorides. This catalyst system offers good substrate scope with a reasonably priced ligand.284 Me

Cl

+

Pd(OAc) 2 (2 mol%) DiPPF (2.4 mol%) NaO-t-Bu

Me HS

Me Me

S

Dioxane, 100 °C 95%

P(i-Pr)2

DiPPF = Fe

P(i-Pr)2

278 Quach, T. D.; Batey, R. A. Organic Letters 2003, 5, 1381–1384. 279 Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M. Bulletin of the Chemical Society of Japan 1980, 53, 1385–1389. 280 Kwong, F. Y.; Buchwald, S. L. Organic Letters 2002, 4, 3517–3520. 281 Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Organic Letters 2002, 4, 2803–2806. 282 Zhai, L.-H.; Guo, L.-H.; Luo, Y.-H.; Ling, Y.; Sun, B.-W. Organic Process Research & Development 2015, 19, 849–857. 283 Chekal, B.; Damon, D.; LaFrance, D.; Leeman, K.; Mojica, C.; Palm, A.; St. Pierre, M.; Sieser, J.; Sutherland, K.; Vaidyanathan, R.; Van Alsten, J.; Vanderplas, B.; Wager, C.; Weisenburger, G.; Withbroe, G.; Yu, S. Organic Process Research & Development 2015, 19, 1944–1953. 284 Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397–7403.

6.13 Pd- and Cu-Catalyzed Aryl C—S Bond Formation

Hartwig and coworkers have reported that the use of Josiphos as a ligand leads to a catalyst with significantly higher turnover numbers and allowed for much lower catalyst loadings (as low as 0.001 mol% with aryl bromides). For large-scale applications, the benefit of these low catalyst loadings is likely to overcome the cost of this ligand.285 In this example, the sterically encumbered ligand serves to suppress catalyst inhibition by the thiol substrate. Pd(OAc)2 (0.1 mol%) Josiphos (0.1 mol%) NaO-t-Bu

Cl + HS(CH2)7CH3

MeO

S(CH2)7CH3

DME, 110 °C

MeO

98% P(t-Bu)2

Josiphos =

Me PCy2

Fe

The much less expensive Xantphos ligand has also been used with both alkyl- and aryl-thiols.286 It does appear that this catalyst system operates best with aryl bromides and iodides; the only example of an aryl chloride is with 4-nitrophenylchloride. Br Me

+ HS

Ph

N Me

Xantphos =

Pd2dba3 (2.5 mol%) Xantphos (5 mol%) i-Pr2NEt Dioxane, reflux

S Me

Ph

N

83%

Me

O PPh 2

PPh 2

Xantphos was also utilized by workers at Pfizer with an aryl iodide.287 This paper describes investigation of several methods for removal of residual palladium, a problem frequently encountered with pharmaceutical applications of this type of chemistry. These workers also described studies on removal of residual sulfur contaminants that interfered with downstream metal-mediated couplings.288 Aryl triflates have also been used as electrophiles in Pd-catalyzed thiol couplings.289 Although they must usually be prepared from the corresponding phenol, a wider range of phenols are typically available than aryl bromides or chlorides. Note that a higher catalyst loading (10 mol%) is required with Tol-BINAP relative to some of the ligands in the previous examples. OTf +

HS(CH2)3CH3

Pd(OAc)2 (10 mol%) (R)-Tol-BINAP (11 mol%) NaO-t-Bu

S(CH2)3CH3

Toluene, 80 °C 95%

Boronic acids have also been successfully coupled with alkylthiols using a stoichiometric copper reagent.290

SH BnO 2C

285 286 287 288 289 290

N H

CO2H

PhB(OH)2 Cu(OAc)2 (1.5 equiv) pyridine (3 equiv) 3A Ms DMF, 110 °C 79%

S BnO 2C

N H

Ph

CO2H

Fernandez-Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. Journal of the American Chemical Society 2006, 128, 2180–2181. Itoh, T.; Mase, T. Organic Letters 2004, 6, 4587–4590. See Note 256. Xiang, Y.; Caron, P.-Y.; Lillie, B. M.; Vaidyanathan, R. Organic Process Research & Development 2008, 12, 116–119. Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III; Volante, R. P. The Journal of Organic Chemistry 1998, 63, 9606–9607. Herradura, P. S.; Pendola, K. A.; Guy, R. K. Organic Letters 2000, 2, 2019–2022.

323

324

6 Selected Catalytic Reactions

6.14 Aryl C—B Bond Formation Given the importance of the Suzuki–Miyaura reaction in organic synthesis, it is not surprising that there has been a lot of work dedicated to the formation of the boronic acid or ester nucleophile. Synthesis of these nucleophiles is primarily done via two different routes: (i) electrophilic borate trapping of aryl lithium (or magnesium) species formed via directed metalation or by metal-halogen exchange and (ii) metal-catalyzed borylation or aryl electrophiles. Both methods have their pros and cons. Electrophilic trapping with borates does not require any transition metal catalyst and can be attractive in this respect. However, the substrate needs to be compatible with hard organometallic reagents (often lithium or magnesium species) and the need for rigorously anhydrous conditions and cryogenic conditions can be problematic. Metal-catalyzed reactions show greater functional group tolerance and proceed under much milder conditions. Given the focus of this Chapter on practical catalytic methods for organic synthesis, only the latter will be discussed here (stoichiometric reaction will be covered in Chapter 12). It is also worth noting that other synthetic methods for the formation of C—B bonds include the direct Ir-catalyzed C—H borylation and the transmetalation of aryl silanes or stannates.291 The typical protocol for the metal-catalyzed synthesis of boronic ester uses diborane (e.g. bis-pinacol diborane or B2 pin2 ) as the nucleophile along with a palladium catalyst and a base (e.g. KOAc). More recently, Dreyer and coworkers have reported the use of bis-boronic acid (B2 (OH)4 ) for direct synthesis of boronic acids.292,293 The absence of pinacol unit can be attractive from an atom-economy standpoint and can also facilitate synthesis and isolation as residual pinacol can lead to complications. The stability of B2 (OH)4 has been discussed, and care must be taken when working with this reagent.294 While less common, boranes (e.g. pinacol borane) have also been employed. Though more atom economical – typically only one B atom from a diborane gets utilized in the reaction – borane nucleophiles are reactive with water as well as protic functionalities and appropriate protection is often required. 6.14.1

Aryl Bromides and Iodides

In the synthesis of a 5-lipoxygenase-activating protein (FLAP) inhibitor, Patel et al. at Boehringer-Ingelheim required the efficient synthesis of a 2-aminopyrimidine boronic acid for a key Suzuki–Miyaura coupling. The Pd-catalyzed formation of the boronic ester is highly efficient and provides the desired product in 80% yield with only 0.1 mol% of Pd2 (dba)3 .295 It is worth noting that the amino group does not require protection for the reaction to be effective. The authors note that the reaction suffers from poor atom economy: only one of the two Bpin unit of bispinacol diborane is transferred to the aryl bromide. N H2N

Bpin–Bpin 0.1 mol% Pd2(dba)3

Br

0.2 mol% Fc(PtBu2)HBF4 2 equiv KOAc 2-MeTHF, 80 °C 80%

N

Bpin

N H 2N

N

The metal-catalyzed borylation has also been carried out with a variety of unprotected functionalities that could potentially be problematic with other methodologies. Karlsson et al. have demonstrated the compatibility of a carboxylic acid with the Miyaura borylation in the presence of a bulky palladium catalyst.296 The material prepared from the borylation can also be used directly in the ensuing Suzuki–Miyaura without isolation. Br

Bpin–Bpin 1 mol% PdCl2(dtbpf)

Me OH O

3.1 equiv KOAc dioxane, 70 °C

Bpin Me OH O

291 Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005, 1–99. 292 Molander, G. A.; Trice, S. L. J.; Dreher, S. D. Journal of the American Chemical Society 2010, 132, 17701–17703. 293 Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. Journal of the American Chemical Society 2012, 134, 11667–11673. 294 Gurung, S. R.; Mitchell, C.; Huang, J.; Jonas, M.; Strawser, J. D.; Daia, E.; Hardy, A.; O’Brien, E.; Hicks, F.; Papageorgiou, C. D. Organic Process Research & Development 2017, 21, 65–74. 295 Patel, N. D.; Zhang, Y.; Gao, J.; Sidhu, K.; Lorenz, J. C.; Fandrick, K. R.; Mulder, J. A.; Herbage, M. A.; Li, Z.; Ma, S.; Lee, H.; Grinberg, N.; Song, J. J.; Busacca, C. A.; Yee, N. K.; Senanayake, C. H. Organic Process Research & Development 2016, 20, 95–99. 296 Karlsson, S.; Soerensen, H.; Andersen, S. M.; Cruz, A.; Ryberg, P. Organic Process Research & Development 2016, 20, 262–269.

6.14 Aryl C—B Bond Formation

Unprotected phenols297 and sulfonamides298 have also been successfully employed in the Miyaura-Borylation as shown in the following. OH

2.5 equiv KOAc dioxane, reflux 86%

F Br

H N O

Br

F Bpin

Bpin–Bpin 2 mol% Pd(OAc)2

O S

OH

Bpin–Bpin 5 mol% Pd(PPh3)4

Me

H N

3 mol% XPhos 6 equiv K3PO4 dioxane, 95 °C 84%

O

Bpin

O S

Me

While the pinacol ester endows a greater degree of stability to the boronic ester relative to the boronic acid, the residual pinacol can lead to difficulties in the development of a suitable crystallization process given oiling out issues. Unfortunately, removal of pinacol from the reaction is tedious299,300 and often requires an oxidation or reduction step that reduces the efficiency of the process. This combined with the low atom economy associated with bis-pinacol diborane – pinacol makes >90% of the mass of this reagent – lead to the development of a methodology for the direct synthesis of boronic acid from aryl electrophiles using bis-boronic acid (BBA). While attractive from an atom economy point-of-view, it is worth noting that care must be taken with this reagent as it is reported that BBA undergoes decomposition at a temperature of 85 ∘ C,301 a temperature close to that at which many such borylation are carried out. Addition of ethylene glycol to the reaction significantly increased the stability of BBA, likely through formation of the ethylene glycol ester, allowing the reaction to be carried out in a safe manner. The application of bis-boronic acid has been demonstrated in a number of cases, and selected examples are described below. The synthesis of hepatitis C inhibitor MK-8876 published by Chen and coworkers features the synthesis of a boronic acid for a key Suzuki–Miyaura coupling.302 Attempts to generate the boronic acid via metal-halogen exchange followed by quenching were not successful given difficulties in forming the anion. Even metal-catalyzed boronic ester formation with B2 pin2 was plagued by high levels of debromination impurity. Hypothesizing that the size of the pinacol unit may be the culprit for the low yields, the authors attempted the Pd-catalyzed borylation with B2 (OH)4 , which proved highly successful. High yields of the desired product were observed with minimal amount of debromination. Additional PCy3 ligand was shown to be beneficial, likely to stabilize the Pd catalyst throughout the reaction. The authors noted that their internal safety assessment revealed no significant concerns.

Br Ms

N Me

HO

CO2NHMe F

O [Pd] =

Pd Cy 3P

297 298 299 300 301 302

HO

B B

OH OH

0.5 mol% [Pd] 0.25 mol% PCy3 3 equiv DIPEA MeOH, reflux 88%

(HO)2B Ms

N Me

NH2 Cl

Yu, J.; Wang, J. Organic Process Research & Development 2017, 21, 133–137. See Note 244. See Note 292. See Note 293. See Note 294. See Note 29.

CO2NHMe O

F

325

326

6 Selected Catalytic Reactions

Papageorgiou and coworkers at Takeda reported a Miyaura borylation of heteroaryl bromide using BBA as the borylating agent.303 Very detailed studies were carried out to examine the O2 sensitivity of the reaction, the stability of BBA in methanol, and the impact of added ethylene glycol on the stability of BBA. The efficiency of the Pd catalyst is worth mentioning with isolated yields of 91% employing only 0.05 mol% Pd. As with other metal-catalyzed borylations, the amine functionality does not need protection. HO Br

N O

NH2

HO

B B

OH

[Pd] = (HO)2B

OH

N

0.05 mol% [Pd] 2.5 equiv KOAc 3 equiv ethylene glycol MeOH, 35 °C 91%

NH2

O

Pd (tBu)3P

NH2 Cl

A tandem borylation/Suzuki coupling sequence was demonstrated by Smith et al. at Bristol-Myers Squibb.304 Although both steps could be carried out with a single charge of 0.2 mol% of the Pd catalyst, operation hold time encountered during the production required an additional charge of catalyst for reproducible reactions. Br CO2H CO2H

HO HO

Br

B B

CO2H

OH OH

0.23 mol% PdCl2(Amphos)2 2.3 equiv DIPEA MeOH, 2-MeTHF 50 °C

B(OH) 2

O N

H N Me

O O

Ph Me

0.23 mol% PdCl2(Amphos)2 2 equiv K3PO4, H2O MeOH, 2-MeTHF, 50 °C 95% overall

O N

H N Me

O O

Ph Me

Campeau and coworkers reported that pinacol borane showed higher conversion, reaction rates, and better purity profiles over bis(pinacolato) diboron in the following borylation of an aryl iodide.305 It is unclear whether these advantages would still hold true with other catalyst systems, or substrates bearing a different electrophilic site. HBPin 2.5 mol% Pd(OAc)2

Me

CO2Me I

6.14.2

5 mol% P(o-tol)3 3 equiv NEt3 2-MeTHF, 77 °C 75%

Me

CO2Me Bpi n

Vinyl Bromide

Vinyl bromides have been employed as electrophiles in Pd-catalyzed Miyaura borylation. In the following example, a tandem borylation-Suzuki sequence was developed by Mitchell and coworkers.306 The authors noted that addition of a small amount of water was required to obtain reproducible reaction on larger scale. It was hypothesized that 303 See Note 294. 304 Smith, M. J.; Lawler, M. J.; Kopp, N.; McLeod, D. D.; Davulcu, A. H.; Lin, D.; Katipally, K.; Sfouggatakis, C. Organic Process Research & Development 2017, 21, 1859–1863. 305 Girardin, M.; Ouellet, S. G.; Gauvreau, D.; Moore, J. C.; Hughes, G.; Devine, P. N.; O’Shea, P. D.; Campeau, L.-C. Organic Process Research & Development 2013, 17, 61–68. 306 Hansen, M. M.; Kallman, N. J.; Koenig, T. M.; Linder, R. J.; Richey, R. N.; Rizzo, J. R.; Ward, J. A.; Yu, H.; Zhang, T. Y.; Mitchell, D. Organic Process Research & Development 2017, 21, 208–217.

6.15 Pd-Catalyzed Aryl C—CN Bond Formation

drier conditions may be attenable when working on larger scale and that addition of water promotes solubilization of the base. Me

O O

Bpin–Bpin F 1 mol% Pd (dba) 2 3 6 mol% PCy3 8 mol% water 1.1 equiv KOAc dioxane, 80–85 °C

Br

6.14.3

O

N F

N H

Br

NO2 0.8 mol% Pd(OAc)2 0.25 mol% PPh3 K2CO3, 80–85 °C 56% overall

Bpin

O

•(CO2H)2

F

Me

O N

N H

NO2

Aryl Chlorides and Triflates

The development of sterically encumbered and electron-rich phosphine ligand has allowed chloride and triflate to be successfully used as electrophile in Miyaura borylation. In the examples below, an aryl chloride and triflate were transformed into a pinacol ester using Xphos307 or DPPF as the ligand.308 HO

Me

HO

Bpin–Bpin 3 mol% Pd(OAc)2

NHBoc Cl

6 mol% XPhos 3 equiv KOAc MeCN, 80 °C 91%

Me NHBoc

PinB

Bpin–Bpin 2.6 mol% PdCl2(dppf)

TfO

N

3 equiv KOAc DMSO, 85 °C Me

Bpin

N

Me

6.15 Pd-Catalyzed Aryl C—CN Bond Formation While cyanation of an arene can be achieved by nucleophilic aromatic substitution (see Section 4.6.1), one of the most reliable method for the conversion of an aryl halide to the nitrile is under palladium-mediated catalysis. The reaction usually utilizes zinc cyanide as the cyanide source in a polar aprotic solvent such as N,N-dimethylformamide (DMF). In some protocols, the zinc cyanide is added slowly to minimize the cyanide concentration since it can act as an inhibitor of the palladium catalyst.309 Zinc powder is also commonly added as an additive for this reaction, but its role is not entirely clear. It has been suggested that Zn allows for reduction of Pd(II) complexes to Pd(0) to initiate catalysis.310 However, formally Pd(0) sources such as Pd2 (dba)3 are also used in combination with Zn powder, suggesting that the Zn may have additional roles in the reaction.311 As shown in the first example below, an aminopyridine may not require protection to undergo the transformation.312 In the second example, the catalyst was activated using diethyl zinc as the reducing agent, and the reaction proceeded 307 Grongsaard, P.; Bulger, P. G.; Wallace, D. J.; Tan, L.; Chen, Q.; Dolman, S. J.; Nyrop, J.; Hoerrner, R. S.; Weisel, M.; Arredondo, J.; Itoh, T.; Xie, C.; Wen, X.; Zhao, D.; Muzzio, D. J.; Bassan, E. M.; Shultz, C. S. Organic Process Research & Development 2012, 16, 1069–1081. 308 See Note 42. 309 Ryberg, P. Organic Process Research & Development 2008, 12, 540–543. 310 Okano, T.; Iwahara, M.; Kiji, J. Synlett 1998, 243–244. 311 Wang, X.; Zhi, B.; Baum, J.; Chen, Y.; Crockett, R.; Huang, L.; Eisenberg, S.; Ng, J.; Larsen, R.; Martinelli, M.; Reider, P. The Journal of Organic Chemistry 2006, 71, 4021–4023. 312 Beaudin, J.; Bourassa, D. E.; Bowles, P.; Castaldi, M. J.; Clay, R.; Couturier, M. A.; Karrick, G.; Makowski, T. W.; McDermott, R. E.; Meltz, C. N.; Meltz, M.; Phillips, J. E.; Ragan, J. A.; Ripin, D. H. B.; Singer, R. A.; Tucker, J. L.; Wei, L. Organic Process Research & Development 2003, 7, 873–878.

327

328

6 Selected Catalytic Reactions

to completion with only 0.6 equiv of zinc cyanide. In the second example, chemoselectivity between the bromide and the chloride was achieved, and the chiral secondary alcohol did not require protection.313 N

EtO

Pd(PPh3)4 (10 mol%) Zn(CN)2 (1.5 equiv)

Br

Me

CN NH2

Pd(OAc)2 (2 mol%) P(o-tol)3(8 mol%) Et2Zn (3 mol%) Zn(CN)2 (0.6 equiv)

OH

N

DMF, 80 °C 70%

NH2

Br

EtO

OH NC

Me

DMF, 55 °C 92%

Cl

Cl

More recently Guimond and coworkers reported the Pd- and Ni-catalyzed cyanation of aryl bromide and chlorides using acetone cyanohydrin.314 While this cyanide sources is highly toxic, it has the advantage of being soluble in a variety of solvents, and its addition to the reaction can easily be controlled. While optimizing the following reaction, the authors noticed a fast drop in the pH of the reaction at early times. Thus, the first third of the acetone cyanohydrin was added at a slower rate to prevent its decomposition, which enabled the cyanation to perform very well on 400 g of aryl bromide. Note that the Cu-catalyzed cyanation using acetone cyanohydrin is also reported.315 Acetone cyanohydrin (1.2 equiv) [Pd(cinnamyl)Cl]2 (1 mol%)

Me O2N

Br

Me O2N

XPhos (3 mol%) NEt3 (2 equiv) i-PrOH, 80 °C 97%

MeO

CN

MeO

Examples of Pd-catalyzed cyanation of aryl chlorides using zinc cyanide have also been reported and typically require more forcing conditions, which may indicate a slower transmetalation of cyanide from Zn to Pd. Stumpf and coworkers carried out the cyanation of an heteroaryl chloride using Pd(OAc)2 and dppf at a temperature of 120 ∘ C. F

Cl

NC

N N Me

O

N Me

N

Zn(CN)2 (0.6 equiv) Pd(OAc)2 (4 mol%) dppf(8 mol%) Zn powder (0.1 equiv) DMAc, 120 °C 72%

F

N Me

O

N Me

Similar conditions were employed by Wang et al. at Amgen for the cyanation of a chloro azaindole.316 Cl

CN Zn(CN)2 (0.6 equiv)

N

N H

Pd2(dba)3 (1 mol%) dppf (3 mol%) Zn(0) (10 mol%) DMAc, 120 °C 70%

N

N H

313 Chen, C.-Y.; Frey, L. F.; Shultz, S.; Wallace, D. J.; Marcantonio, K.; Payack, J. F.; Vazquez, E.; Springfield, S. A.; Zhou, G.; Liu, P.; Kieczykowski, G. R.; Chen, A. M.; Phenix, B. D.; Singh, U.; Strine, J.; Izzo, B.; Krska, S. W. Organic Process Research & Development 2007, 11, 616–623. 314 Burg, F.; Egger, J.; Deutsch, J.; Guimond, N. Organic Process Research & Development 2016, 20, 1540–1545. 315 Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Advanced Synthesis & Catalysis 2011, 353, 777–780. 316 See Note 311.

6.16 Metal-Catalyzed Allylic Substitution

Aryl triflate is also an effective substrate for the Pd-catalyzed cyanation. Like aryl chloride, forcing conditions are typically required.317 Me

Me

TfO

Zn(CN)2 (1.3 equiv) NBoc

NC NBoc

Pd(PPh3)4 (10 mol%) DMF, 120 °C 85%

Buchwald and coworkers have introduced a copper-catalyzed process whereby an aryl bromide is first converted to the aryl iodide that then undergoes the cyanation with sodium cyanide. A 1,2-diamine ligand is used to accelerate the Cu-catalyzed cyanation process.318 Br

Me

CN

NaCN (1.2 equiv) CuI (10 mol%) KI (20 mol%) MeNHCH2CH2NHMe (1 equiv) toluene, 110 °C 90%

Me

Me

Me

As the cyanide sources employed in the examples mentioned previously are highly toxic, special precaution must be taken to be used in a safe manner. In contrast, potassium hexacyanoferrate K4 [Fe(CN)6 ] is nontoxic and is used as a food additive in table salt and to remove metal salts from wine rendering it an attractive cyanation reagent. However, it must be noted that K4 [Fe(CN)6 ] can also promote catalyst deactivation. In the following example, Utsugi et al. used toluene as an antisolvent to allow for a reproducible reaction on up to 160 kg.319 The author also noted the sensitivity of the reaction to oxygen. Br

Me N O

Ph

K4[Fe(CN)6]·3H2O (0.4 equiv) Pd(OAc)2 (2 mol%) P(o-tol)3 (2 mol%) Na2CO3 (1 equiv) 4:2 DMAc:toluene, 125 °C 86%

NC

Me N

Ph

O

6.16 Metal-Catalyzed Allylic Substitution Metal-catalyzed allylic substitution continued to flourish in research and application since the first edition of the book, the scope of this transformation has significantly broadened. The practicality of Ir-catalyzed enantioselective allylation to afford the branched product (Pd-catalyzed processes tend to give mainly linear products) has improved, and many reports in total synthesis of natural product appeared in recent literature.320 Further, stereodivergence in cooperative asymmetric catalysis with simultaneous involvement of two chiral catalysts was reported by Carreira and coworker.321 317 Harris, R. M.; Andrews, B. I.; Clark, S.; Cooke, J. W. B.; Gray, J. C. S.; Ng, S. Q. Q. Organic Process Research & Development 2013, 17, 1239–1246. 318 Zanon, J.; Klapars, A.; Buchwald, S. L. Journal of the American Chemical Society 2003, 125, 2890–2891. 319 Utsugi, M.; Ozawa, H.; Toyofuku, E.; Hatsuda, M. Organic Process Research & Development 2014, 18, 693–698. 320 Qu, J.; Helmchen, G. Accounts of Chemical Research 2017, 50, 2539–2555. 321 Krautwald, S.; Carreira, E. M. Journal of the American Chemical Society 2017, 139, 5627–5639.

329

330

6 Selected Catalytic Reactions

This burgeoning technology demonstrated the independent and simultaneous actions and compatibility of metal catalyst and organo catalyst,322 which will be surely employed more in the total synthesis of natural products, as well as active ingredients of pharmaceuticals. ‡ Cinchona amine H N O Ph +

H

Me

R R

N H

NH

OH

O Me

Ph

H

Ph H Ph

H R

Ph R

Me Ph

>90.5% de; >99.0 ee

[P*] R Ir Cl [P*] R

Chiral phosphoramidite

In terms of nucleophile, in addition to the well-established C, N, and O nucleophiles, S, P, and H have also been reported. While palladium maintained its dominance in this transformation, more Ir- and Rh-catalyzed allylic substitutions have been reported; further, Cu, W, and Mo have also found their niche in this field. A number of excellent reviews on transition metal-catalyzed allylic substitution have been published in recent years, describing the vast horizon of its scope; the readers are encouraged to refer to the first edition of this book for knowledge, as well as the reviews for inspiration. This section will limit the scope to the examples that have been demonstrated on reasonable scale, hence deemed “scalable,” since the first edition. The action of certain low-valent transition metal complexes on substrates containing electronegative leaving groups at an allylic position provides reactive, electrophilic, “π-allyl” intermediates. Pioneering work in the development of this methodology and subsequent application in organic synthesis was carried out by the research groups of Tsuji and coworkers323,324 and Trost and coworkers325,326 and has been a focus area for many others. Although a range of nucleophiles may be employed in these reactions, the method has most generally been applied to the regio- and stereoselective construction of C—C, C—N, and C—O bonds, which will be discussed in this section. X 1

R

2

R

Pd 0

XPd II R1

R2

Nu

Nu 1

R

R

2

Nu

+ R

1

R2

Palladium-catalyzed processes are undoubtedly the most well studied and are typically an appropriate first choice for many substrates.327,328 However, functionality-biased regioselectivity and erosion of stereochemistry in chiral π-allyl intermediates through facile π–σ–π isomerizations are limitations that must be addressed with most Pd-catalyzed allylation reactions. Thus, a number of alternative transition metal complexes have been developed to address the restrictions of more traditional catalysts.329,330,331,332,333,334,335 Today, many catalyst systems are available for the generation of electrophilic π-allyl intermediates from a broad range of allylic alcohol derivatives. Each has advantages and disadvantages when cost, complexity, air- or moisture sensitivity and substrate compatibility are considered. 322 323 324 325 326 327 328 329 330 331 332 333 334 335

Bhaskararao, B.; Sunoj, R. B. Journal of the American Chemical Society 2015, 137, 15712–15722. Minami, I.; Shimizu, I.; Tsuji, J. Journal of Organometallic Chemistry 1985, 296, 269–280. Tsuji, J. Organic Synthesis with Palladium Compounds; Springer-Verlag: Berlin, 1980. Trost, B. M.; Verhoeven, T. R. Journal of the American Chemical Society 1980, 102, 4730–4743. Trost, B. M.; Van Vranken, D. L. Chemical Reviews 1996, 96, 395–422. Frost, C. G.; Howart, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089–1122. Trost, B. M. Accounts of Chemical Research 1980, 13, 385–393. Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005. Evans, P. A.; Nelson, J. D. Journal of the American Chemical Society 1998, 120, 5581–5582. Takeuchi, R.; Kashio, M. Journal of the American Chemical Society 1998, 120, 8647–8655. Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angewandte Chemie, International Edition 2002, 41, 1059–1061. Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind, L. S. Journal of the American Chemical Society 1996, 118, 897–898. Lehmann, J.; Lloyd-Jones, G. C. Tetrahedron 1995, 51, 8863–8874. Bricout, H.; Carpentier, J.-F.; Mortreux, A. Journal of the Chemical Society, Chemical Communications 1995, 1863–1864.

6.16 Metal-Catalyzed Allylic Substitution

6.16.1

Carbon Nucleophiles

Soft, stabilized carbanions such as malonate, acetoacetate, or cyanoacetate salts represent the most common class of nucleophiles for metal-catalyzed allylic substitution reactions. The reaction conditions are often quite mild and are generally tolerant of diverse functionality. In the example below, diethyl malonate is alkylated at the activated α carbon with an allylic carbonate under palladium(0) catalysis.336 The racemic product was obtained in good yield and with a high degree of regioselectivity for the allylic terminus 𝛾 (vs. α) to the sulfone. The product of this reaction was also obtained with excellent selectivity for the (E)-double bond. CH2(CO2Et)2, 4Å MS

SO2Ph

TBSO O

OEt

EtO

THF, reflux, 12 h

O

SO2Ph

TBSO

Pd 2dba 3, dppe

OEt O

81%

O

In the following example from the process group at Merck & Co., palladium-catalyzed allylic alkylation of a protected dialkyl aminomalonate provided the (Z)-olefin preferentially. The reaction is tolerant of acetyl, Boc, or formyl protecting groups on nitrogen, and selectivity for the (Z)-olefin in the product is dependent upon the solvent, ligand, and palladium source utilized.337 NHAc

OCO2Et EtO2C NHBoc MeO

EtO2C

NHAc CO2Et

EtO2C

CO2Et

[Pd(allyl)Cl]2, dppe NaH, DMF, 90 °C 73%, 12:1 Z:E

NHAc CO2Et

+ NHBoc

NHBoc

MeO

MeO

Several asymmetric variations on this reaction have been reported. For racemic allylic electrophiles, asymmetry can be conveyed to alkylation products by using chiral organometallic complexes and taking advantage of facile π–σ–π isomerization of the intermediate.338 In the following example below from Trost and Ariza, allylic alkylation of a geminal diacetate proceeds in high yield and with excellent stereoselectivity.339 This particular example represents the synthetic equivalent of a challenging aldol condensation product. O OAc Ph

+

OAc

i-Pr N

AcO O

[{η3-C3H5PdCl } 2], L*

O Ph

Ph

NaH, DME, 0–5 °C 92%, >19 : 1 dr

i-Pr

O

Ph

N

99% ee

L* = Ph 2P

O

O NH HN

PPh 2

Rhodium catalysis provides an attractive option for asymmetric C—C bond formation in cases where chirality is already present in the electrophilic component since a high degree of regio- and stereochemical integrity is retained from starting material to product with these catalysts. Alkylation of stabilized carbon nucleophiles with chiral allylic carbonates in the presence of a phosphite modified Wilkinson’s catalyst (RhCl(PPh3 )3 /P(OMe)3 ) provided products in high yield and with impressive conservation of enantiomeric excess.340 OCO2Me Me

R 99 : 1 dr

336 337 338 339 340

Me

Rh(PPh 3)3Cl NaCH(CO2Me)2 P(OMe)3, THF, 30 °C 89%

CH(CO2Me)2 Me

R

Me

+

CH(CO2Me)2 Me

S

Me

95 : 5

Krafft, M. E.; Kyne, G. M.; Hirosawa, C.; Schmidt, P.; Abboud, K. A.; L’Helias, N. Tetrahedron 2006, 62, 11782–11792. Steinhuebel, D.; Palucki, M.; Davies, I. W. The Journal of Organic Chemistry 2006, 71, 3282–3284. See Note 327. Trost, B. M.; Ariza, X. Angewandte Chemie, International Edition 1997, 36, 2635–2637. See Note 330.

331

332

6 Selected Catalytic Reactions

Hartwig and coworker have reported that silyl enol ethers of acetophenone derivatives serve as effective carbon nucleophiles for Ir-catalyzed allylic alkylation reactions.341 Silyl enol ethers derived from aliphatic ketones also participate in the reaction to provide alkylation products with excellent regio and enantioselectivities, although lower yields were reported. Evans and Leahy have demonstrated utility with Rh-phosphite catalysts in the allylic alkylation of copper enolates.342,343 OTMS Ph

OBoc

Me O O

P N Me

O

Ph

0.4 CsF, 1.5 ZnF2 DMF 74%, 99 : 1

L1 =

O

O

2% [Ir(COD)Cl ] 2, 4% L1

O

+

O

Ph

96% ee

Ph Ph

Since the first edition of the book, more examples of Ir-catalyzed enantioselective allylation have been reported on more complex molecules and extended functional groups. In the total synthesis of natural product (−)-Communesin F,344 the key transformation required an allylic substitution that includes the formation of the branched product and a quaternary carbon center. While a palladium catalyst afforded the linear product as expected, the use of Ir catalyst reversed the regioselectivity and gave the branched product in excellent selectivity (from 1 : >20 to >10 : 1); the reagent controlled double differentiation on both the nucleophile (C-3) and the electrophile was achieved at very high level, which also set the stage for a substrate controlled addition of nitrogen at the two position to the C=N double bond. Overall, three adjacent chiral centers were set in one step and constructed the skeleton of the natural product. This mid-stage “kill” step was performed on gram scale and produced sufficient amount of the intermediate to finish the total synthesis. OTBS

4 mol% catalyst additive, solvent RT, 12–24 h

Br +

HO

N H

HN Boc

TBSO

TBSO

Br N N H Boc H

O P N O

+

Desired L1

Br BocHN N Undesired

Catalyst

Additives

Solvent

Desired/undesired

ee (%)

Yield (%)

Pd(PPh3 )4

Et3 B

THF

1 : >20

Pd(PPh3 )4

Et3 B, DBU

DCM

1 : >20

[Ir(cod)Cl]2 (S)-L1

Et3 B, KO-t-Bu

1,4-dixoane

>10 : 1

92

68

[Ir(cod)Cl]2 (S)-L1

Et3 B, KO-t-Bu

DCM

9:1

91

60

[Ir(cod)Cl]2 (S)-L1

Et3 B, KO-t-Bu

THF

6:1

91

52

[Ir(cod)Cl]2 (S)-L1

Et3 B, KO-t-Bu

Toluene

>10 : 1

92

65

[Ir(cod)Cl]2 (S)-L1

9-BBN-n-C6 H13 , KO-t-Bu

Toluene

>10 : 1

99

55

81 75

Hard carbon nucleophiles (e.g. organozinc,345 Grignard,346 or organoaluminum347 reagents) participate in transition metal-catalyzed allylic alkylation reactions in a slightly different manner. Rather than attacking metal allyl 341 342 343 344 345 346 347

Graening, T.; Hartwig, J. F. Journal of the American Chemical Society 2005, 127, 17192–17193. Evans, P. A.; Leahy, D. K. Journal of the American Chemical Society 2003, 125, 8974–8975. Evans, P. A.; Leahy, D. K.; Slieker, L. M. Tetrahedron: Asymmetry 2003, 14, 3613–3618. Liang, X.; Zhang, T.-Y.; Zeng, X.-Y.; Zheng, Y.; Wei, K.; Yang, Y.-R. Journal of the American Chemical Society 2017, 139, 3364–3367. Evans, P. A.; Uraguchi, D. Journal of the American Chemical Society 2003, 125, 7158–7159. Hayashi, T.; Konishi, M.; Yokota, K.; Humada, M. Journal of the Chemical Society, Chemical Communications 1981, 313–314. Matsushita, H.; Negishi, E. Journal of the Chemical Society, Chemical Communications 1982, 160–161.

6.16 Metal-Catalyzed Allylic Substitution

intermediates in an SN 2′ fashion, hard carbon-based nucleophiles are thought to add directly to the metal center. Subsequent reductive elimination typically provides carbon–carbon bonds with net inversion of stereochemistry.348 Several catalyst systems have shown effectiveness in allylic alkylation reactions with hard carbon nucleophiles. The representative example below from Kobayashi and coworkers utilizes a boronate ester nucleophile with a nickel catalyst to provide the alkylation product in high yield and with inversion of stereochemistry at carbon.349 O

CO2Me

OCO2Et

– B(OMe) 3

Li+

NiCl2(dppf), THF 55–60 °C 92%

CO2Me O

>95 : 5 dr

Employing stereodivergent synthesis, Carreira and coworkers synthesized Δ9 -tetrahydrocannabinol (THC),350 as well as the other three diastereomers in reagent-controlled manner. Simply by switching the combination of the chiral ligand for the enantioselective allylation from R- to S-, and the chiral amine from R- to S-, these researchers achieved perfect control on the two adjacent chiral centers in complete reagent controlled fashion, which illustrated the power of modern organic synthesis. OMe (R)-L (R)-A

(S)

C5H11

OMe

OMe 3 mol% [{Ir(cod)Cl}2]

(S)-A

(S)

C5H11

(R )

5 mol% Zn(OTf)2 DCE (0.5 M), 25 °C, 20 h

55% 20 : 1 dr >99 : 1 er

Me OMe

15 mol% amine H

CHO

OMe

12 mol% (P,olefin) O

60% 15 : 1 dr >99 : 1 er

OMe (R)-L

+

CHO

Me

OMe OH

C5H11

(S)

(S)-L (R)-A

(R )

C5H11

(S)

CHO

OMe

Me

54% 20 : 1 dr >99 : 1 er

Me OMe

3.0 equiv (S)-L (S)-A

(R )

C5H11

(R )

CHO

OMe

62% 15 : 1 dr >99 : 1 er

Me .................................................................................................................................................................... Amine (P,olefin)

O P N O

(R)-L or (S)-L

N H

Ar Ar OSiMe 3

(R)-A or (S)-A

348 See Note 327. 349 Kobayashi, Y.; Mizojiri, R.; Ikeda, E. The Journal of Organic Chemistry 1996, 61, 5391–5399. 350 Schafroth, M. A.; Zuccarello, G.; Krautwald, S.; Sarlah, D.; Carreira, E. M. Angewandte Chemie International Edition 2014, 53, 13898–13901.

333

334

6 Selected Catalytic Reactions

6.16.2

Nitrogen Nucleophiles

The ability to form C—N bonds in a regio- and stereoselective manner via transition metal-catalyzed allylic amination methodology provides a powerful tool to the practicing synthetic chemist. Trost and Sorum have provided several elegant examples of the use of chiral palladium catalysts for the desymmetrization of diastereomeric allylic carbonates. In the following example, the palladium catalyst was forced to approach the substrate from the face that was sterically hindered by the acetonide functionality. Despite this steric challenge, the reaction proceeded with excellent stereoselectivity to provide a single allylic amine product in high yield.351 O

N K O

Pd 2(dba) 3·CHCl3

OCO2Me O O

O

+

Me

MeO2CO

Me

(n-hex)4NBr, C H2Cl 2

O

O

Me Me

O Ph 2P

O NH HN

N

O O

PPh 2

O

Me Me

64%, 98% ee

In the example below from chemists at GlaxoSmithKline, a palladium-catalyzed allylic amination of an allylic 1,4-diacetate was followed by an intramolecular allylic etherification to yield a chiral, nonracemic morpholine derivative in high yield.352 The Trost ligand proved optimal for enantioselectivity in this reaction, and a slow addition of the amino alcohol was found to minimize formation of a diamine impurity. For more on transition metal-catalyzed allylic etherification, see Section 6.16.3. OAc HO

N H

+ OAc

1 mol% Pd2dba3 3 mol% L*

Cl Cl

Cl

N

THF, 60 °C

O

80%, 90% ee

Cl

L* = O Ph 2P

O NH HN

PPh 2

Evans et al. reported complementary allylic amination methodology utilizing enantiomerically enriched allylic carbonates and a trimethylphosphite-modified Wilkinson’s catalyst (RhCl(Ph3 )4 /P(OMe)3 ). Under the conditions reported, allylation of N-tosyl N-benzylamine proceeds in high yield and with excellent conservation of regio- and stereochemistry.353 OCO2Me Ph

Ts

RhCl(PPh3)3, P(OMe)3 BnNLiTs, THF, 30 °C 89%

N

Ts

Bn +

Ph

N

Bn

Ph 20 : 1

Hartwig and coworker have reported that allylic amination reactions with chiral iridium catalysts provide branched products with high enantioselectivity.354 In the following example, a linear achiral allylic carbonate is converted in 351 352 353 354

Trost, B. M.; Sorum, M. T. Organic Process Research & Development 2003, 7, 432–435. Wilkinson, M. C. Tetrahedron Letters 2005, 46, 4773–4775. Evans, P. A.; Robinson, J. E.; Nelson, J. D. Journal of the American Chemical Society 1999, 121, 6761–6762. Ohmura, T.; Hartwig, J. F. Journal of the American Chemical Society 2002, 124, 15164–15165.

6.16 Metal-Catalyzed Allylic Substitution

good yield to a chiral branched allylic amide via reaction with potassium trifluoroacetamide in the presence of a novel Ir catalyst.355 O OCO2Me

+

2% [Ir(COD)Cl]2 4% L*

O KHN

CF3

HN

THF, rt, 18 h 79%

L* =

O P N O

CF3

96% ee

Me OMe

Ir-catalyzed enantioselective allylation of N-Boc-N-methylhydroxylamine was employed by Helmchem and coworkers in the total synthesis of a series of alkaloid natural products including (+)-prosophyline.356 Importantly, these researchers used commercially available ligand to achieve high regio- and enantioselectivity. OCO2Me R

+

Boc

N H

Boc

C (4 mol%)

OMe

N

OMe

Branched

Substrate

Catalyst

Base

t (h)

Yield (%)

N

OMe

R

R

THF, base, 50 °C

Boc

+

Linear

Branched/linear

ee (%)

R=Ph

C2

TBD

1.5

59

96 : 4

98

R=n-C6 H13

C4

DBU

2

90

98 : 2

94

R=CH2 OBn

C4

DBU

1

71

90 : 10

88

R=CH2 OBn

C3

DBU

3

77

93 : 7

93

+

OTf –

O P O Me

Ir Me Ar

Ar

C1: diene = cod, Ar = Ph

cod

dbcot

C2: diene = cod, Ar = o-(MeO)C6H4 C3: diene = dbcot, Ar = Ph C4: diene = dbcot, Ar = o-(MeO)C6H4

6.16.3

Oxygen Nucleophiles

Ether formation may also be accomplished via metal-catalyzed allylic alkylation methodology, although the scope is somewhat limited in comparison to soft, stabilized carbon or nitrogen nucleophiles. Evans and Leahy reported that 355 Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Organic Letters 2007, 9, 3949–3952. 356 Jaekel, M.; Qu, J.; Schnitzer, T.; Helmchen, G. Chemistry - A European Journal 2013, 19, 16746–16755.

335

336

6 Selected Catalytic Reactions

sterically and electronically encumbered phenols serve as effective nucleophiles in Rh-catalyzed allylic etherification reactions. In the following example, an optically enriched allylic carbonate is converted to a mixture of allyl aryl ethers with excellent selectivity for the branched product.357 This method is especially attractive for target-oriented synthesis in that the stereochemistry of the carbonate is translated to the product without the aid of expensive chiral ligands. This Rh catalyst has also been applied to the regio- and stereoselective allylic etherification of aliphatic copper alkoxides.358 I Rh(PPh 3)3Cl

OCO2Me

O

P(OMe)3, ArONa

BnO

I

BnO

Me

THF, 0 °C to rt 87%

≥99% ee

O

+

BnO

Me

28 : 1

92% ee

Hartwig and coworker have also applied their Ir-based catalyst system to enantioselective allylic etherification reactions.359 In the representative example below, an achiral allylic acetate is converted to a chiral allylic ether in good yield and enantioselectivity, and with excellent preference for the branched regioisomer. 5% [Ir(COD)Cl ] 2

O

5% (R,R,R)-L* OAc

+

Me

20% PhCCMe

n-C6H13OH

PhMe, K 3PO4, rt 71%

O P N O

(R,R,R)-L* =

91% ee

Me Me

In the following example from process chemists at Abbott Laboratories, a very impressive palladium-catalyzed allylic etherification reaction was carried out on an erythromycin A analog.360 In this case, alkylation occurred at a highly sterically congested tertiary alcohol to provide the allylic ether in nearly quantitative yield. Furthermore, the linear product with E olefin geometry was formed exclusively from either the primary or secondary (shown) allylic carbonate. N O i-PrO N Me HO HO Me

N

Me

Me

O Me

TMSO OH O O

O

Me

Me Me

OBoc Pd 2(dba) 3, dppb

O O

Me Me

OTMS OMe

O N Me HO

Me

i-PrO

NMe2

THF, 65 °C 97%

HO Me

O

TMSO

Me

O Me

O O

NMe2

O Me

Me Me

O O

Me Me

OTMS OMe

357 Evans, P. A.; Leahy, D. K. Journal of the American Chemical Society 2000, 122, 5012–5013. 358 Evans, P. A.; Leahy, D. K. Journal of the American Chemical Society 2002, 124, 7882–7883. 359 Ueno, S.; Hartwig, J. F. Angewandte Chemie, International Edition 2008, 47, 1928–1931. 360 Stoner, E. J.; Peterson, M. J.; Allen, M. S.; DeMattei, J. A.; Haight, A. R.; Leanna, M. R.; Patel, S. R.; Plata, D. J.; Premchandran, R. H.; Rasmussen, M. The Journal of Organic Chemistry 2003, 68, 8847–8852.

6.17 Catalytic Metal-Mediated Methods for Fluorination

6.17 Catalytic Metal-Mediated Methods for Fluorination The carbon–fluorine bond continues to gain importance as both a precursor and target in organic synthesis. Fluorinated compounds have the advantage of increased metabolic stability, increased lipophilicity, and high thermal stability.361,362,363,364,365 A growing number of important molecules from the pharmaceutical, agrochemical, material science, and specialty chemical industries contain fluorine, yet there are still limitations in available methods of installation.366,367 In many instances, the ideal synthesis for their preparation cannot be derived from common and largely available fluorinated building blocks, which themselves ultimately are derived from the abundant mineral fluorite.368 Challenged by some of these obstacles, there has been enormous progress toward selective synthetic methodologies focused on the fluorination of carbon. Catalysis presents a practical approach to the synthetic organic chemist, especially when tasked with delivering large quantities of material in an economically viable and sustainable fashion. To meet this increasing demand, as well as provide selectivity and predictability in the installation of fluorine, a number of metal-mediated catalytic methods have been developed.369 Although a number of these transformations still require additional development before implementation on an industrial scale, the use of selective, catalytic processes can be practical and useful for larger scale preparations.370 It should be noted that a number of powerful methods for fluorination have also emerged using photoredox and electrochemical catalysis. These advances are discussed in Chapter 11 of this book. 6.17.1

Aryl Fluorination

In 2006, Sanford and coworkers reported on the first example of a palladium-catalyzed preparation of benzylic and aromatic C—F bonds.371 The addition of electrophilic fluorinating agents to PdII aryl intermediates facilitates an oxidative transformation of the Pd—C bond to furnish the C—F bond. The method can be used to prepare a variety of fluorinated compounds in modest to good yield, and the functional group tolerance included aryl halides, nonenolizable ketones, and esters. This approach provides useful building blocks for further elaboration and target-oriented synthesis. Me

Cl

R N

Pd(OAc) 2 (10 mol%) F N BF4–

N

(2.5–4.5 equiv) MeCN/CF3C6H5 μW, 150 °C, 300 W 1.5–2 h MeO

F 50%

N 60%

N

F

F

F 52%

N

CF3 N

F

F 62%

N

F 75% F3C

F 59%

Yu and coworkers developed a PdII -catalyzed ortho-fluorination of benzoic acids by using weakly coordinating N-arylbenzamide auxiliaries and Pd(OTf )2 to facilitate C—F reductive elimination.372 The method was further demonstrated to be selective for difluorination by a judicious choice of solvent and increasing the equivalents of N-fluoro-2,4,6-trifluoromethylpyridinium triflate. Additional benefits of the methodology included readily available materials to prepare the requisite amide and a base-catalyzed hydrolysis with KOH to furnish the desired carboxylic acids in excellent yield. 361 362 363 364 365 366 367 368 369 370 371 372

Banks, R. E.; Smart, B. E.; Tatlow, J. C.; Editors Organofluorine Chemistry: Principles and Commercial Applications; Plenum, 1994. Kirsch, P. Modern Fluoroorganic Chemistry; 2nd Ed.; Wiley-VCH, 2013. Mueller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. Kirk, K. L. Organic Process Research & Development 2008, 12, 305–321. Yamamoto, H.; Editor Organofluorine Compounds: Chemistry and Applications; Springer-Verlag, 2000. Ojima, I.; Editor Fluorine in Medicinal Chemistry and Chemical Biology; John Wiley & Sons Ltd., 2009. Hollingworth, C.; Gouverneur, V. Chemical Communications 2012, 48, 2929–2942. Vajda, P.; Costantini, J.-M.; Editors Properties Of Fluorite Structure Materials; Nova Science Publishers, Inc., 2013. Petrone, D. A.; Ye, J.; Lautens, M. Chemical Reviews 2016, 116, 8003–8104. Shimizu, N.; Kondo, H.; Oishi, M.; Fujikawa, K.; Komoda, K.; Amii, H. Organic Syntheses 2016, 93, 147–162. Hull, K. L.; Anani, W. Q.; Sanford, M. S. Journal of the American Chemical Society 2006, 128, 7134–7135. Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angewandte Chemie International Edition 2011, 50, 9081–9084.

337

338

6 Selected Catalytic Reactions

Me N

F

F

BF 4 Me Me (1.5 equiv) monofluorination

O

Pd(OTf )2(MeCN)2 (10 mol%) NMP (20 mol%) MeCN, 120 °C

F N H

R F

CF3 F F

16 examples, 36–78% yield

F O R H

F

CF3 F

N H

F

Me F

F BF 4 Me Me (3 equiv) N

difluorination

F

Pd(OTf )2(MeCN)2 (10 mol%) NMP (50 mol%) PhCF3, 120 °C

O

F N H

R

CF3 F F

F 3 examples, 66–88% yield

Ritter et al. reported the fluorination of aryltrifluoroborates using palladium catalysis and demonstrated that other common arylboron reagents, such as pinacol boronic esters, arylboronic acids, and MIDA esters of electron-rich arylboronic acids, were competent coupling partners.373 The reaction proceeds under mild conditions, is stable to moisture, and was demonstrated on multigram scale. Limitations to the chemistry include failure to fluorinate heterocycles, as well as constitutional isomers of electron-poor substrates, but the method is useful for the practical preparation of several arylfluorides. Upon exploring the mechanism of the reaction, the authors suggest a single-electron transfer (SET) event for product formation, and isolated and characterized a PdIII intermediate.

BF 3K

R

2 mol% catalyst 4 mol% terpy NaF (1 equiv)

HO

PhO 71%

Selectfluor (1.2 equiv) DMF or MeCN, 4–40 °C

N N

2 BF4–

Pd II N MeCN terpy = 2,2' : 6',2"-terpyridine

N 99%

86% O

F

O

2+

Catalyst

F

F

F

Me

F t-Bu

70%

F O

98%

83%

Buchwald and coworkers published a major advance by converting aryl triflates to aryl fluorinated compounds using cesium fluoride, the ligand tBuBrettPhos, and readily available precatalyst [PdCl(cinnamyl)]2 .374 Until this time, it had been reported by Hartwig and coworker375,376 and Grushin377,378 that reductive elimination of Pd—F complexes was quite challenging because of the electronegativity of the fluorine atom and often failed to generate arylfluorides despite numerous attempts. The Buchwald and coworker’s method proved quite general and was later expanded to include complex substrates, as well as heterocycles.379 The chemistry was later adapted to a continuous flow process using a microflow packed-bed reactor.380 373 Mazzotti, A. R.; Campbell, M. G.; Tang, P.; Murphy, J. M.; Ritter, T. Journal of the American Chemical Society 2013, 135, 14012–14015. 374 Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–1664. 375 Roy, A. H.; Hartwig, J. F. Journal of the American Chemical Society 2003, 125, 13944–13945. 376 Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 1533–1541. 377 Grushin, V. V.; Marshall, W. J. Organometallics 2007, 26, 4997–5002. 378 Grushin, V. V. Chemistry - A European Journal 2002, 8, 1006–1014. 379 Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. Journal of the American Chemical Society 2011, 133, 18106–18109. 380 Noel, T.; Maimone, T. J.; Buchwald, S. L. Angewandte Chemie International Edition 2011, 50, 8900–8903.

6.17 Catalytic Metal-Mediated Methods for Fluorination

tBuBrettPhos

OTf

(6 mol%)

Ph

CsF

R

F

R

O2N

Reductive elimination

Oxidative addition

Pd II R

R

N Boc 73% yield

P( Bu) 2 i Pr

MeO

OTf

=

t

Ligand exchange

iPr

i

Pr OMe F–

TfO–

6.17.2

Me

tBuBrettPhos

Pd II F

F

63% yield

Ln

Ln

O Ph 63% yield

F

OTf

L nM

R

F

82% yield

Toluene, heat

via:

O

F

[PdCl(cinnamyl)]2 (2 mol%)

Vinyl Fluorides

The use of transition metals in the preparation of vinyl fluorides has received some attention in recent years. In 2007, Sadighi and coworkers reported on the reversible addition of (1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene)AuF ((SIPr)AuF) to 3-hexyne in dichloromethane at room temperature.381 This gold(I)-catalyzed trans-hydrofluorination to prepare fluoroalkenes used the mild reagent Et3 N ⋅ 3HF as the HF source. The methodology had considerable substrate scope, which included application to dialkyl-, diaryl-, aryl/alkyl-, and thienyl/alkyl-substituted alkynes and represents a selective and potentially useful synthetic technique for the incorporation of fluorine. Me

R1

R2

F H

F

n-C6H13

Ph

Ar

Ar or

N

Ar

Ar (SIPr)

N Ar

Cl

F

n-C6H13

H

82% H11C5-n

F Ph 86%

N

H

74%

CH2Cl2, rt, 18–30 h

Ar

MeO

S

LAuX (2.5 mol%) PhNMe2·HOTf (10 mol%) Et3N·3HF (1.5 equiv) KHSO 4 (1 equiv)

H

L=

O

F

H

n-C5H11 81%

n-C6H13

53% + 10% isomer Ph H

F n-C6H13 72% + 6% isomer

Ar N Cl

Ar

(Cl IPr)

Ar = 2,6-( i Pr)2C6H3

Miller and coworkers published additional development for the reaction that included esters or nitrogen-containing directing groups onto the alkyne to allow Au(I)-catalyzed hydrofluorination of alkynes with reversal of regioselectivity. The authors discovered that 2,2,2-trichloroethoxycarbonyl(Troc)-carbamates were superior directing groups, providing high regioselectivity for both alkylarylalkynes and dialkylalkynes, as well as stability under the reaction conditions.382 381 Akana, J. A.; Bhattacharyya, K. X.; Mueller, P.; Sadighi, J. P. Journal of the American Chemical Society 2007, 129, 7736–7737. 382 Gorske, B. C.; Mbofana, C. T.; Miller, S. J. Organic Letters 2009, 11, 4318–4321.

339

340

6 Selected Catalytic Reactions i Pr

N O

O

Au i Pr Cl (2.5 mol%)

R2

R1

N

i Pr

CCl 3

O

HN

i Pr

HN R1

PhNMe 2·HOTf Et 3N·3HF AgBF4, KHSO 4 CH2Cl 2

R1 = H, Ph, i Pr R2 = alkyl, aryl

O H

O

Au L R2 Et 3N·3HF

R1

+ R2

F

O

O

HN R1

CCl 3 F

H

R2

16–74% yields Z selective regioselectivity up to >20 : 1

Proposed intermediates: HN

CCl 3

F

R2

HN

Au O

R1 (Et 3NH·2HF)+BF4–

O

L

CCl 3

Xu and coworkers used a C—H functionalization methodology that combined electrophilic fluoride reagents with vinyl-metal species to prepare vinyl fluorides.383 The chemistry utilized potassium nitrate as promoter, Pd2 (dba)3 or Pd(OAc)2 as metal catalyst, and N-fluorobenzenesulfonimide (NFSI) as the fluoride source for the reaction and provides the fluorinated substrates in moderate yield under mild conditions. R1

NOMe H

R2

Pd 2(dba) 3(10 mol%) KNO 3 (30 mol%)

R1

NFSI (1.5 equiv) CH3NO2, rt

R2

R3

6.17.3

NOMe F

R3 65–78% yield

𝛂-Fluorination of Carbonyl Compounds

In 2005, Sodeoka and coworkers published a Pd-catalyzed α-fluorination of oxindoles using (S)-DM-BINAP as ligand and NFSI as the source of fluorine.384 The optimal conditions included isopropanol or acetone as solvent, and a less acidic Pd complex to preserve the necessary Boc protecting group during the course of the reaction. The method provided good to excellent yields and enantioselectivity with reasonable substrate scope. F Me * F P R1 R2

P

H

N Boc

O

+ NFSI (1.5 equiv)

Pd

H O O H

Pd

P * P 2TfO–

i-PrOH *=

O

N Boc

O N Boc 94%, 84% ee

N Boc 96%, 90% ee

86%, 95% ee

Me OMe PAr2 PAr2

Ar = 3,5-M e2C6H3 (S)-DM-BINAP

* F

* F O N Boc 97%, 86% ee

* F O

* F

Me

O * F

O F3C

N Boc 80%, 75% ee

O N Boc 85%, 86% ee

383 Lou, S.-J.; Xu, D.-Q.; Xu, Z.-Y. Angewandte Chemie International Edition 2014, 53, 10330–10335. 384 Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. Journal of the American Chemical Society 2005, 127, 10164–10165.

6.17 Catalytic Metal-Mediated Methods for Fluorination

Kim and Kwon reported on the preparation of α-fluoro-β-ketoamides in high enantioselectivity using chiral palladium complexes and NFSI as fluorinating agent.385 For reaction optimization, the authors discovered that polar protic solvents and the noncoordinating base 2,6-di-tert-butyl-4-methyl pyridine (DTBMP) at room temperature provided the best results. High selectivity and yields were noted for both electron-donating and electronwithdrawing substitutions on the indanone ring and amide group of the ketoamides. A proposed mechanism of the reaction included activation of the β-ketoamide with a Pd(II) complex, followed by an abstraction of the acidic α-proton and formation of chiral PdII -enolate. Reaction of the enolate-complex with NFSI gives rise to product, while the loss of the N-benzenesulfonimide ligand regenerates the catalyst. The methodology was noted as being operationally simple, tolerant of air and moisture, and therefore could have further applications in organic synthesis.

O

O F

F

NHBn MeO

O O

O

O

NHR Catalyst (5 mol%) DTBMP IPA, rt

NHPh

O

Catalyst =

2+

PAr2 OH 2 Pd 2X– PAr2 NCMe

F

F

90%, 90% ee O

NHPh

O 89%, 85% ee

O

O

* P

NHBn

2+

Pd

O Pd-catalyst

P 2X– O NHBn

N(SO2Ph)2 HB+ +

NHPh

Proposed mechanism:

Ar = 3,5-Me2C6H3, X = PF6

–

F

O 88%, 75% ee

91%, 70% ee

NH Bn

O

90%, 86% ee O

F

F

NHBn

O

91%, 97% ee

FN(SO2Ph)2

O

BH X–

B (base) * L

X

P *

(PhO2S)2N

+

Pd

–

P

X–

O

O F

P

+

Pd

+

BH X–

P O

NFSI

NHBn

NHBn

O

Fu and coworkers reported Fe-catalyzed asymmetric couplings of aryl alkyl ketenes with NFSI and C6 F5 ONa to furnish tertiary α-fluoroesters.386 Mechanistic studies concluded that the addition of C6 F5 ONa facilitated turnover and catalyst release and that enantioselectivity arises from the turnover limiting transfer of fluorine to the chiral Fe-enolate complex from NFSI. The formed products were also used to prepare a variety of useful tertiary alkyl fluorides, including esters, amides, carboxylic acids, and alcohols. 385 Kwon, S. J.; Kim, D. Y. Journal of Fluorine Chemistry 2015, 180, 201–207. 386 Lee, S. Y.; Neufeind, S.; Fu, G. C. Journal of the American Chemical Society 2014, 136, 8899–8902.

341

342

6 Selected Catalytic Reactions

Fe

Me

Ar

Me (3 mol%)

Me

Ar R 84–98% yields 78–99%ee

F

MeO

MeOH, THF

F

C6F5O

O

Et 3N

O

F

Ar R 87%

Me

FN(SO2Ph) 2 C6F5ONa, THF, –78 °C

R

HO

H2O, THF

N Me O C

O

Et 3N

N

Ar R 90% F

HO

NaBH 4

Ar

THF

R

91% O

PhNH 2, Et 3N

PhHN

THF, 65 °C

F

Ar R 96%

An Ir-catalyzed conversion of allylic alcohols to α-fluoroketones was developed by Martín-Matute and coworker in 2011.387 The reaction proceeds by isomerization followed by C—F bond formation using Selectfluor , which was identified as the optimal fluoride source. A proposed mechanism for the reaction involves oxidation of the allylic alcohol, followed by coordination of Ir to the α-β-unsaturated ketone, and formation of an oxy-π-allyl Ir enolate that reacts with the electrophilic fluorinating reagent. The method was performed open to air, simple to set-up, and water was found to improve the reaction.

®

OH R1

R3 R2

[IrCp*Cl 2] 2 (1 mol%) Selectfluor (1.25 equiv) THF/H2O, 30 °C, 1–15 h

O R1

F R2

R3

60–92% yields

Proposed mechanism: O

OH

R1

H

O

R1

F

R1 O

HO

R1

H [Ir]

HO R1

6.17.4

[Ir-H]

R1

[Ir]

[Ir] H

H

Difluoromethylation (—CF2 R)

Compounds that possess the CHF2 R (R = alkyl, aryl, etc.) moiety are becoming increasingly popular in molecular design due to their ability to act as bioisosteres and use as competent mimics of the hydroxyl, amino, and thio functional groups. The CF2 H moiety can also improve binding selectivity in biological systems, since it is weakly acidic and can participate via hydrogen bonding. Given its increasing importance, improved methods for difluoroalkylation are needed.388 Ni catalysis using zinc reagents have been used effectively to install CF2 H onto aryl halides.389 The Zn reagent was prepared by reacting ICF2 H with diethyl zinc in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU). The difluoromethyl complex is easy to handle, free flowing, and reportedly stable under inert atmosphere for 387 Ahlsten, N.; Martín-Matute, B. Chemical Communications 2011, 47, 8331–8333. 388 Yerien, D. E.; Barata-Vallejo, S.; Postigo, A. Chemistry - A European Journal 2017, 23, 14676–14701. 389 Xu, L.; Vicic, D. A. Journal of the American Chemical Society 2016, 138, 2536–2539.

6.17 Catalytic Metal-Mediated Methods for Fluorination

months but is air and moisture sensitive. Although the methodology requires higher catalyst loadings to compensate for lower turnover numbers, the use of a first-row transition metal with a number of aryl bromides, chlorides, and triflates is encouraging. The phosphine ligand is a good starting point to investigate how this could be modified to enable difluoromethylation of electron-rich aryl halide substrates. Following the initial report by Vicic, the group of Mikami published a similar procedure that employs Cu salts as catalyst without any added ligand.390 CF2H R X R

ICF2H + ZnEt 2

DMPU

(DMPU)2Zn

CF2H (dppf)Ni(COD) (15 mol%) DMSO, 20 °C, 24 h

CF2H

entry

X

R

yield

1 2 3 4 5 6 7 8 9

I I I I Br Br Br OTf OTf

H 4-Ph 4-F 4-CHO 4-Ph 4-F 2-COPh H 4-COMe

82% 80% 61% 81% 85% 78% 71% 58% 85%

A similar reagent, (TMEDA)Zn(CF2 H)2 , was used in a palladium-catalyzed process also by the Makami group.391 Electron-rich and electron-withdrawing aryliodides were competent substrates for the difluoromethylation and provided good to excellent yields with the exception of isoquinoline and ortho-disubstituted compounds. Arylbromides possessing electron-donating or withdrawing groups in the ortho and para positions could also be coupled but required the use of Xphos in place of DPPF as ligand. CF2H

CF2H O2N

NC I R

(TMEDA)Zn(CF 2H)2 Pd(dba)2 (5 mol%)

81%

CF2H

Cl

CF2H

EtO2C

80%

97%

71% Cl

DPPF (10 mol%) 1,4 dioxane, 120 °C, 6 h

CF2H

Me

CF2H

N

Ph

N

CF2H AcO O

Me 91%

99%

42%

N

AcO OAc

N N

CF2H

70%

Amii and coworkers described a novel approach to the preparation of difluoromethyl compounds by first using a copper-catalyzed cross-coupling of aryl iodides with α-silylfluoroacetates.392 The coupled products were then hydrolyzed to carboxylic acids that underwent decarboxylation at elevated temperatures to form difluoromethylated substrates in moderate to good yield. Systematic optimization was required to identify 2-(triethylsilyl)-2, 2-difluoroacetate as the coupling partner, DME as the solvent, and KF as the superior promoter for the decarboxylation reaction. Coupling I R

CuI (20 mol%) Me3SiCF 2CO2Et (1.2 equiv) CsF (1.2 equiv) DME, 60 °C

Hydrolysis F

F

CO2Et

R

Decarboxylation F

K 2CO3 MeOH/H2O

F

CO2H

R

40–71% yields

390 Serizawa, H.; Ishii, K.; Aikawa, K.; Mikami, K. Organic Letters 2016, 18, 3686–3689. 391 Aikawa, K.; Serizawa, H.; Ishii, K.; Mikami, K. Organic Letters 2016, 18, 3690–3693. 392 Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Organic Letters 2011, 13, 5560–5563.

CF2H

KF, DMF/NMP 170–200 °C

R 57–89% yields (over 2 steps)

343

344

6 Selected Catalytic Reactions

6.17.5

Trifluoromethylation (—CF3 )

In the agrochemical and pharmaceutical industries, the trifluoromethyl group is often encountered in molecules of interest due to a number of beneficial properties mentioned earlier in this chapter. Many synthetic approaches have appeared in the literature to identify selective and mild conditions to install —CF3 using transition and base metal-catalysis, and it is expected for this area of research to see continued growth.393,394,395,396 Copper catalysis was one of the first metal-mediated processes to appear for installation of the trifluoromethyl functional group. Chen and Wu reported copper-catalyzed trifluoromethylations of aryl, alkenyl, and alkyl halides using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (DFSA) as the —CF3 source.397 Later, Amii and coworkers used a Cu-catalyzed process with triethyl(trifluoromethyl) silane as the —CF3 source to convert aryl iodides to trifluoromethylated arenes.398 The method was tolerant of a number of functional groups and most effective with iodobenzenes containing electron-withdrawing groups. The reaction was also useful in the trifluoromethylation of heteroaromatics. I

CF3

2 equiv TES-CF3 R

10 mol% CuI 10 mol% 1.10-phenantroline 2 equiv KF NMP-DMF (1 : 1), 60 °C, 24 h

CF3

CF3

CN

CO2Et

80%

CF3

Cl

89%

63% CF3

N 99%

CF3

Cl

N 69%

R

CF3

CF3

NO2

Bu

90%

44%

CF3 Me NO2 90%

S

CF3

63%

In 2010, Buchwald and coworkers published a breakthrough palladium-catalyzed trifluoromethylation of aryl chlorides in excellent yields albeit at high temperature by a careful choice of ancillary ligands.399 The chemistry had significant substrate scope and demonstrated the feasibility of C—C reductive elimination from [LPdII (Ar)CF3 ] complexes. To explore the mechanism of the reaction, the group prepared the suspected Ar-Pd-CF3 intermediates and studied the reductive elimination, as well as performing density functional theory calculations to predict the required activation energy of the necessary transition states. This investigation further supported a classical Pd(0)/Pd(II) catalytic cycle. In 2011, the —CF3 methodology was expanded to include coupling with cyclohexenyl triflates and nonaflates using the more hindered phosphine ligand tBuXPhos.400 393 394 395 396 397 398 399 400

Chen, P.; Liu, G. Synthesis 2013, 45, 2919–2939. Schlosser, M. Angewandte Chemie International Edition 2006, 45, 5432–5446. Tomashenko, O. A.; Grushin, V. V. Chemical Reviews 2011, 111, 4475–4521. Chen, C.; Fu, L.; Chen, P.; Liu, G. Chinese Journal of Chemistry 2017, 35, 1781–1788. Chen, Q.; Wu, S. Journal of the Chemical Society, Chemical Communications 1989, 705–706. Oishi, M.; Kondo, H.; Amii, H. Chemical Communications 2009, 1909–1911. Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679–1681. Cho, E. J.; Buchwald, S. L. Organic Letters 2011, 13, 6552–6555.

6.17 Catalytic Metal-Mediated Methods for Fluorination

Cl

CF3

2 equiv TES-CF3 R

3 mol% [(allyl)PdCl]2 9 mol% BrettPhos 2 equiv KF dioxane, 130 °C, 6–20 h CF3

CF3

CF3

nBu

Ph

80%

84%

R

CF3

CF3

CO2Hex

Me

83%

EtO

NO2

OEt

72%

70%

O

N S

CF3

N

CF3

Ph

CF3 90%

94%

N 82%

Iron has also been employed in trifluoromethylation reactions. In 2012, Buchwald reported an FeII -catalyzed trifluoromethylation of potassium vinyltrifluoroborates in good yields and excellent E/Z ratios under mild reaction conditions.401 The researchers noted that although a radical-type mechanism could be invoked to explain this reactivity, it is more likely that the reaction proceeds via a Lewis acid–catalyzed carbocation intermediate. F3C

I

O CF3

O

R

BF3K

(1.0 equiv) FeCl 2 (10 mol%) CH3CN, rt, 24 h

Me

70% (>95:5 E/Z ) CF3

N Ts 65% (>95:5 E/Z )

CF3 Cl

MeO

78% (>95:5 E/Z)

MeO

CF3

CF3

OMe 73% (>95:5 E/Z)

68% (>95:5 E/Z) CF3

S 74% (>95:5 E/Z)

In 2013, Gouverneur and coworkers reported the AgI -catalyzed decarboxylative fluorination of α-fluoro and α,α-difluoro phenylacetic acid derivatives using Selectfluor as the source of fluoride.402 The mild method was capable of furnishing both difluoromethyl and trifluoromethyl aromatic compounds in low to high yields and could prove useful in [18 F]-labeled biomarkers for applications in positron emission tomography (PET). It was found that electron 401 Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angewandte Chemie International Edition 2012, 51, 2947–2950. 402 Mizuta, S.; Stenhagen, I. S. R.; O’Duill, M.; Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Organic Letters 2013, 15, 2648–2651.

345

346

6 Selected Catalytic Reactions

withdrawing groups on the aromatic ring had a negative effect on the fluorination outcome for trifluoromethylated analogs. The authors suggest that this limitation could be due to carboxylic acid substrates lacking a functional group capable of quenching the formed radical.

CO2H F AgOAc (20 mol%) F Selectfluor (2 equiv)

R

CO2H acetone/H2O (1:1) 55 °C, 1 h H F

R

Trifluoromethyl preparation CF3 MeO

OMe

CF3

Me

MeO 82%

86%

88%

N H 86%

Difluoromethyl preparation CHF2

MeO

CHF2

CHF2 Ph

72%

6.17.6

CF3

O

CF3

83%

CHF2 Br

91%

82%

Emerging Methods for Metal-Catalyzed Fluorination

A number of new catalytic methods have been reported for the synthesis of fluorinated organic molecules. Many of these approaches still require additional investigation before application to preparative scale chemistry and practical application, but additional development and mechanistic understanding could provide new possibilities to the practicing synthetic chemist. Doyle and Katcher published formation of enantio-enriched allylic fluorides from racemic allylic chlorides using Pd2 (dba)3 , a commercially available Trost bisphosphine ligand,403 and AgF as the source of fluoride.404 Mechanistic evidence points to an oxidative addition of Pd(0) to the allylic chloride which proceeds with inversion of configuration. A subsequent SN 2-type attack of the fluoride onto a PdII -allyl intermediate proceeds with inversion, which results in overall retention of configuration for the reaction. Outer-sphere fluoride addition LPd II H

X

X X = C, O, N racemic

AgF (1.1 equiv) THF, rt, 24 h

Ligand = O

NH HN PPh 2 Ph 2P

O

N Ts

O 85% yield 88% ee

F

Pd 2(dba) 3 (5 mol%) ligand (10 mol%)

Cl

F

F

F

62% yield 90% ee

F

74% yield 96% ee F

F

CO2Me

CH2OTBS 56% yield 93% ee 7: 1 dr

70% yield 91% ee 3: 1 dr F

CO2Me 68% yield 90% ee 14:1 dr

F

O

Me N OMe

85% yield 85% ee >20 : 1 dr

Me

OH Me

59% yield 87% ee 20 :1 dr

A chemoselective Cu-catalyzed fluorination of alkyl triflates was reported by Lalic and coworkers in 2014.405 Using KF as the fluoride source, the authors proposed an SN 2-type mechanism that proceeded under phase transfer conditions by generating [IPrCuF] in situ. The mild conditions suppressed common side reactions, such as elimination, and showed 403 Trost, B. M.; Van Vranken, D. L.; Bingel, C. Journal of the American Chemical Society 1992, 114, 9327–9343. 404 Katcher, M. H.; Doyle, A. G. Journal of the American Chemical Society 2010, 132, 17402–17404. 405 Dang, H.; Mailig, M.; Lalic, G. Angewandte Chemie International Edition 2014, 53, 6473–6476.

6.18 Selected Metal-Mediated C—H Functionalization

good functional group compatibility overall. Reducing the catalyst to as low as 0.2 mol% was also effective but required 16 hours to reach reaction completion. i

Pr

i Pr

N

N

Cu i Pr OTf (2 mol%) KF (3 equiv)

i

R OTf

Pr

R F 51–95% yields

1,4-dioxane, 45 °C, 1 h

proposed mechanism: LCu OTf R F

KF

R OTf

KOTf

LCu F

In 2012, Letcka and coworkers disclosed the fluorination of C—H bonds using a polycomponent catalytic method that featured Cu(I)bis(imine), the radical precursor N-hydroxyphthalimide, an anionic phase transfer catalyst KB(C6 F5 )4 , and Selectfluor as the source of fluoride.406 Although a thorough investigation of the reaction mechanism was not carried out, the authors noted that initial evidence and preliminary data suggests a radical or SET during the fluorination event. A number of alkyl, benzylic, and allylic C—H bonds were fluorinated selectively in low to moderate yields under these mild conditions. Catalyst (10 mol%) KB( C6F5)4 (10 mol%) NHPI (10 mol%) Selectfluor (2.2 equiv)

R H Catalyst: Ph

N

6.17.7

R F

MeCN, 0 °C NHPI:

Cu I

N

Ph

33–72% yields O N OH O

Summary and Outlook for Metal-Catalyzed Fluorination

Given the importance of fluorinated organic molecules emerging from the pharmaceutical, agrochemical, and material science industries, several metal-catalyzed methodologies have been developed. A variety of aromatic, aliphatic, and vinylic compounds containing fluorine can be synthesized today because of recent advances in the field of transition and base-metal catalysis. It is highly likely that improvements to these methods will include increased focus on abundant and inexpensive first-row transition metals, which will improve the utility and practicality of fluorinations. In addition, a variety of new fluorinated classes of molecules are emerging with interesting properties. New methods will be needed that can identify practical and robust reaction conditions for the preparation of difluoromethyl (—CF2 H), trifluoromethylthio (CF3 S), and trifluoromethoxy (OCF3 ) functionalities.

6.18 Selected Metal-Mediated C—H Functionalization 6.18.1

Introduction

The selective functionalization of ubiquitous C—H bonds can obviate the need for a functional group, such as a halide, as the site of a reaction. This strategy has the potential to significantly impact synthetic organic chemistry. Impressive progress has been made in the past two decades with regard to the selectivity, yield, and ease of operation to convert a C—H bond to a more useful synthon. However, many of the known methodologies have 406 Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angewandte Chemie International Edition 2012, 51, 10580–10583.

347

348

6 Selected Catalytic Reactions

limitations for widespread applications, such as high catalyst loading, high reaction temperatures, and need of a strong oxidant. The progress, scope, and application of C—H functionalization methodologies have been extensively reviewed.407,408,409,410,411,412,413,414 This chapter will focus primarily on metal-mediated C—H functionalization techniques with particular emphasis on identifying robust, reliable, safe, and practical reaction conditions that could be relevant to small and, potentially large-scale applications, based on our judgment. Limitations of the current methodologies with respect to larger scale applications will be discussed where relevant. Our discussion will be focused on the most developed methods based on Pd, Rh, Ir, and Ru catalyst. Several promising methodologies based on nonprecious metals are being reported but will not be a part of our discussions. The C—H functionalization methods will be categorized as directed, functionalization with the aid of an existing functional group, or undirected, functionalization without the requirement of chelation of an existing functional group to the catalyst, for the ease of discussion. Both of these approaches are highly valuable for the synthesis of complex organic molecules. 6.18.2

Metal-Catalyzed, Directed C—H Functionalization

The site selectivity in directed C—H functionalization methods is governed with a preexisting functional group (directing group) on the molecule. Heteroatoms such as oxygen, nitrogen, and silicon are effective directing groups for C—H functionalization. Several transition metals such Ru,415,416,417,418,419 Pd,420,421,422,423 Ir, Rh, etc. have been used for catalytic, directed C—H functionalization. This section is subdivided based on the transition metal used for the catalysis. 6.18.2.1

Ru-Catalyzed Methods

The pioneering report by Murai et al.424 has inspired development of numerous other useful methods. O R1

R2

Y

+

O

RuH2(CO)(PPh3) (2–6 mol%)

R1

R2

Toluene, reflux

Y

Numerous conditions for the functionalization of aryl carboxylic acids have been reported.425,426,427,428 O R1

OH + R 2

X

X = I, Br, Cl, OTf

[Ru] (0.5–10 mol%) L (3–10 mol%) Solvent, base 100–140 °C Base, MeI

O R1

OMe R2

[Ru] = [RuCl2(p-cymene)]2, [Ru(O2CMes)2(p-cymene)], [Ru(t-BuCN)6](BF4)2 L = PCy3, PEt3HBF4, DL-pipecolinic acid, Solvent = NMP, t-BuCN, base = K2CO3, Cs2CO3 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428

He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chemical Reviews 2017, 117, 8754–8786. Hartwig, J. F.; Larsen, M. A. ACS Central Science 2016, 2, 281–292. Hartwig, J. F. Journal of the American Chemical Society 2016, 138, 2–24. Ros, A.; Fernandez, R.; Lassaletta, J. M. Chemical Society Reviews 2014, 43, 3229–3243. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angewandte Chemie International Edition 2012, 51, 8960–9009. Kakiuchi, F.; Murai, S. Accounts of Chemical Research 2002, 35, 826–834. Davies, H. M. L.; Morton, D. The Journal of Organic Chemistry 2016, 81, 343–350. Gensch, T.; James, M. J.; Dalton, T.; Glorius, F. Angewandte Chemie International Edition 2018, 57, 2296–2306. See Note 412. Nareddy, P.; Jordan, F.; Szostak, M. ACS Catalysis 2017, 7, 5721–5745. Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chemical Reviews 2012, 112, 5879–5918. De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Advanced Synthesis & Catalysis 2014, 356, 1461–1479. Ackermann, L. Accounts of Chemical Research 2014, 47, 281–295. See Note 407. Daugulis, O.; Do, H.-Q.; Shabashov, D. Accounts of Chemical Research 2009, 42, 1074–1086. Ye, J.; Lautens, M. Nature Chemistry 2015, 7, 863–870. Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chemical Society Reviews 2011, 40, 4740–4761. Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. Biafora, A.; Krause, T.; Hackenberger, D.; Belitz, F.; Gooßen, L. J. Angewandte Chemie International Edition 2016, 55, 14752–14755. Huang, L.; Weix, D. J. Organic Letters 2016, 18, 5432–5435. Mei, R.; Zhu, C.; Ackermann, L. Chemical Communications 2016, 52, 13171–13174. Simonetti, M.; Cannas, D. M.; Panigrahi, A.; Kujawa, S.; Kryjewski, M.; Xie, P.; Larrosa, I. Chemistry - A European Journal 2017, 23, 549–553.

6.18 Selected Metal-Mediated C—H Functionalization

A wide variety of aryl carboxylic acids couple with aromatic halides to form the corresponding biaryl in synthetically useful yields. The coupled product is typically isolated as a methyl ester. A few examples of heteroaromatic carboxylic acids and heteroaryl halides have also been reported.429 The ability to use heteroaromatic electrophiles is a major advantage of Ru-based method over Pd-catalyzed methods.430,431,432 A few examples of alkenyl and alkynyl halides as electrophiles have also been reported.433 A combination of Ru-precursor with an electron-rich phosphine or nitrogen ligands434 in a polar solvent such as NMP or t-BuCN is required. The reactions are believed to proceed via Ru(II)/Ru(IV) catalysis. Lowering of catalyst loading combined with the use of less polar solvents will likely allow this method to be applied at larger scales.435 Hydroarylation of heterocyclic-2-carboxylic acids have been used to functionalize thiophene, benzothiophene, benzofuran, pyrrole, indole, etc.436 R

CO2H +

X

CO2R

X = O, S, NMe

(i) [RuCl2(p-cymene)]2 (2 mol%) Cu(OAc)2·H2O (2 equiv) LiOAc (3 equiv), DMF, 80 °C (ii) MeI, K2CO3

X

CO2Me

Isocumarins and α-pyrines can be synthesized by annulation reactions with alkynes.437,438 O CO2H

or

R1

+ R2

X

O

R1

R1

CO2H

R3

[RuCl2(p-cymene)]2 (2 mol%) Additive (10–20 mol%) Cu(OAc)2·H2O (0.2–2 equiv) Solvent, 100–120 °C

R2 R3 or R3

R2 O

Additive = KPF6 or AgSbF6 R1 Solvent = t-AmOH or t-BuOH or DCE

X

O

Oxidative Fujiwara-Moritani–type alkenylation with aromatic esters as the directing group is a useful method for the introduction of alkenyl group without the need to prefunctionalize the substrate, as for Heck coupling.439,440,441,442 However, the drawback is need for air or strong oxidants in the reaction. O OR2

R1 H

+

CO2R3

[RuCl2(p-cymene)]2 (5 mol%) AgSbF6 (20–50 mol%) Cu(OAc)2·H2O (0.2–2 equiv) DCE, air, 100–120 °C

O R1

OR2

CO2R3

Ketones are effective directing groups for various C—H arylation 443,444 and alkenylation445 reactions. 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445

See Note 426. Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Accounts of Chemical Research 2012, 45, 788–802. Chiong, H. A.; Pham, Q.-N.; Daugulis, O. Journal of the American Chemical Society 2007, 129, 9879–9884. Cornella, J.; Righi, M.; Larrosa, I. Angewandte Chemie International Edition 2011, 50, 9429–9432. See Note 427. DL-pipecolinic acid is used as the ligand for coupling aryl chlorides. See Note 428. Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Organic Letters 2011, 13, 706–708. Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Organic Letters 2012, 14, 930–933. Chinnagolla, R. K.; Jeganmohan, M. Chemical Communications 2012, 48, 2030–2032. See Note 418. Yang, Y.; Lin, Y.; Rao, Y. Organic Letters 2012, 14, 2874–2877. Padala, K.; Jeganmohan, M. Organic Letters 2011, 13, 6144–6147. Reddy, M. C.; Jeganmohan, M. European Journal of Organic Chemistry 2013, 2013, 1150–1157. Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. Journal of the American Chemical Society 2005, 127, 5936–5945. Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. Journal of the American Chemical Society 2003, 125, 1698–1699. See Note 441.

349

350

6 Selected Catalytic Reactions

O + Ar B

R2

R1

RuH 2(CO)(PPh 3) 2 mol % Toluene, reflux

O O

O R2

R1

Ar

[RuCl2(p-cymene)]2 (2 mol%) AgSbF6 (10 mol%)

O R2

R1

R3

+

O

Cu(OAc)2·H2O (25 mol%) DCE or t-BuOH, 110 °C

R2

R1

R3

Hydroxyl group has also been found as effective directing group for C—H alkynylation.446,447,448,449 R2

R3

OH

R4

[RuCl2(p-cymene)]2 (2.5 mol%) Cu(OAc)2 (2.1 equiv) K2CO3 (2.0 equiv), 1,4-dioxane, 90 °C

R1

R2

R3 R4 O

R1

A few examples of anilides450,451 and amides452,453 as directing groups in hydroarylation of alkynes have also been reported. H N 1

R

H

R2

R

H

+

O

O 1

R3

N H

4

R

R3

R2 +

4

R

[RuCl2(p-cymene)]2 (5 mol%) AgSbF6 (20 mol%) PivOH (5.0 equiv) i-PrOH, 100 °C

[RuCl2(p-cymene)]2 (5 mol%) Cu(OAc)2·H2O (2 equiv) t-AmOH, 100 °C

R2

O

NH R1

R3 R4 O

R

N

1

R4

R2 R3

Several examples of N-heterocyclic arene directed C(sp2 )—H arylations have been reported and have been reviewed.454 Strongly coordinating heterocycles such as pyridine, pyrimidine, pyrazole, oxazoline, etc. have been used as directing groups. Given the low cost of Ru and relatively simple reaction conditions (no stoichiometric salts or requirement of oxidants), these methods are very useful for functionalization of heteroaromatic compounds. A few examples of C(sp3 )—H arylation have also been reported.455,456,457,458 Nitrogen-directed, Ru-catalyzed C—H arylation methods have been used for the synthesis of medicinally relevant compound on multigram to kilo gram scale. For example, C—H arylation was a key step in the synthesis of anacetrapib on kilo scale.459 446 Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang, Y. Journal of the American Chemical Society 2013, 135, 17306–17309. 447 Thirunavukkarasu, V. S.; Donati, M.; Ackermann, L. Organic Letters 2012, 14, 3416–3419. 448 Dooley, J. D.; Reddy Chidipudi, S.; Lam, H. W. Journal of the American Chemical Society 2013, 135, 10829–10836. 449 Reddy Chidipudi, S.; Wieczysty, M. D.; Khan, I.; Lam, H. W. Organic Letters 2013, 15, 570–573. 450 Manikandan, R.; Jeganmohan, M. Organic Letters 2014, 16, 912–915. 451 Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Organic Letters 2012, 14, 728–731. 452 Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M. Organic Letters 2012, 14, 2058–2061. 453 Reddy, M. C.; Manikandan, R.; Jeganmohan, M. Chemical Communications 2013, 49, 6060–6062. 454 See Note 416. 455 Pastine, S. J.; Gribkov, D. V.; Sames, D. Journal of the American Chemical Society 2006, 128, 14220–14221. 456 Peschiulli, A.; Smout, V.; Storr, T. E.; Mitchell, E. A.; Eliáš, Z.; Herrebout, W.; Berthelot, D.; Meerpoel, L.; Maes, B. U. W. Chemistry - A European Journal 2013, 19, 10378–10387. 457 Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D. Organic Letters 2012, 14, 3792–3795. 458 Kumar, N. Y. P.; Jeyachandran, R.; Ackermann, L. The Journal of Organic Chemistry 2013, 78, 4145–4152. 459 See Note 49.

6.18 Selected Metal-Mediated C—H Functionalization

MeO N

F 3C

F

+ Br

O

i-Pr

MeO

F

[RuCl 2(benzene) ] 2 (1 mol%) PPh 3 (2 mol%), K 3PO4 (2 equiv) AcOK (10 mol%), NMP, 120 °C

i-Pr F3C

N 96% (4.4 kg)

O

Angiotensis II receptors were prepared on multigram scale by C—H arylation of 5-aryltetrazoles.460,461 BzO N N N N Bn

[RuCl 2( p-cymene) ] 2 (0.5 mol%) OBz PPh 3 (1.0 mol%) TMBSK (1.0 mol%)

+

N N N N Bn

K 2CO3 (1.0 equiv), NMP, 138 °C Br

Me

Me

KO 3S Me TMBSK

6.18.2.2

Palladium-Catalyzed Methods

Numerous creative methods of directed Pd-catalyzed C—H functionalization, including enantioselective methods, have been reported and reviewed.462,463,464,465,466,467,468,469,470,471 Pd-based catalysts appear to be more effective than other metal catalysts for functionalization of C(sp3 )—H bonds.472 An approach that utilizes transient directing groups to functionalize C—H bonds of aldehydes and ketones is attractive and is likely to be applied for large-scale applications upon further optimization.473,474,475,476

O O

R H

+ X N O X = Br, C l

Pd(OAc)2 (10 mol%) TG (30–50 mol%) AgOOCCF 3 (10 mol%) TFA, DCE, 60 °C H2N

H2N

HO2C

HO2C

O

R X NO2

TG (Transient Group)

460 Seki, M. ACS Catalysis 2014, 4, 4047–4050. 461 Ackermann, L. Organic Process Research & Development 2015, 19, 260–269. 462 Li, G.; Wan, L.; Zhang, G.; Leow, D.; Spangler, J.; Yu, J.-Q. Journal of the American Chemical Society 2015, 137, 4391–4397. 463 See Note 407. 464 See Note 369. 465 See Note 423. 466 Yu, J.-Q.; Giri, R.; Chen, X. Organic & Biomolecular Chemistry 2006, 4, 4041–4047. 467 Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. Journal of the American Chemical Society 2002, 124, 1586–1587. 468 Moghaddam, F. M.; Tavakoli, G.; Saeednia, B.; Langer, P.; Jafari, B. The Journal of Organic Chemistry 2016, 81, 3868–3876. 469 Zhu, C.; Zhang, Y.; Kan, J.; Zhao, H.; Su, W. Organic Letters 2015, 17, 3418–3421. 470 Zhu, R.-Y.; Saint-Denis, T. G.; Shao, Y.; He, J.; Sieber, J. D.; Senanayake, C. H.; Yu, J.-Q. Journal of the American Chemical Society 2017, 139, 5724–5727. 471 Liu, Y.; Ge, H. Nature Chemistry 2017, 9, 26–32. 472 See Note 407. 473 Liu, X.-H.; Park, H.; Hu, J.-H.; Hu, Y.; Zhang, Q.-L.; Wang, B.-L.; Sun, B.; Yeung, K.-S.; Zhang, F.-L.; Yu, J.-Q. Journal of the American Chemical Society 2017, 139, 888–896. 474 Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252–256. 475 Ma, F.; Lei, M.; Hu, L. Organic Letters 2016, 18, 2708–2711. 476 Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. Journal of the American Chemical Society 2016, 138, 12775–12778.

351

352

6 Selected Catalytic Reactions

Primary amines can direct C—H arylation using transient directing groups.477,478,479 N-pentafluoroaryl amide has turned out to be a general directing group is a variety of C(sp3 )—H functionalization reactions. 480,481,482 In a particularly impressive example, diverse 4-aryl-2-quinolines were prepared by cleavage of five C—H bonds in one-pot.483 F F H

F

HN

F O

R

F

F

R + Ar2I

H

F

PdCl2 (10 mol%) 2,5-lutidine (20 mol%)

F

N

Ag2CO3 (2 equiv) t-AmOH, 140 °C, 24 h

Ar2

O 60–85%

F F

C—H functionalization of triflyl- and nosyl-protected amines484,485,486 and sterically hindered secondary amines487,488,489 are other potentially useful synthetic strategies based on Pd catalysis. Anilide directed ortho-C—H functionalization enables reactions of arenes with acrylates under mild reaction conditions.490 Recently, mild conditions were reported for C—H alkenylation of heteroarenes using thioether ligands under mild reaction conditions.491 Highly impressive advances have been made in Pd-catalyzed C—H functionalization; however, only a handful of large-scale applications are known. The most notable limitations of the current methods are high loadings of expensive metal, Pd,492 need for strong oxidatants and synthetically restricting directing group. A few examples that can potentially be applied on large scales, based on our judgment, are discussed in the following. C—H bonds in (hetero)arenes can add across alkynes in the presence of electrophilic Pd(II) catalyst at RT in the absence of strong oxidants and in the presence of low metal loadings in certain cases.493,494 R1

H + R1

R X

O

R

X = O, N

X

Pd(OAc)2 (0.02–5 mol%) TFA/CH2Cl2 (4:1), rt

Pd(OAc)2 (3 mol%) TFA/CH2Cl2 (3:1), rt

H X = O, N

R2

X

R2

O

R R1

R1 H + R1

H R

EtO2C CO2Et

Pd(OAc)2 (5 mol%) AcOH, rt

X

R1

477 Wu, Y.; Chen, Y.-Q.; Liu, T.; Eastgate, M. D.; Yu, J.-Q. Journal of the American Chemical Society 2016, 138, 14554–14557. 478 See Note 471. 479 Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. Nature 2016, 531, 220–224. 480 Wasa, M.; Engle, K. M.; Yu, J.-Q. Journal of the American Chemical Society 2009, 131, 9886–9887. 481 See Note 407. 482 The pentafluoroaryl amide can be hydrolyzed either with 2 N KOH in ethylene glycol at 80 oC or by treatment with MeI/Na2 CO3 followed by 2 N HCl at RT. 483 Deng, Y.; Gong, W.; He, J.; Yu, J.-Q. Angewandte Chemie International Edition 2014, 53, 6692–6695. 484 Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J.-Q. Nature Chemistry 2014, 6, 146–150. 485 Leal, R. A.; Bischof, C.; Lee, Y. V.; Sawano, S.; McAtee, C. C.; Latimer, L. N.; Russ, Z. N.; Dueber, J. E.; Yu, J.-Q.; Sarpong, R. Angewandte Chemie International Edition 2016, 55, 11824–11828. 486 Jiang, H.; He, J.; Liu, T.; Yu, J.-Q. Journal of the American Chemical Society 2016, 138, 2055–2059. 487 McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. 488 Smalley, A. P.; Gaunt, M. J. Journal of the American Chemical Society 2015, 137, 10632–10641. 489 He, C.; Gaunt, M. J. Angewandte Chemie International Edition 2015, 54, 15840–15844. 490 See Note 467. 491 Gorsline, B. J.; Wang, L.; Ren, P.; Carrow, B. P. Journal of the American Chemical Society 2017, 139, 9605–9614. 492 Ru is approximately 10 times cheaper than Pd. 493 Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995. 494 Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Organic Letters 2000, 2, 2927–2930.

6.18 Selected Metal-Mediated C—H Functionalization

6.18.2.3

Rhodium-Catalyzed Methods

Impressive advances in O- and N-directed, Rh-catalyzed C—H functionalization have been reported and reviewed.495,496,497,498,499 Similar to the limitations of Pd-catalyzed methods, the applications of current Rh-catalyzed methods for large-scale applications are currently limited due to high catalyst loading, requirement of stoichiometric additives, specific directing groups, and strong oxidants. A few currently available methods that can potentially be used for large-scale applications are discussed in the following. Ortho olefination and vinylation of acetanilides in the presence of acceptable catalyst loading (1 mol% Rh) is reported.500 Trans-olefin is formed at the least sterically hindered carbon. 501,502,503 H N R H 1 equiv

Me O

+

[RhCp*Cl2]2 (0.5 mol%) AgSbF6 (2 mol%) Cu(OAc)2 (2.1 equiv)

R1

H N R

t-AmOH, 120 °C

Me O

1.5 equiv

R1

R = OCH3, CF3, Cl, OAc R1 = Cl, Br, OMe, Ph, H, CO2n-Bu

Reactions of acetophenone-derived oximes with alkynes in the presence of an Rh catalyst forms isoquinolines under mild conditions.504 Me

R1

NOH

[RhCp*Cl2]2 (1 mol%) CsOAc (30 mol%)

+

H

Me N

MeOH, 60 °C R2

R1 R2

Aromatic benzamides, with built-in oxidants, react with olefins under mild reaction conditions to form E-isomer of the ortho-olefinated product.505 O R H

6.18.3

N H

OMe

+

R1

[RhCp*Cl 2] 2 (1 mol%) CsOAc (30 mol%) MeOH, 40–60 °C

O R

NH2 R1

Metal-Catalyzed Undirected C—H Functionalization

Fewer catalytic methods are reported for selective, undirected C—H transformations than for directed C—H functionalizations. The known methods are capable of converting arene C—H bonds to C—B, C—Si, C—C, and C—X (X = N, O, S) bonds. This section is subdivided based on the identity of the forming bond. The guiding principles for selectivity will be highlighted whenever possible. 6.18.3.1

Formation of C—B Bonds

Ir-catalyzed transformations of C—H bonds in arenes and heteroarenes to C—B bonds is one of the most developed and useful methods. Combinations of Ir (I) precursors with nitrogen ligands catalyze the reactions of arenes with B2 pin2 or HBpin to form aryl boron compounds.506,507 495 Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Accounts of Chemical Research 2012, 45, 814–825. 496 Song, G.; Li, X. Accounts of Chemical Research 2015, 48, 1007–1020. 497 Song, G.; Wang, F.; Li, X. Chemical Society Reviews 2012, 41, 3651–3678. 498 Das, R.; Kumar, G. S.; Kapur, M. European The Journal of Organic Chemistry 2017, 2017, 5439–5459. 499 See Note 423. 500 Patureau, F. W.; Glorius, F. Journal of the American Chemical Society 2010, 132, 9982–9983. 501 Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. Journal of the American Chemical Society 2008, 130, 16474–16475. 502 Zhang, H.-J.; Lin, W.; Su, F.; Wen, T.-B. Organic Letters 2016, 18, 6356–6359. 503 Morita, T.; Satoh, T.; Miura, M. Organic Letters 2017, 19, 1800–1803. 504 Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Advanced Synthesis & Catalysis 2011, 353, 719–723. 505 Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. Journal of the American Chemical Society 2011, 133, 2350–2353. 506 Hartwig, J. F. Accounts of Chemical Research 2012, 45, 864–873. 507 Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Smith, M. R. Journal of the American Chemical Society 2013, 135, 7572–7582.

353

354

6 Selected Catalytic Reactions

H R1

+

B 2Pin 2

[Ir](0.2–3 mol%) L (0.2–3mol%) Solvent

Bpin R1

[Ir] = [Ir(OMe)(COD)]2, Solvent = Hexane, THF Ligand (L) t-Bu

t-Bu N

Me

Me

Me

N

N

Me

N

The regioselectivity in arenes is governed exclusively by steric effects508,509 and by a combination of steric and electronic effects in hetero arenes.510,511 Excellent functional group tolerance is observed under the reaction conditions. The standard reaction conditions to functionalize arenes have been applied for the synthesis of natural products512 and biomolecules.513 [Ir(OMe)(COD)] 2 (0.8–1 mol%) 2,2ʹ-bpy (3.2–4 mol%) I B 2Pin 2

Cl

Cl

I

Cyclohexane, 50 °C BPi n

75 Kg

6.18.3.2

Oxone (25% H2O) Acetone 0–10 °C 94%

Cl

I

OH

Formation of C—Si Bonds

The transformation of (hetero)arene C—H bonds to C—Si bonds is most effectively catalyzed by combination of Rh precursors with bidentate phosphine ligands514 and by combination of Ir precursors515,516 with phenanthroline ligands.517,518,519,520,521 The most popular approach is conversion of Aryl C—H bonds to C—Si (Si = SiMe(OSiMe3 )2 ) bond in the presence of [Rh(coe)2 (OH)]2 and MeO-BIPHEP ligand at 45 ∘ C.522 H R1 1 equiv

+ H-SiMe(OSiMe 3)2 2 equiv

[Rh(coe)2OH] 2 (1 mol%) MeO-BIPHEP(2.2 mol%) Cyclohexene (2 equiv), THF, 45 °C

SiMe(OSiMe 3)2 R1

OMe MeO MeO

PAr2 PAr2

Ar =

OMe OMe

MeO-BIPHEP

508 Chotana, G. A.; Rak, M. A.; Smith, M. R. Journal of the American Chemical Society 2005, 127, 10539–10544. 509 Hartwig, J. F. Chemical Society Reviews 2011, 40, 1992–2002. 510 Kallepalli, V. A.; Sanchez, L.; Li, H.; Gesmundo, N. J.; Turton, C. L.; Maleczka, R. E., Jr.; Smith, M. R. Heterocycles 2010, 80, 1429–1448. 511 Larsen, M. A.; Hartwig, J. F. Journal of the American Chemical Society 2014, 136, 4287–4299. 512 See Note 408. 513 Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk, K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. Organic Process Research & Development 2016, 20, 1476–1481. 514 Cheng, C.; Hartwig, J. F. Science 2014, 343, 853–857. 515 Alberico, D.; Scott, M. E.; Lautens, M. Chemical Reviews 2007, 107, 174–238. 516 See Note 422. 517 Cheng, C.; Hartwig, J. F. Journal of the American Chemical Society 2015, 137, 592–595. 518 Cheng, C.; Hartwig, J. F. Chemical Reviews 2015, 115, 8946–8975. 519 Kakiuchi, F.; Chatani, N. Advanced Synthesis & Catalysis 2003, 345, 1077–1101. 520 Choi, J.; Goldman, A. S.; Andersson, P. G. Iridium Catalysis, Editors; Springer-Verlag: Heidelberg: 2011; Vol. 34, 139–168. 521 Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. Chemical Society Reviews 2016, 45, 546–576. 522 See Note 514.

6.18 Selected Metal-Mediated C—H Functionalization

The arene is used as the limiting reagent. Functional groups such as OMe, Cl, OSiMetBu, NMe2 , CONEt2 , and Bpin are tolerated under the mild reaction conditions. The regioselectivity is dictated by sterics for disubstituted arenes, and in many cases, better regioselectivity is observed compared to C—H borylation reaction. For monosubstituted arenes, the regioselectivity is dictated by the electronic properties of the substituents: electron-donating substituents favor functionalization at the para-position and electron-withdrawing substituents at meta-positions. Ir-catalyzed silylations utilize relatively inexpensive 2,4,7-trimethylphenanthroline ligand (compared to BIPHEP) and tolerate wider variety of functional groups than the Rh-catalyzed methods; however, a slightly lower regioselectivity is observed than the Rh-catalyzed methods.523

H R1

Ligand =

[Ir(cod)OMe]2 (1.5 mol%) Ligand (3.1 mol%) cyclohexene (1 equiv), HSiMe(OSiMe3)2 (1.5 equiv) THF, 80–100 °C, 1–2 d

1 equiv

SiMe(OSiMe3)2

R1

Me

Me N

N

Me

Combinations of [Ir(cod)OMe]2 and bidentate nitrogen ligands such as dtbpy and Me4 -phen form highly effective catalyst for intramolecular transformation of aryl and alkyl C—H bonds to C—Si bonds.524,525,526,527,528 The resulting arylsilanes can be easily converted to aryl alcohols and participate in Hiyama coupling. 6.18.3.3

Formation of C—C Bonds

Reactions of heteroarenes with aryl halides to form C—C bonds is one of the most versatile C—H functionalization method529,530,531,532 and has been utilized for the synthesis of medicinally relevant molecules.533 The reaction usually occurs at the most acidic C—H bond of the heteroarene. These reactions are catalyzed by complexes of Pd534,535 and Ru. Pd-catalyzed C—H arylation was a key step in kilo-scale synthesis of GABAa α2/3 -selective agonist.536 Me OH Me OH Me

HCl N H2O +

N N

N

Br CN F

F

Pd(OAc) 2 (1 mol%) PPh 3 (1 mol%) KOAc, DMAc 130 °C, 4 h 86%

Me

N N

N N NC

F F

Pd-catalyzed direct benzylation was used to prepare a JAK2 inhibitor on 200 g scale.537 523 See Note 517. 524 Simmons, E. M.; Hartwig, J. F. Journal of the American Chemical Society 2010, 132, 17092–17095. 525 Li, Q.; Driess, M.; Hartwig, J. F. Angewandte Chemie International Edition 2014, 53, 8471–8474. 526 Kuznetsov, A.; Onishi, Y.; Inamoto, Y.; Gevorgyan, V. Organic Letters 2013, 15, 2498–2501. 527 Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70–73. 528 Li, B.; Driess, M.; Hartwig, J. F. Journal of the American Chemical Society 2014, 136, 6586–6589. 529 See Note 515. 530 Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. The Journal of Organic Chemistry 2009, 74, 1826–1834. 531 Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian, A.; Fagnou, K. The Journal of Organic Chemistry 2011, 76, 749–759. 532 Rousseaux, S.; Liégault, B.; Fagnou, K. In Modern Tools for the Synthesis of Complex Bioactive Molecules; John Wiley & Sons, Inc.: 2012, 1–32. 533 See Note 411. 534 See Note 515. 535 See Note 422. 536 Gauthier, D. R.; Limanto, J.; Devine, P. N.; Desmond, R. A.; Szumigala, R. H.; Foster, B. S.; Volante, R. P. The Journal of Organic Chemistry 2005, 70, 5938–5945. 537 Campbell, A. N.; Cole, K. P.; Martinelli, J. R.; May, S. A.; Mitchell, D.; Pollock, P. M.; Sullivan, K. A. Organic Process Research & Development 2013, 17, 273–281.

355

356

6 Selected Catalytic Reactions

O N

O N N Cl

N

+

Pd(OAc) 2 (4 mol%) PPh 3 (10 mol%)

Cl F

Me

N 1 equiv

Cl

N N

Cl

K 2CO3, 1–4 dioxane 101 °C, 16 h 50%

1.5 equiv

Me

N

F Cl

A combination of Pd(OAc)2 and Cu(OTf )2 was used to arylate benzoxazole with an aryl bromide to prepare an intermediate for PDE4 inhibitor.538

O

N N

Br

O

+

N

CH3

O

Pd(OAc)2 (5 mol%) Cu(OTf )2 (20 mol%) PPh 3 (12.5 mol%)

N

Cs 2CO3 (2 equiv) toluene, reflux

O

N

CH3

N

>90%

Benzothiazole was functionalized on multikilogram scale in the presence of 0.25 mol% Pd and 1 mol% (Xantphos)CuI.539

N

+ Br

S

R

[Pd] (0.25 mol%) (Xantphos)CuI (1 mol%)

N

Cs 2CO3 (2.5 equiv) toluene, 100 °C

S

R

[Pd] = (PtBu2Cl)2PdCl2

Oxidative cyclization was performed on 3 kg scale to prepare Rebeccamycin aglycone.540

O

R N

O

Pd(OAc)2 (5 mol%) CuCl 2 (100 mol%)

H Cl

N H

H

N H

R = p-tBu-Bn

Cl

R N

O

DMF, air sparge 90 °C Cl

N H

O

N H

Cl

Fagnou demonstrated the benefits of pivalic acid in Pd-catalyzed oxidative cyclization reactions.541 Tetrahydropyridines can be prepared via Rh-catalyzed C—H functionalization under mild reaction conditions and low metal loading (0.5 mol% Rh).542 538 Kuroda, K.; Tsuyumine, S.; Kodama, T. Organic Process Research & Development 2016, 20, 1053–1058. 539 Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. Journal of the American Chemical Society 2010, 132, 3674–3675. 540 Wang, J.; Rosingana, M.; Watson, D. J.; Dowdy, E. D.; Discordia, R. P.; Soundarajan, N.; Li, W.-S. Tetrahedron Letters 2001, 42, 8935–8937. 541 Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. The Journal of Organic Chemistry 2008, 73, 5022–5028. 542 Mesganaw, T.; Ellman, J. A. Organic Process Research & Development 2014, 18, 1105–1109.

6.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies

6.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies 6.19.1

Introduction

The concepts of “atom economy” and “redox economy” have received significant attention in the past decade or so. As many synthetic methods were developed for the establishment or disruption of carbon-heteroatom bonds, recent advancements have been made toward the formation of carbon–carbon bonds by taking advantage of catalysts based on transfer hydrogenation reaction pathways. The methods presented herein are based on the temporary oxidation of alcohols to mediate a range of alkylation reactions under unconventional conditions. It is noteworthy that these novel transformations have not been demonstrated on multigram scales yet, and economic considerations brought forth by the metal catalysts used along with synthetic applicability will dictate their practical use. This section presents selected transformations with the aim to highlight the potential of these novel technologies. 6.19.2

C—C Bond formation

6.19.2.1

Allylation/Crotylation

The direct allylation or crotylation of primary alcohols can be mediated by iridium or ruthenium catalysts. Besides the overall atom economy, the main advantage of the method relies in its ability to bypass the standard requirements for the preformation of stoichiometric stereolabile aldehydes. The reactions typically proceed under mildly basic conditions and generate the corresponding stereochemically defined homoallylic secondary alcohols in mid to high yield with good selectivity.543 Cl MeO MeO Cl

Ph 2 P P Ir O Ph 2 O O2N

OH + AcO

TBDPSO

NO2

OH

(S)-Cl,MeO-BIPHEP (5 mol%) 3,4-dinitrobenzoic acid (10 mol%) Cs2CO3 (1 equiv), THF, H2O, 100 °C

Me

TBDPSO Me 79%, 32 : 1 d.r.

Krische and coworkers have also demonstrated the allylation of a variety of primary alcohols with allyl acetate mediated by chiral iridium catalysts. Double functionalization of diol substrates under catalyst control was found to provide C 2 -symmetrical diols as single enantiomers.544 The direct crotylation of primary alcohols can be effected using a ruthenium catalyst modified with a chiral acid and using butadiene as nucleophile. Enantioenriched α-methylalcohols were obtained yields from benzylic alcohols and in synthetically useful yield and selectivity.545 [RuH 2(CO)(PPh 3)3] (7 mol%) OH R

Me

Me

(S)-SEGPHOS (7 mol%)

+

TADDOL acid (14 mol%) acetone, 95 °C 69%

O O

Ar

OH O Me 4 : 1 dr, 95% ee

Ar O O P O OH

Ar

Ar

Ar = m-xylyl

543 Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J. Angewandte Chemie International Edition 2014, 53, 2–11. 544 Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J. Angewandte Chemie International Edition 2009, 48, 5018–5021. 545 Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Kirsche, M. J. Science 2012, 336, 324–327.

357

358

6 Selected Catalytic Reactions

Alternatively, the crotylation of a variety of alcohols with α-methyl allyl acetates or benzoates has been demonstrated under iridium catalysis.546 Complex stereochemically defined homoallylic alcohols are thus obtained in a single operation from nonchiral precursors. Interestingly, the reactions proceed in similar yields starting with alcohols or their aldehyde analogs by using isopropanol as sacrificial hydrogen donor. Moreover, the method allows for prenylation reactions to occur under mild conditions, thus constituting a complement to typical conditions requiring reagents that can pose challenges on scale.

O O

CF3

R

Cl

67% yield, >20 : 1 dr, 89% ee RCHO RCH2OH 60% yield, >20 : 1 dr, 87% ee

i-PrOH (2 equiv) Na2CO3 (1 equiv) H2O (2 equiv), THF, 70 °C

O H

R

Ph CF3

OH

(S)-Cl,MeO-BIPHEP (5 mol%)

or

+

OH

Cl OMe OMe

NO2 NO2

OH OBz

Ph 2 P Ir P Ph 2

(CH2)7Me CF3 69% yield, 10 : 1 dr, 92% ee RCHO RCH2OH 64% yield, 10 : 1 dr, 92% ee

The preformation of complex catalysts may represent a drawback of the method. However, in some instances, in situ formation of the catalyst from commercially available precursors has been demonstrated as viable option.547 OH Me

Me Me

OAc

+

[Ir(cod)Cl]2 (2.5 mol%) ligand (5 mold%) 3-nitrobenzoic acid (10 mol%) Cs 2CO3 (20 mol%) Cl

Ligand = Ph 2P Ph 2P

OH Me

Me Me

86% ee

THF, 100 °C 76%

OMe OMe Cl

The versatility of this mode of catalysis was highlighted by Krische and coworkers in a number of natural product syntheses.548 A three-step synthesis of cis-2,3-disubstituted oxetanes exemplifies the potential of this transformation to access functionalized heterocycles that would be otherwise difficult to obtain.549 OH

O

Br

OH 5 : 1 dr, 99% ee

6.19.2.2

O

(i) NaH, TsCl

O 68%

Br

OH

O

(ii) n-BuLi, THF 75%, 2 steps

Br

Alkylation of Aromatics

The direct alkylation of methyl-substituted aromatic moieties proceeds readily using alcohols as electrophiles. Accordingly, a variety of methyl-substituted heteroaromatic substrates have been demonstrated as suitable nucleophiles in such reactions.550 The reaction was shown to be compatible with unprotected aromatic amines, and aliphatic alcohols were used to form the desired aliphatic side chains in moderate yields. The pK a of the pendant methylated substrates, 546 547 548 549 550

Hassan, A., Krische, M. J. Organic Process Research & Development 2011, 15, 1236–1242. Kim, I. S.; Nagi, M.-Y.; Krische, M. J. Journal of the American Chemical Society 2008, 130, 14891–14899. Dechert-Schmitt, A.-M. R.; Schmitt, D. C.; Gao, X.; Itoh, T.; Krische, M. J. Natural Product Reports 2014, 31, 504–513. Han, S. B.; Han, H. H.; Krische, M. J. Journal of the American Chemical Society 2010, 132, 1760–1761. Blank, B.; Kempe, R. Journal of the American Chemical Society 2010, 132, 924–925.

6.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies

established as a critical parameter for this reaction, will require consideration for the application of this methodology to other methyl-substituted aromatic compounds. [Ir(cod)Cl]2 Py2NP(i-Pr)2

Me + Me

OH

NH2

Me

KOtBu, diglyme, 110 °C 62%

NH2

These applications have also paved the way for the untraditional production of a variety of heterocycles via tandem C—C and C—N bond formations using this technology.551 6.19.3

Redox Neutral Homologation of Alcohols

The direct homologation of alcohols offers a potentially attractive method to avoid the handling of sensitive aldehyde intermediates in these carbon–carbon bond-forming reactions. This transformation was demonstrated by Williams and coworkers on benzylic and heterocyclic alcohols with Wittig reagents.552,553 The methodology presents an interesting one-pot alternative to traditional sequences but is currently limited by the concomitant formation of stoichiometric triphenylphosphine oxide. The extension of this methodology to reductive amination reactions is presented in Section 9.2.3.

Ph 3P S

OtBu (1.1 equiv) SiMe 3 (2 mol%)

OH

L Ph 3P OC

Me

L=

O

Ru

Me

O S

Ot Bu

H

H PPh 3

Me

N

Me

N

Me

Me

(1 mol%)

toluene, 80 °C

Me

84%

6.19.4

Me

Ketone Functionalization

Following the basic principle where alcohols serve as electrophiles via transient oxidation to the corresponding carbonyl species, the methodology has been applied to a vast array of nucleophiles with proven reactivity in aldol-type additions. The reader is directed to the review of Dobereiner and Crabtree for a summary of potent reaction partners.554 In complement to other catalytic systems presented herein, Pack and coworkers reported the use of palladium nanoparticles entrapped in aluminum hydroxide for the homologation of methyl ketones555 . Catalysts loadings below 1% were reported, although the choice of base was a critical factor for the reaction’s success. O Me Me HO

Me +

Ph

OH

O Me

Pd/Al (0.2 mol% ) K3PO4

Ph

Me

Toluene, 110 °C 84% HO

551 Haniti, M.; Hamid, S. A.; Slatford, P. A.; Williams, J. M. J. Advanced Synthesis & Catalysis 2007, 349, 1555–1575. 552 Burling, S.; Paine, B. M.; Nama, D.; Brown, V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.; Whittlesey, M. K.; Williams, J. M. J. Journal of the American Chemical Society 2007, 129, 1987–1995. 553 Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.; Edney, D. D. Chemical Communications 2004, 90–91. 554 Dobereiner, G. E.; Crabtree, R. H. Chemical Reviews 2010, 110, 681–703. 555 Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.; Park, J. Angewandte Chemie International Edition 2005, 44, 6913–6915.

359

360

6 Selected Catalytic Reactions

In light of the problems associated with monomethylation of nucleophiles using potent electrophiles such as methyl iodide, borrowed hydrogen-based methodologies offer an opportunity to bypass traditional limitations and provide an expedited access to methylated adducts. Donohoe and coworkers have demonstrated the versatility of this method in the construction of a variety of substituted ketone analogs.556 While clean methylation adducts were obtained under iridium catalysis, double alkylation could be achieved by the introduction of a second nucleophile. This novel method holds promise for the construction of substituted arylketones in a single reaction vessel. O

O Ph

O

O Ar

R

Ar = pMeOC6H4

[Ir(cod)Cl]2 (2 mol%) catacXium (8 mol%) 3 equiv KOH MeOH, 65 °C

O

65% SiliaMetS

+ O Ar

Ph

O2

R

Ar

R

Ar

R

R = CH2Ph

DMT resin base t-BuOOH

OMe

89%

O Ar

R O

R = (CH2)2CH(CH3)2

6.19.5

C—N Bond Formation

The use of hydrogen borrowing methodologies in the context of C—N bond formation offers a unique opportunity from environmental and reactivity perspectives. This strategy provides a complementary approach to traditional amine alkylations, where alcohols can now be used as electrophile surrogates under mild conditions. The transient formation of carbonyl species as electrophiles also avoids the use of often unstable aldehydes as in reductive aminations. 6.19.5.1

Primary Amines

As methods to prepare primary amines from alcohols are rare, Milstein and coworker developed a method based on ruthenium-catalyzed hydrogen borrowing conditions.557 The catalyst was reported to be air-stable, but the reaction conditions were found to be sensitive to adventitious water.

OH

iPr iPr P Cl N Ru CO H P iPr (0.1 mol%) iPr

NH2

NH3 (7.5 atm ) toluene, reflux 87%

6.19.5.2

Secondary Amines

The first application of this type of method on kilogram scale was reported by researchers at Pfizer in the preparation of a GlyT1 inhibitor.558 Extensive development efforts led to the identification of optimal conditions featuring a simple iridium catalyst which could be used at loadings as low as 0.25 mol%. Along with producing kilogram quantities of the 556 Shen, D.; Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J. Angewandte Chemie International Edition 2015, 54, 1642–1645. 557 Gunanathan, C.; Milstein, D. Angewandte Chemie International Edition 2008, 47, 8661–8664. 558 Berliner, M. A.; Dubant, S. P. A.; Makowski, T.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y. Organic Process Research & Development 2011, 15, 1052–1062.

6.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies

desired benzylic amine over multiple batches, work-up protocols for the removal of the metal catalysts were evaluated. Accordingly, using a Darco KBB treatment allowed for the purge of iridium to 60 ppm level. F OH

H2N

H

H

Cl

+ Cl

N Me

NH

(Cp*IrC l 2)2 (0.25 mol%)

F

1N NaHCO3 (0.5 equiv) toluene, 110 °C

H

H

76%

N Me 4.6 kg produced

Interestingly, observations on the impact of water on the process were made. It was thus found that water was essential for the performance and robustness of the process. This key observation led them to use an aqueous base in their optimal conditions. Similar observations were previously made by Williams and coworkers, where the use of ionic liquids as reaction solvent was also reported to be effective in the preparation of a variety of secondary and tertiary amines.559 Electron deficient amides have also been demonstrated as suitable partners for these reactions, at the expense of requiring elevated reaction temperatures.560 Although typical conditions are harsh, this strategy still offers unique opportunities compared with traditional alkylation methods. O Ph

O

RuCl 2(PPh 3)2 (2.0 mol%) NH2

6.19.5.3

Octanol, 180 °C 78%

Ph

N H

C8H17

Tertiary Amines

The selective formation of tertiary amine has been the main focus in C—N bond formation by hydrogen borrowing methodologies. Researchers at AstraZeneca have published a study aimed at evaluating various conditions in the context of the synthesis of nitrogen-rich intermediates reminiscent of compounds of interest in the pharmaceutical industry.561 Their studies, focusing on air stable commercially available complexes, revealed that conditions previously reported by Del Zotto and coworkers562 showed high efficiency for the preparation of N-methylpiperazines in high selectivity over other side reactions. Ruthenium-based catalysts such as [Ru(p-cymene)Cl2 ]2 also provided high yields of various tertiary amines.563 Ru(Cp)Cl(PPh 3)2 (1 mol%)

HN N

Me

N N

MeOH, reflux 89%

OH

OH

Reasonable stereoinduction can be obtained by this method by using chiral components. Me Ph

NH2

+

HO

Me

(Cp*IrC l 2)2 (1.5 mol%)

Ph OH

KOAc (6.0 equiv) toluene, 100 °C 76%

Ph

Ph

N

86% ee, 92% de

559 Saidi, O.; Blacker, A. J.; Lamb, G. W.; Marsden, S. P.; Taylor, J. E.; Williams, J. M. J. Organic Process Research & Development 2010, 14, 1046–1049. 560 Watanabe, Y.; Ohta, T.; Tsuji, Y. Bulletin of the Chemical Society of Japan 1983, 56, 2647–2651. 561 Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. Organic Process Research & Development 2015, 19, 1400–1410. 562 Del Zotto, A.; Baratta, W.; Sandri, M.; Verardo, G.; Rigo, P. European Journal of Inorganic Chemistry 2004, 524–529. 563 Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. Journal of the American Chemical Society 2009, 131, 1766–1774.

361

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6 Selected Catalytic Reactions

6.20 Alkene and Alkyne Metathesis Reactions 6.20.1

Introduction

Catalytic metathesis reactions have been used in the petrochemical and polymer industries since the 1950s but it was not until the 1990s that catalytic metathesis found significant use in the synthesis of complex molecules.564 Since then, catalytic metathesis has become a reliable, efficient, and functional group tolerant reaction that chemists can count on as a key reaction in the later stages of complex molecule synthesis.565,566,567,568 In recognition of the significance of this reaction to the field of organic chemistry, the 2005 Nobel Prize in Chemistry was awarded to Yves Chauvin, Robert Grubbs, and Richard Schrock.569 Although a variety of different metals have been shown to be active in the olefin metathesis reaction, the two most popular metals are by far ruthenium (Grubbs catalyst) and molybdenum (Schrock catalyst). Selected example of the Ru and Mo catalysts are shown in the following scheme. Ph

Ph

Cl Cy 3P

Cl Ru

PCy 3

H2IMes

Cl

Cl Ru

PCy 3

H2IMes

Ru

Cl

OiPr Cl

C(Me)2Ph i

i

Pr N

H3C(F3C)2O H3C(F3C)2O

Mo

Pr Me Ph Me

H3C(F3C)2O H3C(F3C)2O

Mo

NAr N

N

While the Schrock family of catalysts displays high activity and a degree of chemo-570,571 and enantioselectivity572,573 unrivaled by the Grubbs catalyst, its sensitivity toward air and moisture as well as its limited functional group tolerance has been a significant drawback to widespread application into organic synthesis. Although strategies targeted at facilitating the handling of the Mo catalysts have been reported (e.g. addition of a bipyridine ligand was reported by Fuerstner and coworker to render selected Schrock-type catalyst air stable),574 no industrial process using these catalysts have been disclosed. Since the discovery of the “user-friendly” catalyst by Grubbs and coworkers catalyst in 1992,575 its application in organic synthesis has seen a rapid uptake. Grubbs and coworker have proposed that the ability of the Ru catalyst to tolerate a large variety of functional groups arises from its preferred reactivity with olefins.576 However, substrates bearing protic group as well as aldehydes remain a challenge for the Ru catalysts.577,578,579 A recent review by Fogg and coworkers showed examples of contaminants that proved detrimental to the Ru metathesis catalysts during various processes as well as the steps taken for their removal. Despite these shortcomings, large-scale application of olefin metathesis using Ru catalysts has been disclosed,580 and selected examples will be discussed. 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580

Astruc, D. New Journal of Chemistry 2005, 29, 42–56. Nicolaou, K. C.; Ortiz, A.; Denton, R. M. Chimica Oggi 2007, 25, 70–72, 74–76. Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. Grubbs, R. H. Handbook of Metathesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2003. Hughes, D.; Wheeler, P.; Ene, D. Organic Process Research & Development 2017, 21, 1938–1962. Rouhi, M. Chemical & Engineering News 2005, 83, 8. Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. Journal of the American Chemical Society 2009, 131, 3844–3845. Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Muller, P.; Hoveyda, A. H. Journal of the American Chemical Society 2009, 131, 7962–7963. Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456, 933–937. Cortez, G. A.; Baxter, C. A.; Schrock, R. R.; Hoveyda, A. H. Organic Letters 2007, 9, 2871–2874. Heppekausen, J.; Fuerstner, A. Angewandte Chemie International Edition 2011, 50, 7829–7832. Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. Journal of the American Chemical Society 1992, 114, 3974–3975. Trnka, T. M.; Grubbs, R. H. Accounts of Chemical Research 2001, 34, 18–29. Sheddan, N. A.; Arion, V. B.; Mulzer, J. Tetrahedron Letters 2006, 47, 6689–6693. Young, D. G. J.; Burlison, J. A.; Peters, U. The Journal of Organic Chemistry 2003, 68, 3494–3497. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. Journal of the American Chemical Society 1993, 115, 9856–9857. Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Angewandte Chemie International Edition 2016, 55, 3552–3565.

6.20 Alkene and Alkyne Metathesis Reactions

6.20.2

Ring-closing Metathesis

Ring-closing metathesis (RCM) is the most commonly applied metathesis strategy in organic synthesis, but this reaction does present some challenges, particularly when strained medium/large rings are the desired target. The reactions are typically dilute to avoid competing intermolecular processes, and the necessary catalyst loadings are sometimes high.581 Despite these challenges, RCM is a valuable reaction that can typically be counted on to be efficient, chemoselective, and tolerant of various functional groups. 6.20.2.1

Alkene Ring-Closing Metathesis

Intramolecular metathesis is often referred to as RCM. Mechanistically, the RCM of alkenes proceeds by an initial formal [2+2] reaction between a metal alkylidene and one of the alkene on the substrate.

R + ( )n

M R

( )n

( )n

M

R

+

M

M

( )n R

M ( )n

The resulting metallacyclobutane can then undergo a cycloreversion reaction to provide starting materials (via degenerate metathesis) or a new alkene and metal alkylidene pair. The new metal alkylidene can then react with the second olefin of the starting diene to provide a cyclized product. All metathesis reactions are, in principle, reversible, and this needs to be accounted for, particularly when attempting cross-metathesis (Section 6.20.3). In the majority of RCM reactions, however, ethylene is extruded as a co-product of the reaction and helps drive the reaction forward. Some RCM reaction have been carried out under negative pressure582 or with active sparging with nitrogen583 to facilitate removal of ethylene, which has also been shown to promote catalyst deactivation.584,585 In addition to challenges associated with reversibility, mixtures of E and Z olefin products are typically obtained, which can also be problematic.586 While there are many impressive and elegant examples of RCM in the literature,587 the large-scale synthesis of hepatitis C protease inhibitor BILN 2061 by scientists at Boehringer-Ingelheim stands out as a landmark achievement in metathesis chemistry.588,589,590,591,592,593 This process is impressive for several key reasons: (i) The reaction concentration is relatively high for an RCM reaction, which allows for reasonable throughput in standard 581 Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251. 582 Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 479, 88–93. 583 Kong, J.; Chen, C.-Y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; Zacuto, M. J. The Journal of Organic Chemistry 2012, 77, 3820–3828. 584 Ulman, M.; Grubbs, R. H. The Journal of Organic Chemistry 1999, 64, 7202–7207. 585 Burdett, K. A.; Harris, L. D.; Margl, P.; Maughon, B. R.; Mokhtar-Zadeh, T.; Saucier, P. C.; Wasserman, E. P. Organometallics 2004, 23, 2027–2047. 586 See Note 581. 587 See Note 565. 588 Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H. Organic Process Research & Development 2009, 13, 250–254. 589 Randolph, J. T.; Zhang, X.; Huang, P. P.; Klein, L. L.; Kurtz, K. A.; Konstantinidis, A. K.; He, W.; Kati, W. M.; Kempf, D. J. Bioorganic & Medicinal Chemistry Letters 2008, 18, 2745–2750. 590 Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, V.; Senanayake, C. H. Organic Letters 2008, 10, 1303–1306. 591 Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. The Journal of Organic Chemistry 2006, 71, 7133–7145. 592 Tsantrizos, Y. S.; Ferland, J.-M.; McClory, A.; Poirier, M.; Farina, V.; Yee, N. K.; Wang, X.-J.; Haddad, N.; Wei, X.; Xu, J.; Zhang, L. Journal of Organometallic Chemistry 2006, 691, 5163–5171. 593 Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llinas-Brunet, M. Organic Letters 2004, 6, 2901–2904.

363

364

6 Selected Catalytic Reactions

manufacturing equipment;594 (ii) The reaction is performed in toluene, which is much “greener” (for additional details on Green Chemistry, see Chapter 16) than dichloromethane, the typical solvent for RCM reactions; (iii) The reaction is complete in 30 minutes; (iv) The reaction proceeds with a very low catalyst loading (0.1 mol%). The low catalyst loading is important for two reasons. First, the catalyst is expensive and therefore needs to be minimized for an industrial process. Second, the removal of ruthenium impurities from the product required “heroic efforts” using earlier technology,595 which utilized higher catalyst loadings, while no special efforts were required for ruthenium removal using this optimized approach.596 NO2

PNBO N

H N

O

Boc N O

CO2Me

Cl H2IMes Ru

O

PNBO

OiPr (0.1 mol%) Cl O

Toluene (0.2 M), 110 °C

O

H N

Boc

CO2Me

N

N O

O

O

93%

Another impressive application of RCM was disclosed by Kong et al. to form the macrocyclic core of the HCV protease inhibitor Vaniprevir.597 The second-generation Grubbs-Hoveyda catalyst was found to be the optimal catalyst for this reaction. Key to success in this reaction was the simultaneous addition of two different reagent streams: one containing the diene and the other containing the catalyst. This protocol mimics high dilutions as only a small amount of the reactive diene is present at any time in the reaction. Furthermore, removal of the ethylene co-product via gentle subsurface bubbling of the reaction with nitrogen was found to be beneficial. One of the impurities observed during the RCM reaction was the 19-membered macrocycle arising from RCM of the styryl isomer, which presumably originates from isomerization of the allylic olefin by a ruthenium hydride decomposition product of the catalyst. As quinones are known to suppress this side reaction, a survey of various quinones found 2,6-dichloroquinone to be efficient in limiting this side product without loss of conversion. NO2

O

N

Cl H2IMes Ru

O OMe

Me Me

H N

O O

6.20.2.2

N

O O

O

OiPr (0.2 mol%) Cl

OMe

10 mol% 2,6-dichloroquinone toluene, 100° C

tBu

O

N

91%

H N

O Me Me

O

N

O O

tBu

Alkyne Ring-Closing Metathesis

Ring-closing alkyne metathesis (RCAM) is mechanistically similar to alkene RCM (see Section 6.20.2), except that the reaction mechanism proceeds through a metallacyclobutadiene intermediate. Typically, RCAM is not efficient for the synthesis of ring sizes smaller than 12 because the strain due to alkyne incorporation is too significant for the reaction to be favorable.598 However, RCAM does have a significant advantage over RCM for the formation of larger rings because there are no E:Z isomer issues, and methods have been developed for the synthesis of both E and Z alkenes via RCAM and partial reduction.599 For this reason, RCAM is complementary to RCM for the synthesis of large rings. 594 595 596 597 598 599

See Note 588. See Note 592. See Note 588. See Note 583. Furstner, A.; Seidel, G. Angewandte Chemie International Edition 1998, 37, 1734–1736. Zhang, W.; Moore, J. S. Advanced Synthesis & Catalysis 2007, 349, 93–120.

6.20 Alkene and Alkyne Metathesis Reactions

R1

R1 +

M

R2 ( )n

R3

( )n R2

M

R2 ( )n

R3

R1

M ( )n

R1

R1

R2

R2

R3

R3

R1 M

+

R3

M

R1 M

( )n

( )n

( )n

M

The preparation of Z-alkenes via alkyne metathesis can be accomplished in a straightforward fashion by Lindlar-type reduction of the cyclic alkyne to the corresponding Z-alkene. This strategy was used by Fürstner and Grela for the synthesis of prostaglandin E2 -1,15-lactone.600 Me [Mo{N(tBu)(Ar)}3]

O

(7.5 mol%)

O TBSO

O

O

Me Me

CH2Cl 2 toluene 80 °C 68–73%

O

TBSO

O

H2 Lindlar Catalyst

Ar = 3,5-dimethylphenyl

Me

hexane 86%

O

TBSO

O O

Me

The synthesis of E-alkenes by RCAM and partial reduction is a more involved process, but both Trost et al.601 and Fürstner and coworkers602 have developed hydrosilylation/desilylation approaches for this purpose. In the following example, Fürstner and coworkers utilize a tungsten catalyst for RCAM and a ruthenium catalyst for hydrosilylation, followed by desilylation using silver fluoride. The end result is selective formation of the macrocylic E-alkene. It is worth noting that, as this example shows, it is possible to perform alkyne metathesis in the presence of alkenes; however, it is difficult to perform alkene metathesis in the presence of alkynes.603 600 601 602 603

Furstner, A.; Grela, K. Angewandte Chemie International Edition 2000, 39, 1234–1236. Trost, B. M.; Ball, Z. T.; Joege, T. Journal of the American Chemical Society 2002, 124, 7922–7923. Lacombe, F.; Radkowski, K.; Seidel, G.; Furstner, A. Tetrahedron 2004, 60, 7315–7324. See Note 599.

365

366

6 Selected Catalytic Reactions

O

O Me

(tBuO) 3W CCMe3 (10 mol%)

O

(i) (EtO)3SiH, CH2Cl 2 [CpRu(MeCN) 3 ]PF6 O (15 mol%) 64%

O

Toluene, 80 °C

(ii) AgF, H2O TFH, MeOH 79%

84%

E/Z 95 : 5

Me

6.20.2.3

O

Enyne Ring-closing Metathesis

Enyne ring-closing metathesis (RCEYM) is a metal-mediated ring-closing reaction that converts a tethered alkene and alkyne into a cyclic diene.604,605 Me

Me Me

+ M

Me M

M

M

Me

+ M

While not as commonly employed as RCM, the fact that this process generates a ring and a readily functionalized diene makes this a valuable reaction. In the key step of their synthesis of (+)-anatoxin-A, Martin and coworkers generated the bridged bicyclic core via RCEYM.606 Ph Cl H2IMesRu PCy 3 Cl

Cbz N Me

(10 mol%)

N Cbz

Me

CH2Cl 2 87%

6.20.2.4

Z-Selective Olefin Metathesis

For many years, reliable methods for the direct formation of Z-olefins via olefin metathesis remained elusive. This transformation is challenging because many metathesis reactions proceed under thermodynamic control and therefore favor the thermodynamically more stable E-olefin product. However, recent advances have overcome this inherent challenge and rendered Z-selective reactions a viable synthetic option for both ring-closing and cross-metathesis.607,608,609 The utility of this approach was demonstrated by Grubbs and coworkers in the preparation of a series of lepidopteran female insect sex pheromones,610 which have been approved by the United Stated Environmental Protection Agency (EPA) for control of crop-damaging moth and butterfly larvae. N

NMes

O Ru N O O O Me Me Me

(1 mol%)

+ HO

THF 73%

604 605 606 607 608 609 610

Me

HO

43 : 7 Z : E

Mori, M. Advanced Synthesis & Catalysis 2007, 349, 121–135. Villar, H.; Frings, M.; Bolm, C. Chemical Society Reviews 2007, 36, 55–66. Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301–7314. Endo, K.; Grubbs, R. H. Journal of the American Chemical Society 2011, 133, 8525–8527. Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. Journal of the American Chemical Society 2013, 135, 1276–1279. Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 471, 461–466. Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angewandte Chemie International Edition 2013, 52, 310–314.

6.20 Alkene and Alkyne Metathesis Reactions

6.20.3

Cross-Metathesis

Intermolecular metathesis is often referred to as cross-metathesis. This process is widely used in polymerization reactions (see Section 6.20.4) but is less common in organic synthesis where most applications of metathesis reactions are intramolecular ring-closing reactions (RCM) (see Section 6.20.2). Mechanistically, the cross metathesis of alkenes proceeds by formal [2+2] reaction of a metal alkylidene with an alkene.611,612

R2

R1

R1

M

M

+

R1

+

R2

M

R2

The resulting metallacyclobutane can then undergo a cycloreversion reaction to provide starting materials (via degenerate metathesis) or a new alkene and metal alkylidene pair. As metathesis reactions are reversible, unless a volatile alkene product like ethylene is expelled from solution, self-metathesis (metathesis of two identical olefins) is often in competition with the desired cross-metathesis reaction. In addition to challenges associated with reversibility and self-metathesis, mixtures of E and Z olefin products can also be problematic. For these reasons, alkene cross-metathesis is a challenge with many classes of alkene substrates. Nonetheless, cross-metathesis reactions can be effective, especially if it is practical to use an excess of one alkene component. 6.20.3.1

Alkene Cross-Metathesis

A synthetically useful yield was obtained cross-metathesis by using an excess of one of the olefin, which was shown by Morimoto et al. during the course of their synthesis of (+)-omaezakianol.613 In this case, the use of 4.7 equiv of the triepoxy alkene component is unfortunate, but the 87% yield of E-alkene and the functional group compatibility of the reaction are impressive.

Me

Me O

O

H Me HO Me

Me

O

+

Me OH

(1.0 equiv)

O Me

PCy 3

O Me

HO

O

Me

Me

Me

Me

Ph

Cl 10 mol%

Me

O

(4.7 equiv)

Cl H2IMes Ru

Me

O

H Me

O

Me OH

CH2Cl 2 (0.05 M) 40 °C 87%

O

O

O

Me

Me

Me

Me

Electron-deficient olefins are one of the best substrate classes for alkene cross-metathesis because they typically undergo very slow self-metathesis and often allow for good E/Z selectivity.614 List and coworker were able to take advantage of this reactivity in their synthesis of ricciocarpin A.615 In this case, the relatively high reaction concentration, the relatively low catalyst loading, and the low cost of the alkene used in excess (crotonaldehyde) make this a very practical way to functionalize the terminal alkene. It is noteworthy that the sterically hindered enone is not reactive in this metathesis reaction. Sterically hindered alkenes react much slower than electronically similar sterically unhindered alkenes in metathesis reactions.616 611 612 613 614 615 616

Waetzig, J. D.; Hanson, P. R. Chemtracts 2006, 19, 157–167. Connon, S. J.; Blechert, S. Angewandte Chemie International Edition 2003, 42, 1900–1923. Morimoto, Y.; Okita, T.; Kambara, H. Angewandte Chemie International Edition 2009, 48, 2538–2541. See Note 612. Michrowska, A.; List, B. Nature Chemistry 2009, 1, 225–228. See Note 611.

367

368

6 Selected Catalytic Reactions

NO2 Cl H2IMes Ru O + Me Me

OiPr Cl 2 mol%

CHO

Me

6.20.3.2

O

CH2Cl 2 (0.1 M) 40 °C 90%

O

(1.0 equiv)

CHO

(3.0 equiv)

Me Me

O

Alkane Cross-Metathesis

Alkane cross-metathesis is a valuable reaction that allows for the modification of alkane chain lengths at industrial scales, but this process will not be discussed in detail here because the mechanism of this process (dehydrogenation/metathesis/hydrogenation) is identical to alkene cross-metathesis during the key carbon–carbon bond forming/breaking steps.617 6.20.3.3

Alkyne Cross-Metathesis

While alkyne cross-metathesis has not yet reached a level of practicality that would allow it to be counted on in organic synthesis, the oligomerization of diynes can be quite effective. Mechanistically, alkyne metathesis is analogous to alkene metathesis (see Section 6.20.2), except that the reaction proceeds via a metallacyclobutadiene intermediate instead of a metallacyclobutane intermediate. R1 + R2

M

R1

R3

R2

R1

M R3

R2

R2 M

+ R3

R3

M R1

It is also worth noting that terminal alkynes, unlike terminal alkenes, are not typically suitable substrates.618 Like alkene metathesis, alkyne metathesis reactions suffer from reversibility and self-metathesis pathways, but E/Z selectivity is not an issue with alkyne metathesis. While many alkene and alkyne metathesis strategies limit reversibility by expelling a volatile alkene/alkyne by-product from solution, another practical strategy in alkyne metathesis is the precipitation of an insoluble alkyne by-product from solution.619 This strategy was developed by Moore and coworker for the synthesis of shape-persistent arylene ethynylene macrocycles and was successfully used to generate 3.8 g of a carbazole-based macrocycle.620

H3C(H2C)13

H3C(H2C)13 N

R Et

N

N

Mo[NAr(tBu)]3 p-nitrophenol

+

CCl 4, 50 °C

R

Insoluble

O

617 618 619 620

R

61%

R

R=

(CH2)13CH3

Ph

H3C(H2C)13

N

N

(CH2)13CH3

Basset, J.-M.; Coperet, C.; Soulivong, D.; Taoufik, M.; Thivolle-Cazat, J. Angewandte Chemie International Edition 2006, 45, 6082–6085. Schrock, R. R. Polyhedron 1995, 14, 3177–3195. See Note 599. Zhang, W.; Moore, J. S. Journal of the American Chemical Society 2004, 126, 12796.

6.21 Organocatalysis

6.20.4

Metathesis Polymerization

While a thorough discussion of metathesis polymerization reactions is well beyond the scope of this book, it is worth noting that acyclic diene metathesis (ADMET), acyclic diyne metathesis (ADIMET), ring-opening alkyne metathesis, and ring-opening alkene metathesis polymerization (ROMP) have all proven to be valuable methods for the synthesis of polymers with unique physical and/or biological properties.621,622,623,624

6.21 Organocatalysis 6.21.1

Introduction

Organocatalysis is a dynamic field of chemical research pertaining to catalysis by small organic molecules. The field is broad and has been extensively reviewed.625,626,627,628,629,630,631,632,633,634,635,636 Here, some of the more well-developed reaction classes of organocatalysis will he discussed, with an emphasis on systems that have proven to be sufficiently robust for execution on large scale. 6.21.2

Phase Transfer Catalysis

Phase transfer catalysts enable reactivity by transporting catalytic amounts of reactants between phases of multiphasic reactions wherein reactants are partitioned in immiscible phases.637 This class of catalysis is characterized by mild reaction conditions, environmentally friendly solvents and reagents, and simple experimental operations. A variety of reaction classes can be promoted by phase transfer catalysts,638,639,640,641 a selection from classes that are more prevalent in the literature are discussed in the following. 6.21.2.1

Carbon Alkylation

Carbonyl α-alkylation is commonly catalyzed via phase transfer catalysis, which allows the use of inorganic bases, such as hydroxide, to form the requisite enolate for alkylation. The following illustrates the mild nature of phase transfer-catalyzed conditions, as alkylation of the malonate occurs without any observable ester hydrolysis.642 In this case, the reaction is carried out in the absence of an organic solvent, with the starting materials and product serving as the organic phase. MeO2C

CO2Me Br

Cl

BnEt 3N+Cl – (0.25 mol%)

O OtBu

10 N NaOH 100%

MeO2C

Cl

CO2Me CO2tBu

621 Bielawski, C. W.; Grubbs, R. H. Progress in Polymer Science 2007, 32, 1–29. 622 Nomura, K.; Yamamoto, N.; Ito, R.; Fujiki, M.; Geerts, Y. Macromolecules 2008, 41, 4245–4249. 623 Weychardt, H.; Plenio, H. Organometallics 2008, 27, 1479–1485. 624 See Note 599. 625 Erkkilä, A.; Majander, I.; Pihko, P. M. Chemical Reviews 2007, 107, 5416–5470. 626 Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chemical Reviews 2007, 107, 5471–5569. 627 Wurz, R. P. Chemical Reviews 2007, 107, 5570–5595. 628 Gaunt, M. J.; Johansson, C. C. C. Chemical Reviews 2007, 107, 5596–5605. 629 Enders, D.; Niemeier, O.; Henseler, A. Chemical Reviews 2007, 107, 5606–5655. 630 Hashimoto, T.; Maruoka, K. Chemical Reviews 2007, 107, 5656–5682. 631 Doyle, A. G.; Jacobsen, E. N. Chemical Reviews 2007, 107, 5713–5743. 632 Akiyama, T. Chemical Reviews 2007, 107, 5744–5758. 633 Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chemical Reviews 2007, 107, 5759–5812. 634 McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chemical Reviews 2007, 107, 5841–5883. 635 Brak, K.; Jacobsen, E. N. Angewandte Chemie International Edition 2013, 52, 534–561. 636 Ikunaka, M. Organic Process Research & Development 2008, 12, 698–709. 637 Starks, C. M. Journal of the American Chemical Society 1971, 93, 195–199. 638 See Note 630. 639 See Note 636. 640 Maruoka, K. Organic Process Research & Development 2008, 12, 679–697. 641 Tan, J.; Yasuda, N. Organic Process Research & Development 2015, 19, 1731–1746. 642 Beaulieu, P. L.; Gillard, J.; Bailey, M.; Beaulieu, C.; Duceppe, J.-S.; Lavallée, P.; Wernic, D. The Journal of Organic Chemistry 1999, 64, 6622–6634.

369

370

6 Selected Catalytic Reactions

In 1984, scientists at Merck reported that a cinchona-alkaloid-derived quaternary ammonium bromide salt catalyzed enantioselective indanone alkylation.643 This groundbreaking work opened the door to the field of asymmetric phase transfer catalysis, which has matured significantly in the past 40 years. A more recent application of this class of cinchona-alkaloid-derived catalyst by scientists at GSK is shown in the following.644

O N Br –

N

Ph Ph

Br

Ph O N

O

N

5 mol %

t-Bu F

45% aq KOH, CH2Cl2 56%, >99 : 1 er

F

Ph O O

F

t-Bu

F

A variety of chiral scaffolds have been developed and implemented in phase transfer catalysis. An example of such is the phase transfer catalyst developed by Maruoka shown below that is used to facilitate the alkylation of the alanine derived imine with high enantioselectivity.645

Me OtBu

N

F

O

Cl

nBu F

N Br

F

F

nBu –

F

F

1.3 mol % OnPr

I

6.21.2.2

OnPr

O

CsOH·H2O, MTBE, 0 °C then 6N HCl, iPrOH 70 %,

HO H2N Me

96% ee

Heteroatom Alkylation

Alkylation at oxygen or nitrogen to form ethers, esters, amines, and amides is also possible under phase transfer catalysis. In the following example, the alkylation at oxygen takes place with excellent selectivity over N-alkylation under phase transfer conditions. In this case, these conditions were used as a replacement for a DMF/NaH mediated ethylation, which was significantly less selective and also posed a safety hazard.646

tBu

643 644 645 646

iPr

O O

N H

OH

0.015 equiv Bu4N+Cl– 1.5 equiv Et2SO4 50% aq NaOH heptanes, 20–35 °C 75%

tBu

iPr

O O

N H

OEt

Dolling, U. H.; Davis, P.; Grabowski, E. J. J. Journal of the American Chemical Society 1984, 106, 446–447. Patterson, D. E.; Xie, S.; Jones, L. A.; Osterhout, M. H.; Henry, C. G.; Roper, T. D. Organic Process Research & Development 2007, 11, 624–627. Jiang, X.; Gong, B.; Prasad, K.; Repiˇc, O. Organic Process Research & Development 2008, 12, 1164–1169. Liu, Y.; Ciszewski, L.; Shen, L.; Prashad, M. Organic Process Research & Development 2014, 18, 1142–1144.

6.21 Organocatalysis

Process chemists at Genentech reported the phase transfer-catalyzed annulation shown in the following. In this case, alkylation at nitrogen proceeds first, followed by alkylation at oxygen to close the six-membered ring. Here, the use of phase transfer catalysis allowed the chemists to avoid the use of DMF as the solvent for alkylation, which required extensive processing to be removed prior to downstream chemistry.647 O

O Bu4N+Br–(0.3 equiv) 1,2-dibromoethane (3 equiv)

N Me N Me N H

HO

6.21.2.3

KOH (3 equiv), H2O 47 °C, 20 h 67%

N N

Cl

N Me

Me N

O

N

N

N

Cl

Conjugate Additions of Carbon Nucleophiles

The addition of a variety of nucleophiles to electron deficient double bonds can also be achieved under phase transfer catalysis. Below, the Shiff base anion is reacted with the cinnamate under phase transfer conditions to provide the racemic lactone following deprotection and cyclization.648 OMe

MeO Ph 2CO

N NH2

CO2Et

N N

PTSA

Ph

(i) BnEt3N+Cl–, 50% NaOH

Ph

N

(ii) aq HCl

O

(iii) aq NH4OH 72%

N H

Asymmetric phase transfer catalysis has also been applied to conjugate addition reactions of carbon nucleophiles. During process development toward an estrogen receptor-β selective agonist, scientists at Merck developed the conjugate addition to methyl vinyl ketone shown below.649 Although the enantioselectivity of the transformation is modest, an upgrade in enantiopurity was realized via recrystallization of a downstream intermediate.

O OPh

MeO Cl

Methyl ethyl ketone toluene / 50% aq NaOH

O

OPh

Cl 52% ee

MeO

N H AcOH, toluene 85%

Cl O

OPh

Me

MeO

catalyst = N

MeO

O

O

Catalyst (15 mol%)

OH N+

Br –

Cl

647 Stumpf, A.; McClory, A.; Yajima, H.; Segraves, N.; Angelaud, R.; Gosselin, F. Organic Process Research & Development 2016, 20, 751–759. 648 Yee, N. K.; Nummy, L. J.; Byrne, D. P.; Smith, L. L.; Roth, G. P. The Journal of Organic Chemistry 1998, 63, 326–330. 649 Scott, J. P.; Ashwood, M. S.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.; Dolling, U.-H.; Emerson, K. M.; Gibb, A. D.; Goodyear, A.; Oliver, S. F.; Stewart, G. W.; Wallace, D. J. Organic Process Research & Development 2008, 12, 723–730.

371

372

6 Selected Catalytic Reactions

6.21.2.4

Addition of Heteroatom Nucleophiles

Asymmetric oxo-Michael and aza-Michael addition reactions can also be accomplished via phase transfer catalysis. Below, the asymmetric intramolecular conjugate addition of a guanidine nucleophile proceeds with good enantioselectivity in the presence of a cinchonidine-based phase transfer catalyst. This key transformation enabled a highly efficient synthesis of the antiviral candidate letermovir.650

CF3

CO2Me HN N

F3C

CF3 N

CF3

OH

N

MeO

·2 Br –

N

CF3

O

1.5 equiv K3PO4 Toluene/water 0 °C 98% assay yield, 76% ee

N F

N

MeO

5 mol %

OMe

OMe

N

N N F

OMe

6.21.3

Amino Organocatalysis via Iminium and Enamine Intermediates

Aldehydes and ketones can react with primary and secondary amines to form iminium ions, which are more reactive than their parent carbonyl compounds as electrophiles. The C—H acidity at the α position to the carbonyl is also significantly increased by iminium formation, and in certain cases can allow facile enamine formation and eventual functionalization at the α position via nucleophilic addition. Both of these modes of reactivity have deep roots in the chemical literature and have experienced a marked increase in their rate of development in the past 20 years.651,652 6.21.3.1

Iminium Catalysis: Conjugate Addition

Langenbeck’s 1937 report that piperidinium acetate catalyzed the conjugate addition of water to crotonaldehyde is the seminal example of iminium catalysis in conjugate addition chemistry.653 More recently, a variety of nucleophiles have been shown to react with α,β-unsaturated carbonyls via iminium catalysis, often with high levels of enantioselectivity when chiral catalysts are employed. The example shown below of secondary amine catalysis of nitromethane addition to cinnamaldehyde has been carried out on industrial scale.654 OTMS Ph Ph

F

F

CHO

N H 5 mol %

t-BuCO2H (5 mol%) B(OH)3 (50 mol%) THF, MeNO2 73%

F

F

NO2 CHO

95% ee

650 See Note 154. 651 See Note 625. 652 See Note 626. 653 Langenbeck, W.; Sauerbier, R. Berichte der deutschen chemischen Gesellschaft 1937, 70B, 1540–1541. 654 Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.; Devine, P. The Journal of Organic Chemistry 2010, 75, 7829–7841.

6.21 Organocatalysis

6.21.3.2

Iminium Catalysis: Cycloadditions

Although it had been established previously that α,β-unsaturated carbonyls could be activated via iminium formation,655 it was not until MacMillan’s Report in 2000 that this activation mode was applied to a catalytic system.656 The disclosure that simple imidazolidinones catalyze highly enantioselective cycloadditions triggered the development of a broad range of iminium-catalyzed processes and attracted significant interest to secondary amine organocatalysis in general. O

Catalyst (5 mol%)

H Ph

O

Me

Catalyst (20 mol%)

H

O

Ph

99% 93% ee 1 : 1.3 endo:exo

H

O

Ph

endo

H

exo

Me

O

84% 89% ee

CHO

Catalyst Ph

6.21.3.3

Me N Me N Me H •HCl

Enamine Catalysis: Aldol/Mannich

An early example of enamine catalysis in aldol processes is the Hajos–Parish–Eder–Saur–Wiechert reaction, in which proline catalyzes the intramolecular aldol reaction of triketones such as the one shown in the following.657 O

Me O

Me O

3 mol% (S)-proline

Me

DMF, rt 100%, 93% ee

O

O

Me O

p-TsOH O

OH

The first asymmetric amine-catalyzed intermolecular transformation was reported by List et al. in 2000,658 and since then an incredible amount of development has occurred in the field. The following is an example of a prolinol-catalyzed cross-aldol reaction that was used in the synthesis of an HIV protease inhibitor.659 OH Ph Ph

O

BnO H

O

OEt

H O

N H 3 mol %

THF/H2O

H

BnO H

OH OEt O

O

CH(OMe)3 p-TsOH 86%

H

BnO MeO

OH OEt O OMe

94 : 6 dr 95% ee

Numerous examples of Mannich-type reactions have also been reported that proceed in a similar fashion as the aforementioned reaction. 6.21.4

Nucleophilic Catalysis

Generally, nucleophilic catalysts react with a substrate to form a covalent intermediate that is on the reaction path to the desired product. This class of catalyst can be quite diverse, but in most cases, the catalyst is a Lewis base, is a good nucleophile, and is also a good leaving group. 655 Baum, J. S.; Viehe, H. G. The Journal of Organic Chemistry 1976, 41, 183–187. 656 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. Journal of the American Chemical Society 2000, 122, 4243–4244. 657 Hajos, Z. G.; Parrish, D. R. The Journal of Organic Chemistry 1974, 39, 1615–1621. 658 List, B.; Lerner, R. A.; Barbas, C. F. Journal of the American Chemical Society 2000, 122, 2395–2396. 659 Hayashi, Y.; Aikawa, T.; Shimasaki, Y.; Okamoto, H.; Tomioka, Y.; Miki, T.; Takeda, M.; Ikemoto, T. Organic Process Research & Development 2016, 20, 1615–1620.

373

374

6 Selected Catalytic Reactions

6.21.4.1

Acyl Transfer Reactions

4-dimethylaminopyridine (DMAP)-catalyzed acyl transfer is perhaps the most well-known reaction proceeding via nucleophilic catalysis.660,661 In the following example, which is carried out at >50 kg scale, the use of DMAP allowed for faster reaction times, higher yields, and allowed the use of less acylating reagent.662 O

OMe

O O

H

Cl Cl

NMe H

O

1 mol% DMAP Cl

Cl

H

N H

CH2Cl2

Cl

OMe

94%

HN

O

Cl Cl

O

HN

Chiral DMAP derivatives have also been developed.663,664 Scientists at Pfizer recently utilized such a catalyst to realize a highly regioselective and enantioselective acylation during a large-scale synthesis of a PCSK9 inhibitor.665 F3C

N

O

CF3 CF3

HO N

I N N Me

N N N N H

Me

I

CF3

N

3 mol %

N N Me

MeCHO, Et 3N (iPrCO) 2O, MBTE

O Me

O

Me

94% ee

100%

6.21.4.2

N N N N

Reactions Proceeding via Acyl Anion Equivalents

The reactions of nucleophilic catalysts with aldehydes followed by deprotonation of the resultant intermediate generates acyl anion equivalents, which have great synthetic utility.666 The Stetter reaction proceeds via this pathway and allows access to 1,4-dicarbonyls from aldehydes and enones. An N-heterocyclic carbene (NHC)-catalyzed Stetter reaction is utilized in the synthesis of Lipitor to access the alpha diketone precursor to the pyrrole fragment of the molecule (see the following structure).667 Me Me O

O NHPh

iPr Ph

HO

O H F

N+

S 20 mol %

O Br –

O NHPh

iPr O

Ph

EtOH, Et 3N 80% F

660 Höfle, G.; Steglich, W.; Vorbrüggen, H. Angewandte Chemie International Edition 1978, 17, 569–583. 661 Ragnarsson, U.; Grehn, L. Accounts of Chemical Research 1998, 31, 494–501. ˇ 662 Casar, Z.; Mesar, T. Organic Process Research & Development 2015, 19, 378–385. 663 See Note 627. 664 Fu, G. C. Accounts of Chemical Research 2004, 37, 542–547. 665 Akin, A.; Barrila, M. T.; Brandt, T. A.; Dechert-Schmitt, A.-M. R.; Dube, P.; Ford, D. D.; Kamlet, A. S.; Limberakis, C.; Pearsall, A.; Piotrowski, D. W.; Quinn, B.; Rothstein, S.; Salan, J.; Wei, L.; Xiao, J. Organic Process Research & Development 2017, 21, 1990–2000. 666 Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chemical Reviews 2015, 115, 9307–9387. 667 Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Letters 1992, 33, 2283–2284.

6.21 Organocatalysis

The benzoin condensation also proceeds via the intermediacy of an acyl anion, but the electrophilic reaction partner in this case is an aldehyde, therefore providing α-hydroxy ketone products. Enantioselective variants of the reaction have been developed, an intramolecular example of which is shown in the following.668

N

Ph N+ N BF4–

O Me O

6.21.4.3

O

10 mol %

H

9 mol% KOtBu toluene, rt 93%

Me OH

94% ee

Morita–Baylis–Hillman Reactions

α,β-Unsaturated carbonyls can react with nucleophilic catalysts at the β-position to form intermediates that are nucleophilic at the α-position. Following reaction with an electrophile at the α-position, the catalyst is regenerated via elimination. This reaction pathway is commonly known as the Morita–Baylis–Hillman reaction and is catalyzed by a variety of nucleophilic catalysts, most commonly tertiary amines or phosphines. In the following example, a 3-quinuclidinol catalyzed process was used to access a key hydroxymethacrylate building block in the synthesis of Sampatrilat.669 OH

t-BuO O

+

CH2O

N 25 mol % MeCN, H2O 64%

OH t-BuO O

668 Enders, D.; Niemeier, O.; Balensiefer, T. Angewandte Chemie International Edition 2006, 45, 1463–1467. 669 Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Organic Process Research & Development 2003, 7, 244–253.

375

377

7 Rearrangements David H. Brown Ripin 1 and Chad A. Lewis 2 1

Clinton Health Access Initiative, Boston, MA, USA

2 Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 377 [1,2]-Rearrangements, 377 Other Rearrangements, 402 Miscellaneous Migrations, 420

7.1 Introduction Rearrangement reactions can be powerful methods for the relay of stereochemistry, functional group interconversion, and altering the atomic connectivity. Simple and easily prepared substrates can in many cases be transformed into significantly more complex molecules. The distinction of a rearrangement from other varieties of chemical transformations can be difficult; for the purposes of this chapter, rearrangements are defined as a change in atomic connectivity of a molecule in a concerted or stepwise manner. Some of the reactions shown in this chapter are not synthetically useful but are worth being aware of as mechanisms for impurity formation.

7.2 [1,2]-Rearrangements 7.2.1 7.2.1.1

Carbon-to-Carbon Migrations of Carbon and Hydrogen Wagner–Meerwein and Related Reactions

The Wagner–Meerwein rearrangement is a term used to describe the cationic [1,2]-shift of carbon or hydrogen. These reactions can be initiated with an acid catalyst ionizing an alcohol or halide or through the generation of halonium ions from the treatment of olefins with a halogenating agent. In cases where there is a driving force favoring a single product, the reaction can be synthetically useful.1,2 Aluminum trichloride is typically employed in generating cations from alkyl chlorides, while protic acids are often employed for the ionization of alcohols. Solvents for the chloride processes must be aprotic and unreactive with the carbocation intermediates. In the case of alcohol ionization, a solvent that reversibly traps the cations can be employed.

1 Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Poindexter, G. S. Organic Syntheses 1980, 59, 85–94. 2 Salaun, J.; Fadel, A. Organic Syntheses 1986, 64, 50–56. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

378

7 Rearrangements

*

*

* Cl

AlCl3

Cl

60–63%

OH *

* Cl * *

OH

HCl

* *

57%

*

On more complex substrates, selectivity for a single product can be problematic. One system in which the Wagner–Meerwein rearrangement is frequently employed is in the functionalization of camphor and related bicyclic compounds. In the terpene literature, Wagner–Meerwein rearrangement is used to refer to carbon substituents other than methyl, and the reactions with a [1,2]-shift of a methyl group are considered Nametkin rearrangement.3 In the following example, the [1,2]-shift occurs with a CH2 substituent bound to a carbon atom of a tertiary alcohol, resulting in a ketone product. Me

OH

Me

NBS

Me

96%

Me

Br

O

HO Br Me Me

Cationic [1,2]-shifts are frequently employed in the rearrangement of pyrroles and thiophenes; these rearrangements are followed by loss of a proton to produce the aromatic system.4,5 In the first example below, the migrating group is a carbomethoxy substituent. MeO2C

1

Me OH 2

Me Br

HN O N

O

MeN

86%

OMe

N

OMe

O

CO2Me

HN O

MsOH H N

N

1 2

N

O

MeN

Br

H N

O

O MeO

7.2.1.2

S

1 2

OMe OMe

OMe

OMe

OMe

PPA H3PO4 70%

1

MeO

S

2

OMe

Pinacol Rearrangement: Vicinal Diols to Ketones or Aldehydes

The pinacol rearrangement of vicinal diols is an acid-catalyzed cationic rearrangement process. The more highly substituted alcohol departs, leaving a carbocation. A neighboring hydrogen or carbon migrates to the cation, resulting in the formation of a ketone or aldehyde.6,7 Brönsted acids are most frequently employed, although other ionization 3 de la Moya Cerero, S.; Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Maroto, B. L. The Journal of Organic Chemistry 2003, 68, 1451–1458. 4 Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T.; Kasai, M. Organic Process Research & Development 1998, 2, 344–350. 5 Vicenzi, J. T.; Zhang, T. Y.; Robey, R. L.; Alt, C. A. Organic Process Research & Development 1999, 3, 56–59. 6 Martinelli, M. J.; Khau, V. V.; Horcher, L. M. The Journal of Organic Chemistry 1993, 58, 5546–5547. 7 Barnier, J. P.; Champion, J.; Conia, J. M. Organic Syntheses 1981, 60, 25–29.

7.2 [1,2]-Rearrangements

methods have been used. A number of Lewis acids have been utilized to effect the semipinacol rearrangement including the easily handled BF3 ⋅OEt2 . In the first example below, the ethyl group transfers in preference to the methyl group, which is expected, given the electronic propensity for more highly substituted alkyl groups to migrate.

Me

HO Me

O

H2SO4

Me OH

Me

Et Me

82%

OH OH

Me Et

BF3 • OEt2

O

65–80%

H

Epoxides or β-haloalcohols can also undergo a similar reaction called the semipinacol rearrangement. The ready availability of diols and epoxides from olefins provides rapid access to pinacol substrates, allowing preparation of many potentially challenging compounds.8

Ph

O

MeAl(OAr)2

Ph O

Ph

87%

H Ph

In the case of an asymmetric diol, the more highly substituted bridgehead carbon can ionize first, followed by [1,2]-hydride shift. The unusual method for the generation of the cation was preferred in this case to avoid decomposition of the acid-sensitive substrate.9 TBSO

O O

O Me

Me Me Me

O

H

Me

TBSO Ph3P Cl3CCCl3 i-Pr2NEt

O

O Me

82%

Me Me

O

Me

OH OH

O

O

H

Me

H

In some substrates, the migration can occur with stereocontrol.10 The rearrangement below delivers product of >99% ee. It proceeds via mesylation of the less hindered alcohol, and migration of the indolyl substituent with inversion of configuration at the secondary chiral center, possibly through a concerted process.

OH N Me

Me

Ph OH

(i) MsCl, Et 3N (ii) Et 3Al 85%

Me N Me

O Ph

In the following example, the semipinacol rearrangement of the epoxide shown proceeds with a [1,4]-sigmatropic shift of the hydride in an allylic variant of the reaction.11 8 Ooi, T.; Maruoka, K.; Yamamoto, H. Organic Syntheses 1995, 72, 95–103. 9 DeCamp, A. E.; Mills, S. G.; Kawaguchi, A. T.; Desmond, R.; Reamer, R. A.; DiMichele, L.; Volante, R. P. The Journal of Organic Chemistry 1991, 56, 3564–3571. 10 Shionhara, T.; Suzuki, K. Synthesis 2003, 141–146. 11 Dolle, R. E.; Kruse, L. I. The Journal of Organic Chemistry 1986, 51, 4047–4053.

379

380

7 Rearrangements

Me

Me

Me

Me

Me

Me

HCl

Me

Me

Me

58%

O BzO

Me

Me

BzO

Me Me

Me O

Me Me

The semipinacol rearrangement can use either Brönsted acids as shown (conducted on 1.5 kg of material) or Amberlyst-15 ion exchange resin in similar yield.12 Me O

O Me

Me Me

O

OH

H2SO4, DCM (70%)

Me Me

OH O

Me Me

Me

7.2.1.3

Me O

O

Expansion and Contraction of Rings

Cationic [1,2]-shifts including Wagner–Meerwein rearrangements and pinacol rearrangements are frequently employed in the expansion or contraction of ring systems. The pinacol transformation below goes through an expanded ring intermediate.13 4

3

Me Me O

O

SnCl4

2

NCO2Et

Me 1 O

2

Me Me 3

90%

Me

1 O

4

NCO2Et

Al Me O Me 3 + 4 2

NCO2Et

Me 1 O

The following are two pinacol rearrangements that result in ring expansion.14,15 OEt

Me

OH EtO OTMS

O

O

HBF4 66–74%

TFA

Me O

81–90% O

The Tiffeneau–Demyanov ring expansion is similar to a pinacol rearrangement, but the carbocation is generated from a diazo intermediate that is in turn generated from an α-hydroxy amine.16

12 Smejkal, T.; Gopalsamuthiram, V.; Ghorai, S. K.; Jawalekar, A. M.; Pagar, D.; Sawant, K.; Subramanian, S.; Dallimore, J.; Willetts, N.; Scutt, J. N.; Whalley, L.; Hotson, M.; Hogan, A.-M.; Hodges, G. Organic Process Research & Development 2017, 21, 1625–1632. 13 Overman, L. E.; Rishton, G. M. Organic Syntheses 1993, 71, 63–71. 14 Miller, S. A.; Gadwood, R. C. Organic Syntheses 1989, 67, 210–221. 15 Nakamura, E.; Kuwajima, I. Organic Syntheses 1987, 65, 17–25. 16 Steinberg, N. G.; Rasmusson, G. H.; Reynolds, G. F.; Hirshfield, J. H.; Arison, B. H. The Journal of Organic Chemistry 1984, 49, 4731–4733.

7.2 [1,2]-Rearrangements

O

N3 Me

NEt2 OH

Me

NEt2

O Me

(i) Zn, HOAc (ii) NaNO2, HOAc

O

Me

50% N H Me

O

N H Me

O

The Ciamician–Dennstedt reaction is the cyclopropanation of a pyrrole or indole, followed by ring expanding rearrangement to the 3-halopyridine or quinoline.17 H N

H N

CHCl3, NaOH Et3NBnCl

Cl

53%

Cl Me

MeCl

Me

7.2.1.4

N

Rearrangements of Ketones and Aldehydes

The α-ketol rearrangement is a rearrangement of an α-hydroxy ketone, where the alcohol and ketone are transposed. In the following case shown, hemiketal opening was followed by enolization of the ester and aldol reaction with the C-3 carbonyl.18 The resulting tertiary alcohol underwent a [1,2]-migration of the carbon subsistent to produce the tertiary alcohol shown on multikilogram scale. HO

HO Me

MeO Me O

OH O

Et

Me OH

O O

O

Me

O

OMe

1

2

Me 4

HO

Et Me

3 OH

N

OMe

O

Me

Et3N KOH

Me

N 1 O 2 OHO O 3 Me 4

MeO

O

Me OMe OMe

The α-ketol rearrangement can be run under acidic conditions as well.19 The product to starting material distribution in the rearrangement is under thermodynamic control; therefore, a driving force for the reaction such as relief of ring strain or 1,3-dicarbonyl formation as opposed to a 1,2-dicarbonyl is a requirement for a complete reaction. OH EtO

POEt2 OEt

7.2.1.5

HCl 70%

O HO

POEt2

Dienone to Phenol Rearrangement

When a 4,4-disubstituted cyclohexadienone is treated with acid, one of the C-4 substituents migrates to the 3 or 5 position with concomitant aromatization of the six-membered ring to a phenol. The direction of migration is dominated by electronic considerations.20

17 18 19 20

Kwon, S.; Nishimura, Y.; Ikeda, M.; Tamura, Y. Synthesis 1976, 249. Koch, G.; Jeck, R.; Hartmann, O.; Kuesters, E. Organic Process Research & Development 2001, 5, 211–215. Page, P.; Blonski, C.; Perie, J. Tetrahedron Letters 1995, 36, 8027–8030. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. The Journal of Organic Chemistry 1994, 59, 1831–1834.

381

382

7 Rearrangements

OH

O HO

HO

HCl 90%

Ph Ph

Ph Ph

7.2.1.6

Benzil to Benzilic Acid Rearrangement

The benzil to benzilic acid rearrangement is formally the following reaction shown. Hydroxide bases are most commonly employed, but other nucleophilic bases will work as well. O Ph

Ph Ph

HO−

Ph

OH OH

O

O

This rearrangement has been utilized in a synthesis of dihydropyrroles in a reaction with acetonitrile.21 O Ph

Ph O

O Ph

−O

7.2.1.7

NaH MeCN

Ph

68%

O

CN

Ph

CN

N H

Me

Ph O− CN Ph

Ph

O

Favorskii Rearrangement: Anionic Rearrangement of 𝛂-Haloketones

The Favorskii rearrangement occurs when an α-haloketone is treated with a strong, nucleophilic base. The mechanism has been the subject of extensive study, with surprising results. The rearrangement is not a simple migration of the carbon substituent that does not bear the halide (bottom pathway shown in the following), as either the R1 bearing carbon or the R2 bearing carbon can migrate regardless of the position of the halogen. This finding, in conjunction with labeling experiments, points to the intermediacy of a cyclopropanone which ring opens on addition of alkoxide to result in the more stable anion, which is protonated by the alcoholic solvent. It is important to take this into consideration when planning a synthesis utilizing this rearrangement, which is most useful for symmetrical substrates. O R2

R2

R1

O

O

− OR

X

X X

R1 −O

OR

R2

R1

R1

OR R2

Favorskii reactions can be a powerful means for ring contractions and useful for producing strained rings. The most common ring contraction from a six to a five-membered carbocycle, can be merged with the chiral pool to provide difficulty to procure synthons. Scale-ups of this chemistry have been achieved with pulegone on multikilogram scale.22

21 Akabori, S.; Ohtomi, M.; Takahashi, K.; Sakamoto, Y.; Ichinohe, Y. Synthesis 1980, 900–901. 22 Lane, J. W.; Spencer, K. L.; Shakya, S. R.; Kallan, N. C.; Stengel, P. J.; Remarchuk, T. Organic Process Research & Development 2014, 18, 1641–1651.

7.2 [1,2]-Rearrangements

Me

(i) Br2, NaHCO3, CH2Cl2, −10 °C (ii) NaOEt, EtOH

O

Me Me

Me

CO2Et

Me

60% 2 : 3 cis:trans

Me

O Me

Me

In the following case, treating the bromoketone with NaOMe results in a ring contraction of the bicyclo[3.2.1]octane ring system to a bicyclo[2.2.1]heptane.23 Alkoxide bases are most commonly employed for this transformation. EtO2C N Br

NaOMe

EtO2C N

56%

CO2Me

O

A rare Favorskii ring contraction from a five to a four-membered carbocycle was essential in the synthesis of a cubane dicarboxylate.24 Br O (iii) 50% KOH(aq) (iv) HCl

(i) Diels–Alder (ii) hν (Hg)

O Br

CO2H HO2C

Br O

In the case where the α-carbon of the ketone not appended to the halide is not enolizable, the reaction is called the quasi-Favorskii rearrangement.25 This rearrangement does not proceed via the cyclopropanone intermediate but rather by the aforementioned [1,2]-shift mechanism. In the following case shown, an aniline base was used resulting in an amide product rather than an ester. Me

Me Br

Me

PhNHK 82%

O

NHPh

Me

O

Amines with a more nucleophilic lone-pair of electrons can also effect the quasi-Favorskii rearrangement.26 H N

O

H N

MeNH2 Me Br Me

80%

Me

NHMe Me O

Quasi-Favorskii rearrangements of ketones and ketals can be induced on treatment of appropriate substrates with a Lewis acid.27

23 24 25 26 27

Bai, D.; Xu, R.; Chu, G.; Zhu, X. The Journal of Organic Chemistry 1996, 61, 4600–4606. Falkiner, M. J.; Littler, S. W.; McRae, K. J.; Savage, G. P.; Tsanaktsidis, J. Organic Process Research & Development 2013, 17, 1503–1509. Ares, J. J.; Outt, P. E.; Kakodkar, S. V.; Buss, R. C.; Geiger, J. C. The Journal of Organic Chemistry 1993, 58, 7903–7905. Sanchez, J. P.; Parcell, R. F. Journal of Heterocyclic Chemistry 1990, 27, 1601–1607. Maiti, S. B.; Chaudhuri, S. R. R.; Chatterjee, A. Synthesis 1987, 806–809.

383

384

7 Rearrangements

(i) ZnCl2, MeOH (ii) t-BuOK, DMSO Br Me

O

90%

MeO

Me CO2H MeO

(i) NaOAc, Δ (ii) KOH Br MeO OMe

7.2.1.8

69%

CO2H

Arndt–Eistert Synthesis: Homologation of Carboxylic Acids via Wolff Rearrangement of 𝛂-Diazoketones

The Ardnt–Eistert synthesis is an effective synthetic method for the homologation of carboxylic acids by one methylene. In the first step of the process, diazomethane is added to the activated carboxylic acid to form the α-diazoketone intermediate, which then undergoes Wolff rearrangement on treatment with a silver salt to produce the desired homologated product. Two examples are shown in the following. The use of diazomethane is highly hazardous and is a significant drawback to this process.28,29 Diazomethane can be generated in a continuous process to reduce the risks on larger scale.30 Ph OH

BocHN

(i) Et3N, EtOC(O)Cl (ii) CH2N2

Ph BocHN

O

O

AgCF3CO2 Et3N N2

BocHN

AgPhCO2 Et3N EtOH

(i) Et3N, EtOC(O)Cl (ii) CH2N2 Cl

61–65%

Ph OH

85–92%

O

O

84–92%

N2

O

OEt O

An alternative to Ardnt–Eistert synthesis is shown in the following and does not require the use of diazomethane.31

O Ph

O

LiCHBr2 OEt

7.2.1.9

92%

(i) LiHMDS (ii) n-BuLi (iii) EtOH

Ph

77%

CHBr2

OEt

Ph O

Homologation of Aldehydes and Ketones

The homologation of ketones and the conversion of aldehydes to ketones can be accomplished through the use of a variety of methods involving rearrangements. O R1

28 29 30 31

O

‶C R3 ″ R2

R1, R2, R3 = H, C

R2

R1 R3

Linder, M. R.; Steurer, S.; Podlech, J. Organic Syntheses 2003, 79, 154–164. Lee, V.; Newman, M. S. Organic Syntheses 1970, 50, 77–80. Proctor, L. D.; Warr, A. J. Organic Process Research & Development 2002, 6, 884–892. Kowalski, C. J.; Reddy, R. E. The Journal of Organic Chemistry 1992, 57, 7194–7208.

7.2 [1,2]-Rearrangements

A traditional method for effecting this transformation is through the reaction of a diazo compound with a ketone or aldehyde in the presence of a Lewis acid.32 In the second example shown, the use of the large Lewis acid MAD ((2,6-di-t-Bu-4-MePhO)2 AlMe) improved selectivity to 97 : 3 from 60 : 40 with Me3 Al.33 The aryldiazomethanes can be generated in situ from the corresponding tosyl hydrazones.34 O Ph

O

PhCHN2, LiBr 92%

H

Ph

Ph

O

O

Me

MeCHN2, MAD 87% 97 :3 diastereoselectivity

t-Bu

t-Bu

For the insertion of a CH2 group, diazomethane can be used in the aforementioned procedures. A number of safer alternatives to diazomethane have also been developed for use in this reaction including TMSCHN2 35 and ethyl diazoacetate.36 (i) TMSCHN2, MgBr2 (ii) HCl

O C9H19

H

O Me

C9H19

71%

Some methods involving a similar rearrangement without the use of diazo compounds have also been reported.37,38,39 (i) n-BuCBr2Li (ii) n-BuLi (iii) HCl

O

O n-Bu

60% (i) A (ii) ZnBr 2

O Ph

H

63%

O

(i) B (ii) EtMgBr

N N N

A=

Ph

67%

7.2.1.10

Li

NMe2

O

Me2N O Cl

B=

Ph

O S

Li

Cl Cl

Fritsch–Buttenberg–Wiechell Rearrangement: Acetylenes from 1,1-Disubstituted Olefins

The Fritsch–Buttenberg–Wiechell rearrangement is a synthesis of acetylenes from 1,1-disubstituted-2-haloolefins. The reaction is useful for converting asymmetrically substituted ketones, which can be readily accessed, into asymmetrically substituted acetylenes. 32 33 34 35 36 37 38 39

Loeschorn, C. A.; Nakajima, M.; McCloskey, P. J.; Anselme, J. P. The Journal of Organic Chemistry 1983, 48, 4407–4410. Maruoka, K.; Concepcion, A. B.; Yamamoto, H. Synthesis 1994, 1283–1290. Angle, S. R.; Neitzel, M. L. The Journal of Organic Chemistry 2000, 65, 6458–6461. Aoyama, T.; Shioiri, T. Synthesis 1988, 228–229. Dave, V.; Warnhoff, E. W. The Journal of Organic Chemistry 1983, 48, 2590–2598. Villieras, J.; Perriot, P.; Normant, J. F. Synthesis 1979, 968–970. Katritzky, A. R.; Toader, D.; Xie, L. The Journal of Organic Chemistry 1996, 61, 7571–7577. Satoh, T.; Mizu, Y.; Kawashima, T.; Yamakawa, K. Tetrahedron 1995, 51, 703–710.

385

386

7 Rearrangements

R M

R

R

R

X

In general, the R groups are aryl groups, olefins, or acetylenes. The following example depicts the synthesis of diynes using this method.40 OMe

n-BuLi

TMS

82%

Br

OMe

Br

TMS

The rearrangement can be combined with the formation of the 1,1-disubstituted olefin, as shown in the following example.41 O Ph

Ph

+

7.2.1.11

Cl

PO(OEt)2

LiHMDS

Cl

Cl

Cl

Ph

Ph

n-BuLi 95%

Ph

Ph

Other Carbon-to-Carbon Migrations of Carbon

An oxidative ring contraction using hydrogen peroxide and sulfuric acid has been accomplished in the following quaternary cyclohexanone.42 O

O 1

2

3

4 Me

H2O2 H2SO4

CO2Bu

HO 1

O 2 3

O

OH 4 Me CO2Bu

BuO2C 2

HO2C 1

3

O Me 4 OH

The Simmons–Smith cyclopropanation has been slowly evolving into a more user friendly reaction. The usual requirements of several equivalents of reagent, heterogenous reaction conditions, and safety concerns for the zinc carbenoid have limited this reaction. New methods for carbenoid generation have resurrected the cyclopropanation and have been demonstrated by the use of this chemistry on scale.43 The typical generation of the cyclopropanating reagent has been simplified by the use of diethylzinc, and more cleanly affords the desired EtZnCH2 I reagent. Interestingly, the use of diarylphosphoric acid produces a new reagent Ar2 P(O)OZnCH2 I, which increases solubility and reduces the usual decomposition of the Simmons–Smith reagent.

40 Shi Shun, A. L. K.; Chernick, E., T.; Eisler, S.; Tykwinski, R. R. The Journal of Organic Chemistry 2003, 68, 1339–1347. 41 Mouries, V.; Waschbuesch, R.; Carran, J.; Savignac, P. Synthesis 1998, 271–274. 42 Challenger, S.; Derrick, A.; Silk, T. V. Synthetic Communications 2002, 32, 2911–2918. 43 Austad, B. C.; Hague, A. B.; White, P.; Peluso, S.; Nair, S. J.; Depew, K. M.; Grogan, M. J.; Charette, A. B.; Yu, L.-C.; Lory, C. D.; Grenier, L.; Lescarbeau, A.; Lane, B. S.; Lombardy, R.; Behnke, M. L.; Koney, N.; Porter, J. R.; Campbell, M. J.; Shaffer, J.; Xiong, J.; Helble, J. C.; Foley, M. A.; Adams, J.; Castro, A. C.; Tremblay, M. R. Organic Process Research & Development 2016, 20, 786–798.

7.2 [1,2]-Rearrangements

Me H

Me BnO

ArO

NCbz H

Me O

O

(i) Et2Zn, CH2I2, CH2Cl2

O

BnO

Ar = Me

O

Me BnO

NCbz H

O

O

H

H

Me

H

Me

Me

H

H

H

NCbz H

Me O Me

O

Me Cbz H N

Me

H

BnO

Me O

Me

Me

H

Me

(55–80%)

H

H

OAr

O OH (ii) MsOH, CH2Cl2

Me

H

P

H

H

H

O LA

Me

O

O

Me Me O BnO

Cbz Me H N O

H

H

H

O

Me

Me Me

LA

O

LA = MsOH

BnO

H

Cbz Me H N O

H

Me

LA

H

O

In the case of the cyclopamine derivative, the exposure of the cyclopropanation product to Lewis acids resulted in ring expansion to the cycloheptene product. A by-product of the carbamate capturing the penultimate carbocation was noted. 7.2.1.12

Other Carbon-to-Carbon Migrations of Hydrogen

The anion migration shown in the following was run on a 50 g scale.44 NEt2 O

7.2.2 7.2.2.1

i-Pr2NMgBr Δ

NEt2

− O

NEt2

− O

I2 56%

NEt2

I O

Carbon-to-Carbon Migrations of Other Groups Migration of Halogen, Hydroxy, Amino, and Other Groups

The migration of a heteroatom from carbon-to-carbon is not uncommon. A variety of migrations is shown in the following, but it is not all encompassing. Heteroatoms can migrate to a radical, cationic, or anionic center to create a more stable intermediate, which then goes on to further reactions.45,46 44 Cai, S.; Dimitroff, M.; McKennon, T.; Reider, M.; Robarge, L.; Ryckman, D.; Shang, X.; Therrien, J. Organic Process Research & Development 2004, 8, 353–359. 45 Giese, B.; Groeninger, K. S. Organic Syntheses 1990, 69, 66–71. 46 Lucca, G. V. D. The Journal of Organic Chemistry 1998, 63, 4755–4766.

387

388

7 Rearrangements

AcO AcO

OAc O

Bu3SnH AIBN

AcO Br

79–81%

OAc O

AcO AcO

OAc

O N Ph

HO

O N

DAST

Ph

N Ph

OH

N Ph

H OH F

The Willgerodt reaction is a useful method for the migration of a carbonyl oxygen to the end of a carbon chain, resulting in a carboxylic acid. This rearrangement was utilized early in the development of naproxen on 500 kg scale.47,48 O Me

CO2H

S8, morpholine MeO

MeO

The Rupe rearrangement also involves the migration of oxygen, in this case a propargylic alcohol.49 Me OH

O

Me

Me Amberlyst A252C

Me

78% MeO

7.2.2.2

MeO

Neber Rearrangement: Carbon-to-Carbon Migration of Nitrogen of Activated Oximes

The Neber rearrangement involves the enolization of an activated oxime, displacement of the leaving group by the enolate to form an azirine, and hydrolysis or ketalization of the azirine to the α-aminoketone or α-aminoketal. A Neber rearrangement has been utilized to synthesize a 3-pyridylaminomethyl ketal.50,51,52 While this was an effective method for the synthesis of kilogram quantities of the material, it has been noted that the tosyloxime intermediate in the rearrangement reaction is shock sensitive53 and decomposes at a low temperature via a Beckmann rearrangement (Section 7.2.3.5).54 One solution to the instability of this intermediate is to keep the intermediate in solution and bring it directly into the rearrangement reaction.

47 Harrington, P. J.; Lodewijk, E. Organic Process Research & Development 1997, 1, 72–76. 48 Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski, A.; Tomolonis, A.; Fried, J. H. Journal of Medicinal Chemistry 1970, 13, 203–205. 49 Tilstam, U.; Weinmann, H. Organic Process Research & Development 2002, 6, 384–393. 50 Chung, J. Y. L.; Ho, G.-J.; Chartrain, M.; Roberge, C.; Zhao, D.; Leazer, J.; Farr, R.; Robbins, M.; Emerson, K.; Mathre, D. J.; McNamara, J. M.; Hughes, D. L.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Letters 1999, 40, 6739–6743. 51 LaMattina, J. L.; Suleske, R. T. Organic Syntheses 1986, 64, 19–26. 52 LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. 53 See Note 50. 54 am Ende, D. J.; Brown Ripin, D. H.; Weston, N. P. Thermochimica Acta 2004, 419, 83–88.

7.2 [1,2]-Rearrangements

OTs

N

EtO

OEt

EtOK

Me

NH2

N

N

OTs

N

N

K N

N

The Neber rearrangement can also be executed on hydrazonium salts as shown in the following.55 +

N

−

NMe3I

(i) NaOEt (ii) HCl

Ph

74%

H2 N Ph

O

An interesting variant on the procedure was reported directly from the primary amine. The authors note that the dichloroamine intermediate explodes at 100 ∘ C, so caution is advised when utilizing this procedure.56 NH2 Me

Me

7.2.2.3

NaOCl

NCl2 Me

NaOMe

Me

MeO OMe Me Me

56%

NH2

Payne Rearrangement: Rearrangement of 𝛂-Hydroxyepoxides

The Payne rearrangement is the transformation of a 1-hydroxy-2,3-epoxide to a 3-hydroxy-1,2-epoxide. The rearrangement is under thermodynamic control, but the rearrangement can be synthetically useful when the rearranged epoxide reacts preferentially to the starting material.57 OBn OH

O

NaOH t-BuSH

HO

90%

HO

OBn St-Bu

In an analogous rearrangement, an intermediate sulfate ester rendered the reaction irreversible and provided a good yield of product.58

O O S

O O

OBn OTBS

(i) TBAF (ii) NaSPh (iii) H2SO4

−

O3SO

HO

OBn 89% O

HO

OBn SPh

55 Parcell, R. F.; Sanchez, J. P. The Journal of Organic Chemistry 1981, 46, 5229–5231. 56 Coffen, D. L.; Hengartner, U.; Katonak, D. A.; Mulligan, M. E.; Burdick, D. C.; Olson, G. L.; Todaro, L. J. The Journal of Organic Chemistry 1984, 49, 5109–5113. 57 Behrens, C. H.; Ko, S. Y.; Sharpless, K. B.; Walker, F. J. The Journal of Organic Chemistry 1985, 50, 5687–5696. 58 See Note 25.

389

390

7 Rearrangements

7.2.3

Carbon-to-Nitrogen Migrations of Carbon

7.2.3.1

Hofmann Rearrangement: Primary Amides to Amines or Carbamates

The conversion of esters/carboxylic acids to amines requires a [1,2] rearrangement typically via a nitrene/nitrenoid type intermediate. The generation of this intermediate can be achieved via hypervalent iodide on the amide (in this section), decomposition of an acyl azide (Section 7.2.3.2), or activation of a hydroxamic acid (Section 7.2.3.3). The Hofmann rearrangement transforms a primary amide into a carbamate, essentially transposing the carbon and nitrogen of the amide functionality. The mechanism of the reaction proceeds via oxidation of the amide nitrogen to install a leaving group, typically a halide, followed by [1,2]-migratory displacement of the leaving group by the carbon appended to the carbonyl, resulting in an isocyanate which is then quenched with a nucleophile, typically an alcohol. Formation of ureas, hydrolysis to the carboxylic acid, and other degradation products are typical. Two preparations demonstrate the utility of the Hofmann rearrangement utilizing different oxidants: PhI(TFA)2 59 and N-bromosuccinimide (NBS) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).60 CONH2

PhI(OTFA)2

NH3Cl

69–77%

O NH2 MeO

NBS DBU MeOH 93%

H N

OMe O

MeO

Hofmann rearrangements are used on large scale to afford a transformation similar to that of the Curtius (Section 7.2.3.2), without the intermediacy of an acyl azide. Common oxidants used on commercial scale are the inexpensive and easy to handle NaOCl and NaOBr.61 The second transformation shown is noteworthy as it produces an N-aminomethyl amide.62 i-Pr CONH2 CO2H O Me Me H2N O

N H

Me

NaOBr NaOH 70%

i-Pr NH2 CO2H O Me Me

NaOCl NaOH H2N

Me

N H

Me

Me

A Hofmann rearrangement was utilized to convert 5-cyanovaleramide to methyl N-cyanobutyl carbamate using bromine as the oxidant.63 In this procedure, the brominated amide intermediate was added to refluxing methanol to effect rearrangement.

CONH2 CN

Br2 NaOMe 94%

NHCO2Me CN

59 White, E. Organic Syntheses 1973, Coll. Vol. V , 336–339. 60 Keillor, J. W.; Huang, X. Organic Syntheses 2002, 78, 234–238. 61 Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Organic Process Research & Development 1997, 1, 26–38. 62 Ogasa, T.; Ikeda, S.; Sato, M.; Tamaoki, K. Preparation of N-(2,2,5,5-tetramethylcyclopentanecarbonyl)-(S)-1,1-diaminoethane p-toluenesulfonate as a sweetener intermediate JP02233651 1990 5 pp. 63 Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. The Journal of Organic Chemistry 2001, 66, 5772–5782.

7.2 [1,2]-Rearrangements

The following reaction was performed on over 23 kg material64 ; in this case, iodosobenzene was found to provide superior results to hypochlorites and other common oxidants. O NH2 BocHN

NH2

PhI(OAc)2 75%

CO2H

BocHN

CO2H

The Hofmann rearrangement can be operated in aqueous conditions, which can mitigate the formation of urea by-products by decomposition of the isocyanate intermediate. One such example can be found to proceed in high yield under mild conditions on 120 kg scale using phenyliodine (III) diacetate (PIDA).65 NHBoc CONH2 H

MeO

(ii) Toluene recrystallization

N

NHBoc NH2

(i) PIDA, KOH MeCN/H2O, 24–28 °C 85%

MeO

MeO

H N

MeO

Alternatively, simple bleach can also be used for the rearrangement.66 O Br

NH2

Br

NaOCl 13.9% w/v then NaOH, 80 °C

N

NH2 N

86%

OMe

OMe

7.2.3.2

Curtius Rearrangement: Acyl Azides to Amines or Carbamates

The Curtius rearrangement effects essentially the same transformation as the Hofmann rearrangement. In this process, an acyl azide, generally formed either from an acid chloride/activated ester and sodium azide or through oxidation of an acyl hydrazide, rearranges via liberation of nitrogen to an isocyanate which is then trapped with a variety of nucleophiles. The following transformation depicts the rearrangement of a dienyl substrate that would not be compatible with the conditions of the Hofmann rearrangement.67

CO2H

(i) EtOCOCl, i-Pr2NEt (ii) NaN3 (iii) BnOH, Δ

NHCbz

49–57%

A number of examples of Curtius rearrangements are reported in the literature. A well-studied Curtius rearrangement in which the issues critical to running the process safely were identified as depicted in the following.68,69 (i) NaN3 (ii) Δ, BnOH

O Cl

65–72%

H N

OBn O

64 Zhang, L.-H.; Chung, J. C.; Costello, T. D.; Valvis, I.; Ma, P.; Kauffman, S.; Ward, R. The Journal of Organic Chemistry 1997, 62, 2466–2470. 65 Abrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes, A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Organic Process Research & Development 2011, 15, 503–514. 66 Daver, S.; Rodeville, N.; Pineau, F.; Arlabosse, J.-M.; Moureou, C.; Muller, F.; Pierre, R.; Bouquet, K.; Dumais, L.; Boiteau, J.-G.; Cardinaud, I. Organic Process Research & Development 2017, 21, 231–240. 67 Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Organic Syntheses 1980, 59, 1–9. 68 am Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Organic Process Research & Development 1998, 2, 382–392. 69 Govindan, C. K. Organic Process Research & Development 2002, 6, 74–77.

391

392

7 Rearrangements

As the Curtius rearrangement involves the intermediacy of an acyl azide that must be heated to promote rearrangement, extensive safety testing was undertaken in order to run this reaction on a large scale. The key to safe operation in this case was the controlled addition of a solution of acyl azide to a heated solution of benzyl alcohol in toluene in order to keep the quantity of azide being heated to a minimum. The decomposition of azide to isocyanate and reaction with benzyl alcohol to generate product is rapid, and thus, the addition rate controls the rate of decomposition of the azide intermediate. Addition of potassium carbonate to the benzyl alcohol solution minimized an acid-catalyzed addition of benzyl alcohol to the product that formed an aminal side product. A modification was made to the procedure in which the acyl azide is added to hot toluene, and the resultant isocyanate was distilled into a receiving vessel containing benzyl alcohol at lower (0 ∘ C) temperature. This process also reduced the amount of side product and provided the product in high enough purity to crystallize directly from the reaction mixture. There are also some large-scale examples of Curtius rearrangements wherein the acyl azide was generated by oxidation of an acyl hydrazine. 3-Phenoxypropionyl hydrazide was oxidized to the acyl azide in solution using NaNO2 and HCl; this acyl azide was then rearranged by slowly adding the acyl azide to a hot solvent to effect rearrangement.70 An ergoline derivative was synthesized using a similar procedure.71 H N OPh O

NaNO2 HCl

NH2

H2N

NCO OPh

O H H

H N

OEt

88%

OPh

NHNH2

NMe H

O

O

H

NaNO2 H2SO4

N H

N H

H N

OEt O

NH2

H

NMe H

78% HN

HN

The high energy density of the acyl azide and thermal requirements for decomposition have left the Curtius reaction as a relatively small-scale reaction until safe protocols are established for larger scale. Recent updates using flow chemistry and controlling the generation of these high-energy structures has now been demonstrated on large scale.72 COOi Pr COOH•NHBn2

COOi Pr O O

7.2.3.3

COOi Pr

(i) 15% H3PO4

OEt O

(ii) ClCOOEt, NaN 3 t-BuOH

COOiPr N3

NHBoc

COOi Pr

(iii) TsOH

NH2•HOTs

65% 3 steps

COOi Pr N

•

O

O

Lossen Rearrangement: Hydroxamic Imides to Amines or Carbamates

The Lossen rearrangement has been a standard transformation for the exchange of a carboxylate for an amine. Similar to a Hofmann and proceeding through an identical isocyanate intermediate, the Lossen proceeds through the activation of a hydroxamic acid. The reagents typically employed are dehydrative (TsCl, MsCl, N,N′ -dicyclohexylcarbodiimide (DCC)). The common isolated products are carbamates or ureas after reaction of the isocyanate intermediate with an alcohol or amine, respectively.

70 Madding, G. D.; Smith, D. W.; Sheldon, R. I.; Lee, B. Journal of Heterocyclic Chemistry 1985, 22, 1121–1126. 71 Baenziger, M.; Mak, C. P.; Muehle, H.; Nobs, F.; Prikoszovich, W.; Reber, J. L.; Sunay, U. Organic Process Research & Development 1997, 1, 395–406. 72 Tang, W.; Wei, X.; Yee, N. K.; Patel, N.; Lee, H.; Savoie, J.; Senanayake, C. H. Organic Process Research & Development 2011, 15, 1207–1211.

7.2 [1,2]-Rearrangements

O R

N H

Base

R′

O

R′′OH

O

H N

R

OR′′ O

Imides of hydroxylamine also undergo Lossen rearrangement to carbamates in a transformation similar to the Curtius or Hofmann rearrangement. In the following reaction, the utility of N-Boc-O-mesyl hydroxylamine for effecting the Lossen rearrangement of activated carboxylic acids is demonstrated.73 N,O-Bis(ethoxycarbonyl)hydroxylamine has also been demonstrated to be a useful reagent for this transformation.74

CO2H

Ph

(i) i-BuOCOCl NMM (ii) BocNHOMs

O CO2t-Bu N OMs

Ph

82%

Zn(OTf)2 BnOH 2,6-di-t-butylpyridine

NHCbz

Ph

69%

NMM = N-methyl morpholine

A Lossen rearrangement was employed in the synthesis of benz[cd]indol-2(1H)-one and a derivative thereof.75 Safety concerns drove the workers to employ o,p-dinitrophenol rather than chloride as a leaving group.

O

N

NaOH

O

O

77%

NH

O O2 N

NO2

An interesting observation was made regarding the nature of a trapped isocyanate-hydroxamic acid pseudo dimer.76 The dimer can break down to the desired products but require an initial amount of isocyanate that can be obtained in small quantities. Once the isocyanate is present, the reaction can proceed in an autocatalytic type manifold to provide the product. Sacrificial isocyanate, metal salts, anhydrides, and carbonates have been utilized. The process group at Bristol-Myers Squibb noted that acetonitrile can act as a surrogate for an isocyanate intermediate to begin the reaction. O R

O R

N H

OH

O

MeCN Slow

R

N H

O

OH

O

Me NH

N H

•

O

Me R

R

N

O

H N

O O

NH2 R

H N

N H

OH O

R

R

NH2

CO2

The Bristol-Myers Squibb group developed the chemistry for a complex steroid derivative.77 The reaction appears to work well with tertiary hydroxamic acids, and less so with secondary or primary hydroxamic acids thus far. 73 Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. The Journal of Organic Chemistry 1998, 63, 10040–10044. 74 Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Letters 2000, 41, 5291–5293. 75 Marzoni, G.; Varney, M. D. Organic Process Research & Development 1997, 1, 81–84. 76 Strotman, N. A.; Ortiz, A.; Savage, S. A.; Wilbert, C. R.; Ayers, S.; Kiau, S. The Journal of Organic Chemistry 2017, 82, 4044–4049. 77 Ortiz, A.; Soumeillant, M.; Savage, S. A.; Strotman, N. A.; Haley, M.; Benkovics, T.; Nye, J.; Xu, Z.; Tan, Y.; Ayers, S.; Gao, Q.; Kiau, S. The Journal of Organic Chemistry 2017, 82, 4958–4963.

393

394

7 Rearrangements

Me

Me

H Me

Me

H

H

O

H HN

Me

Me

OH

H

H Me Me

MeO2C

Me

NH2

H

Me

H Me Me

MeO2C

Initial work toward catalytic Lossen rearrangements was shown using dimethylcarbonate and a structurally similar base 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) to DBU. The reaction was successful for a series of aryl (equation below) and aliphatic hydroxamic acids.78 H N

N N

5–40 mol% O Ar

N H

OH

Dimethylcarbonate (20 equiv) Methanol (0–2.0 equiv), reflux

Ar

NH2

Self-propagative Lossen’s can also be effected using simply base or catalytic activating agents.79 Base-induced condensation of two hydroxamic acids with elimination of hydroxylamine affords the activated intermediate. The difficulties inherent with the condensation are evident by the sluggish rate of reaction. Catalytic activating agents such as isocyanates, sulfonyl chlorides, acid chlorides, and anhydrides have been demonstrated in good yields. Phenyl isocyanate proved capable of clean conversion under catalytic loading. OMe O N H OMe

K2CO3 (1 equiv) PhNCO (1 mol%) DMSO, 25–50 °C

OH

OMe NH2 OMe

A safer alternative to the acyl azide requisite functionality of the Curtius, the Lossen rearrangement arrives at the nitrene via activation of a hydroxamic acid. 1,1′ -carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), and other reagents are sufficient for isocyanate formation.80

HO

(i) CDI, NH2OH, THF (75%) (ii) CDI, tol, 60 °C then N OH

Me Me N O

F

O Me Me

N

O

(71%)

S

N

N H

S N

CDI, NH2OH

HO

H Me Me N N O

F

O F

OH

Me Me •

S

N

N

F

S CDI O O

N

Δ

Me Me N O

F

S

78 Kreye, O.; Wald, S.; Meier, M. A. R. Advanced Synthesis and Catalysis 2013, 355, 81–86. 79 Hoshino, Y.; Shimbo, Y.; Ohtsuka, N.; Honda, K. Tetrahedron Letters 2015, 56, 710–712. 80 Zhao, J.; Gimi, R.; Katti, S.; Reardon, M.; Nivorozhkin, V.; Konowicz, P.; Lee, E.; Sole, L.; Green, J.; Siegel, C. S. Organic Process Research & Development 2015, 19, 576–581.

7.2 [1,2]-Rearrangements

7.2.3.4

Schmidt Rearrangement: Ketones to Amides

The ketone to amide transformation achieved in the Beckmann rearrangement (Section 7.2.3.5) can also be effected by treating a ketone with azide under acidic conditions, although the Beckmann rearrangement is preferred. The azidoalcohol initially formed rearranges to an amide with displacement of nitrogen.81 O

NaN3 MsOH

Me

Me

H N

O

98%

A modified procedure for this transformation has been published; in this case, the rearrangement is photochemically induced.82 N3 OTIPS

H N

hv

O

83%

Interestingly, the reaction can be carried out in an intramolecular fashion with an azidoketone substrate.83,84 This is an efficient method for taking relatively simple aliphatic azides and converting them into complex nitrogen-containing ring systems. O

O

N3

H Me

82%

O

EtO OEt

N

TiCl4

Me

H O O

TMSOTf

Me

N3

81%

H

Me

N

Trapping the azide in an intramolecular fashion with a carbocation instead of a ketone results in the formation of an amine after reduction of the intermediate imine.85 n-Bu

n-Bu OH

N3

(i) SnCl4 (ii) NaBH4 60%

N H

7.2.3.5

Beckmann Rearrangement: Oximes to Amides

The Beckmann rearrangement involves the rearrangement of an oxime to an amide through the migration of an alkyl group from the oxime carbon to nitrogen with displacement of an activated oxygen. Quenching the iminium ion with water produces an amide. This transformation is frequently used to expand carbocycles. The oxygen of the oxime must be activated for displacement, and this is typically accomplished through the use of an acid catalyst or dehydrative reagents such as tosyl chloride. These reactions tend to be very exothermic. A useful preparation using an aluminum catalyst is shown in the following.86

81 Galvez, N.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A. Tetrahedron 1996, 52, 1609–1616. 82 Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Candelario, A.; Huffman, M. A.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. J.; Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.; Reamer, R. A.; Welch, C. J.; Mathre, D. J.; Tsou, N. N.; McNamara, J. M.; Reider, P. J. Journal of the American Chemical Society 2003, 125, 2129–2135. 83 Iyengar, R.; Schildknegt, K.; Morton, M.; Aube, J. The Journal of Organic Chemistry 2005, 70, 10645–10652. 84 Mossman, C. J.; Aube, J. Tetrahedron 1996, 52, 3403–3408. 85 Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081–5089. 86 Maruoka, K.; Nakai, S.; Yamamoto, H. Organic Syntheses 1988, 66, 185–193.

395

396

7 Rearrangements

MsO

(i) i-Pr3Al (ii) DIBAL-H

N

Me

H N

Me

53–58%

A Beckmann rearrangement was utilized in the synthesis of azithromycin. In this case, the alcohol is activated for displacement by sulfonylation. The facile Beckmann rearrangement of O-tosyloximes leads to low levels of stability in the intermediates used in Neber rearrangements (Section 7.2.2.2).87,88 OH Me N Me HO HO HO Me O Me O

NMe2 Me O

Me

O

Me O O Me

TsCl pyr 85%

Me

MeO Me

Me

O

HO

OH

HN Me HO HO HO Me O Me O

NMe2 HO

Me O

O

Me O O Me

Me Me

MeO Me

OH

A Beckmann fragmentation results in some cases if there is an oxygen substituent α to the oxime. This fragmentation was used to transform milbemycin VM-44866 into SB-201561.89 The five-step sequence was carried out in 30% overall yield. OH Me

H

O Me O O OH H O

H

N

Me

N O

Me

Me Me

NosCl Et3N

Me OTIPS

OH O

Me O

Me Me

Me O O OH H O

H

Me OTIPS

The Tiemann rearrangement is a variant of the Beckmann rearrangement; in this case, the oxime of an amide is rearranged to produce a diimide product. A large excess of base is required for this transformation, limiting its utility.90 This methodology is useful for synthesizing strained or asymmetrically substituted carbodiimides. HO

N NH

7.2.3.6

(i) MsCl, pyr (ii) NaOH

N •

N

81%

Stieglitz Rearrangements and Related Reactions: Cationic C to N Migration of Carbon

The Stieglitz rearrangement is similar to the Wagner–Meerwein rearrangement, but with a nitrogen-centered cation. The cation is traditionally generated from the N-chloride with a silver salt. Activation of a hydroxylamine as the sulfonate ester is also sufficient to initiate rearrangement and has obvious advantages over the silver method.91 87 Kerdesky, F. A. J.; Premchandran, R.; Wayne, G. S.; Chang, S.-J.; Pease, J. P.; Bhagavatula, L.; Lallaman, J. E.; Arnold, W. H.; Morton, H. E.; King, S. A. Organic Process Research & Development 2002, 6, 869–875. 88 Yang, B. V.; Goldsmith, M.; Rizzi, J. P. Tetrahedron Letters 1994, 35, 3025–3028. 89 Andrews, I. P.; Dorgan, R. J. J.; Harvey, T.; Hudner, J. F.; Hussain, N.; Lathbury, D. C.; Lewis, N. J.; Macaulay, G. S.; Morgan, D. O.; et al. Tetrahedron Letters 1996, 37, 4811–4814. 90 Richter, R.; Tucker, B.; Ulrich, H. The Journal of Organic Chemistry 1983, 48, 1694–1700. 91 Hoffman, R. V.; Kumar, A.; Buntain, G. A. Journal of the American Chemical Society 1985, 107, 4731–4736.

7.2 [1,2]-Rearrangements

Me

Me Me

EtOAc −20 °C

N ONs

Me NsO

48%

Me N Me

The following sequence depicts a Diels–Alder reaction followed by Stieglitz rearrangement.92 TsO Me

+

N

O

O O

OTs N O O O

Me Me2AlCl

O

O

Me Me

7.2.4

pH 7 buffer Me

Me

Me

O N

42% O

O Me O Me

Carbon to Oxygen Migrations of Carbon

7.2.4.1

Baeyer–Villiger Oxidation: Ketones or Aldehydes to Esters

Carbonyls, especially ketones, remain the “backbone” of organic synthesis. The oxidation of a ketone to an ester can be quite useful but remains problematic due to a small subset of reagents capable of performing this reaction. The reagents that are available, typically peracids and peroxides, can have restrictions due to safety concerns and decomposition. The Baeyer–Villiger oxidation is widely used, and selection of reagents and reaction conditions can often have an effect on the selectivity of rearrangement. Isatin can be converted selectively to either isatoic anhydride or 2,3-dioxo-1,4-benzoxazine.93 The product obtained is dependent on the oxidant used; hydrogen peroxide in acetic acid leads to the formation of anhydride, while the use of K2 S2 O8 in sulfuric acid results in production of the benzoxazine. H2O2 HOAc cat. H2SO4

O O N H

O

79%

O

N H

O

K2S2O8 H2SO4

O

O

95%

N H

O

In general, there is selectivity for more highly substituted carbons to migrate. The compatibility of functionalities such as amines94 and epoxides95 are demonstrated by the following examples. In the case of the synthesis of a prostaglandin analog, the generation of N-oxides as intermediates in the reaction appears to improve selectivity for the desired lactone over the undesired, and careful control of conditions resulted in the hydrolysis of the undesired lactone in the presence of desired one, thereby facilitating purification. H2SO4 MeCO3H

N

N

60–63% OR Ph 8

O

O

O

O

OR

R = p-PhPh Ph

O

m-CPBA Naphth

87%

8

O

CO2Naphth

92 Renslo, A. R.; Danheiser, R. L. The Journal of Organic Chemistry 1998, 63, 7840–7850. 93 Reissenweber, G.; Mangold, D. Angewandte Chemie, International Edition in English 1980, 92, 196–197. 94 Coleman, M. J.; Crookes, D. L.; Hill, M. L.; Singh, H.; Marshall, D. R.; Wallis, C. J. Organic Process Research & Development 1997, 1, 20–25. 95 Flisak, J. R.; Gombatz, K. J.; Holmes, M. M.; Jarmas, A. A.; Lantos, I.; Mendelson, W. L.; Novack, V. J.; Remich, J. J.; Snyder, L. The Journal of Organic Chemistry 1993, 58, 6247–6254.

397

398

7 Rearrangements

Finally, a notable example of subtle regiochemical control by selection of reagents is presented.96 Using trifluoroperacetic acid as the oxidant, generated in situ from urea–hydrogen peroxide complex (UHP) and trifluoroacetic anhydride (TFAA), very high (98 : 2) selectivity for the desired product was observed at 80% conversion. Using other oxidant systems, the selectivity was notably lower. O TFAA, UHP

O

O

OTBS Me

Me

OTBS

The Baeyer–Villiger oxidation is enjoying a renaissance due to the expanding biocatalysis field for process chemistry. Baeyer–Villiger monooxygenases (BVMOs) have proven capable of the conversion of ketones to esters with stereocontrol and scalable conditions.97 O

O

Cyclohexanone monooxygenase Acinetobacter calcoaceticus NCIMB 9871 O2, water, pH 7, 37 °C

O

O

7.2.5 7.2.5.1

O

O

Heteroatom to Carbon Migrations Stevens Rearrangement – [1,2]-Rearrangement of N, O, or S Ylides with Migration of Carbon

The Stevens rearrangement is the [1,2]-migration of a carbon substituent from a tetrasubstituted ammonium salt, a sulfur ylide, or an oxonium ylide. The rearrangement requires a strong base to deprotonate a carbon adjacent to the heteroatom. As more than one substituent of the ammonium salt frequently has a proton that can be abstracted, mixtures of products are not unusual in this reaction. Further, if one of the substituents is allylic or benzylic, the potential for a [2,3]-rearrangement (the Sommelet–Hauser rearrangement in the case of an aryl group, Section 7.3.2.10) is competitive. Me

X− Stevens

NMe2

+

N

Sommelet– Hauser

Me

Me NMe2

Me Me

The ammonium ylide is generated by any of a number of methods, including deprotonation with a strong base such as NaNH2 ,98 treating a methyltrimethylsilane group with fluoride,99 or the reaction of a tertiary amine with a diazonium.100 Me N+

Br −

Ph

CO2Me

I−

N+

TMS

Me Me O

Me

N N2 Bn

53%

Ph

CO2Me NMe2 7

O Me O

NaNH2

CsF 81%

Me N

Cu(0)

O

Ph :

3 O

O −

N+ Me Bn O

NMe2 CO2Me

Me

79%

O

N Bn O Me

Me

96 Varie, D. L.; Brennan, J.; Briggs, B.; Cronin, J. S.; Hay, D. A.; Rieck, J. A., III; Zmijewski, M. J. Tetrahedron Letters 1998, 39, 8405–8408. 97 Baldwin, C. V. F.; Wohlgemuth, R.; Woodley, J. M. Organic Process Research & Development 2008, 12, 660–665. 98 Elmasmodi, A.; Cotelle, P.; Barbry, D.; Hasiak, B.; Couturier, D. Synthesis 1989, 327–329. 99 See Note 5. 100 West, F. G.; Naidu, B. N. The Journal of Organic Chemistry 1994, 59, 6051–6056.

7.2 [1,2]-Rearrangements

Oxonium ylides generated from the diazo compound can also undergo a Stevens rearrangement, although this reaction is plagued by the formation of side products.101 O BnO

O

Rh2(OAc)4 64%

N2

O

Bn

Interestingly, it was found that small variations in the reaction conditions for the rearrangement of a benzylic ammonium system could drive the reaction via a Stevens or a Sommelet–Hauser pathway.102 CsF HMPA DBU NMe2

MeO

65%

CsF HMPA hv

I− + NMe2 MeO

Me

57%

TMS

MeO

NMe2

Ring contraction has been achieved on a sulfur ylide system as shown in the following.103 Me

Me

S

Me

KHMDS MeI

CO2Et CO2Et

CO2Et

74%

CO2Et

Me

SMe

The rearrangement has evolved from simple tetraalkyl ammonium salts with base to include α-substitution (TMS, R3 Sn, CN) allowing more flexible reaction conditions. Predictive and high fidelity of group transfer has promoted the Stevens rearrangement to a critical strategy for alkaloid synthesis. Interestingly, the use of an α-substituted cyano group allows mild base to produce the ylide and facilitate the alkyl transfer.104 A powerful example can be found in the synthesis of polycyclic alkaloids. The main drawback is the use of cyanide to form the precursor, and then the reductive removal of the cyanide. (i) HCO2H, Δ (ii) PCl5

MeO MeO

NH2

MeO MeO

N

MeO

87%

(iii) MeI N

MeO

MeO

Me (vi) KHMDS

CN

MeO

N

N

MeO

Me

(iv) KCN, H2O 99% Br MeO

R2

N

MeO

R2 MeO N Me NC

R2

(vii) NaCNBH3 82–87% R1 (two steps)

Me

CN

R2 R1

Me

I

(v) R1

Br CN

R1

MeO

MeO

MeO MeO

N

Me R2 R1

Un-natural amino acids remain a critical component for the study of biological processes. The synthesis of α-amino acids is enabled by the Stevens rearrangement starting from glycine (1) or proline (2).105

101 Eberlein, T. H.; West, F. G.; Tester, R. W. The Journal of Organic Chemistry 1992, 57, 3479–3482. 102 Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. The Journal of Organic Chemistry 1992, 57, 5034–5036. 103 Larsen, R. D.; Corley, E. G.; King, A. O.; Carroll, J. D.; Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.; et al. The Journal of Organic Chemistry 1996, 61, 3398–3405. 104 Orejarena Pacheco, J. C.; Lahm, G.; Opatz, T. The Journal of Organic Chemistry 2013, 78, 4985–4992. 105 Arbore, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.; Middleton, M. L. Synlett 2000, 236–238.

399

400

7 Rearrangements

Bn N

Me

MeI, DMF, K2CO3 then DBU 40 °C

O

Bn Me

O

N

OMe

OMe

(1)

Me

I DMF, K2CO3, DBU 5 °C, 3 d

O N Bn

Bn

48%

OMe

O

O N

OMe

N Bn

OMe

(2)

86% ee

7.2.5.2

[1,2]-Meisenheimer Rearrangement – Rearrangement of R3 NO to R2 NOR

The Meisenheimer rearrangement of N-oxides proceeds via a similar mechanism as the Stevens rearrangement (Section 7.2.5.1). This reaction can be synthetically useful for converting an amine into an aminoalcohol as shown in the following or can be a side reaction if another pathway of reaction is desired for the N-oxide.106 O N

O

(i) H2O2 (ii) Δ

O

64%

O

O

N

In another example, rearrangement occurs at low temperature once the substrate is oxidized.107 CO2Me

HO

NBoc H

N Cl

7.2.5.3

CO2Me (i) m-CPBA (ii) HCl

HO

NH

61%

Me

N Cl

O

H

Me

Other Heteroatom to Carbon Rearrangements

The following sulfenyl transfer reaction was useful in the preparation of a geminal aminosulfide in the synthesis of an antibiotic.108 Me

Me S N O

H

PPh3, SiO2

S

73%

N

N

CO2Bn

Me

N N N

H2N

S H

O

S

N

N

CO2Bn

Me

N N N

The Aggarwal [1,2] metallate rearrangement is capable to stereospecifically delivering quaternary centers with high fidelity. The quaternary stereocenter synthesis utilizes a carbamate trapped chelate usually generated with alkyllithium reagents.109 The trapped chelate then condenses with an alkylboronate ester producing the quaternary boronate. Alkyl

106 Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563–14576. 107 Didier, C.; Critcher, D. J.; Walshe, N. D.; Kojima, Y.; Yamauchi, Y.; Barrett, A. G. M. The Journal of Organic Chemistry 2004, 69, 7875–7879. 108 Gordon, E. M.; Chang, H. W.; Cimarusti, C. M.; Toeplitz, B.; Gougoutas, J. Z. Journal of the American Chemical Society 1980, 102, 1690–1702. 109 Fandrick, K. R.; Mulder, J. A.; Patel, N. D.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.; Daeubler, J.; Desrosiers, J.-N.; Zeng, X.; Rodriguez, S.; Ma, S.; Qu, B.; Li, Z.; Fandrick, D. R.; Grinberg, N.; Lee, H.; Bosanac, T.; Takahashi, H.; Chen, Z.; Bartolozzi, A.; Nemoto, P.; Busacca, C. A.; Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C. H. The Journal of Organic Chemistry 2015, 80, 1651–1660.

7.2 [1,2]-Rearrangements

group transfer from the boronate via displacement of the carbamate provides the tertiary boronate. The rearrangement proceeds stereospecifically when using chiral carbamates.

MeMe Me Me

O NiPr2

O

O

Me

B

O

LDA (1.2 equiv) MTBE, −10 to 0 °C

iPr2N O

O

(1)

Me 98.6% ee

Br

Me Me Me Me

iPr2N

O Li

O

B

(99%)

99.9% ee

Br

MeMe Me

Me

O O B O

O

Me

Me

Br

Br

The chiral tertiary boronate can then be reacted with lithiated chloroalkanes to produce the quaternary boronate with the α-chloro substituent. Subsequent bond migration of the quaternary center to displace the chloride regenerates the tertiary boronate with the alkyl group installed.

Me

(i) DCM (2 equiv), LDA (1.5 equiv), THF/diox 4/1, −45 °C to rt (ii) NaOH, H2O2

MeMe Me O

B

O

O (2)

Me

Me

Br

Br Cl Cl

Me Me Me B O Me

Bpin

Cl

O

Me Br

Me Br

Considering the prevalence of phenol containing natural products and polyphenols found in a variety of secondary metabolites, the Fries rearrangement is a powerful method to build off existing readily available phenols. The [1,3] Fries rearrangements are usually milder and have higher regiocontrol than Friedel–Crafts rearrangements and have found a niche with phenolic materials. Simple acylation of phenols, followed by catalytic Lewis acid–mediated rearrangement can provide high-yielding arene acyl products.110 OAc

OH O BF3 • Et2O

MeO

OMe OAc

Toluene 110 °C

Me MeO

OMe OH 60%

OMe

OH O Me

+ MeO

OMe OAc

MeO

O

HO OH O

35%

110 Martin-Benlloch, X.; Elhabiri, M.; Lanfranchi, D. A.; Davioud-Charvet, E. Organic Process Research & Development 2014, 18, 613–617.

401

402

7 Rearrangements

7.2.6

Carbon to Heteroatom Rearrangements

7.2.6.1

Brook Rearrangement, Carbon-to-Oxygen Migration of Silicon

The Brook rearrangement is the anionic [1,2]-shift of silicon from carbon to oxygen. The retro-Brook rearrangement is sometimes called the silicon-Wittig rearrangement and requires the use of strong bases such as alkyl lithium reagents or metal amides. The most common Brook rearrangement is the [1,2]-shift, but longer range shifts are also reported.111 Some examples of Brook rearrangements are shown in the following.112,113 O TBS

OTBS

NaHMDS

CN

CN

73%

ONa

OTBS CN

TBS

O TBS

t-BuO O

CN

Na

(i)

MgBr

(ii)

O

c-C6H11

O

OH

t-BuO TBSO

H O

MgBr

c-C6H11

O t-BuO TBS

OMgBr

t-BuO

H

OMgBr OTBS

The well-studied rearrangement has been utilized to provide new arenas of bond formation and allowed anion relay chemistry to construct complex molecules efficiently. The Smith group has provided several key examples of Brook rearrangements including photoredox-catalyzed alkylations and arylations.114 OH TBS

+

Ir[dF(CF3)ppy]2(dtbpy)PF6 (3 mol%) DCE, KOPiv, CsOAc Blue LED, rt 24 h

O Me

O TBSO

Me

88–83%

7.3 Other Rearrangements 7.3.1 7.3.1.1

Electrocyclic Rearrangements Rearrangements of Cyclobutenes and 1,3-Cyclohexadienes

The thermal conversion of cyclobutenes to butadienes is a conrotatory process. In general, the ring opening process is of more utility than the reverse photochemically induced reaction of butadienes to the cyclobutene. The reaction is useful in the preparation of quinines as shown in the following.115 111 112 113 114 115

Moser, W. H. Tetrahedron 2001, 57, 2065–2084. Okugawa, S.; Masu, H.; Yamaguchi, K.; Takeda, K. The Journal of Organic Chemistry 2005, 70, 10515–10523. Nicewicz, D. A.; Johnson, J. S. Journal of the American Chemical Society 2005, 127, 6170–6171. Deng, Y.; Liu, Q.; Smith, A. B. Journal of the American Chemical Society 2017, 139, 9487–9490. Perri, S. T.; Rice, P.; Moore, H. W. Organic Syntheses 1990, 69, 220–225.

7.3 Other Rearrangements

EtO

O

EtO

OH

O

O

(i) 138 °C (ii) FeCl3

EtO

>83%

EtO

O

O

Cyclohexadienes can be converted to 1,3,5-trienes photochemically in a disrotatory process, the reverse reaction can be achieved thermally and is also useful. A useful application of this chemistry is to the synthesis of vitamin D analogs from cholesterol precursors.116 The process shown involves photochemical ring opening, photochemical olefin inversion, and a thermally induced [1,7] sigmatropic hydride transfer reaction in the conversion of ergosterol to a vitamin D prodrug. Me Me

Me Me

H

Me

Me

Me

"tachy-isomer"

h𝜈 9-acetylantracene

+ Me

H

Me

H

Me OH

Me Me

Me Me

H

"pro-isomer" ergosterol

HO

Me Me

hv p-Me2NC6H4CO2Et

Me Me

(i) Δ (ii) RCOCl, pyr

Me H "pro-vitamin D"

Me

41–50% from ergosterol

Me

H Me

H HO

Me

"pre-isomer"

ROCO

7.3.1.2

Stilbenes to Phenanthrenes

Stilbenes can be converted to phenanthrenes in a photochemically induced process followed by air oxidation. This reaction was utilized in a synthesis of steganone on 3 g scale.117 HO2C OMe

O O

7.3.2 7.3.2.1

HO2C

hv I2, O2 MeO

81%

OMe

O O

OMe

MeO

OMe

Sigmatropic Rearrangements Cyclopropylimine Rearrangement

The cyclopropylimine rearrangement is a [1,3]-carbon shift from carbon to nitrogen. The rearrangement is a cationic process and proceeds under conditions where the imine is protonated.118 CHO NO2

(i) BnNH2, MgSO4 (ii) TMSCl, NaI 96%

NBn NO2

116 Okabe, M. Organic Syntheses 1999, 76, 275–286. 117 Krow, G. R.; Damodaran, K. M.; Michener, E.; Wolf, R.; Guare, J. The Journal of Organic Chemistry 1978, 43, 3950–3953. 118 Rawal, V. H.; Michoud, C.; Monestel, R. Journal of the American Chemical Society 1993, 115, 3030–3031.

403

404

7 Rearrangements

The reverse of this reaction can be accomplished photochemically and has been utilized in the following preparation.119 O N

hv t-BuOH

NHBoc

56–64%

OEt

OEt

Nitrogen variants of the rearrangement can be used to construct heterocycles.120 The following route depicted uses the Neber rearrangement (Section 7.2.2.2) to synthesize the azirine intermediate. O

N

(i) H2NOH (ii) TFAA F

N

F

72%

N

71%

F

N N

CF3

CF3

CF3

7.3.2.2

200 °C

Cyclopropanes to Allenes: The Skattebøl and Related Rearrangements

1,1-Dihalocyclopropanes undergo rearrangement to allenes when treated with an alkyl lithium reagent at low temperature in a process known as the Doering–Moore–Skattebøl rearrangement. This process, which involves the intermediacy of a carbene, has been well reviewed,121 and an example is provided below.122 Br

Br

Cl

n-BuLi

TBSO

•

TBSO

79%

Cl

When the cyclopropane is substituted with a vinyl group, cyclopentadienes are formed in a variant of the rearrangement known as the Skattebøl rearrangement.123 Br

Br MeLi

Me

78–80%

Me

Me

Me

The same transformation can be accomplished thermally. In the case of a cyclopropene, the vinyl carbene can be trapped with an electron deficient olefin as shown in the following preparation.124 This process has also been well reviewed.125 NC O

CN

O + Ph

Δ 60–64%

NC O

O

NC Ph

119 Crockett, G. C.; Koch, T. H. Organic Syntheses 1980, 59, 132–140. 120 Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain, S. D.; Peel, M. R. Organic Letters 2005, 7, 4753–4756. 121 Sydnes, L. K. Chemical Reviews 2003, 103, 1133–1150. 122 Patterson, J. W. The Journal of Organic Chemistry 1990, 55, 5528–5531. 123 Paquette, L. A.; McLaughlin, M. L. Organic Syntheses 1990, 68, 220–226. 124 Boger, D. L.; Brotherton, C. E.; Georg, G. I. Organic Syntheses 1987, 65, 32–41. 125 Baird, M. S. Chemical Reviews 2003, 103, 1271–1294.

7.3 Other Rearrangements

7.3.2.3

Cope Rearrangement

The Cope rearrangement is a classic in organic synthesis. The rearrangement is a [3,3]-sigmatropic rearrangement of a 1,5 hexadiene under thermal conditions. The reaction is under thermodynamic control and requires a driving force to go to completion. Two driving forces commonly used are ring strain relief126 and rearomatization. In the second example below, Claisen rearrangement (Section 7.3.2.4) is followed by Cope rearrangement to provide the desired product.127 H H

Me

Me Me O

CH2=CH2 Grubbs catalyst

H

Me Me O

N

Me

Me Me

74%

H

Δ

CO2Et

F

H

O H

OH

O F

Me

H H

F

85%

Me

CO2Et N

F

Much more frequently employed is the oxy-Cope rearrangement, where the driving force is the formation of an enol, which tautomerizes to the ketone. The rearrangement is greatly accelerated if the alcohol is deprotonated, resulting in an enolate product.128 HO

O

H

KHMDS 88%

H

Me

O

Me

Me

An analog to the Cope rearrangement is the divinylcyclopropane rearrangement, which can be effectively utilized to prepare seven-membered rings.129

Me

Me

Me Me

195 °C

Me OH

OH 1 : 2.2

Me

80% OH

New methods to influence the Cope rearrangement for stereochemical induction are rare and typically are difficult to control. Organocatalysis proved successful to leverage a vinyl aldehyde for clean conversion to the rearranged product via a proposed transition state (Eq. 1).130 Modest stereoinduction was also achieved using the chiral hydrazidoesters (Eq. 2).

126 127 128 129 130

Limanto, J.; Snapper, M. L. Journal of the American Chemical Society 2000, 122, 8071–8072. Newhouse, B. J.; Bordner, J.; Augeri, D. J.; Litts, C. S.; Kleinman, E. F. The Journal of Organic Chemistry 1992, 57, 6991–6995. Paquette, L. A.; Poupart, M. A. The Journal of Organic Chemistry 1993, 58, 4245–4253. Wallock, N. J.; Bennett, D. W.; Siddiquee, T.; Haworth, D. T.; Donaldson, W. A. Synthesis 2006, 3639–3646. Kaldre, D.; Gleason, J. L. Angewandte Chemie, International Edition 2016, 55, 11557–11561.

405

406

7 Rearrangements

‡ HN N (10 mol%) CO2Et TfOH (10 mol%) MeCN, rt, 24 h

O

Me Me

Ph

7.3.2.4

R

R

Ph HN N (20 mol%) CO2Et TfOH (10 mol%) MeCN, rt, 72 h

O

N CO2Et

(1)

49–93%

R

N

O

O Me Me

54%, 47% ee

Ph

*

(2)

Claisen Rearrangement

The Claisen rearrangement is a close analogy of the Cope rearrangement, but in this case, the 1,5-diene contains heteroatoms. A key difference from the Cope rearrangement is the thermodynamic stability of the newly formed products, thus leading to complete reaction. A number of variants of the Claisen rearrangement have been reported.131,132,133 The following example is an example of a classical Claisen rearrangement.134 CO2H

O

160–180 °C

O

84–91%

Ph

Ph

The rearrangement can occur with multiple heteroatoms in the system.135 H N

S

S

Cl N

O

O O

Me

N

i-Pr2NEt

O N

O

97%

Me

O Me Me

Me

Me

There are a number of variations on the classical Claisen rearrangement, some of which are detailed here. The Eschenmoser–Claisen reaction is the reaction of an allylic alcohol with dimethyl acetamide dimethylacetal (DMA–DMA) to generate an enamine intermediate which undergoes rearrangement and hydrolysis to result in the amide product.136

Me BnO

OH

MeO OMe Me

NMe2

O Me2N Me

92% BnO

Oxy-Claisen or Eschenmoser–Claisen rearrangements can be useful for converting allylic alcohols to γ–δ unsaturated esters. Further substitution of the allylic alcohol can provide interesting cascade or domino reactions. A 3-vinyl 131 132 133 134 135 136

Lutz, R. P. Chemical Reviews 1984, 84, 205–247. Castro, A. M. M. Chemical Reviews 2004, 104, 2939–3002. Ziegler, F. E. Chemical Reviews 1988, 88, 1423–1452. Vogel, D. E.; Buechi, G. H. Organic Syntheses 1988, 66, 29–36. Pilgram, K. H.; Skiles, R. D.; Kleier, D. A. The Journal of Organic Chemistry 1988, 53, 38–41. Daniewski, A. R.; Wovkulich, P. M.; Uskokovic, M. R. The Journal of Organic Chemistry 1992, 57, 7133–7139.

7.3 Other Rearrangements

substituted lactone was required and obtained using 2-butene-1,4-diol with triethyl orthoacetate.137 The rearranged unsaturated ester is cyclized with the remaining carbinol to provide the racemic taniguchi lactone. Resolution via sec-phenethylamine provided a crystallization purge point of one diastereomer. Acid-mediated cyclization provided the enantioenriched (S)-taniguchi lactone. NH2 Me MeC(OEt)3 (1.44 equiv) hydroquinone (4.8 mol%)

HO

OH

Ti(OiPr)4 (1.5 equiv)

(86%)

(i) Crystallize diasteromer (70%) (ii) H2SO4 (90%)

EtOH OEt HO

O

EtOH

OEt Me

OH

HN Me

O

O

O

EtOH OEt

OEt HO

OEt

O

O

O

(S)-taniguchi lactone

O

HO

O

HO

The Johnson–Claisen is analogous to the Eschenmoser–Claisen with an orthoester replacing the DMA–DMA. Two cases where this reaction was used to synthesize allenes are shown in the following.138,139 The stereochemistry of the allene is dictated by the stereochemistry of the alcohol. OTBS

H OH

THPO

MeC(OEt)3 AcOH 84%

OH

EtO2C •

THPO MeC(OEt)3 EtCO2H 82–91%

H

H

THPO

OPh

THPO

C5H11

OTBS

•

C5H11

OPh

CO2Et

The Ireland–Claisen is a powerful method for the formation of C—C bonds by generating an enolate-ester with a pendent allylic ester functionality.140 The rearrangement typically proceeds under mild reaction conditions driven by enthalpy. Competing hydrolysis of the ester or quenching of the enolate remain the source of low yield. Me

Me

O

BocHN O

(i) LDA, THF −65 to 20 °C (72%) (ii) (S)-phenylglycinol MeCN/MeOH (43%) (iii) HCl (100%)

Me

Me OH

BocHN O

137 von Kieseritzky, F.; Wang, Y.; Axelson, M. Organic Process Research & Development 2014, 18, 643–645. 138 Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A. R.; Li, T. T. The Journal of Organic Chemistry 1993, 58, 4280–4286. 139 Tsuboi, S.; Masuda, T.; Mimura, S.; Takeda, A. Organic Syntheses 1988, 66, 22–28. 140 Rossi, F.; Corcella, F.; Caldarelli, F. S.; Heidempergher, F.; Marchionni, C.; Auguadro, M.; Cattaneo, M.; Ceriani, L.; Visentin, G.; Ventrella, G.; Pinciroli, V.; Ramella, G.; Candiani, I.; Bedeschi, A.; Tomasi, A.; Kline, B. J.; Martinez, C. A.; Yazbeck, D.; Kucera, D. J. Organic Process Research & Development 2008, 12, 322–338.

407

408

7 Rearrangements

Another Ireland–Claisen variant is the rearrangement of a silylketene acetal, as shown in the following.141 LHMDS TMSCl TiCl4

OMe

O O

OMe

OH O OBn

77%

OBn

The Carroll rearrangement entails the conversion of a B-ketoester to the substituted B-ketoacid.142 O

O

O LDA

Me

O

Me

HO

97%

C6H13

O

C6H13

Claisen rearrangements on aromatic systems are usually followed by rearomatization. In the following case, a propargylic phenol undergoes rearrangement despite the distance between the reacting centers.143 H NC

220 °C

NC O

Me Me

98%

Me Me

O

A few methods for the asymmetric catalysis of the Claisen reaction have been reported, such as the preparation below to produce chiral allylamines from trichloroacetimidates.144 i-Pr N

Cl Pd

O Ph Co Ph

NH Cl3C

Me

O

Ph

CCl3

Ph

O

NH Me

97%, 94% ee

Asymmetric catalysis is possible due to an acceleration of the rate of rearrangement when the allylic oxygen is cationic. An example below demonstrates the facile rearrangements of allylic oxonium ions.145 +

O O Me

Me

Me

Cl3C

Cl , Zn(0) 58%

O Me

Cl

Me Cl

Me OMe O−

Me Me

Cl Cl

O

The stereochemical outcome of the Claisen and Cope rearrangements is determined by olefin and enolate geometry, stereocenters in the cyclic transition-state, and exocyclic stereocenters including ring geometries. Some simplistic generalizations are discussed in the following but do not take into consideration the stereocenters outside the transition state such as ring geometries that can affect the stereochemical outcome of the reaction. When possible, the reaction proceeds through a chair transition state. Which chair is accessed is dependent on the substitution patterns of the 141 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kuesters, E. Organic Process Research & Development 2002, 6, 652–659. 142 Wilson, S. R.; Augelli, C. E. Organic Syntheses 1990, 68, 210–219. 143 Bogaert-Alvarez, R. J.; Demena, P.; Kodersha, G.; Polomski, R. E.; Soundararajan, N.; Wang, S. S. Y. Organic Process Research & Development 2001, 5, 636–645. 144 Anderson, C. E.; Overman, L. E.; Watson, M. P.; Maddess, M. L.; Lautens, M. Organic Syntheses 2005, 82, 134–139. 145 Malherbe, R.; Rist, G.; Bellus, D. The Journal of Organic Chemistry 1983, 48, 860–869.

7.3 Other Rearrangements

carbons in the six-membered ring transition state. For the trans/trans case depicted in the following, R2 and/or R4 groups with a larger A values lead to higher selectivity for the indicated product. R2 O

R1

R1 R3

R2

R2

R4

O

R3

R1 R3

R4

R4

O

X

R2 O

R3

R1 R3

O

R4

R2

R3 R2

R4

R4

R1

O

R1

R1 R3

R2

R4 O

Variants of the Claisen rearrangement with nitrogen, sulfur, and other heteroatoms are also known. An example of the aza-Claisen rearrangement used to make quinolines is shown in the following.146 Me

Me 155 °C aza-Claisen

N

H H

N

NO2

NO2 [1,5] H shift Me

Me Air 82%

N

N H NO2

NO2

In the following example, the cationic aza-Claisen rearrangement is followed by a Mannich reaction to form the product shown.147 t-BuO N

t-BuO

Me N

H

HO N

N

N

(CH2O)n Na2SO4 98% Me

N

Me

Ar

N

O N

O N

Me

Ot-Bu

A thermal Claisen rearrangement using a propargyl ether provided the desired pyran and other impurities.148 Suspected generation of the ketene that can be captured by the resultant phenol to form either a furan or pyran. Alternatively, the acetamide also proved competent to form the indole. Continuous processing was critical for reproducible formation of the desired pyran and was conducted on 9.6 kg scale successfully.

146 Qiang, L. G.; Baine, N. H. The Journal of Organic Chemistry 1988, 53, 4218–4222. 147 Knight, S. D.; Overman, L. E.; Pairaudeau, G. Journal of the American Chemical Society 1995, 117, 5776–5788. 148 Walker, A. J.; Adolph, S.; Connell, R. B.; Laue, K.; Roeder, M.; Rueggeberg, C. J.; Hahn, D. U.; Voegtli, K.; Watson, J. Organic Process Research & Development 2010, 14, 85–91.

409

410

7 Rearrangements

OMe

OMe

Dowtherm A 220 °C

O

O

Cl

OMe

Cl NHAc

O

NHAc

Me

Cl NHAc OMe

OMe

OMe O

OH

OH Cl

Cl

Cl NHAc

AcN

NHAc

Me

The ortho-alkylation of phenols can be achieved using the [3,3]-Claisen rearrangement. The most common alkylation, an allyl group, can provide wide-ranging chemical diversity once appended. The rearrangement itself can be problematic for catalysis due to weak chelation of metals or Lewis acids. Dimerization and degradation are the main sources of yield loss. Thermal Claisen rearrangements with aprotic solvents in flow can mitigate the degradation problem by limited exposure to high temperature and precise control of residence time in the flow loop.149 High thermal conditions for batch reactions present several disadvantages including variability in thermal transfer and safety issues making a flow reaction competitive. O

230 °C flow loop NMP, 15 bar, 4 h

Me

73%, 93% purity

O

O Me OH

Tandem rearrangements can provide incredible changes in molecular skeletons, in particular with contiguous rings in steroids and other terpene derivatives.150 Odd-ring sizes, such as seven membered rings, remain problematic. The chemists successfully capitalized on a tandem rearrangement sequence to build two seven-membered rings using an Ireland Claisen/Cope approach. Me Me

TIPSO

O

H H

H

TIPSO

PhMe2SiO

Me

O PhMe2SiO

Me Me

H TIPSO

Me

H H

64% 3 steps TIPSO

OSiMe2Ph

Me

TIPSO

OSiMe2Ph

Me

Me

Me (ii) HCl (iii) TMSCHN2

O

O OH

Me

Me

(i) Me2PhSiCl, DBU Me PhCF3, 140 °C

O H

OMe

O

Me O

Me

OSiMe2Ph

OSiMe2Ph

149 Rincon, J. A.; Barberis, M.; Gonzalez-Esguevillas, M.; Johnson, M. D.; Niemeier, J. K.; Sun, W.-M. Organic Process Research & Development 2011, 15, 1428–1432. 150 Plummer, C. W.; Wei, C. S.; Yozwiak, C. E.; Soheili, A.; Smithback, S. O.; Leighton, J. L. Journal of the American Chemical Society 2014, 136, 9878–9881.

7.3 Other Rearrangements

7.3.2.5

Fischer Indole Synthesis

The Fischer indole synthesis involves the [3,3]-sigmatropic rearrangement of an aryl hydrazone under acid catalysis, and when combined with the hydrazone formation provides a convergent method for coupling an aldehyde or ketone partner with an aryl hydrazine. Two batch examples of this process are depicted in the following.151,152 For meta-substituted aryl rings, regioselectivity can be an issue in this process. Protic acids are commonly used in this reaction. SO2NHMe

CHO

OH

SO2NHMe

(i) NHNH2

N H

SO2NHMe

R N H

(ii) H3PO4

N

OH 50%

PPA

NH3Cl + Me O

N H

78%

Br

N H

Br

An oxo variant of the Fischer process is depicted in the following where an O-aryl oxime undergoes [3,3] sigmatropic rearrangement to produce the benzofuran shown.153 NMe2 HOAc HCl

O2N O

N

NMe2 O2N

47%

O F

F

Continuous manufacturing offers several advantages including the use of flow to remove batch scale hydrazine, high thermal conditions for short periods of time, and minimal use of acid for the rearrangement. Regioselectivity for cyclization for substituted arenes, degradation of substrate, and dimerization remains problematic for Fischer indole syntheses. Continuous manufacturing offers greater control of reaction conditions allowing mitigation of contributing factors to degradation including strong acids or bases and extended thermal events.154

Et

N H O

NH3Cl

Hastelloy 150 °C, 3 min

Stainless steel room temperature OH

MeOH/H2O 2:1 Et

N H

In situ formation of the hydrazine from aniline can also be telescoped to the Fischer indole synthesis.155 The use of sodium nitrite followed by ascorbic acid afforded the oxalyl hydrazide as a calcium salt. The avoidance of isolation for diazonium salts or hydrazines is advantageous for worker exposure and possible decomposition.

151 Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R., Sr.; Smith, P. R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil, J. K.; Wang, S. The Journal of Organic Chemistry 1997, 62, 9192–9202. 152 Ikemoto, N.; Liu, J.; Brands, K. M. J.; McNamara, J. M.; Reider, P. J. Tetrahedron 2003, 59, 1317–1325. 153 Guzzo, P. R.; Buckle, R. N.; Chou, M.; Dinn, S. R.; Flaugh, M. E.; Kiefer, A. D., Jr.; Ryter, K. T.; Sampognaro, A. J.; Tregay, S. W.; Xu, Y.-C. The Journal of Organic Chemistry 2003, 68, 770–778. 154 Gutmann, B.; Gottsponer, M.; Elsner, P.; Cantillo, D.; Roberge, D. M.; Kappe, C. O. Organic Process Research & Development 2013, 17, 294–302. 155 Ashcroft, C. P.; Hellier, P.; Pettman, A.; Watkinson, S. Organic Process Research & Development 2011, 15, 98–103.

411

412

7 Rearrangements

Me N R

O O CO2H

HO2C NH2

N

R

Me

NaNO2, H2SO4 H2O, MeCN, L-ascorbic acid

N H

75% R N H

7.3.2.6

R = CH2CH2SO2Ph

O

H N

OH O

Boekelheide Rearrangement: 2-Alkylpyridine N-Oxide Rearrangements

The Boekelheide rearrangement is commonly used to functionalize the carbon substituent at the C-2 position of a pyridine. The N-oxide is acylated, and loss of a proton from the C-2 position sets up a [3,3]-sigmatropic shift to produce the product shown. Acetic anhydride is most frequently used for this transformation. This reaction is used frequently in industry to exploit the relatively facile N-oxide formation to functionalize the C-2 position under relatively mild conditions.156 (i) Ac 2O (ii) HCl (iii) NaOH

C4H9

N+ O−

7.3.2.7

C4H9

86%

N OH

[2,3]-Wittig Rearrangement: O-to-C Shift of Carbon

The [2,3]-Wittig rearrangement,157 sometimes called the [2,3]-Wittig–Still rearrangement, involves the anionic rearrangement of allylic ethers as shown in the following. The reaction utilizes the relatively facile alcohol alkylation reaction, relaying that into a carbon-to-carbon bond-forming step. The requirement for strong bases to achieve this transformation limits functional group compatibility and solvent choice.158,159 OTBS

OTBS

n-BuLi O

Me

O Me

H Me

68%

OH

Me

n-BuLi 71%

Me H

Me OH

Electron withdrawing groups or metal exchangeable groups, such as a stannane, are frequently appended to the ether to increase the acidity of the proton to be abstracted.160,161

156 Bell, T. W.; Cho, Y. M.; Firestone, A.; Healy, K.; Liu, J.; Ludwig, R.; Rothenberger, S. D. Organic Syntheses 1990, 69, 226–237. 157 Nakai, T.; Mikami, K. Chemical Reviews 1986, 86, 885–902. 158 Liang, J.; Hoard, D. W.; Khau, V. V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. The Journal of Organic Chemistry 1999, 64, 1459–1463. 159 Wovkulich, P. M.; Shankaran, K.; Kiegiel, J.; Uskokovic, M. R. The Journal of Organic Chemistry 1993, 58, 832–839. 160 Ghosh, A. K.; Wang, Y. Tetrahedron 1999, 55, 13369–13376. 161 Pollex, A.; Millet, A.; Mueller, J.; Hiersemann, M.; Abraham, L. The Journal of Organic Chemistry 2005, 70, 5579–5591.

7.3 Other Rearrangements

Me

Me

O

Me

(i) KH, Bu3SnCH2I (ii) n-BuLi

O

BnO

O

O OH

81%, 5.4 : 1 dr

OH

OBn

Me

OBn

CO2i-Pr

BnO

LDA

O

BnO

57%

i-PrO2C

BnO

OH

The stereochemical outcome of this reaction has been well studied, and predictive models now exist.162,163 Me Me

n-BuLi O H Me

HO

72%

H Me

n-BuLi

O

HO

56%

H

H

The use of chiral bases has been shown to induce asymmetry in some systems.164 Me Ph

CO2H O

Me

N Li

Ph

57%, 33% ee

C7H15

•

C7H15

HO

CO2H

The nitrogen analog of the Wittig rearrangement is also useful. In the following example, the silyl group on the olefin profoundly effects selectivity; on the substrate lacking a TMS group, the diastereoselectivity was 1 : 1.165 TMS

TMS Et Boc

N

7.3.2.8

Et

n-BuLi, HMPA 92%, 18:1 dr

Ph

BocHN

Ph

[2,3]-Meisenheimer Rearrangement: N-to-O Migration of Carbon in Tertiary N-Oxides

The [2,3]-Meisenheimer rearrangement is the allylic version of the [1,2]-variant discussed earlier (Section 7.2.5.2). This rearrangement can occur under very mild conditions.166

Ph

Me N

Me m-CPBA 95%

Me

162 163 164 165 166

Ph

N

O Me

Mikami, K.; Nakai, T. Synthesis 1991, 594–604. Mikami, K.; Azuma, K.; Nakai, T. Tetrahedron 1984, 40, 2303–2308. Marshall, J. A.; Wang, X. J. The Journal of Organic Chemistry 1992, 57, 2747–2750. Anderson, J. C.; Siddons, D. C.; Smith, S. C.; Swarbrick, M. E. The Journal of Organic Chemistry 1996, 61, 4820–4823. Majumdar, K. C.; Jana, G. H. The Journal of Organic Chemistry 1997, 62, 1506–1508.

413

414

7 Rearrangements

7.3.2.9

[2,3]-Sulfoxide, Selenoxide, and Sulfilimine Rearrangements

The [2,3]-rearrangement of sulfoxides, selenoxides, and their analogs provide a method for stereochemical relay of an established stereocenter bearing S or Se into an alcohol or amine. In the case of sulfur, the reverse reaction is also synthetically useful. When this method is used following the ene reaction of selenium dioxide or a reagent of the structure RN=Se=NR or RN=S=NR (Section 10.3.8.2), the allylic position of an olefin can be oxidized to the alcohol or amine. Allylic sulfoxides undergo [2,3]-rearrangement to form an allylic sulfinate, which can be reduced to the allylic alcohol using mild reducing agents such as a phosphite; this reaction is known as the Mislow–Evans rearrangement. The rearrangement is under thermodynamic control. As a result, the allylic sulfoxide is typically favored unless a driving force is present, such as a phosphine that acts as a reducing agent. Allylic alcohols can be converted to the rearranged sulfoxide by derivatization of the alcohol with a sulfinyl chloride.167,168 (EtO)2OPO

Et S

HO

(MeO)3P

O Me

OPO(OEt)2 Me

70%

O Ph

SO2

Me

O H

H

PhSCl, Et3N 62%

OH

PhO2S

•

SOPh

Me

The nitrogen analog to this rearrangement is the sulfilimine rearrangement. Again, the use of a reducing agent to drive the reaction and free the amine is necessary.169 SMe

(i) H2NOSO2Mes, P(OEt)3 (ii) CbzCl, NaHCO3

OTBS

Me O

NTBS

NHCbz

OTBS

Me

79%

O

NTBS

Selenoxides undergo a more facile [2,3]-rearrangement to the selenate, which is readily reduced to the allylic alcohol. Hydroxide can be used instead of a reducing agent to displace the selenium from the newly formed alcohol.170,171 NMe

NMe

(i) H2O2 (ii) KOH

OH

60% MeO

O

O2NPhSe

CO2Me n-Pent TBSO

167 168 169 170 171

MeO

SePh

O

CO2Me

H2O2 60%

n-Pent HO

TBSO

Koprowski, M.; Krawczyk, E.; Skowronska, A.; McPartlin, M.; Choi, N.; Radojevic, S. Tetrahedron 2001, 57, 1105–1118. Ni, Z.; Wang, X.; Rodriguez, A.; Padwa, A. Tetrahedron Letters 1992, 33, 7303–7306. Dolle, R. E.; Li, C. S.; Novelli, R.; Kruse, L. I.; Eggleston, D. The Journal of Organic Chemistry 1992, 57, 128–132. Kshirsagar, T. A.; Moe, S. T.; Portoghese, P. S. The Journal of Organic Chemistry 1998, 63, 1704–1705. Zanoni, G.; Porta, A.; Castronovo, F.; Vidari, G. The Journal of Organic Chemistry 2003, 68, 6005–6010.

7.3 Other Rearrangements

This rearrangement also has a nitrogen analog.172 O H2N OCH2CCl3 (MeO)3CH, TsOH, NCS

SePh Me

CO2Me

7.3.2.10

NHCO2CH2CCl3 Me

72%

CO2Me

Sommelet–Hauser Rearrangement and Related Reactions – [2,3]-Sigmatropic Rearrangements of Ylides

The Sommelet–Hauser rearrangement is the [2,3]-migration of a dialkylamino group from a benzylic ammonium salt. The reaction can be categorized as a [2,3]-sigmatropic rearrangement of a nitrogen ylide, and examples of a sulfur ylide or an oxonium ylide undergoing the same transformation can be found. This is the [2,3]-variant of the [1,2]-Stevens rearrangement discussed in Section 7.2.5.1. The rearrangement requires a strong base to deprotonate one of the hydrogens on a carbon adjacent to the nitrogen. As more than one substituent of the ammonium salt frequently has a proton that can be abstracted, mixtures of products are not unusual in this reaction. Further, the potential for a [1,2]-rearrangement (the Stevens rearrangement) to compete exists. X−

Me NMe2

+

N

Stevens

Me

Me Me

Sommelet– Hauser

Me NMe2

An example of a sulfur variant of the Sommelet–Hauser rearrangement is shown in the following. In this case, a weak base, triethylamine, is sufficient to deprotonate the ylide to initiate the rearrangement.173 (i) i-PrSCH2CH2CO2Me, SO2Cl2 (ii) Et 3N OH

O

7.3.2.11

CO2Me OH

77% i-Pr S+

i-PrS

CO2Me

Benzidine Rearrangement

The benzidine rearrangement is formally the reaction shown in the following. The major product is shown, but others with a different substitution pattern are also formed. The synthetic utility of this reaction is limited, but chemists should be aware of this rearrangement when handling diarylhydrazines.

N H

H N

H+

H2N

NH2

While not particularly useful synthetically, a variant of the reaction was used in the following example.174 On treatment with polyphosphoric acid (PPA), the following substrate underwent a Fischer indole synthesis with a second molecule of substrate, leading to the benzidine rearrangement substrate. After rearrangement and Friedel–Crafts acylation, the product shown was formed in low yield.

172 Shea, R. G.; Fitzner, J. N.; Fankhauser, J. E.; Spaltenstein, A.; Carpino, P. A.; Peevey, R. M.; Pratt, D. V.; Tenge, B. J.; Hopkins, P. B. The Journal of Organic Chemistry 1986, 51, 5243–5252. 173 Inoue, S.; Ikeda, H.; Sato, S.; Horie, K.; Ota, T.; Miyamoto, O.; Sato, K. The Journal of Organic Chemistry 1987, 52, 5495–5497. 174 Kornet, M. J.; Thio, A. P.; Tolbert, L. M. The Journal of Organic Chemistry 1980, 45, 30–32.

415

416

7 Rearrangements

O

N HN

O NH Me

PPA

O

N Me

7.3.2.12

NHMe

NHMe

Me

O

NH2

Me N

N Me

Me

O 28%

Me

Me

N Me

Overman Rearrangement

A useful stereospecific [3,3]-sigmatropic rearrangement of allylic O-carbamates to allylic N-carbamates, leverages the multiple methods for chiral allylic alcohol formation, to fill the gap for chiral allylic amine synthesis. Indeed, several stereospecific and enantioselective versions have appeared in the literature. The reaction of an allylic alcohol with trichloroacetonitrile provides the trichloroacetimidate.175 Treatment of this intermediate with base under high thermal conditions results in the thermodynamically favored rearrangement. Metal-mediated conditions have also been used to effect this transformation. The sequence shown was successfully conducted on over 25 kg successfully. OH (i) xylenes NaO-t-amyl N Cl3C

N

O

(ii) 114 °C, 6 h (iii) conc HCl

NH

Ph

7.3.2.13

CCl3

N

(74%)

Ph

N

H N

H Cl

Ph

CCl3

O

Propargyl O-to-N Migration

Thermal suprafacial sigmatropic [3,3] O-to-N rearrangements, the formal [1,3] rearrangement, uses similar alkylated pyridine substrates and can be catalyzed by transition metals. The proposed mechanism for the propargylic rearrangement includes a key Cu-alkynyl that is π-coordinated to another Cu atom chelated to the pyridine.176 1,1-Dicopper ketene formation and recapture by pyridine formed the alkylated pyridone. R O

R N

CuTC (10 mol%) ligand (12 mol%) tol, −40 °C, 3 h

R

R

R′

P(4-tol)2 P(4-tol)2

N

O R′

R O

R N

R

R N

O

R′

R′ CuL

CuL

R R

O O R′

R

R N CuL

CuL

N CuL

Cu R′ 175 Chandramouli, S. V.; Ayers, T. A.; Wu, X.-D.; Tran, L. T.; Peers, J. H.; Disanto, R.; Roberts, F.; Kumar, N.; Jiang, Y.; Choy, N.; Pemberton, C.; Powers, M. R.; Gardetto, A. J.; D’Netto, G. A.; Chen, X.; Gamboa, J.; Ngo, D.; Copeland, W.; Rudisill, D. E.; Bridge, A. W.; Vanasse, B. J.; Lythgoe, D. J. Organic Process Research & Development 2012, 16, 484–494. 176 Cheng, L.-J.; Brown, A. P. N.; Cordier, C. J. Chemical Science 2017, 8, 4299–4305.

7.3 Other Rearrangements

7.3.3

Other Cyclic Rearrangements

7.3.3.1

Di-𝛑-Methane and Related Rearrangements

The di-π-methane rearrangement has been well reviewed.177 The reaction is a photochemically induced diradical rearrangement that results in a dramatic transformation. Use of this method is limited by the requirement for a photochemical apparatus. Most commonly used are the aza-di-π-methane rearrangement and the oxa-di-π-methane rearrangement, which can generate some highly complex and strained ring systems. Some examples of two manifolds of the aza-di-π-methane rearrangement are shown in the following.178,179 Me Me hv acetophenone

N

OH

N

67%

OH

hv m-methoxyacetophenone

Me Me N Ph

Me Me

78%

Ph

Me Me N

Ph

Ph

Some examples of the oxa-di-π-methane rearrangement are shown in the following.180,181 The first example was demonstrated on 2-g scale. H

H hv , acetone

H

H

75%

CO2Me

Me

hv , acetone

OH

H

H

O O

H

O

70%

O CO2Me

HO Me H

H H

7.3.4 7.3.4.1

Acyclic Rearrangements Migration of Double Bonds

Olefin migrations as a result of electrocyclic or sigmatropic rearrangements (Sections 7.3.1 and 7.3.2) and allylic displacement reactions are covered elsewhere in this book. Olefins and acetylenes can be migrated into conjugation with other olefins or acetylenes with strong bases such as hydroxide.182,183 Ph

NaOH H

54–75%

Ph

Me

177 Zimmerman, H. E.; Armesto, D. Chemical Reviews 1996, 96, 3065–3112. 178 Armesto, D.; Gallego, M. G.; Horspool, W. M.; Agarrabeitia, A. R. Tetrahedron 1995, 51, 9223–9240. 179 Armesto, D.; Caballero, O.; Ortiz, M. J.; Agarrabeitia, A. R.; Martin-Fontecha, M.; Torres, M. R. The Journal of Organic Chemistry 2003, 68, 6661–6671. 180 Schultz, A. G.; Lavieri, F. P.; Snead, T. E. The Journal of Organic Chemistry 1985, 50, 3086–3091. 181 Singh, V.; Vedantham, P.; Sahu, P. K. Tetrahedron 2004, 60, 8161–8169. 182 Taniguchi, H.; Mathai, I.; Miller, S. I. Organic Syntheses 1970, 50, 97–101. 183 Stoeckel, K.; Sondheimer, F. Organic Syntheses 1974, 54, 1–10.

417

418

7 Rearrangements

Acetylenes can be migrated to the terminal position in the zipper reaction.184 Me

Li, t-BuOK, 65 °C

16

H2 N

HO

17

NH2

HO

To migrate an olefin into conjugation with a carbonyl, a weak acid or base is needed.185 Me C8H17

Me C8H17 Oxalic acid

Me

Me

>70% O

O

Allylic amines can be isomerized to the enamines using a rhodium catalyst. The use of a chiral ligand allows for the introduction of stereochemistry in some cases.186 Me NEt2

Me

[Rh{(−)-BINAP}{cod}]ClO4 68 °C

NEt2

94% Me

Me

Me

Me

Me

Me

[Rh{(+)-BINAP}{cod}]ClO 4 68 °C NEt2

Me

NEt2

92%

Me

Me

Me

Allyl ethers can be isomerized to the enol ether using a variety of reagents including Pd/C,187 KOt-Bu, and Rh(PPh3 )3 Cl. The enol ether can then be hydrolyzed to remove the allyl group. O

O

7.3.4.2

CO2Me

Pd/C TsOH MeOH

OH

O

Me

O

O

CO2Me

OH

84%

HO

CO2Me

OH

Hydride Shifts

Long- or short-range hydride shifts can occur when a radical or cationic intermediate rearranges to a more stable radical or cation. This process does not have to be a sigmatropic rearrangement. A preparation utilizing a hydride shift is shown in the following.188 These rearrangements are possible any time a radical or cationic intermediate is present in a reaction, and the shift of a proximal hydride would result in a more stable intermediate or an intermediate more easily trapped than the original.

Me

184 185 186 187 188

H

Me OSPh

hv , Bu3SnH 53%

Me Me

OH SPh

Hoye, R. C.; Baigorria, A. S.; Danielson, M. E.; Pragman, A. A.; Rajapakse, H. A. The Journal of Organic Chemistry 1999, 64, 2450–2453. Fieser, L. F. Organic Syntheses 1955, 35, 43–49. Tani, K.; Yamagata, T.; Otsuka, S.; Kumobayashi, H.; Akutagawa, S. Organic Syntheses 1989, 67, 33–43. Boss, R.; Scheffold, R. Angewandte Chemie, International Edition in English 1976, 15, 558–559. Patrovic, G.; Saicic, R. N.; Cekovic, Z. Organic Syntheses 2005, 81, 244–253.

7.3 Other Rearrangements

An example of a [1,5]-hydride shift is shown in the following. In this case, the transfer of hydride results in an iminium ion that can be trapped with an electron-rich aromatic ring to form a diazocine.189

Me N

CHO

Me H N+

(i) POCl 3 (ii) ArNMe2

Me

Me

Me N Me

7.3.4.3

N Me

Me

N 44%

N Me

H

Me

N Me +

Newman–Kwart Rearrangement – O-phenylthiocarbanate to S-phenylcarbamate

The Newman–Kwart rearrangement is a high temperature procedure for the conversion of a phenol to a thiophenol. Temperatures in excess of 200 ∘ C are required for the rearrangement to proceed, limiting solvent choice for the transformation.190 MeO

MeO 218 °C

Br NMe2

O

O

S

7.3.4.4

Br NMe2

S

66%

Nitrosamide Decomposition

Nitrosation of an amide is sometimes employed to activate the amide to hydrolysis. If this strategy is employed, there are a couple of rearrangements that need to be considered to prevent by-product formation. When a nitrosamide is heated gently, nitrogen is extruded, resulting in the ester product. This is a strategic procedure for converting an amine to an alcohol.191 NO Ph

N

Ph

56–59%

O

76 °C

O

Ph

O

Ph

In other cases, the N-nitrosylcarbamate decomposes to the diazo compound.192 O O S Me

NO N OEt Alumina O

66–76%

O O N2 S Me

189 Cheng, Y.; Yang, H.-B.; Liu, B.; Meth-Cohn, O.; Watkin, D.; Humphries, S. Synthesis 2002, 906–910. 190 Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Organic Process Research & Development 2004, 8, 33–44. 191 See Note 59. 192 Van Leusen, A. M.; Strating, J. Organic Syntheses 1977, 57, 95–102.

419

420

7 Rearrangements

7.3.4.5

The Achmatowitz Reaction: Oxidative Furan Rearrangement

Under oxidative conditions, appropriately substituted furans can be rearranged to the pyridinium salt or a pyrone.193,194 Me

Br2 H2O

O

N H

Me

O−

N+

65%

CN

CN NBS H2O

OH O

OH O

84%

OTBS

O

OTBS

7.4 Miscellaneous Migrations 7.4.1

Hunsdiecker

The Hunsdiecker reaction, originally employing silver carboxylates, has been expanded to avoid silver salts and apply to aliphatic, alkenyl, and alkynyl substrates. The carboxylic group is abundant and generally underutilized as a functional group for reactions besides esterification/amidation. The mechanism can diverge depending on the nature of the carboxylate. For example, using α-carboxylate enamides, the bromination of the α–β unsaturation is captured by the free carboxylate to form a β-lactone.195 Decarboxylation regenerates the unsaturation resulting in an α-bromide and Hunsdiecker-type product. This transformation was carried out on multikilo scale. O N F

Br OH

N

N H

O

NBS, LiOAc THF, 20 °C

N F

(89%)

+

Br O N

N

O

−

N

O N H

O

O

F

N

N H

O Br O

F

F

7.4.2

N H

F

F

F

N

Jocic

The Jocic reaction employs trichloromethyl carbinols to in situ generate dichloroepoxides. The activated epoxide is sufficiently electrophilic to react and form an acid chloride via oxygen migration. The acid chloride is usually trapped as an ester in alcoholic solvent. The utility of this rearrangement is found by the simple conversion of dialkyl ketones 193 Guo, H.; O’Doherty, G. A. Organic Letters 2006, 8, 1609–1612. 194 Peese, K. M.; Gin, D. Y. Organic Letters 2005, 7, 3323–3325. 195 Milburn, R. R.; Thiel, O. R.; Achmatowicz, M.; Wang, X.; Zigterman, J.; Bernard, C.; Colyer, J. T.; DiVirgilio, E.; Crockett, R.; Correll, T. L.; Nagapudi, K.; Ranganathan, K.; Hedley, S. J.; Allgeier, A.; Larsen, R. D. Organic Process Research & Development 2011, 15, 31–43.

7.4 Miscellaneous Migrations

to homologated quaternary centers. The reaction also proceeds stereospecifically with enantio- or diastereomerically enriched substrate.196 H2N HO

F O

CCl3 MeO

DBU, MeOH, rt N

H N

Me

N

Cbz

Me

Cbz

DBU Cl O

N

MeOH H2N

Cl

F

O

H N

Cl N

Me

F

Me

Cbz

Cbz

7.4.3

F

Smiles/Truce–Smiles

The Smiles rearrangement leverages alkyl migration from sulfones, sulfonates, amines, and ethers to forge C—C bonds usually via a spirocyclic 5,5 or 5,6 membered rings. The requirements are a sufficiently electron-deficient aromatic ring and a reasonable nucleophile for the aromatic substitution. Radical versions of the Smiles rearrangement have been described with initial radical generation occurring by photoirradiation to homolytically cleave a carbon-halogen bond. This process can use radical sensitizers such as Ru(bpy)3 Cl2 , thermal, or simply LEDs.197

O O S O S

Br

CO2Me

O O S O S

CO2Me

F F

F F

300 W white led NEt3 (1.5 equiv) formic acid (1.5 equiv) DMSO, 30 °C (64%)

F F S

CO2Me

O O S O S

F F CO2Me

OH

F F S

O

CO2Me

S O

O

An efficient synthesis of a 2,3-disubstituted indole was achieved using a Truce–Smiles rearrangement.198 The difficult to procure disubstituted indole was previously prepared using a Suzuki cross-coupling at the 2-position, or a Larock reaction with an aniline and alkyne. The difficulties in procuring the starting materials and regioselectivity issues required a new approach. The preparation of the nitro ester phenylether was straightforward as a simple SN Ar of the fluoride. Base-mediated enolization of the ketone began the rearrangement by formation of the spirocyclic intermediate, which collapses to the desired α-alkylated product. Hydrogenation of the nitro to the aniline with mild acid results in immediate cyclization to the desired indole. 196 Henegar, K. E.; Lira, R.; Kim, H.; Gonzalez-Hernandez, J. Organic Process Research & Development 2013, 17, 985–990. 197 Douglas, J. J.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J. Organic Process Research & Development 2016, 20, 1148–1155. 198 Alorati, A. D.; Gibb, A. D.; Mullens, P. R.; Stewart, G. W. Organic Process Research & Development 2012, 16, 1947–1952.

421

422

7 Rearrangements

OH O

MeO2C O

K2CO3

O

O2 N

20% Pd/C, H2

NO2

DMF, Δ

AcOH, THF

87%

74% CO2Me

MeO2C

N H

HO

O MeO2C

MeO

O O2 N

7.4.4

O

O O

N

O O

Dakin–West–Dimroth

The Dakin–West reaction uses anhydrides to convert amino acids to keto-amides. The reaction proceeds through a cyclic intermediate that is acylated and decarboxylates to form the product. Asymmetric variants of this reaction are rare due to the heterocyclic intermediate that aromatizes and erases any stereochemical memory. Novartis chemists were in need of an aminopyrrole and utilized the Dakin–West reaction to obtain their critical keto-amide intermediate.199 They found the liberation of the carbon dioxide was a self-accelerating kinetic reaction and was intensely studied for plant safety. Control of gas evolution was ultimately achieved using alanine addition as the critical control. Ac2O, AcOH NEt3, DMAP

NH2 Me

COOH

Me

NHAc Me O CO2

Me HN

O O

Me O

O

Me

Me OH

Me O

O

N

Me

O AcHN

O

Me

Me

O N

Me O

Me

O

Using their newly formed keto-amide, malonodinitrile was used to form the aminopyrrole. Formylation using triethylorthoformate, followed by amination with the aniline provided the intermediate amidine. The Dimroth rearrangement was then applied to liberate the amidine, and cyclize to the pyrrolopyrimidine via a formamide intermediate.

199 Fischer, R. W.; Misun, M. Organic Process Research & Development 2001, 5, 581–586.

7.4 Miscellaneous Migrations

Me

NHAc Me

CN NC NaOH 83% 2 steps

O

Me Me

3-chloroaniline HC(OEt)3

CN N H

NH2

HN

Me

N

EtOH, AcOH 78%

Me

7.4.5

92%

HN

HN

Me Me

N

N H

N

N H

Cl

Cl N H

N H

Cl

OH

HO

EtOH, H2O

N

N H

Me Me

Cl

HN

Me

NH

O Me

N H

N H

O

Meinwald

Rearrangement of a disubstituted epoxide to an aldehyde via thermal or Lewis acid catalysis has been named the Meinwald rearrangement.200 Subsequent substitution patterns have emerged including tri and tetrasubstituted epoxides. The difficulty with additional substitution is the possibility for loss of regiocontrol and emergence of nearly inseparable keto constitutional isomers. The α–α substituted epoxide remains the more popular variant due to its predictivity and generally mild conditions for rearrangement.201 A Lewis acid–catalyzed variant has been demonstrated recently.202 O

Br

O

DMSO/THF 25 °C

O

O

OiPr Me3SOI, KOtBu Br

OiPr O

(Not isolated)

H

ZnBr2 (25 mol%) toluene 25 °C 91%

OiPr Br

O

200 Meinwald, J.; Labana, S. S.; Chadha, M. S. Journal of the American Chemical Society 1963, 85, 582–585. 201 Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.; Emerson, K. M. Organic Process Research & Development 2014, 18, 215–227. 202 Hughes, D. L. Organic Process Research & Development 2017, 21, 1227–1244.

423

425

8 Eliminations Sally Gut Ruggeri Pfizer Worldwide R&D, Groton, CT, USA (retired)

CHAPTER MENU Introduction, 425 Formation of Alkenes, 425 Formation of Dienes, 438 Formation of Alkynes, 442 Formation of C=N bonds, 444 Formation of Nitriles, 445 Formation of Ketenes and Related Compounds, 447 Fragmentations, 449 Dehydrating Reagents, 451

8.1 Introduction Elimination chemistry is one of the classical approaches for the formation of multiple bonds (C=C, C=X, etc.). Many of the oldest methods for carrying out eliminations are still synthetically practical, although some modern variations have increased the scope of sensitive functional groups that can be tolerated. The following discussion describes useful methods for carrying out eliminations, where the elimination is the focus of the reaction. For a few functional groups, there is no practical method for elimination from a scale-up perspective. In these cases, a method is provided but is not recommended for other than small-scale use. Other transformations where the elimination is not the primary focus, such as the elimination of water in the formation of an imine from a carbonyl, or amide formation from carboxylic acids, are captured elsewhere in this book.

8.2 Formation of Alkenes Alkenes are readily formed by the elimination of a wide variety of functional groups. The four most general and widely applicable types of conditions to effect this transformation, depending on the substituent being eliminated, are treatment with acid, base, dehydrating reagents and/or heat. The references listed in the following cite some of the most mild or generally useful conditions to effect these transformations. While the reactivity is usually straightforward, the selectivity of the elimination can be complicated, and competitive formation of regioisomers and geometrical isomers can be an issue. In some cases, the control is excellent, due either to substrate or reagent bias. The section is roughly divided by elimination of H–X or X–X′ .

Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

426

8 Eliminations

8.2.1

Elimination of Alcohols

The elimination of water under acidic conditions is one of the classical reactions of organic synthesis. Mineral acids are good reagents for this transformation,1 if the rest of the substrate is stable to their use. OH Me

H2SO4, Δ

Me

Me

Me

80%

If mineral acids are not tolerated by the substrate, organic sulfonic acids are good substitutes.2 OMe p-TsOH PhCH3 reflux

OMe

HO

87%

N

N

Me

Me

This method works best for tertiary or secondary alcohols; primary alcohols require very forcing conditions to lose water and should be functionalized for elimination. The classic method of water removal is preferred: use of toluene or another suitable water-immiscible solvent that forms an azeotrope with water, attached to a Dean–Stark trap or equivalent. 8.2.2

Elimination of Ethers

The elimination of an unactivated alkyl ether is not a facile reaction and usually requires relatively harsh conditions.3 Me

CO2H

P2O5 , Δ

Me OMe

Me

CO2H

95%

For some substrates, the elimination will occur under milder conditions, such as treatment with a sulfonic acid, but usually only when the ether is tertiary.4 Me MeO Me O

O

N N

HN

H

O

CO2Et

O

Me

p-TsOH PhCH3 reflux

Me O

82–89%

HN

N N H

O

CO2Et

There are some special cases in which an ether will eliminate more easily. One example is the elimination of an epoxide to form an allylic alcohol, which is accomplished by treatment with a hindered alkyl amide base.5 Me

Me

OTBS

OTBS

LCIA O

64%

OH

Me LCIA = lithium cyclohexylisopropylamide 1 2 3 4 5

Norris, J. F. Organic Syntheses 1927, 7, 76–77. Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. The Journal of Organic Chemistry 1989, 54, 4795–4800. Weizmann, C.; Sulzbacher, M.; Bergmann, E. Journal of the American Chemical Society 1948, 70, 1153–1158. Sebahar, P. R.; Williams, R. M. Journal of the American Chemical Society 2000, 122, 5666–5667. Mander, L. N.; Thomson, R. J. The Journal of Organic Chemistry 2005, 70, 1654–1670.

8.2 Formation of Alkenes

Ethers activated by neighboring groups can be readily induced to eliminate under relatively mild conditions. Elimination of acetals or ketals is usually accomplished by treatment with a Brønsted or Lewis acid,6 and elimination will occur if no nucleophile is present to trap the resulting oxocarbenium ion. TMSOTf, DIPEA –50 °C

OBn O OMe

BnO BnO

70%

OBn O

BnO BnO

The elimination of an allylic ether to a diene is also relatively facile (see Section 8.3.1). If the ether is β to an electron-withdrawing group, the elimination will occur under mild or neutral conditions (see Section 8.2.12). 8.2.3

Elimination of Esters

Some of the mildest and most commonly used conditions for elimination of an alcohol utilize an ester to facilitate the elimination. The ester can take the form of an acetate,7 sulfate,8 sulfonate,9 or phosphate10 and is often generated in situ. An interesting variation of the sulfonate elimination is the use of Furukawa’s reagent (mesyl chloride and 4-dimethylaminopyridine [DMAP]), where addition of water as a cosolvent is necessary for efficient conversion.11 Primary, secondary, and tertiary alcohols will eliminate when activated in this way. Ms

Ms

N

N

MeO HO

N

N

(i) TFAA (ii) DBU, 60 °C

N

80% NO2 Me O

S O HO Me

O Me

O

NO2 NMe2

HO OH Me O O

N

MeO

Me O

S O

Me O

Me Me

SOCl2 TEA

O

0 °C 56%

O Me

OAc Me OMe O2N

MsCl DBU

HO OH Me O O

O

Me O

NMe2

O

Me Me

OAc Me OMe

O2N

0 °C 83%

HO

OH Me CN

Me CN

POCl3 pyridine reflux

MeO

74%

MeO

6 Castro, S.; Peczuh, M. W. The Journal of Organic Chemistry 2005, 70, 3312–3315. 7 Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.; Davies, I. W.; Hughes, D. L. The Journal of Organic Chemistry 2005, 70, 2555–2567. 8 Hauske, J. R.; Guadliana, M.; Kostek, G.; Schulte, G. The Journal of Organic Chemistry 1987, 52, 4622–4625. 9 Subramanyam, C.; Noguchi, M.; Weinreb, S. M. The Journal of Organic Chemistry 1989, 54, 5580–5585. 10 McGuire, M. A.; Sorenson, E.; Owings, F. W.; Resnick, T. M.; Fox, M.; Baine, N. H. The Journal of Organic Chemistry 1994, 59, 6683–6686. 11 Comins, D. L.; Al-Awar, R. S. The Journal of Organic Chemistry 1992, 57, 4098–4103.

427

428

8 Eliminations

8.2.4

Elimination of Xanthates

Xanthates are typically used to effect the reduction of alcohols, but in the absence of a radical initiator or hydride source will eliminate instead (Chugaev elimination). For unactivated xanthates, high temperatures are generally required.12 Me

Me

Me

Me

diglyme, Δ

S MeS

O

80%

OTHP

OTHP

Where a neighboring leaving group is present, radical initiation of the xanthate cleavage leads to an alkene. When the leaving group is nitro, this methodology presents an alternative to alkene formation from carbonyls via the Henry reaction.13 The product of the elimination is usually the thermodynamically favored isomer. S S

EtO

DLP, Δ 75%

NO2

BnO

BnO

CN

CN OMe

OMe DLP = lauroyl peroxide

8.2.5

Elimination of Ammonium or Sulfonium Salts

Amines do not readily eliminate under most reaction conditions. However, elimination of the corresponding quaternary ammonium salts, also known as the Hofmann elimination, can be achieved under basic conditions. If the quaternary ammonium salt is not activated for elimination by neighboring groups, high temperatures are required.14 This methodology has been exemplified on many cyclic ammonium salts as an indirect method to control the stereochemistry or olefin geometry of acyclic systems.15 Me

N+Me3 Br−

Me Me

I− N+

Me

Me

t-BuOK 100 °C 70%

Me

Me 96 : 4

KOH

Me

Me

100 °C 64%

Substrates in which the leaving group is activated by an electron-withdrawing group occur at lower temperatures and with milder bases.16 Ph

N Ph

12 13 14 15 16

CO2Me N+Me3 I−

K2CO3 93%

N

Ph

CO2Me

Ph

Paquette, L. A.; Tsui, H.-C. The Journal of Organic Chemistry 1996, 61, 142–145. Ouvry, G.; Quiclet-Sire, B.; Zard, S. Z. Organic Letters 2003, 5, 2907–2909. Matsubara, S.; Matsuda, H.; Hamatani, T.; Schlosser, M. Tetrahedron 1988, 44, 2855–2863. Decodts, G.; Dressaire, G.; Langlois, Y. Synthesis 1979, 510–513. Tarzia, G.; Balsamini, C.; Spadoni, G.; Duranti, E. Synthesis 1988, 514–517.

8.2 Formation of Alkenes

The variation in which the leaving group is sulfonium is also known and eliminates under similar conditions.17 Me2S+

t-Bu Me Me

t-Bu

8.2.6

BF4− t-Bu

t-BuOK 81%

t-Bu

Me Me

Elimination of N-Oxides

The elimination of N-oxides to produce alkenes (Cope elimination) is most easily performed by heating the substrate; elimination occurs at relatively low temperatures.18,19 There can be an inherent safety issue with these reactions, as N-oxides are often high-energy intermediates, and the thermal decomposition of the starting material should be assessed before carrying out the reaction. Interestingly, the corresponding Hofmann elimination in the first example below gave the regioisomeric alkene, i.e. elimination toward the less-substituted carbon. N+ − O

− Me O N+ Me

Me S O O

N Boc

8.2.7

58%

OCOPh

Me

90 °C

85 °C 87%

OAc

S O O OCOPh N Boc

OAc

Elimination of Diazonium Salts

Treatment of diazo species with rhodium catalysts gives the formal elimination product.20 These reactions actually occur via β-hydride transfer, and transfer of a nonhydride substituent is often a competing, if not preferential process. One interesting aspect of these reactions is that they often give exclusively the cis olefin, which can be difficult to produce from most elimination processes. MeO2C

N2

MeO2C Rh2(O2CCF3)4, –78 °C

Ph

8.2.8

94%

Ph

Elimination of Hydrazones

The elimination of hydrazones with base is well precedented. When sterically undemanding bases21 or thermolytic conditions are used, the reaction usually gives rise to the thermodynamically favored product (Bamford–Stevens reaction), while bulkier bases usually yield the kinetically favored product (Shapiro reaction). For cases in which only one 17 Yamato, T.; Kobayashi, K.; Arimura, T.; Tashiro, M.; Yoshihira, K.; Kawazoe, K.; Sato, S.; Tamura, C. The Journal of Organic Chemistry 1986, 51, 2214–2218. 18 Woolhouse, A. D.; Gainsford, G. J.; Crump, D. R. Journal of Heterocyclic Chemistry 1993, 30, 873–880. 19 Langlois, N.; Rakotondradany, F. Tetrahedron 2000, 56, 2437–2448. 20 Taber, D. F.; Herr, R. J.; Pack, S. K.; Geremia, J. M. The Journal of Organic Chemistry 1996, 61, 2908–2910. 21 Loev, B.; Kormendy, M. F.; Snader, K. M. The Journal of Organic Chemistry 1966, 31, 3531–3534.

429

430

8 Eliminations

mode of elimination is possible, the conditions of the Shapiro reaction are generally preferred, as they proceed at lower temperatures. A variety of bases have been used, but alkyl lithium22 and lithium amide bases23 are generally preferred. NNHTs NaOMe, Δ

S O N H O

67%

NNHTs H OH

N H

H OH

n-BuLi TMEDA, rt 75%

H

S O O

H

In the following example, the use of methyl lithium complexed with lithium bromide in methyl t-butyl ether (MTBE) allowed Faul et al. to avoid reduction of the aryl bromide through metal–halide exchange.24 TsHN

N

Me Me

Me Me

Br

MeLi •LiBr Et2O, MTBE

Me

99%

Me Me

Br Me

Me Me

α,α′ -Tetrasubstituted ketones, although traditionally poor substrates, can be eliminated via their corresponding hydrazones by the use of lithium diisopropylamide (LDA) as the base. The desired trisubstituted olefin can thus be obtained in high yield.25 TsHN

N

Ph

Ph

LDA, THF, rt

N

N

80%

Ph

Ph

N

N

Additionally, Yamamoto and coworkers reported that the use of a cyclopropyl-derived hydrazone allows for the use of only catalytic amounts of LDA.26 Ph N

N

Me

0.1 equiv LDA ether, 0 °C

Me

>79%

TBSO

8.2.9

TBSO

Elimination of Sulfoxides and Selenoxides

Sulfides and selenides can be oxidized to their corresponding sulfoxides and selenoxides and will eliminate to produce an alkene. The elimination of sulfoxides usually requires more forcing conditions, i.e. higher temperatures, while the selenoxides eliminate more easily.27 NHCBz MeO2C

22 23 24 25 26 27

NHCBz X

MeO2C

X = SOMe

mesitylene, Δ, 62%

X = SePh

30% H2O2, rt, 83%

Tsantali, G. G.; Takakis, I. M. The Journal of Organic Chemistry 2003, 68, 6455–6458. Siemeling, U.; Neumann, B.; Stammler, H.-G. The Journal of Organic Chemistry 1997, 62, 3407–3408. Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. The Journal of Organic Chemistry 2001, 66, 5772–5782. See Note 23. Maruoka, K.; Oishi, M.; Yamamoto, H. Journal of the American Chemical Society 1996, 118, 2289–2290. Bartley, D. M.; Coward, J. K. The Journal of Organic Chemistry 2005, 70, 6757–6774.

8.2 Formation of Alkenes

The key to selecting the best conditions for a given elimination is the proper choice of oxidant that is compatible with other functional groups (see Chapter 10). 8.2.10

Elimination of Halides

Halides are readily eliminated under basic conditions to form alkenes. A wide variety of bases and substrates are accommodated by the reaction, and many substitution patterns can be achieved, including the formation of enol ethers.28,29,30 Use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as the base is preferred where competitive nucleophilic displacement is an issue. Br O

O O

TEA 60%

C16H33

O

DBU, 90 °C

O

C16H33

88%

I

Me

O

OMe

OMe OH

OMe O

O

t-BuOK

Cl

95% CN

CN

CN

If the substrate has 1,1- or 1,2-dihalo substitution, a vinyl halide is produced.31 The vinyl halide can be further eliminated to the corresponding alkyne with excess strong base (see Section 8.4.4). Br

Br TEA

Br

90 °C

HCl • N

N

83%

The halogenation and elimination can also be carried out in one pot under mild conditions from a ketone and under conditions that are amenable to flow.32 O

Br

(i) P(OPh)3, Br2 CH2Cl2 (ii) TEA 85–90%

CO2Et

8.2.11

CO2Et

Elimination of Nitriles

Unactivated cyano groups are difficult to eliminate, but the reaction can be accomplished under strongly basic conditions.33 Me

CN Me N

t-BuOK PhH reflux

Me N

63% 28 Baker, S. R.; Harris, J. R. Synthetic Communications 1991, 21, 2015–2023. 29 Frey, L. F.; Marcantonio, K. M.; Chen, C.-y.; Wallace, D. J.; Murry, J. A.; Tan, L.; Chen, W.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron 2003, 59, 6363–6373. 30 Price, C. C.; Judge, J. M. Organic Syntheses 1965, 45, 22–24. 31 Champness, N. R.; Khlobystov, A. N.; Majuga, A. G.; Schroder, M.; Zyk, N. V. Tetrahedron Letters 1999, 40, 5413–5416. 32 Likhite, N., Ramasamy, S.; Tendulkar, S.; Sathasivam, S.; Luzung, M.; Zhu, Y.; Strotman, N.; Nye, J.; Ortiz, A.; Kiau, S.; Eastgate, M. D.; Vaidyanathan, R. Organic Process Research & Development 2016, 20, 977–981. 33 Palecek, J.; Paleta, O. Synthesis 2004, 521–524.

431

432

8 Eliminations

Nitriles with an α-amino group will eliminate when treated with trimethylsilyl trifluoromethanesulfonate (TMSOTf).34 NH2 Me

N(TMS)2 Me

TMSOTf, TEA

Me

87%

CN

The reverse Strecker reaction or cyanohydrin formation also formally involve the elimination of a nitrile but will be addressed in the chapter on their formation and/or reaction (see Section 2.24). Elimination 𝛃 to an Electron-withdrawing Group

8.2.12

The elimination of a functional group β to an electron-withdrawing group (retro conjugate addition) is extremely facile under mild conditions. The elimination can occur under acidic, basic, or neutral conditions. Carbonyl groups,35,36 sulfones,37 and nitriles and nitro groups are among the many that facilitate the elimination. N O

N • TFA

(i) Ac2O, TEA (ii)TFA

OH

O

65% O

TMSO

O

FeCl3

NaOAc Cl

Me

Me O

MsCl, DIPEA 90%

Me

Me

The epoxides usually give inversion while the episulfides generally proceed with retention of configuration. Because the elimination of epoxides with these reagents only occurs at very high temperatures, an alternative method to form the betaine is to open the epoxide with a metal phosphide and quaternize in situ.52 H OH

Et

H O Et

Me

Me OTHP

(i) LiPPh2 (ii) MeI >60%

OTHP H

Et

Me

44 Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5485–5506. 45 Chu, C. K.; Bhadti, V. S.; Doboszewski, B.; Gu, Z. P.; Kosugi, Y.; Pullaiah, K. C.; Van Roey, P. The Journal of Organic Chemistry 1989, 54, 2217–2225. 46 Sarma, D. N.; Sharma, R. P. Chemistry & Industry 1984, 712–713. 47 Sonnet, P. E. The Journal of Organic Chemistry 1978, 43, 1841–1842. 48 Caputo, R.; Mangoni, L.; Neri, O.; Palumbo, G. Tetrahedron Letters 1981, 22, 3551–3552. 49 Righi, G.; Bovicelli, P.; Sperandio, A. Tetrahedron 2000, 56, 1733–1737. 50 Denney, D. B.; Boskin, M. J. Journal of the American Chemical Society 1960, 82, 4736–4738. 51 Neureiter, N. P.; Bordwell, F. G. Journal of the American Chemical Society 1959, 81, 578–580. 52 Vedejs, E.; Fuchs, P. L. Journal of the American Chemical Society 1971, 93, 4070–4072.

8.2 Formation of Alkenes

Alternatively, the epoxide can be converted to the episulfide to lower the temperature for elimination; this method is less attractive because of the need for extra steps and the conditions required for the conversion. Elimination of 𝛂-Halo Sulfones

8.2.15

Alkenes can be formed by elimination of α-halo sulfones (Ramberg–Bäcklund reaction) under strongly basic conditions. Substrates containing sensitive functionality have been reacted successfully, despite the relatively harsh conditions.53 The halide may be an existing functional group in the substrate or can be generated in situ.54 Me

Me

Me

Me SO2Ph

O

Me O

Me S

Me

Me

Me

Me

SO2Ph Me

O

O

NaOMe, CCl4 73%

Me

Me

O Me SO2Ph

Me SO2Ph

Me

Me

Me

Me Me

O

Ph

OTBS O

O O

OMe O

Ph

KOH/Al2O3 CBr2F2

S

Ph

O

O O

OTBS O OMe

70%

Ph H

The intermediate episulfone can also be eliminated under thermolytic conditions.55 Et

O

S

O Et

H

PhCH3 reflux

TMS

8.2.16

Et H

70%

Et TMS

Elimination of Aziridines

Aziridines are not easily eliminated under reaction conditions that tolerate a wide range of functional groups. The N-nitroso derivative eliminates at low temperatures but is likely to have safety issues with regard to thermal decomposition.56 H N Ph

N2O4, TEA −43 °C 92%

Ph

Ph

Ph

Iodonium salts can also give the eliminated product, but the reaction often results in multiple by-products.57 Ph (Ph2I)I, Δ

N

Ph

Ph O

75%

Ph Ph

O

53 Choi, B. S.; Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; Nam, D. H.; Shin, H. Organic Process Research & Development 2005, 9, 311–313. 54 Pasetto, P.; Franck, R. W. The Journal of Organic Chemistry 2003, 68, 8042–8060. 55 Muccioli, A. B.; Simpkins, N. S.; Mortlock, A. The Journal of Organic Chemistry 1994, 59, 5141–5143. 56 Lee, K.; Kim, Y. H. Synthetic Communications 1999, 29, 1241–1248. 57 Padwa, A.; Eastman, D.; Hamilton, L. The Journal of Organic Chemistry 1968, 33, 1317–1322.

435

436

8 Eliminations

8.2.17

Elimination of Dihalides

Dihalides can be eliminated to form alkenes under relatively mild conditions, such as treatment with iodide58 or metallic samarium.59 Br

Br

O

O

Br

NaI Br

Br Ph

Ph

98%

Br

Sm, aq NH4Cl 98%

Br

O

Ph

O

Br

Ph

Dehalogenation in dry DMF at elevated temperatures has also been reported.60 Br

DMF, Δ

CO2Me

Ph

Ph

93%

Br

CO2Me

Depending on the relative stereochemistry of the dihalide and the conditions used, either cis or trans alkenes can be produced. If the first elimination can occur away from the vicinal halide, a diene may be produced instead (see Section 8.3.1).

8.2.18

Elimination of Haloethers

The elimination of haloethers can be accomplished via metal-halogen exchange.61 The resulting alkene is the product of syn elimination, although some trans product may be observed. OMe C5H11

C5H11

C5H11

n-BuLi, –78 °C

C5H11

77%

I

More classically, the elimination can be carried out using zinc dust (Boord reaction).62 O O

Me

OH

O

Zn, EtOH reflux

O

O

89% I

The corresponding halothioethers can also be eliminated, generally under milder conditions. The reaction is most easily carried out with iodide63 and gives the product of anti elimination. SMe Me

Me Br

58 59 60 61 62 63

NaI

Me

Me

>97%

Yang, J.; Bauld, N. L. The Journal of Organic Chemistry 1999, 64, 9251–9253. Wang, L.; Zhang, Y. Tetrahedron 1999, 55, 10695–10712. Khurana, J. M.; Maikap, G. C. The Journal of Organic Chemistry 1991, 56, 2582–2584. Maeda, K.; Shinokubo, H.; Oshima, K. The Journal of Organic Chemistry 1996, 61, 6770–6771. Beusker, P. H.; Aben, R. W. M.; Seerden, J.-P. G.; Smits, J. M. M.; Scheeren, H. W. European Journal of Organic Chemistry 1998, 2483–2492. Helmkamp, G. K.; Pettitt, D. J. The Journal of Organic Chemistry 1964, 29, 3258–3262.

8.2 Formation of Alkenes

8.2.19

Elimination of Hydroxy- or Haloacids

Several methods exist for simultaneous dehydration and decarboxylation of hydroxyacids. One of the mildest is treatment of the starting material with DMF dimethyl acetal and moderate heating, which gives the product of anti elimination.64 OH

DMF-DMA reflux

CO2H

Me

Me

Ph

87%

Ph

The elimination can also be effected by treatment with acetic anhydride and heat.65 OH CO2H Ph

MeO

Ac2O, NaOAc 100 °C 75%

Ph MeO

Several groups have used Mitsunobu conditions for this type of elimination, but these conditions are generally less preferable because of the difficulty in purging the by-products, such as triphenylphosphine oxide and substituted hydrazines. Haloacids give rise to alkenes with good stereospecificity by treatment with a mild base.66 Br TEA

CO2H

Me Br

8.2.20

Me Br

57%

Elimination of Hydroxysulfones

The elimination of β-hydroxyphenylsulfones (Julia–Lythgoe olefination, see Section 2.21) has classically been accomplished by reduction with sodium amalgam. The stereochemistry of the resulting alkene is not usually controlled, unless the substrate possesses an inherent bias in the elimination.67 OR O Me

O

SO2Ph

OH

OBn NHBoc

OR

Na–Hg, Na2HPO4 0 °C 72%

Me

O Me

O

OBn NHBoc

Me

R = TBDPS

The elimination is better controlled, and the use of amalgam can be avoided, by using heterocycle-substituted sulfones.68 After addition of the corresponding anion to an aldehyde, the intermediate eliminates in situ, and the stereocontrol can be high with the correct choice of base and solvent. N N O N N S O Ph

(i) KHMDS, DME, −55 °C (ii) c-C6H11CHO Me

Me

71% 97 : 3

64 65 66 67 68

Frater, G.; Mueller, U.; Guenther, W. Tetrahedron 1984, 40, 1269–1277. Alexander, B. H.; Barthel, W. F. The Journal of Organic Chemistry 1958, 23, 389–391. Fuller, C. E.; Walker, D. G. The Journal of Organic Chemistry 1991, 56, 4066–4067. Wang, Q.; Sasaki, N. A. The Journal of Organic Chemistry 2004, 69, 4767–4773. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–28.

437

438

8 Eliminations

Elimination of 𝛃-Silyl Alcohols

8.2.21

The elimination of a β-silyl alcohol (Peterson reaction) is well documented. The reaction is stereospecific and gives the product of syn elimination under basic conditions.69 Under acidic conditions, the reaction results in antielimination.70 OH O

t-BuOK

O

SiMe2Ph OTBS

HO

O

94%

TMS

HO

OH

p-TsOH

OBn

HO

95%

OBn

O

OBn OBn

Elimination of 𝛃-Silyl Esters, Sulfides, and Sulfones

8.2.22

The elimination of groups other than an alcohol β to a silyl group is less well known than the Peterson reaction but has also been demonstrated. Esters71 and sulfones72 readily eliminate on treatment with fluoride ion. F

F OBz TMS

C6H13

84%

F

C6H13

TBAF 0 °C

I

TMS

F

TBAF

I

80%

O S O Me

Enol silanes can be generated from addition of nucleophiles to acyl silanes with a β-leaving group.73 The intermediate alkoxide undergoes a Brook rearrangement (see Section 7.2.6.1) followed by elimination. O Me

TMS SPh

PhLi –78 to 0 °C 89%

OTMS Me

Ph

8.3 Formation of Dienes Dienes can usually be formed under very similar conditions to those used for generation of alkenes. In this section, substrates and conditions are described that would not eliminate in the analogous “monoene” system or that present issues that would not be otherwise encountered.

69 70 71 72 73

Keck, G. E.; Romer, D. R. The Journal of Organic Chemistry 1993, 58, 6083–6089. Heo, J.-N.; Holson, E. B.; Roush, W. R. Organic Letters 2003, 5, 1697–1700. Shibuya, A.; Okada, M.; Nakamura, Y.; Kibashi, M.; Horikawa, H.; Taguchi, T. Tetrahedron 1999, 55, 10325–10340. Najera, C.; Sansano, J. M. Tetrahedron 1994, 50, 5829–5844. Reich, H. J.; Holtan, R. C.; Bolm, C. Journal of the American Chemical Society 1990, 112, 5609–5617.

8.3 Formation of Dienes

8.3.1

From Allylic Systems

Allylic X systems, where X can be alcohol, ether, ester, halide, sulfone, or other leaving groups can yield dienes. Allylic alcohols eliminate under acidic conditions at temperatures much lower than the saturated analogues.74,75 OH Me

Me

Me

MeO2C

H NHBoc

MeO2C

p-TsOH, 80 °C

H NHBoc

83% N Ts

N Ts

Ph

Ph TFA, –30 °C 89%

HO t-BuPh2Si

t-BuPh2Si

Allylic ethers also eliminate under neutral or mildly acidic conditions with heat.76 MeO

OMe Me

MeO KHSO4, 130 °C 98%

Me

Me

Allylic esters, halides, and sulfones eliminate by treatment with Pd(0); if a nucleophile is not present to trap the π-allyl intermediate, hydride elimination may occur.77 Me

Me

AcO

OAc

Pd(OAc)2, PPh3, Δ

OAc

91%

Allylic sulfones and halides will also eliminate under basic conditions.78,79,80 n-Bu

SO2Ph

n-Bu t-BuOK, 80 °C 78% Cl

I

Cl I

Cl

OTBS

DBU

I

81%

I

(i) t-BuOK Aliquat 336

OH

+

Br Br

(ii) Dowex H 84%

74 Hikawa, H.; Yokoyama, Y.; Murakami, Y. Synthesis 2000, 214–216. 75 Cuadrado, P.; Gonzalez-Nogal, A. M.; Sanchez, A.; Sarmentero, M. A. Tetrahedron 2003, 59, 5855–5859. 76 Hajos, Z. G.; Doebel, K. J.; Goldberg, M. W. The Journal of Organic Chemistry 1964, 29, 2527–2533. 77 Shim, S.-B.; Ko, Y.-J.; Yoo, B.-W.; Lim, C.-K.; Shin, J.-H. The Journal of Organic Chemistry 2004, 69, 8154–8156. 78 Hill, K. W.; Taunton-Rigby, J.; Carter, J. D.; Kropp, E.; Vagle, K.; Pieken, W.; McGee, D. P. C.; Husar, G. M.; Leuck, M.; Anziano, D. J.; Sebesta, D. P. The Journal of Organic Chemistry 2001, 66, 5352–5358. 79 Sellen, M.; Baeckvall, J. E.; Helquist, P. The Journal of Organic Chemistry 1991, 56, 835–839. 80 Bridges, A. J.; Fischer, J. W. The Journal of Organic Chemistry 1984, 49, 2954–2961.

439

440

8 Eliminations

Since allylic groups eliminate so readily, the choice of reaction conditions should be selected based on consideration of the other functional groups in the substrate, and what they will tolerate. 8.3.2

From 1,4-Dihalo-2-butenes

Treatment of 1,4-dihalo-2-butene derivatives with reducing agents such as Zn0 results in reductive elimination to produce the corresponding diene.81 Cl Cl

Me O B O Me Me Me

Zn

O B O

50–70%

If these substrates are exposed to basic conditions, simple allylic elimination occurs, as noted in Section 8.3.1. However, if a nucleophile capable of displacing one of the halides under basic conditions is present, a substituted diene is produced.82 OMe

Cl + Cl NaO

DMSO, 85 °C 78%

OMe O 3 : 1 E:Z

8.3.3

From Diols

Vicinal diols can be eliminated to form dienes, most easily under the same kinds of conditions that convert alcohols to alkenes, such as via conversion to and elimination of a diester derivative.83 Me OH

Me

OAc 80%

HO Me

AcO

OAc

Ac2O, AcCl AcO

Me

If the diols are inherently susceptible, i.e. tertiary, benzylic, or allylic, they will eliminate under solvolytic conditions.84 These eliminations are complicated by the potential to undergo a pinacol rearrangement, which is often a competitive or even dominant process (see Section 7.2.1.2). Me

Me

O

8.3.4

H3PO4 90%

Me OH

HMPA

HO Me

71%

From 𝛅-Elimination

Analogously to the elimination of a β-leaving group, activated groups δ to an α,β-unsaturated system will eliminate to form a diene. The reaction is readily accomplished under basic conditions.85 CHO

CHO DABCO

AcO 81 82 83 84 85

OAc

99%

AcO

Kamabuchi, A.; Miyaura, N.; Suzuki, A. Tetrahedron Letters 1993, 34, 4827–4828. Burke, S. D.; Cobb, J. E.; Takeuchi, K. The Journal of Organic Chemistry 1990, 55, 2138–2151. Niederl, J. B.; Silverstein, R. M. The Journal of Organic Chemistry 1949, 14, 10–13. Wagner, R. A.; Brinker, U. H. Synthesis 2001, 376–378. Areces, P.; Carrasco, E.; Mancha, A.; Plumet, J. Synthesis 2006, 946–948.

8.3 Formation of Dienes

8.3.5

From Sulfolenes

Dienes can be synthesized by extrusion of SO2 from sulfolenes. The preferred conditions employ a mild base at elevated temperatures. Activated substrates will eliminate in refluxing ethanol,86 while less activated substrates require the higher temperatures that can be achieved with toluene.87 Me Me

H

Me Me

I

NaHCO3, EtOH

H TBSO S

H

I

H

92%

O O

OTBS Me

O

S O O

8.3.6

Me

NaHCO3, PhCH3 Me

94%

O Me

Via Retro Diels–Alder Reactions

A pericyclic rearrangement can be used to build dienes. The substrate for the fragmentation often arises from a Diels–Alder reaction, with the reverse reaction eliminating an alternate dienophile. Acetylenes have been used as the eliminating group, but usually require high temperatures. Other groups, such as nitriles88 or CO2 ,89 eliminate under milder conditions. O

O Me Me

NMeOMe Me N S

(i) LiCCTMS (ii) MeOH

Me Me S

O

Me

N O

PhCH3 reflux O

O

Me Me

–MeCN O

S

O

Bn

86 87 88 89

O Me Me

S

N

PhCH3 reflux –CO2

O N

88% over 3 steps

Me

O

quant.

N

O

Bn

Manchand, P. S.; Yiannikouros, G. P.; Belica, P. S.; Madan, P. The Journal of Organic Chemistry 1995, 60, 6574–6581. Winkler, J. D.; Quinn, K. J.; MacKinnon, C. H.; Hiscock, S. D.; McLaughlin, E. C. Organic Letters 2003, 5, 1805–1808. Selnick, H. G.; Brookes, L. M. Tetrahedron Letters 1989, 30, 6607–6610. Noguchi, M.; Kakimoto, S.; Kawakami, H.; Kajigaeshi, S. Bulletin of the Chemical Society of Japan 1986, 59, 1355–1362.

441

442

8 Eliminations

8.3.7

From Extrusion of CO

Fragmentation of molecules containing a cyclopentenone in which CO can be extruded are synthetically useful and occur thermolytically at reasonable temperatures to give dienes.90 OH OH

O

DME reflux

OH OH

82%

8.4 Formation of Alkynes A variety of functional groups can be eliminated to form alkynes, and many of the conditions are similar to those used for formation of alkenes. Substituted alkynes are generally formed by introduction of an intact acetylene unit but can be synthesized by elimination. The most useful methods for disubstituted alkynes rely on formation of a terminal alkyne followed by functionalization of the terminus, often in the same pot. The methods available for directly generating disubstituted alkynes are often limited to substrates containing at least one aromatic substituent, where the direction of elimination is fixed. 8.4.1

From Ketones

Conversion of ketones to alkynes is most easily carried out via the intermediacy of phosphoranyl enolates.91 Me

Me

Me

Me

(i) LDA, ClPO(OEt)2

O

Me

(ii) LDA, –78 °C to rt Me

72–85%

Me

An analogous reaction has also been carried out on β-phosphoranyl ketones, but these substrates generally require very high temperatures92 or microwave assistance93 to eliminate, making them less useful. Alkyl-substituted alkynes can be generated by a two-step procedure in which benzotriazole (Bt) serves as a dummy ligand during the alkyne formation then can be displaced by an alkyl- or arylmetal species.94 (i) Tf2O, lutidine (ii) NaOH

O Bt

Ph

MgBr Ph

76%

Bt

79%

Ph

Pyridinium salts have been shown to effect the dehydration of α-ketosulfonamides.95

N+

O SO2NMe2 O2 N

90 91 92 93 94 95

Cl Me I−, TEA 78%

O2N

SO2NMe2

Lin, C. T.; Chou, T. C. The Journal of Organic Chemistry 1990, 55, 2252–2254. Negishi, E.; King, A. O.; Tour, J. M. Organic Syntheses 1986, 64, 44–49. Heard, N. E.; Turner, J. The Journal of Organic Chemistry 1995, 60, 4302–4304. RamaRao, V. V. V. N. S.; Reddy, G. V.; Maitraie, D.; Ravikanth, S.; Yadla, R.; Narsaiah, B.; Rao, P. S. Tetrahedron 2004, 60, 12231–12237. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. The Journal of Organic Chemistry 2002, 67, 7526–7529. Leclercq, M.; Brienne, M. J. Tetrahedron Letters 1990, 31, 3875–3878.

8.4 Formation of Alkynes

8.4.2

From Bis(hydrazones)

Alkynes are readily formed from bis(hydrazones) by treatment with a copper salt96 or iodine in the presence of guanidine bases.97

NNH2

Cu(OAc)2 76%

NNH2

NNH2 Me NNH2

I2, BTMG

Me

95%

BTMG = t-butyltetramethylguanidine

8.4.3

From Dihalides

Alkynes may be synthesized from 1,1- or 1,2-dihalides by treatment with a strong base.98,99 The reaction can also be catalyzed by the use of phase transfer catalysts.100 Br

Br

Br

KOH, IPA CO2Et

Br OTs TBSO Me

Cl

OEt Br

8.4.4

CO2H

(i) n-BuLi, −78 °C Cl (ii) (CH2O)n TBSO

OEt Br

96%

82%

OH Me

KOH, PTC, 80 °C

OEt

79%

OEt

From Vinyl Halides

Alkynes can also be formed from vinyl halides, which are often intermediates in the elimination from the dihalides. The elimination is successful with mono-halo,101 1,1-dihalo,102 or 1,2-dihalo alkenes.103 Of these, the most commonly 96 Ito, S.; Nomura, A.; Morita, N.; Kabuto, C.; Kobayashi, H.; Maejima, S.; Fujimori, K.; Yasunami, M. The Journal of Organic Chemistry 2002, 67, 7295–7302. 97 Barton, D. H. R.; Bashiardes, G.; Fourrey, J. L. Tetrahedron 1988, 44, 147–162. 98 Chen, J. C., T.; Hu, Q.; Püntener, K.; Ren, Y.; She, J.; Du, Z.; Scalone, M. Organic Process Research & Development 2014, 2014, 1702–1713. 99 Marshall, J. A.; Yanik, M. M. The Journal of Organic Chemistry 2001, 66, 1373–1379. 100 Dehmlow, E. V.; Lissel, M. Tetrahedron 1981, 37, 1653–1658. 101 Toussaint, D.; Suffert, J. Organic Syntheses 1999, 76, 214–220. 102 Mori, M.; Tonogaki, K.; Kinoshita, A. Organic Syntheses 2005, 81, 1–13. 103 Kende, A. S.; Fludzinski, P. Organic Syntheses 1986, 64, 73–79.

443

444

8 Eliminations

used in recent times is the Corey–Fuchs reaction. As with many syntheses in which a terminal alkyne is generated, the product is often trapped under the basic reaction conditions with an electrophile.

Me

OH

(i) n-BuLi

Br

Ph

(ii) Ph

Me

CHO 92%

CBr4, PPh3

CHO

Ph

96%

Br OH (i) HO p-TsOH

Cl Me Cl

O

8.4.5

Br

Ph

(ii) n-BuLi 52–60%

OH

(i) n-BuLi (ii) (CH2O)n 86%

Ph

Me O O

From Elimination of Sulfones

Elimination of a sulfur-containing moiety has been used to generate alkynes. The most preparatively useful reactions involve elimination of a vinyl sulfone, either as an isolated intermediate104 or generated in situ in the course of the reaction.105 The latter reaction can be particularly useful, since the intermediate vinyl metal species can be used to introduce more functionality prior to the elimination.

Ph

SO2Ph Ph OAc

t-Bu

(i) t -BuOK (ii) t -BuOK 86% (i) MeLi, –78 °C (ii) PhCHO

SO2Ph

(iii) MeLi

Ph

t-Bu

Ph

Ph OH

85%

Sulfide106 and sulfoxide107 eliminations are also known but are generally only feasible on small scale due to the conditions required.

8.5 Formation of C=N bonds Imines are readily formed by the addition of reasonably nucleophilic amines to aldehydes or ketones followed by dehydration (see Section 2.7.1). Other C=N functional groups may be formed by standard dehydrating conditions from a suitable precursor. 104 105 106 107

Otera, J.; Misawa, H.; Sugimoto, K. The Journal of Organic Chemistry 1986, 51, 3830–3833. Yoshimatsu, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. Journal of the Chemical Society, Chemical Communications 1995, 583–584. Sato, T.; Tsuchiya, H.; Otera, J. Synlett 1995, 628–630. Nakamura, S.; Kusuda, S.; Kawamura, K.; Toru, T. The Journal of Organic Chemistry 2002, 67, 640–647.

8.6 Formation of Nitriles

8.5.1

Carbodiimides from Ureas

Ureas are readily dehydrated by activation with sulfonyl chlorides to form the corresponding carbodiimides.108 They may also be formed by treatment with a phosphine and halogen.109

O N

N H

O

O

PhSO2Cl, TEA, 70 °C

O

N

73%

N H

O

N C N

O O

N H

O

Me

N H

O

Me

Me

Ph3P, Br2, TEA

O

O

89%

Me

Me

N C N O Me

O

O Me

Me

8.6 Formation of Nitriles Nitriles are readily formed by dehydration of amides, oximes, and similar functional groups. The standard conditions for dehydration of an alcohol are most commonly used. Newer methods tend to be milder than the older conditions and, therefore, more compatible with sensitive functional groups. 8.6.1

Nitriles from Amides

Several relatively mild conditions have been reported for the dehydration of amides, preferably by activation as a sulfonate,110 acetate,111 or iminoyl chloride.112 O Ph

NH2 NHBoc

p-TsCl, pyridine 72%

NHBoc

F

F NH2

N

TFAA, TEA N

85%

O O Me

CN

Ph

NH2 Me

SOCl2, 80 °C 86–94%

Me

CN

CN Me

108 Zhang, M.; Vedantham, P.; Flynn, D. L.; Hanson, P. R. The Journal of Organic Chemistry 2004, 69, 8340–8344. 109 Gibson, F. S.; Park, M. S.; Rapoport, H. The Journal of Organic Chemistry 1994, 59, 7503–7507. 110 McLaughlin, M.; Mohareb, R. M.; Rapoport, H. The Journal of Organic Chemistry 2003, 68, 50–54. 111 Ashwood, M. S.; Alabaster, R. J.; Cottrell, I. F.; Cowden, C. J.; Davies, A. J.; Dolling, U. H.; Emerson, K. M.; Gibb, A. D.; Hands, D.; Wallace, D. J.; Wilson, R. D. Organic Process Research & Development 2004, 8, 192–200. 112 Krynitsky, J. A.; Carhart, H. W. Organic Syntheses 1952, 32, 65–67.

445

446

8 Eliminations

A more unusual, but exceedingly mild elimination has been reported for the sulfonamide derivative, which eliminates by treatment with a mild base.113 The limitation to this method is the need to make the acyl sulfonamide, which can be generated from the acid114 or installed directly, as shown in the following. O CSI O

CN

TEA, 0 °C

NHSO2Cl

84%

O

O

CSI = chlorosulfonylisocyanate

8.6.2

Nitriles from Cleavage of N—O Bonds

The cleavage of N—O bonds has been used to generate nitriles, particularly the dehydration of oximes. A wide range of dehydrating conditions has been employed. Some of the mildest involve formation of the silyl aldoximine followed by base decomposition115 or dehydration with thionyl chloride.116

MeO

TBSCl, imidazole NOH

MeO

60%

NOH

CN

NOH

SOCl2

Cl

Cl

50%

NOH

CN

Oximes substituted with a carboxylic acid can spontaneously decarboxylate during the dehydration. This is most conveniently accomplished by treatment with an anhydride.117

t-Bu O

CO2H

t-Bu

Ac2O, Δ 86%

O

NOH

CN

Isoxazoles can also serve as latent cyanoaldehydes but must usually be trapped in situ. The ring opening occurs readily with almost any base.118

N

113 114 115 116 117 118

O

NaOH, (EtO)2SO2 87%

NC

OEt

Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50, 6549–6558. Lohaus, G. Organic Syntheses 1970, 50, 18–21. Ortiz-Marciales, M.; Pinero, L.; Ufret, L.; Algarin, W.; Morales, J. Synthetic Communications 1998, 28, 2807–2811. Kozikowski, A. P.; Adamcz, M. The Journal of Organic Chemistry 1983, 48, 366–372. Divald, S.; Chun, M. C.; Joullie, M. M. The Journal of Organic Chemistry 1976, 41, 2835–2846. Tarsio, P. J.; Nicholl, L. The Journal of Organic Chemistry 1957, 22, 192–193.

8.7 Formation of Ketenes and Related Compounds

8.6.3

Isonitriles from Formamides

Isonitriles are readily formed from the corresponding N-formyl precursors. Most of the standard dehydrating conditions work well for this transformation, including the elimination of sulfonate,119 sulfate,120 and phosphate derivatives.121 NHCHO

NC MsCl, pyridine 0 °C

Me Me O

O

96%

Me Me

Me Me

Ot-Bu NHCHO NO2

O Me

SOCl2, DMF –50 °C

Me

Me

O

NO2 F Me

O

87%

O

OHCHN

Ot-Bu NC

85%

POCl3, TEA –25 °C

F

O

CN

O

8.7 Formation of Ketenes and Related Compounds Ketenes, isocyanates, and isothiocyanates are all readily formed by elimination from a suitable precursor, such as an acid, amide, or carbamate derivative. 8.7.1

Ketenes

Ketenes are easily formed by treatment of the corresponding activated acid precursor with mild base or heating. Acid chlorides are the preferred precursor to ketenes, as they eliminate with very mild bases122 or spontaneously on standing. Me

Me TEA, 0 °C O

Me

86%

Cl

Me

C O

A ketene may also be formed by treatment of an α-halo acid halide with zinc.123 Me

Me O Br

119 120 121 122 123

Br

Zn, 0 °C

Me

Me

C

O

63%

Swindell, C. S.; Patel, B. P.; DeSolms, S. J.; Springer, J. P. The Journal of Organic Chemistry 1987, 52, 2346–2355. Meyers, A. I.; Bailey, T. R. The Journal of Organic Chemistry 1986, 51, 872–875. Cristau, P.; Vors, J.-P.; Zhu, J. Tetrahedron 2003, 59, 7859–7870. Schmittel, M.; Von Seggern, H. Journal of the American Chemical Society 1993, 115, 2165–2177. Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. T. Journal of the American Chemical Society 1985, 107, 5391–5396.

447

448

8 Eliminations

Esters with α-activating groups have been demonstrated to eliminate to the corresponding ketene on heating and can be trapped in situ with an alcohol or amine to form the ester or amide product.124 In this approach, hindered esters are preferred over less-substituted esters, since the ketene formation occurs at lower temperatures. O

O

Me

MeMe

H2N O

NH

HO

O

Me

xylene reflux

O-t-Bu

Me

toluene reflux

O MeMe O

72%

83%

8.7.2

O

Isocyanates and Isothiocyanates

Isocyanates form readily from the corresponding carbamoyl chloride by treatment with a mild base.125 Me

H N

PhSCl

SEt

Me

H N

O

Me

TEA, 0 °C

Cl

62%

O

N C O

Isocyanates are also formed during the Curtius rearrangement (see Section 7.2.3.2) but are not usually isolated during that reaction. The potential for high-energy decomposition of the intermediate acyl azide makes it a less than desirable method. Isothiocyanates may be formed from amines by a two-step procedure involving formation of the dithiocarbamate followed by carboxylation and elimination with base. Caution should be used with this procedure as it liberates carbonyl sulfide (COS).126 NH2

H N

CS2

EtOCOCl, TEA

N

80%

Me

S Me

Me

8.7.3

S−

C

S

Ketimines

Substituted amides can be dehydrated to form ketimines. The elimination requires relatively strong dehydrating conditions to be successful. The most commonly employed conditions utilize triphenylphosine/bromine to effect the transformation.127 Other dehydrating conditions, such as PCl5 have also been demonstrated.128 O

O

(EtO)2P Me

Me

N H

Me

Me Me H N H

Me

Ph O

PPh3, Br2

O

TEA 82%

PCl5, 80 °C 95%

C

(EtO)2P

N

Me

Me

Me

Me Me H

N C

Me Ph

124 Witzeman, J. S.; Nottingham, W. D. The Journal of Organic Chemistry 1991, 56, 1713–1718. 125 Sitzmann, M. E.; Gilligan, W. H. The Journal of Organic Chemistry 1985, 50, 5879–5881. 126 Hodgkins, J. E.; Reeves, W. P. The Journal of Organic Chemistry 1964, 29, 3098–3099. 127 Motoyoshiya, J.; Teranishi, A.; Mikoshiba, R.; Yamamoto, I.; Gotoh, H.; Enda, J.; Ohshiro, Y.; Agawa, T. The Journal of Organic Chemistry 1980, 45, 5385–5387. 128 Hiroi, K.; Sato, S. Chemical & Pharmaceutical Bulletin 1985, 33, 2331–2338.

8.8 Fragmentations

8.8 Fragmentations 8.8.1

Grob Fragmentations

Carbon frameworks containing an alcohol at one terminus and a leaving group at the other, of the general structure HO–C–C–C–X, can be fragmented to give a carbonyl and an alkene (Grob fragmentation). A base strong enough to deprotonate the alcohol is all that is needed to effect this transformation.129 The fragmentation is frequently employed to synthesize medium-sized rings.130

MsO

Me Me

Me Me

NaH, THF, Δ

OH

Me Me

79%

Me

Me

HO

MeO

Me

Me

OMs

NaOMe

MeO

80%

Me

O

O

Me

The product aldehyde or ketone is not always stable to isolation, so sodium borohydride or another reducing agent is often added to reduce the carbonyl produced in situ.131 OH

CO2Et NaOEt, NaBH 4

H Me

OH

CO2Et

77% Me

Br

The 3-aza variant of this fragmentation gives rise to an amino alcohol after reduction of the resulting imine and aldehyde.132

N

O

NaBH4 N

MeO

MeO

OH NHMe

129 130 131 132

O−

95%

N

O

Mehta, G.; Karmakar, S.; Chattopadhyay, S. K. Tetrahedron 2004, 60, 5013–5017. Villagomez-Ibarra, R.; Alvarez-Cisneros, C.; Joseph-Nathan, P. Tetrahedron 1995, 51, 9285–9300. Lamers, Y. M. A. W.; Rusu, G.; Wijnberg, J. B. P. A.; De Groot, A. Tetrahedron 2003, 59, 9361–9369. See Note 59.

449

450

8 Eliminations

8.8.2

Eschenmoser Fragmentations

The elimination and subsequent fragmentation of an epoxy-hydrazone to a keto-alkyne (Eschenmoser fragmentation) is readily accomplished under very mild conditions. The hydrazone is usually formed in situ, and the reaction can be carried out at low temperatures in acetic acid133 or with mild heating.134

H O

Ts

TsNHNH2 HOAc, 0 °C

Me O

N

N O

91%

Me

Me

Ts

Me

N

N

O

Me O− Me

Me

8.8.3

Me

Formation of Arenes

Bicyclo[3.1.0]hexane rings that are appropriately substituted with leaving groups, usually halogens, will spontaneously or under basic conditions fragment to give benzene rings.135 This methodology has been used to synthesize rings with substitution patterns that would be difficult to achieve by nucleophilic or electrophilic aromatic substitution reactions (see Chapters 4 and 5). Cl

Cl

Me

Me

Cl

8.8.4

Cl

PhCH3, reflux (95%)

Me

or t-BuOK, DMSO (80%)

Cl

Me

Cl

Extrusion of N2

Cyclopropanes can be synthesized in good yield by the extrusion of nitrogen from 1-pyrazolines. The reaction is most easily carried out by refluxing the starting material in a medium- to high-boiling solvent.136 The isomeric 2-pyrazolines will also eliminate, but only under conditions that isomerize it to the 1-isomer first.

BocHN Me Me

N

N

O

PhCH3 reflux

O

88%

Me Me

NHBoc O O

NO2

NO2

133 134 135 136

Kocienski, P. J.; Ostrow, R. W. The Journal of Organic Chemistry 1976, 41, 398–400. Dai, W.; Katzenellenbogen, J. A. The Journal of Organic Chemistry 1993, 58, 1900–1908. Jenneskens, L. W.; De Wolf, W. H.; Bickelhaupt, F. Synthesis 1985, 647–649. Srivastava, V. P.; Roberts, M.; Holmes, T.; Stammer, C. H. The Journal of Organic Chemistry 1989, 54, 5866–5870.

8.9 Dehydrating Reagents

Triazolines will also extrude nitrogen to form aziridines. The temperature of the extrusion can vary depending on the nitrogen substituent; the carbamate derivative eliminates at moderate temperatures,137 while alkyl or aryl substituents can require much higher temperatures. N N N CO2Et

8.8.5

MeOH, 40 °C

NCO2Et H H

87%

Extrusion of S

As noted earlier, sulfur extrusion from episulfides is a well-established method for formation of alkenes (see Section 8.2.14). A special case arises when the sulfur is part of a β-dicarbonyl system or some functional equivalent. Treatment of these systems with a phosphine also results in extrusion of the sulfide, in this case to form the β-dicarbonyl or a tautomer, but at much lower temperatures.138 (i) CHCl3, 60 °C

S

N H

(ii)

+

CO2Me

Br

Me2N 85%

O

8.8.6

2PPh

N H

O

CO2Me

Multicomponent Extrusions

Several different multicomponent extrusions, of the general formula shown in the following, have been carried out to form alkenes. While these eliminations are generally not practical as truly preparative processes, they can be carried out on the laboratory scale. The most useful usually involve a sulfide as one of the components, removed with a phosphine, and another group that eliminates under the high temperatures of the reaction, such as nitrogen.139 X

R1 R2

Y

N N S

R3 R4

R1

R3

R2

R4

PPh3 100 °C 75%

8.9 Dehydrating Reagents Table 8.1 summarizes some of the more commonly used reagents for dehydration. Specific references may be found in the relevant sections aforementioned for the reagents that have the widest applicability or are preferred options. References given below for these reagents are for review articles on their use. The final three entries in the table are not generally suitable for large-scale use because of availability, stability, safety, or toxicological concerns. However, they may be well suited to small-scale use, especially in the academic environment. Finally, the series Encyclopedia of Reagents for Organic Synthesis140 is a good reference source on the physical properties, handling recommendations and reactivity of these and other reagents. 137 Tanida, H.; Tsuji, T.; Irie, T. The Journal of Organic Chemistry 1966, 31, 3941–3947. 138 Roth, M.; Dubs, P.; Goetschi, E.; Eschenmoser, A. Helvetica Chimica Acta 1971, 54, 710–734. 139 Barton, D. H. R.; Willis, B. J. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1972, 305–310. 140 Paquette L. A. Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons Ltd: West Sussex, U.K., 1995.

451

452

8 Eliminations

Table 8.1 Reagents for dehydration. Reagent

Sulfuric acid (H2 SO4 )

Structure

O

Uses

Limitations

Alkenes from 2∘ , 3∘ OH, β-silyl OH

Not compatible with acid-sensitive functionality and some solvents

Alkenes from 1∘ , 2∘ , 3∘ OH

May not be compatible with acid-sensitive functionality

HO S OH O

SO3H

p-Toluenesulfonic acid (tosic acid, p-TsOH)141

Nitriles from oximes

Me

N-oxides from nitro compounds O

Acetic anhydride (Ac2 O)

O

Me

Alkenes from 1∘ , 2∘ , 3∘ OH Me

O

Nitriles from aldoximes

Competitive acylation of other nucleophilic functional groups Oximes give N-acyl enamines

Trifluoroacetic anhydride (TFAA)

Methanesulfonyl chloride (MsCl)

O F3C

O O

O Me S Cl

Alkenes from 1∘ , 2∘ , 3∘ OH, β-silyl OH, iodohydrins

Competitive sulfonylation and/or chlorination without elimination

Isonitriles from formamides

SO2Cl

Toluenesulfonyl chloride (TsCl)

Nitriles from amides Isonitriles from formamides

Me

Phosphorus oxychloride (POCl3 )142

Competitive acylation of other nucleophilic functional groups

CF3

O

Thionyl chloride (SOCl2 )

Nitriles from amides, oximes

Carbodiimides from ureas O

Nitriles from amides, oximes

Cl S Cl

Isonitriles from formamides

O

Nitriles from amides

Cl P Cl

Isonitriles from formamides

Cl

Carbodiimides from ureas Cl

Cyanuric chloride (trichloroiso-cyanuric acid)143

N Cl

Sulfonylation of alcohols or amines may be competitive

Nitriles from amides, aldoximes N

N

May not be compatible with acid-sensitive functionality

May not be compatible with acid-sensitive functionality; competitive chlorodehydration

Competitively converts alcohols to chlorides

Cl

(Continued)

141 D’Onofrio, F.; Scettri, A. Synthesis 1985, 1159–1161. 142 Sharma, S. D.; Kanwar, S. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1998, 37B, 965–978. 143 Giacomelli, G.; Porcheddu, A.; de Luca, L. Current Organic Chemistry 2004, 8, 1497–1519.

8.9 Dehydrating Reagents

Table 8.1 (Continued) Reagent

Phosphorus pentoxide (P2 O5 ) (Eaton’s reagent when in MsOH)

Burgess reagent144

Martin sulfurane145,146

Dicyclohexylcarbodiimide (DCC)

Structure

O

Uses

Limitations

Nitriles from amides

O P O O O P O P O O P O O

Et3N+

N− OMe S O O O

Ph

Ph Ph S F3C O O CF3 CF3 Ph CF3

N C N

Alkenes from 2∘ , 3∘ , allylic alcohols

Does not work for 1∘ alcohols

Nitriles from 1∘ amides

Competitive SN 2 pathway

Isonitriles from formamides

Cost, availability

Alkenes from 2∘ , 3∘ alcohols or activated 1∘ alcohols

Cost, availability

Alkenes from activated alcohols

Severe irritant, potential sensitizer

Nitriles from amides, oximes

Difficult to remove urea by-products

Ketenes from carboxylic acids

144 Khapli, S.; Dey, S.; Mal, D. Journal of the Indian Institute of Science 2001, 81, 461–476. 145 Martin, J. C.; Arhart, R. J. Journal of the American Chemical Society 1971, 93, 4327–4329. 146 Brain, C. T.; Brunton, S. A. Synlett 2001, 382–384.

453

455

9 Reductions Sally Gut Ruggeri 1 , Stéphane Caron 1 , Pascal Dubé 2 , Nathan D. Ide 3 , Kristin E. Price Wiglesworth 4 , John A. Ragan 1 , and Shu Yu 1 1 Pfizer Worldwide R&D, Groton, CT, USA 2

MATSYS, Inc., Sterling, VA 20164, USA Abbvie Inc., North Chicago, IL, USA 4 Keller and Heckman LLP, Washington, DC, USA 3

CHAPTER MENU Introduction, 455 Reduction of C—C Bonds, 455 Reduction of C—N Bonds, 471 Reduction of C—O Bonds, 479 Reduction of C—S Bonds, 494 Reduction of C—X Bonds, 500 Reduction of Heteroatom–Heteroatom Bonds, 504

9.1 Introduction The reduction of functional groups is one of the fundamental reactions of organic chemistry. Many bond-forming transformations are carried out on highly oxidized molecules because they possess greater reactivity. For example, the deprotonation of a methylene α to a carbonyl is trivial compared to an analogous substrate where the carbonyl is reduced. After facilitating the desired chemistry, the oxidized functionality often needs to be reduced to a lower oxidation state to synthesize the compound of interest. Many methods have been developed to effect the reduction of a wide variety of functional groups; the two most commonly used are hydride-based reagents or conditions that employ hydrogen gas with a catalyst. The following chapter describes the most successfully utilized conditions and is arranged by the type of bond being reduced.

9.2 Reduction of C—C Bonds 9.2.1 9.2.1.1

Reduction of Alkynes Reduction of Alkynes to Alkenes

The reduction of alkynes to cis alkenes is most frequently achieved by hydrogenation using a poisoned palladium catalyst, such as a Lindlar catalyst (palladium on calcium carbonate, lead-poisoned). A Lindlar catalyst is specific to the reduction of alkynes to cis alkenes and is rarely used to mediate other hydrogenations. The efficiency of this transformation is often improved when pyridine or quinoline is used as an additive. Under such conditions, overreduction and migration of the multiple bond(s) are rare. The utility of this transformation is exemplified in Loreau’s synthesis of (9Z,12E)-[1-13C]-octadeca-9,12-dienoic acid1 ; note that chemoselectivity was achieved and no migration of the C—C double bond occurred. 1 Loreau, O.; Maret, A.; Poullain, D.; Chardigny, J. M.; Sebedio, J. L.; Beaufrere, B.; Noel, J. P. Chemistry and Physics of Lipids 2000, 106, 65–78. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

456

9 Reductions

H2, Lindlar 5

n-C5H11

OH

n-C5H11

quinoline EtOAc 97%

5

OH

While alkynes are efficiently reduced to cis alkenes by catalytic hydrogenation, they cannot be easily reduced to trans alkenes under similar conditions. Instead, hydride-based reducing agents are employed. A limitation to this methodology is poor chemoselectivity due to the reactivity of the hydride. This transformation is more often used early in the synthesis of simpler substrates, as illustrated in Novartis’ process for a dual MMP/TNF inhibitor.2 Red-Al

HO OBn

HO

OBn

THF, 0 °C 80%

Red-Al: sodium bis(2-methoxyethoxy)aluminum hydride

It should be pointed out that alkynyl ethers can also be reduced to cis or trans enol ethers using the method described earlier. For example, both (Z)- and (E)-1-methoxy-1-butene are successfully produced from 1-methoxy-1-butyne, as reported by Greene and coworkers.3 Me

Me LiAlH4 O

Me

94%

Me

9.2.1.2

Me

THF

Me

O Me

Me

Pd/BaSO4 pyridine H2 (1 atm)

O

90%

Me

Me

Me

Me

Reduction of Alkynes to Alkanes

The reduction of alkynes to alkanes is well precedented for both alkyl- and aryl-substituted alkynes and can be carried out routinely by catalytic hydrogenation in high yield. The reactions are often carried out in alcohols, particularly ethanol and methanol. The most frequently used catalysts involve carbon-supported palladium, which is a readily available (see Section 19.3.4.3). For most reactions, the addition of hydrogen is diffusion-controlled; sufficient hydrogen pressure (45 psi) as well as good agitation is required for fast conversion. For less reactive substrates, mild heating is sometimes required to effect reaction completion. The catalyst is generally safe to store and handle, but can ignite the vapor in the head space of a reaction vessel, particularly when methanol is used as solvent. Water-wet catalysts should be used whenever possible to reduce this potential. Another way to charge the catalyst is to make a toluene or 2-propanol slurry of the catalyst; the transfer of the slurry rarely causes any problems. The catalyst is easily removed (and potentially recycled as well) after the reaction by simple filtration through diatomaceous earth. The alcohol-wet catalyst can also ignite when left dry in air, and should be treated with water before disposal. Under these reaction conditions, a few other functional groups, such as olefins, benzyl ethers, and esters, are also reduced. The aforementioned principles are exemplified in Novartis’ practical synthesis of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-ethylquinazoline.4 OMe OMe Me N

OMe N

H2, 10% Pd/C

Me

i-PrOH, 40 °C 78% after crystallization

N OMe

N

2 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kuesters, E. Organic Process Research & Development 2002, 6, 652-659. 3 Kann, N.; Bernardes, V.; Greene, A. E. Organic Syntheses 1997, 74, 13–22. 4 Koenigsberger, K.; Chen, G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 2003, 7, 733-742.

9.2 Reduction of C—C Bonds

Another example is from the synthesis of a renin inhibitor, where the reduction was carried out selectively in the presence of an aryl bromide.5 CH3 Br

CH3

OCH3

Br

OCH3

H2, wet PtO2 TEA, toluene O

NH

9.2.2

O

91%

NH

Reduction of Alkenes

For the reduction of alkenes that are not in conjugation with an electron-withdrawing group(s), the most commonly used method is again hydrogenation, which will be discussed in this section. For conjugate reduction, see Section 9.2.4. 9.2.2.1

Reduction of Alkenes to Alkanes Without Facial Selectivity

The reduction of alkenes to alkanes can be achieved using heterogeneous catalysts under similar conditions to the hydrogenation of alkynes (vide supra). This is a technology that has been utilized extensively, especially when no stereocontrol is necessary. Suitable substrates include terminal alkenes, 1,2-disubstituted alkenes, and other alkenes with certain symmetry in the product. 1,2-Alkenes with aryl substituents are more challenging to reduce, as conjugation is lost in the process. In these cases, mild heating can increase the likelihood of reduction, as demonstrated by Novartis in their synthesis of methyl 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate.6 OMe

OMe H2, Pd/C EtOAc, 40 °C

OMe

OH CO2Me

OMe

OH CO2Me

Catalytic hydrogenation works equally well on enamides. In Pfizer’s synthesis of a thromboxane receptor,7 an enamide function was reduced using 5% Pd/C as catalyst. Note that the alkene in conjugation with the ethyl ester was also reduced in this example. For more on the reduction of α,β-unsaturated carbonyl compounds, see Section 9.2.4. F

F H2 (50 psi), 5% Pd/C EtOAc

O N O

CO2Et

92%

O N

CO2Et

O

In the reduction of 1,1-disubstitued alkenes where the two substituents are different, the product will be racemic. If the racemates can be easily resolved, this is a viable route to a chiral target (see Chapter 14). This strategy was used by Neurocrine Biosciences in the synthesis of NBI-75043.8 Note that a platinum catalyst was employed in this case, an approach often used for sulfur containing substrates, where poisoning of a palladium catalyst can be severe. 5 Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.; Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Organic Process Research & Development 2011, 15, 1138-1148. 6 Kucerovy, A.; Li, T.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 1997, 1, 287-293. 7 Waite, D. C.; Mason, C. P. Organic Process Research & Development 1998, 2, 116-120. 8 Gross, T. D.; Chou, S.; Bonneville, D.; Gross, R. S.; Wang, P.; Campopiano, O.; Ouellette, M. A.; Zook, S. E.; Reddy, J. P.; Moree, W. J.; Jovic, F.; Chopade, S. Organic Process Research & Development, ACS ASAP.

457

458

9 Reductions

NMe2

S

NMe2

S PtO2, EtOH Me

H2, 120 psi 85%

N

N

When multiple olefin moieties are present, it is possible in some substrates to effect selective reduction. One general rule is that the difficulty of hydrogenation increases as substitution increases, i.e. in terms of reactivity: terminal alkene > disubstituted olefin > trisubstituted olefin > tetrasubstituted olefin. The selectivity is amplified when a soluble palladium catalyst is used, such as Wilkinson’s catalyst [chlorotris(triphenylphosphine)rhodium(I)], as illustrated by Ireland in the following example; note that the enone function remains intact.9 O

Me

H2 (1 atm) (PPh3)3RhCl Me

O Me

Benzene

Me

90–94%

Me

For highly substituted olefins, especially tetrasubstituted olefins, heterogeneous hydrogenation is sometimes difficult, and undesired olefin isomerization can occur prior to hydrogenation, which will afford undesired product. For instance, in the synthesis of (R)-muscone, Firmenich scientists noticed that Pd/C was efficient for reduction of the olefin shown,10 but partial racemization occurred in the process due to olefin migration. On the other hand, when Crabtree’s catalyst [(tricyclohexylphosphine)(1,5-cyclooctadiene)(pyridine)iridium(I) hexafluorophosphate] was used,11 (R)-muscone formed cleanly. O

Me

O

Me

H2, [Ir(COD)(Py)(PCy3)][PF6] 98%

Electron-rich olefins can be reduced by hydrogenolysis, but often require forcing conditions.12 F3C

F3C H2, Pd/C, CH3OH

O

N CH3

9.2.2.2

50 °C, 200 psi 99%

O

N CH3

Reduction of Alkenes to Alkanes with Facial Selectivity

When 1,1-disubstituted, trisubstituted, and tetrasubstituted olefins are hydrogenated, the delivery of dihydrogen to different faces of the olefin have the potential to afford a pair of isomers. A high degree of facial selection can be achieved based on the presence of preexisting chiral centers in the substrate (diastereotopic), which makes one face easier to access than the other (substrate controlled, diastereoselective). In this regard, homogeneous hydrogenation using Crabtree’s catalyst is particular effective, as illustrated in Padwa’s total synthesis of (+)-stenine.13

9 Ireland, R. E.; Bey, P. Organic Syntheses 1973, 53, 63-65. 10 Branca, Q.; Fischli, A. Helvetica Chimica Acta 1977, 60, 925-944. 11 Saudan, L. A. Accounts of Chemical Research 2007, 40, 1309-1319. 12 Tang, W.; Patel, N. D.; Wei, X.; Byrne, D.; Chitroda, A.; Narayanan, B.; Sienkiewicz, A.; Nummy, L. J.; Sarvestani, M.; Ma, S.; Grinberg, N.; Lee, H.; Kim, S.; Li, Z.; Spinelli, E.; Yang, B.-S.; Yee, N.; Senanayake, C. H. Organic Process Research & Development 2013, 17, 382-389. 13 Ginn, J. D.; Padwa, A. Organic Letters 2002, 4, 1515-1517.

9.2 Reduction of C—C Bonds

MeO2C HO

MeO2C H N

O

H

HO

H2, [Ir(COD)(Py)(PCy3)][PF6] CH2Cl2

H

80%

H

N

O

When the substrate is achiral and facial selection is desired, a chiral reagent can be used (reagent-controlled, enantioselective). For instance, if the metal center is modified by a chiral ligand(s), the delivery of dihydrogen can occur preferentially at one face, giving high enantio excess in the product. This possibility was first demonstrated on a special family of olefins-enamides by Knowles in the now famous Monsanto process for the commercial manufacture of L-DOPA (Rh/CAMP), see Section 9.2.4.2. In the last 40 years, great improvements have been made in the efficiency of the catalysts for the hydrogenation of enamides, the most remarkable being the one made by Burk at DuPont, who introduced DuPhos in 1991. DuPhos is to date the most general ligand for the hydrogenation of enamides, often with >98% selectivity in the first attempt. Unfortunately, for the hydrogenation of other families of C—C double bonds, the outcomes are much less predictable. This brings about a sad, but true fact: there is no “best” catalyst for any given enantioselective reduction, in spite of claims otherwise. It is not typical to just pick a chiral catalyst/ligand off the shelf and get good results on the first try; for each specific substrate, some screening of reaction conditions will likely be required, including metal, ligand, additive, solvent, temperature, and hydrogen pressure among others. In addition, screening of known ligands may not provide satisfactory results. Under such circumstances, one needs to systematically synthesize chiral ligands and study the ligand structure–activity relationship, using empirical results to guide the design of more efficient ligands. Last but not least, homogeneous hydrogenations often require elevated temperature and much higher hydrogen pressures (20–50 bar are commonplace), an aspect that should be considered before investing a large amount of resources. In part for these reasons, there are fewer successful homogeneous hydrogenation precedents, and most of them are reported by industry. However, some trends have been observed since 2000 that warrant further discussion. Most of the successfully scaled up homogeneous hydrogenations were reported on olefins with Lewis basic heteroatom(s) in the vicinity, such as allyl alcohols or allyl amines. These heteroatoms may serve as ligands (anchoring points) in the transition state that brings the olefin, hydride, and chiral ligands together on the metal center. Such tight transition states are required for high-level facial differentiation. The classic example of a ruthenium-catalyzed enantioselective hydrogenation of allylic alcohols is from Noyori’s work on (S)-(−)-citronellol.14 Note that the distal trisubstituted olefin is intact, indicating again the role of coordination of the allylic hydroxyl group to the catalyst.

PPh 2 PPh 2 Me Me

Me

Me OH

Ru(OAc)2 H2, MeOH/H2O

Me

Me OH

Merck has reported15 the rhodium-catalyzed hydrogenation of a trisubstituted olefin with an amide function at the allylic position. Despite extensive screening of reaction conditions, the maximum ee achieved was only 88%, demonstrating the challenge of enantioselective hydrogenation. The chemistry has been scaled up on pilot plant scale.

14 Takaya, H.; Ohta, T.; Inoue, S.-i.; Tokunaga, M.; Kitamura, M.; Noyori, R. Organic Syntheses 1995, 72, 74-85. 15 Limanto, J.; Shultz, C. S.; Dorner, B.; Desmond, R. A.; Devine, P. N.; Krska, S. W. The Journal of Organic Chemistry 2008, 73, 1639-1642.

459

460

9 Reductions

Me

Me

Me

NHAc Me

Cl

Ph 2P

Me

P

Fe

Me

Me

Me

Me

Me

Me

Cl

[Rh(COD)2][BF4] 500 psi H2 THF, 40 °C

N Boc

NHAc

N Boc 88% ee

98.5% yield

The most difficult class of substrates for enantioselective hydrogenation is an alkene without proximal heteroatoms that can bind the catalyst. In this arena, Pfaltz’s P,N ligand-based iridium catalyst is one of the better systems to try. Although these transformations have not been demonstrated on scale, they hold the promise to become powerful tools in the future. At least on lab scale, this class of catalyst has been reported to catalyze the hydrogenation of trisubstituted vinyl ethers, trisubstituted allylic alcohols, and trisubstituted alkyl/alkyl olefins.16 In the latter case, remarkable chemoselectivity was achieved as well. +

Me Me

Me

O O N o-tol P Ir o-tol COD t-Bu

Me

BArF–

Me

Me H

Me

Me H

Me

25 bar H2 CH2Cl2, rt, 2 h OMe Me

Me

OMe Me

90%, single diastereomer

BArF– = tetrakis[3, 5-bis(trifluoromethyl)phenyl]borate Ph O Cy 2P

O

Ph

N Ir COD

Me

+ BAr F–

O

50 bar H 2

O

CH2Cl 2, rt, 2 h >99% conv., >94% ee

Pfaltz reported that the counterion is critical for the performance of the catalyst. Considering its importance, a few extra remarks are warranted. Pfaltz and coworkers observed that although hydrogenation is fast at the initial stage for a number of iridium catalysts, the reaction slows down rapidly as the reaction progresses, probably due to product inhibition of the catalyst. Catalyst deactivation is markedly reduced when a non-coordinating counterion, such as

16 Bell, S.; Wuestenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz, A. Science 2006, 311, 642-644.

9.2 Reduction of C—C Bonds

tetraarylborate, is employed. Caution should be taken not to introduce extra counterion that could potentially poison the catalyst. This catalytic system tolerates diverse substitution patterns and the presence of heteroatoms in the substrates. +

Me Me O O lot-o P Ir N lot-o COD t-Bu

BAr F–

Me S

S

50 bar H2

Me

*

Me

Me

CH2Cl2, rt, 2 h 100% conv., 98% ee

Reduction of unactivated tetrasubstituted olefins is the most challenging hydrogenation. In this field, iridium is again the metal that has performed the best. Earlier pioneering work by Crabtree, who showed that his reagent can catalyze hydrogenation of tetrasubstituted olefins, laid the foundation for asymmetric hydrogenation. Pfaltz’s P,N-ligands are the most efficient.17 Note that the hydrogenation of tetrasubstituted olefins generates two adjacent chiral centers in a single step. [Ir(L)(COD) ] + BAr F– 50 bar H2 CH2Cl2, rt

H H

>99% conversion 94% ee O L=

PPh 2 N Me

9.2.3

Me

Reduction of Aromatic Rings and Heterocycles

The reduction of aromatic rings generally requires forceful conditions, as aromaticity is lost in the process. For this reason, benzene rings are difficult to reduce, while partial reduction of naphthalene rings is easier than benzene rings. Similar trends have been observed for five-, and six-membered heterocycles and their benzo-fused counter parts. There are two general methods for aromatic ring reduction: dissolving metal reduction (Birch reduction) and hydrogenation. The former is an older technology that requires little experimentation (typical conditions are lithium or sodium in refluxing liquid ammonia). Since many functional groups are reduced under these conditions, the utility of this transformation is limited. Hydrogenation is more amenable to a broader class of substrates and can be enantioselective. Screening of the catalyst and ligands is to be expected for this type of substrate and the required hydrogen pressure is often high. 9.2.3.1

Reduction of Benzene and Naphthalene Rings

The classic method to partially reduce benzene or naphthalene rings is a dissolving metal reduction, commonly known as a Birch reduction. This method works for both electron-rich18 and electron-deficient19 benzene rings to yield 17 Roseblade, S. J.; Pfaltz, A. Accounts of Chemical Research 2007, 40, 1402-1411. 18 Paquette, L. A.; Barrett, J. H. Organic Syntheses 1969, 49, 62-65. 19 Kuehne, M. E.; Lambert, B. L. Organic Syntheses 1963, 43, 22-24.

461

462

9 Reductions

dihydrobenzene with isolated double bonds as justified by the principle of least motion.20 Alkyl and alkoxy benzenes yield 2,5-dihydro products; benzoates afford 1,4-dihydro products.21 The yields are normally high. Me Me

Me

Na, NH3 Ether, –33 °C

Me

77–92%

CO2H

CO2H

Na, NH3 Ether, –33 °C 89–95%

The benzene ring can also be reduced to cyclohexane by hydrogenation under forcing conditions.22 Hoffmann-La Roche reported an efficient synthesis of oseltamivir phosphate (Tamiflu), where they fully reduced a pentasubstituted benzene ring.23 Among the metal catalysts investigated, platinum and nickel were inactive, while rhodium and ruthenium both gave desired product. The best conditions were Ru/Al2 O3 in ethyl acetate at 60 ∘ C, but 100 bar H2 was required to effect the desired transformation. The high level of stereocontrol is very impressive. Me

Me OMe

O

OMe CO2Me

Me MeO

H2 (100 bar) 5% Ru–Alox EtOAc, 60 °C

CO2Me

CO2Me

O Me MeO

CO2Me

82%

Novartis reported a reduction of a naphthalene moiety using lithium in butanol at 95 ∘ C to afford 1,4-dihydronaphthalene.24 The reduction occurs at the more substituted side of the naphthalene. The transformation was scaled up to 8.2 kg without incident. The fact that the naphthalene ring was only partially reduced, and the benzene ring is intact in the product, once again demonstrates the striking difference in the reactivity of these ring systems. OMe

OMe

O OH O Me

9.2.3.2

NH2

O

Li/BuOH 95 °C

OMe OLi

O Me

NH2

O

HCl (aq)

OH N+ Cl – H

Reduction of Pyridines and Quinolines

Compared to a phenyl ring, a pyridine ring is easier to reduce by hydrogenation (not in absolute terms, but relative to all-carbon arenes).25 This is especially true when the nitrogen atom on the substrate is activated with an alkyl or acyl group. Pfizer reported the synthesis of cis-N-protected-3-methylamino-4-methylpiperidine via the hydrogenation of the corresponding pyridine using a 5% Rh/C catalyst.26 Screening of solvents revealed that acetic acid is optimal, likely because the pyridine ring is hydrogenated more easily when protonated. Under such conditions, only a moderate 70–80 psi hydrogen pressure is required. The chemistry has been successfully demonstrated on >50 kg scale.

20 Hine, J. Advances in Physical Organic Chemistry 1977, 15, 1-61. 21 Birch, A. J.; Hinde, A. L.; Radom, L. Journal of the American Chemical Society 1980, 102, 3370-3376. 22 Rylander, P. Catalytic Hydrogenation in Organic Syntheses; Academic Press: New York, N. Y., 1979. 23 Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. The Journal of Organic Chemistry 2008, 73, 4895-4902. 24 Baenziger, M.; Cercus, J.; Stampfer, W.; Sunay, U. Organic Process Research & Development 2000, 4, 460-466. 25 Freifelder, M. Advan. Catalysis 1963, 14, 203-253. 26 Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.; Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.; White, T. D. Organic Process Research & Development 2005, 9, 51-56.

9.2 Reduction of C—C Bonds

Me N

HN O

Me

H2 (70–80 psi) Rh/C (type 23)

OMe

N

HN

HOAc, 72–78 °C

O

75%

H

OMe

For partial reduction of pyridines, the classical approach is to treat a pyridinium salt with sodium borohydride. This approach was also employed by Pfizer scientists in the large-scale synthesis of cis-N-benzyl-3-methylamino-4methylpiperidine.27 Me

Me

NaBH4

N+

N

EtOH, 15 °C

Cl –

73%

Benzo-fused heterocycles are easier to hydrogenate, as only part of the aromaticity is lost during the process. For this family of compounds, even enantioselective hydrogenation has been achieved on a reasonable scale. Often times, the strategy is to simultaneously activate the catalyst (by addition of iodine), as well as the substrate (by addition of acid). Iridium-based catalysts are more successful than others, in part because Ir(I) can be activated with iodine, presumably due to the oxidation of Ir(I) to more active Ir(III). Although this transformation has only been demonstrated on lab scale, as illustrated in the synthesis of (−)-angustrureine,28 its application on large scale is expected in the future.

MeO MeO

PPh2 PPh2

[Ir(COD)Cl ] 2/I2 N

600 psi H2

Me

N H

>94%, 94% ee

Me

In addition to hydrogen gas, Hantzsch esters have also been employed as the hydrogen source for the enantioselective reduction of quinolines, in a fashion similar to the Meerwein–Ponndorf–Verley (MPV) reaction (see Section 9.4.2.2). The advantage of using Hantzsch esters as the hydrogen source is that no special equipment is required. The transformation below provides yet another example for the empirical rules of arene reduction: partial reduction is easier than full reduction, and pyridine rings are easier to reduce than phenyl rings.29 O PPh 2 PPh 2

O O

N

OMe

O [Ir(COD)Cl ] 2/I2 MeO2C

CO2Me

OMe Me

N H

N H

OMe OMe

Me

92%, 88% ee

27 Ripin, D. H. B.; Abele, S.; Cai, W.; Blumenkopf, T.; Casavant, J. M.; Doty, J. L.; Flanagan, M.; Koecher, C.; Laue, K. W.; McCarthy, K.; Meltz, C.; Munchhoff, M.; Pouwer, K.; Shah, B.; Sun, J.; Teixeira, J.; Vries, T.; Whipple, D. A.; Wilcox, G. Organic Process Research & Development 2003, 7, 115-120. 28 Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Journal of the American Chemical Society 2011, 133, 9878-9891. 29 Wang, D.-W.; Zeng, W.; Zhou, Y.-G. Tetrahedron: Asymmetry 2007, 18, 1103-1107.

463

464

9 Reductions

9.2.3.3

Reduction of Pyrroles and Indoles

Pyrroles can be partially reduced via dissolving metal reduction. The transformation works well on those pyrroles that bear electron-withdrawing groups, as described in the following example by Cowley,30 which provided the trans isomer as the major product. The authors also demonstrated the scalability of the reaction and the utility of the partially reduced pyrrole in the total synthesis of hyacinthacine A1 and 1-epiaustraline.31 Boc N CO2Me

MeO2C

Li/NH3

MeO2C

NH4Cl

Boc N CO2Me

Pyrroles are not normally reduced by hydrogenation, as the pyrrolidine products typically poison the catalyst.32 However, there are examples where it has been successfully carried out, as demonstrated by workers from Pfizer.33

CH3 N

O O

CH3 CH3

(i) H2, Rh/C, EtOH 70 °C, 100 psi (ii) fumaric acid, CH3OH EtOAc

CH3 N

O O HO2C

95%

CH3 CH3 CO2H

The pyrrole moiety of an indole, on the other hand, can be easily reduced with borohydride, hydrogen, or silanes. BMS reported that Et3 SiH/TFA (trifluoroacetic acid) is particularly efficient in their process for a 5HT2C receptor agonist.34 The authors did not report the yield of the transformation, as the crude product showed satisfactory purity and was used directly in the next step, but the chemistry was demonstrated on 15 kg scale. H N

H

H N

(i) Et3SiH/TFA N O

9.2.3.4

N H

(ii) Resolution O

Reduction of Furans

Pfaltz has reported35 the enantioselective hydrogenation of furans with respectable chiral induction. The potential and utility of this transformation has yet to be explored.

30 Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C.; Cowley, A. Organic Letters 2003, 5, 999-1002. 31 Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. The Journal of Organic Chemistry 2005, 70, 7297-7304. 32 Hegedus, L.; Mathe, T. Applied Catalysis A 2002, 226, 319-322. 33 Ashcroft, C. P.; Hellier, P.; Pettman, A.; Watkinson, S. Organic Process Research & Development 2011, 15, 98-103. 34 Hobson, L. A.; Nugent, W. A.; Anderson, S. R.; Deshmukh, S. S.; Haley, J. J., III; Liu, P.; Magnus, N. A.; Sheeran, P.; Sherbine, J. P.; Stone, B. R. P.; Zhu, J. Organic Process Research & Development 2007, 11, 985-995. 35 Saiser, S.; Smidt, S. P.; Pfaltz, A. Angewandte Chemie, International Edition in English 2006, 45, 5194-5197.

9.2 Reduction of C—C Bonds

+ BF 4–

O N t-Bu P Ir t-Bu COD

O

O

CH2Cl2, 50 bar H2 40 °C, 24 h

*

84% conversion, 78% ee + O t-Bu P Ir N t-Bu COD

BF 4–

OEt

O

CH2Cl2, 100 bar H2 40 °C, 24 h

O

O

*

OEt O

>99% conversion, 93% ee

9.2.4

Conjugate Reductions

This section will focus on reductions of alkenes and alkynes that are conjugated to an electron withdrawing group such as a ketone or ester. 9.2.4.1

Reduction of Conjugated Alkynes

Reduction of conjugated alkynes can be challenging in terms of chemoselectivity and avoiding over-reduction to the alkane, but with the proper choice of catalyst and reaction conditions, useful levels of selectivity can be realized. For conversion to the Z-olefin, conjugated alkynes can be hydrogenated over a poisoned catalyst, also known as a Lindlar reduction. The poisoned catalyst is necessary to prevent over-reduction to the saturated alkane. An example of reduction to a Z-enoate is shown below.36 MeO2C Ts N Boc

H2 Pd/CaCO3/Pb PhCH3 99%

CO2Me Ts N Boc

Reduction to an E-olefin can be achieved with Red-Al, as shown in the example below.37,38 This reaction requires an adjacent free hydroxyl and is not specific to conjugated alkynes.39 Remarkably, the ester and epoxide functionalities are not affected by the reaction conditions. 36 Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.; Garg, N. K.; Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.; Ng, F. W.; Overman, L. E. Journal of the American Chemical Society 2007, 129, 11987-12002. 37 Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Czaicki, N. L.; Koide, K. Journal of the American Chemical Society 2007, 129, 2648-2659. 38 Meta, C. T.; Koide, K. Organic Letters 2004, 6, 1785-1787. 39 Jones, T. K.; Denmark, S. E. Organic Syntheses 1986, 64, 182-188.

465

466

9 Reductions

Red-Al THF, –72 °C

OH Me

81%

O

MeO2C

OH MeO2C

Me O

Red-Al = NaAlH2(OCH2CH2OMe)2

If full reduction to the saturated ester is desired, this can be readily affected with standard hydrogenation catalysts. An example is shown below.40

O

O

CO2Me

H2 Pd/C

Me

9.2.4.2

O

EtOAc

O

Me

97%

CO2Me

Reduction of 𝛂,𝛃-Unsaturated Acids and Derivatives

Olefins conjugated with esters, amides, and nitriles can frequently be selectively reduced by metal-catalyzed hydrogenation. Two examples are shown below for an N-acyloxazolidinone41 and an ester-nitrile.42 O

O

(t-BuO)2

O P

N

O

82%

Ph

CN CO2Et OMe OMe

(t-BuO)2

O P

N

O

Ph

CN

H2, Pt/C EtOH, THF 79%

O

O

H2 Pd black EtOH

CO2Et OMe OMe

An example in which a pyridine ring is simultaneously hydrogenated over a Rh/Al2 O3 catalyst is shown below.43 CO2H

N

CO2H

H2 Rh/Al2O3 aq NH3 100%

N H

The reduction may be carried out asymmetrically using chiral ligands, as shown by workers from Hoffmann-La Roche.44

40 White, J. D.; Somers, T. C.; Reddy, G. N. The Journal of Organic Chemistry 1992, 57, 4991-4998. 41 Burke, T. R.; Liu, D.-G.; Gao, Y. The Journal of Organic Chemistry 2000, 65, 6288-6291. 42 Baenziger, M.; Kuesters, E.; La Vecchia, L.; Marterer, W.; Nozulak, J. Organic Process Research & Development 2003, 7, 904-912. 43 Cohen, J. H.; Bos, M. E.; Cesco-Cancian, S.; Harris, B. D.; Hortenstine, J. T.; Justus, M.; Maryanoff, C. A.; Mills, J.; Muller, S.; Roessler, A.; Scott, L.; Sorgi, K. L.; Villani, F. J., Jr.; Webster, R. R. H.; Weh, C. Organic Process Research & Development 2003, 7, 866-872. 44 Adam, J.-M.; Foricher, J.; Hanlon, S.; Lohri, B.; Moine, G.; Schmid, R.; Stahr, H.; Weber, M.; Wirz, B.; Zutter, U. Organic Process Research & Development 2011, 15, 515-526.

9.2 Reduction of C—C Bonds

O

O H2 (15 bar), CH3OH

O

O

[Ru(OAc)2((R)-3,5-t-Bu-MeOBIPHEP)]

F

F 96–97% ee

92–93% t-Bu

H3CO H3CO

P

t-Bu

P

t-Bu t-Bu

2

2

A particularly useful subset of this reaction class is the asymmetric hydrogenation of α,β-unsaturated amides and esters containing an α- or β-amino (or N-acyl) moiety. While working at Monsanto in the 1970s, Knowles pioneered this class of reaction.45,46 This chemistry plays an important role in the production of many fine chemicals and pharmaceuticals. Noyori has also been a major contributor in this area, and developed the widely used BINAP ligand.47 Numerous other chiral disphosphine ligands have also been developed. Feringa has developed a BINOL-derived monodentate ligand (MonoPhos) which is also useful in the asymmetric hydrogenation of enamides.48 This ligand is particularly attractive because of its low cost. CO2H NHAc

L*, H2 Rh(COD)2BF4 EtOAc

CO2H NHAc

>99% conversion 97% ee

L* = MonoPhos: O P NMe2 O

A useful example from Burk’s group is shown below, using the commercially available Et-DuPHOS ligand.49 CO2Me TBSO

NHAc

H2, MeOH

NHAc

TBSO

96% L* = (R,R)-Et-DuPHOS:

CO2Me

[(COD)Rh(L*)]OTf

>98% ee

Et

Et P

P Et Et

45 Knowles, W. S. Accounts of Chemical Research 1983, 16, 106-112. 46 Knowles, W. S.; Noyori, R. Accounts of Chemical Research 2007, 40, 1238-1239. 47 Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. Journal of the American Chemical Society 1980, 102, 7932-7934. 48 van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Journal of the American Chemical Society 2000, 122, 11539-11540. 49 Burk, M. J.; Allen, J. G.; Kiesman, W. F. Journal of the American Chemical Society 1998, 120, 657-663.

467

468

9 Reductions

An example from the synthesis of sitagliptin phosphate is shown below.50 The chiral phosphine ligand JOSIPHOS was used in this reaction. A dramatic pH dependence for this substrate (possibly related to the presence of the unprotected NH2 moiety) was noted, and residual ammonium chloride was identified as serving the role of enhancing both reaction rate and enantioselectivity. JOSIPHOS [(COD)RhCl]2 H2, MeOH NH4Cl

F F

NH2 O N

N F

N

N

F

F

NH2 O

95%

CF3

N

N F

N

N

CF3

96% ee Me JOSIPHOS = Fe

P(t-Bu)2 PPh2

As the above examples demonstrate, a variety of chiral phosphine ligands have been used for these asymmetric hydrogenations, and identification of the optimal ligand will frequently be substrate specific. An interesting reduction of a β-amino enone was developed at Abbott for the synthesis of ritonavir. Unlike the previous examples, this reduction utilizes an achiral reagent, and the resulting diastereoselectivity arises due to induction from the pre-existing stereocenter in the substrate. With careful choice of acid and solvent, useful levels of diastereoselectivity were realized on 30 kg scale (83 : 6 : 4 : 2).51 The two-stage reduction is necessary to optimize diastereoselectivity; the first charge of reagent reduces the enamine, and the subsequent charge reduces the ketone.

O

NH2 Ph

Ph NBn2

NaBH 4 MeSO3H DME i-PrOH; N(CH2CH2OH)3 NaBH 4 DMAc

OH

NH2 Ph

Ph NBn2

83 : 6 : 4 : 2 stereoselectivity (only major isomer shown)

>98% conversion

Hydrogenolysis conditions may also be employed, as demonstrated in the example below, in which a chiral auxiliary was used to induce asymmetry in the reduction.52 The minor isomers formed in the reaction were purged in the salt formation. EtO2C O

H N

CH3 Ph

O

(i) H2, Pt/C, EtOH, HOAc (ii) p-TsOH, 2-MeTHF 70%

EtO2C O

p-TsOH H N

CH3 Ph

O 99.7% de

50 Clausen, A. M.; Dziadul, B.; Cappuccio, K. L.; Kaba, M.; Starbuck, C.; Hsiao, Y.; Dowling, T. M. Organic Process Research & Development 2006, 10, 723-726. 51 Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.; Fitzgerald, M.; Hannick, S. M.; Kerdesky, F. A. J.; Menzia, J. A.; Parekh, S. I.; Robbins, T. A.; Scarpetti, D.; Tien, J.-H. J. Organic Process Research & Development 1999, 3, 94-100. 52 Deerberg, J.; Prasad, S. J.; Sfouggatakis, C.; Eastgate, M. D.; Fan, Y.; Chidambaram, R.; Sharma, P.; Li, L.; Schild, R.; Müslehiddino˘glu, J.; Chung, H.-J.; Leung, S.; Rosso, V. Organic Process Research & Development 2016, 20, 1949-1966.

9.2 Reduction of C—C Bonds

A cobalt-catalyzed reduction of an α,β-unsaturated thiazolidine-2,4-dione is shown below. A series of Design of Experiments (DOE) studies led to the optimal conditions for this reduction.53 NaBH4 aq NaOH MeOH CoCl2–DMG

O

Et O

N

N H

S

N

83%

O

O

Et O

S

N H O

Me

DMG (dimethylglyoxime) = HO

N

N

OH

Me

9.2.4.3

Reduction of Enones

Conjugated enones have most frequently been reduced by transition metal-catalyzed hydrogenation or by dissolving metal reduction. The stereochemical outcome can be different for the two methods, with the former method typically delivering hydrogen from the less hindered face of the olefin, while the latter method delivers the more thermodynamically stable isomer (via protonation of the intermediate radical anion). Examples of both a hydrogenation54 and a dissolving metal reduction55 are given below; they exemplify the divergent stereochemical outcomes described above. Me

X2

O

Me

H2, Pd/C 95% EtOH 90%

O

X2

H

X2 = OCH2CH2O

Me Me O

Me

Me

Li, N H3, t-BuOH Et 2O, –78 °C; NH4Cl 80%

Me O

Me

H

Asymmetric enone reductions have been reported by Buchwald,56,57 Lipshutz,58,59 Mashima,60 and others. An interesting dynamic kinetic resolution from Buchwald is shown below, which utilizes a copper-catalyzed hydrosilylation with polymethylhydrosiloxane (PMHS).61

53 Les, A.; Pucko, W.; Szelejewski, W. Organic Process Research & Development 2004, 8, 157-162. 54 McMurry, J. E. Journal of the American Chemical Society 1968, 90, 6821-6825. 55 Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.; Blackwell, C. M.; Anderson, L. G. Journal of the American Chemical Society 1992, 114, 7375-7387. 56 Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. Journal of the American Chemical Society 2000, 122, 6797-6798. 57 Jurkauskas, V.; Buchwald Stephen, L. Journal of the American Chemical Society 2002, 124, 2892-2893. 58 Lipshutz, B. H.; Frieman, B. A. Angewandte Chemie International Edition in English 2005, 44, 6345-6348. 59 Lipshutz, B. H.; Frieman, B. A.; Tomaso Jr., A. E. Angewandte Chemie International Edition in English 2006, 45, 1259-1264. 60 Ohshima, T.; Tadaoka, H.; Hori, K.; Sayo, N.; Mashima, K. Chemistry-A European Journal 2008, 14, 2060-2066. 61 Jurkauskas, V.; Buchwald Stephen, L. Journal of the American Chemical Society 2002, 124, 2892-2893.

469

470

9 Reductions

O

O

CuCl/(S)-p-tol-BINAP t-BuONa, t-BuOH

t-BuO2C

PMHS, PhCH3; Bu4NF

Ph

t-BuO2C

Ph

90 : 10 diastereoselectivity 93% ee

91%

Lipshutz has also developed a copper-catalyzed hydrosilylation catalyst with wide substrate generality, reducing ketones, imines, and α,β-unsaturated esters in addition to enones. An enone reduction is shown below.62 Cu/C (2.5 mol%) PhONa (10 mol%) DTBM–segphos (0.1 mol%)

O

Me

Me

PMHS PhCH3

Me

O

Me

Me

Me

70%

92% ee

DTBM–segphos = O O O

PAr 2 PAr 2

Ar =

t-Bu OMe

O

t-Bu

An asymmetric hydrogenation using a Ru-Me-DuPHOS catalyst was used by workers at Firmenich to generate (+)-cis-methyl dihydrojasmonate,63 the active component in the perfume ingredient methyl dihydrojasmonate. Interestingly, this perfume agent was originally used as a racemate containing a 90 : 10 mixture of trans:cis isomers, such that the commercial mixture contained just 5% of the active olfactory component. Ru cat * (–)–Me–DuPHOS HBF4·Et2O BF3·Et2O (1–3 mol%)

CO2Me

Me

O

CO2Me

Me

O

MTBE, H2

>99 : 1 diastereoselectivity 88% ee Ru cat* = Ru(η4-1,5-COD)(η3-2-propenyl)2 =

(–)-Me-DuPHOS = Me P

Ru P

Me Me

Me

62 Lipshutz, B. H.; Frieman, B. A.; Tomaso Jr., A. E. Angewandte Chemie International Edition in English 2006, 45, 1259-1264. 63 Dobbs, D. A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch, V.; Lenoir, J.-Y.; Genet, J.-P.; Wiles, J.; Bergens, S. H. Angewandte Chemie, International Edition in English 2000, 39, 1992-1995.

9.3 Reduction of C—N Bonds

9.3 Reduction of C—N Bonds This section will review practical methods for the reduction of various carbon–nitrogen bonds. These include popular reactions such as the cleavage of benzyl amines and reductive amination of carbonyl species. With regard to the latter, emphasis will be on the reduction itself as opposed to the overall transformation from the carbonyl species (see Section 2.7.1). 9.3.1

Reduction of Nitriles to Imines or Aldehydes

The chemoselective reduction of nitriles to imines, which often yields aldehydes after hydrolysis, is traditionally performed using diisobutylaluminum hydride (DIBAL-H) as the reducing agent.64 CN N

O

CHO DIBAL-H toluene, 0 °C

N

O

97% N N O

N N O

Substrates sensitive to hydride can be reduced under hydrogenation conditions; palladium on carbon or Raney nickel are the most common metals for this transformation. Performing the reaction in the presence of an acid additive and water enables a facile reduction to the primary imine, which is then kinetically suited for hydrolysis, thus avoiding formation of the undesired primary amine. Bell and coworkers have demonstrated this method in the reduction of an aminocyano pyrimidine.65 NH2 CN

N

Pd/C, H2 aq TFA

NH2

64%

N

CHO

N N

Raney nickel is also a common metal for this type of catalysis, and alternative sources of hydrogen can be used. Moss et al. disclosed an example of formic acid serving a dual purpose: hydrogen precursor and acid additive.66 CN CO2Me

Ra-Ni, HCO2H

CHO CO2Me

75 °C 69%

9.3.2

Reduction of Nitriles to Primary Amines

The reduction of nitriles to primary amines can be accomplished with various borohydrides. In situ-generated sodium trifluoroacetoxyborohydride was used by Denyer to effect the chemoselective reduction of a benzylnitrile in the presence of a nitro group.67 O2N EtO2CHN

CN

NaBH4, TFA THF

O2N

NH2

EtO2CHN

73%

64 Ruggeri, S. G.; Bill, D. R.; Bourassa, D. E.; Castaldi, M. J.; Houck, T. L.; Ripin, D. H. B.; Wei, L.; Weston, N. Organic Process Research & Development 2003, 7, 1043-1047. 65 Bell, T. W.; Beckles, D. L.; Debetta, M.; Glover, B. R.; Hou, Z.; Hung, K.-Y.; Khasanov, A. B. Organic Preparations and Procedures International 2002, 34, 321-325. 66 Moss, N.; Ferland, J.-M.; Goulet, S.; Guse, I.; Malenfant, E.; Plamondon, L.; Plante, R.; Deziel, R. Synthesis 1997, 32-34. 67 Denyer, C. V.; Bunyan, H.; Loakes, D. M.; Tucker, J.; Gillam, J. Tetrahedron 1995, 51, 5057-5066.

471

472

9 Reductions

Merck scientists have used zinc borohydride to fully reduce an ester and a nitrile. The reducing agent was preformed from zinc chloride and lithium borohydride.68 ZnCl 2, LiBH4 toluene, THF

CN Cl

CO2Me

NH2 OH

Cl

70%

Lithium aluminum hydride (LAH) may also be a practical way to reduce a nitrile, as demonstrated by Crawford and coworkers.69 S

S (i) LiAlH4, MTBE

HN N

(ii) ArCO2H, EDCI HOBt, CH2Cl2

CN CH3

HN N

H3C H N

N

O

CH3

CH3

72–85%

Cl

Raney nickel has commonly been used for the reduction of nitriles. The use of ammonia was found to be essential for high conversion on a larger scale.70,71 O

OMe

9.3.3 9.3.3.1

O

Ra-Ni, H2 MeOH, NH3 N

CN

OMe

93%

NH2

N

Reduction of Imines or Imine Derivatives Achiral Reductions

Metal hydrides are the reagents of choice for the reduction of imine derivatives. Among these, sodium triacetoxyborohydride (STAB) is one of the most commonly employed reagents to effect reductive aminations due to its mildness and stability over a wide pH range. A review of its chemical properties and synthetic scope, including large-scale applications, has been published,72 and a representative example is presented.73 Me N N

Me

Me

Me

N

CO2t-Bu

+ NH

Me NaBH(OAc) 3 HOAc, C H2Cl 2 92–99%

OHC F

N N

Me

Me

Me CO2t-Bu

N

N

F

68 Nelson, T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.; Mitten, J. V.; Weaver, D. G.; Moore, J. C.; Kim, J. M.; Boyd, R.; Kim, P.-Y.; Gbewonyo, K.; Brower, M.; Sturr, M.; McLaughlin, K.; McMasters, D. R.; Kress, M. H.; McNamara, J. M.; Dolling, U. H. The Journal of Organic Chemistry 2004, 69, 3620-3627. 69 Crawford, J. B.; Chen, G.; Carpenter, B.; Wilson, T.; Ji, J.; Skerlj, R. T.; Bridger, G. J. Organic Process Research & Development 2012, 16, 109-116. 70 Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King, S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.; Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang, W. Organic Process Research & Development 2004, 8, 897-902. 71 Watson, T. J.; Ayers, T. A.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.; Horgan, S.; Carey, J. P. Organic Process Research & Development 2003, 7, 521-532. 72 Abdel-Magid, A. F.; Mehrman, S. J. Organic Process Research & Development 2006, 10, 971-1031. 73 Conlon, D. A.; Jensen, M. S.; Palucki, M.; Yasuda, N.; Um, J. M.; Yang, C.; Hartner, F. W.; Tsay, F.-R.; Hsiao, Y.; Pye, P.; Rivera, N. R.; Hughes, D. L. Chirality 2005, 17, S149-S158.

9.3 Reduction of C—N Bonds

Borane–amine complexes are often used as alternatives to borohydrides. These compounds are often solids, facilitating handling and storage. Borane can be released using acids or other protic additives. Connolly has reported the reduction of a nitro-containing imine using tert-butylamine-borane activated with methanesulfonic acid.74 N

t-BuNH2·BH3 MsOH, CH2Cl2

Me

87%

NO2

Me

N H NO2

In the absence of sensitive functional groups, LAH can be used to reduce carbon–nitrogen bonds. In the following example, a reductive amination is carried out in very high yield using hydroxylamine as the nitrogen source. The LAH reduces both the double bond and the N—O bond.75 CHO

(i) NH2OH·HCl

NH2

(ii) LiAlH4 96%

Metal-catalyzed hydrogenations of imines have been extensively utilized, with impressive selectivity and tolerance of a wide variety of functional groups. Palladium on carbon under an atmosphere of hydrogen is the standard system for such reductions.76,77 CF3 Me

CF3

O

O

CF3 (i) Pd/C, H2 EtOH (ii) TsOH·H2O 94%

N

Me

CF3

O

O N H •TsOH

F

F

In cases where chemoselectivity is hard to obtain by other methods, rhodium may be a useful alternative. Its use can also alleviate issues arising from catalyst deactivation through amine coordination or reduction of carbon–halide bonds.78 HO

N

EtO2C Cl

9.3.3.2

N

NH2

N

CO2Me

Rh/C, H2 NH4OAc, EtOH 70%

NH2 EtO2C Cl

N

NH2

N

CO2Me

Substrate Control in Stereoselective Reductions

Imines bearing chiral non-racemic substituents can be reduced with high stereoselectivity by various methods. Additionally, various temporary chiral auxiliaries have been developed to access enantioenriched primary amines. Colyer and coworkers,79 along with the group of Ellman,80 have studied the reagent-controlled reduction of sulfinyl imines. The 74 Connolly, T. J.; Constantinescu, A.; Lane, T. S.; Matchett, M.; McGarry, P.; Paperna, M. Organic Process Research & Development 2005, 9, 837-842. 75 Breining, S. R.; Genus, J. F.; Mitchener, J. P.; Cuthbertson, T. J.; Heemstra, R.; Melvin, M. S.; Dull, G. M.; Yohannes, D. Organic Process Research & Development 2013, 17, 413-421. 76 Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. The Journal of Organic Chemistry 2002, 67, 6743-6747. 77 Brands, K. M. J.; Krska, S. W.; Rosner, T.; Conrad, K. M.; Corley, E. G.; Kaba, M.; Larsen, R. D.; Reamer, R. A.; Sun, Y.; Tsay, F.-R. Organic Process Research & Development 2006, 10, 109-117. 78 Thompson, W. J.; Jones, J. H.; Lyle, P. A.; Thies, J. E. The Journal of Organic Chemistry 1988, 53, 2052-2055. 79 Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul, M. M. The Journal of Organic Chemistry 2006, 71, 6859-6862. 80 Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A. The Journal of Organic Chemistry 2007, 72, 626-629.

473

474

9 Reductions

reduction of such imines with either sodium borohydride or L-selectride provides complementary diastereoisomers with high selectivity.

H O S

N

NaBH4, MeOH

N

O S

t-Bu

84%, >99% de

t-Bu

H

L-Selectride THF

N

O S

t-Bu

90%, >99% de

This reactivity of sulfinyl imines has been exploited by Han and coworkers using 9-borabicyclo[3.3.1]nonane (9-BBN) as the reducing agent. Following the reduction, the sulfinyl group is smoothly cleaved using methanolic HCl.81 O S

N

NH3Cl

t-Bu (i) 9-BBN (ii) MeOH, HCl 50–56%

Cl

Cl

Cl

Cl

Phenethyl imines have also been used to effect stereoinduction. Reduction of the imine has traditionally been performed with Raney nickel or palladium on carbon, since the reductive cleavage of the auxiliary can be performed in situ following the reduction.82 Me N O

Me

Ph Me

92%

O

N

Ph Me

O

O

9.3.3.3

H

Ra-Ni, H2 toluene

Enantioselective Reductions

Access to enantioenriched secondary amines through racemic reduction followed by resolution is often more economical and practical than the enantioselective reduction with chiral nonracemic reagents and catalysts (see Chapter 14). A few enantioselective reductions of imines have been performed on gram scale, and some of the most promising methods will be discussed herein. Catalytic hydrogenation employing chiral ligands is a practical method for asymmetric imine reduction. In an example from Merck, the protected imine was reduced under very mild conditions.83

81 Han, Z.; Koenig, S. G.; Zhao, H.; Su, X.; Singh, S. P.; Bakale, R. P. Organic Process Research & Development 2007, 11, 726-730. 82 Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L., Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Organic Process Research & Development 2002, 6, 54-63. 83 McLaughlin, M.; Belyk, K.; Chen, C.-y.; Linghu, X.; Pan, J.; Qian, G.; Reamer, R. A.; Xu, Y. Organic Process Research & Development 2013, 17, 1052-1060.

9.3 Reduction of C—N Bonds

O O N S O

F

O O HN S O

F

H2, Pd(OAc)2, L*, CH3OH 40 °C, 40 psi

F

F

L* =

Fe

94%, 96–97% ee CH3 H P(t-Bu)2

Ph 2P

Another method is the reduction of N-benzoyl hydrazones using a cationic rhodium catalyst, as per the work of Burk.84,85 Although many enantioselective hydrogenation procedures require over 1000 psi of hydrogen, Burk’s system proceeds with pressures of 60 psi while still giving high yields and enantioselectivities for a range of aromatic and glyoxylic hydrazones.

N

H N

Bz

Me

H

0.2 mol% [(COD)RhL*]OTf H2 (60 psi), i-PrOH, 0 °C

Bz

Me

Quantitative

O2N

N

H N

O2N 97% ee

Et

L* = (R,R)-Et-DuPHOS:

Et P

P Et

Et

Ruthenium-based catalytic transfer hydrogenation can also be employed in the enantioselective reduction of imines.86 The hydrogenation of dihydroisoquinolines has been extensively studied and typically provides the desired tetrahydroisoquinolines with high selectivities.87 MeO MeO

MeO Catalyst HCO2H, Et 3N

N Br

MeO

72%

N H

H Br

>99% ee Ph

SO2Ar Ru

Catalyst = Ph

N H2

C6H6 Cl

Ar = p-MeC6H4

A novel approach features air stable rhenium catalysts with dimethylphenylsilane (DMPS-H) as the stoichiometric reducing agent. Taking advantage of the umpolung reactivity of these high oxidation state catalysts enabled the mild reduction of a variety of aryl, heteroaryl, and alkyl ketimines.88 84 85 86 87 88

Burk, M. J.; Feaster, J. E. Journal of the American Chemical Society 1992, 114, 6266-6267. Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399-4428. Noyori, R.; Hashiguchi, S. Accounts of Chemical Research 1997, 30, 97-102. Vedejs, E.; Trapencieris, P.; Suna, E. The Journal of Organic Chemistry 1999, 64, 6724-6729. Nolin, K. A.; Ahn, R. W.; Toste, F. D. Journal of the American Chemical Society 2005, 127, 12462-12463.

475

476

9 Reductions

Ph 2(O)PN

Me

Ph 2(O)PN

Catalyst (3 mol%) DMPS-H, CH2Cl2, rt

N Ts

N Ts

81%, >99% ee

O

Catalyst = NC

Me

R O N Cl Re Cl N

O

R

R = 4-t-Bu–Ph

Several organocatalysts have been developed and are complementary to the metal-catalyzed hydrogenation. With these catalysts, the use of high pressures of hydrogen gas can be circumvented by alternative hydride sources. An enantioselective reduction of N-aryl ketimines can be induced by sulfinamide89 or amino acid-derived catalysts with trichlorosilane.90,91

Ph

N

Me

t-Bu

O S

20 mol %

OH N H

H

F

N

2 equiv HSiCl3, CH2Cl2, –20 °C

O2 N

Ph Me

O2N

94%

90% ee

Alternatively, List92 and MacMillan93 have used BINOL-derived phosphonic acids in conjunction with Hantzsch esters as the reducing agent to perform the enantioselective reduction of a variety of ketimines. For some substrates, the reduction can also be highly chemoselective, as shown by the reductive amination of a methyl ketone in the presence of an ethyl ketone. O Me

OMe

10 mol% catalyst p-anisidine 1.2 equiv HEH, 40°C

Et

5 Å MS, benzene O

85%

H

N Me

Et O

96% ee R

EtO2C HEH =

CO2Et

O

Catalyst = Me

N H

O

Me

P

O OH

R R = SiPh3

89 90 91 92 93

Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Organic Letters 2006, 8, 5913-5915. Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P. Organic Letters 2004, 6, 2253-2256. Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Organic Letters 2006, 8, 999-1001. Hoffmann, S.; Seayad, A. M.; List, B. Angewandte Chemie, International Edition in English 2005, 44, 7424-7427. Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. Journal of the American Chemical Society 2006, 128, 84-86.

9.3 Reduction of C—N Bonds

Additionally, this catalytic system has provided the best results for aliphatic ketones, being able to stereodifferenciate nearly symmetrical ketones. 10 mol% catalyst p-anisidine 1.2 equiv HEH, 40 °C

O Et

Me

OMe H

5 Å MS, benzene

N

Et

Me

71%

9.3.4

83% ee

Reduction of Hydrazones to Alkanes

The reduction of imines to methylenes, as originally developed by Wolff and Kishner, has received very sparse attention in the literature. Typical conditions to perform such transformations involve derivatization of a ketone into a hydrazone followed by treatment with a base at elevated temperature.94 Myers has recently reported the synthesis of N-tert-butlydimethylsilylhydrazones and their use in Wolff–Kishner reactions under scandium triflate catalysis.95 Using these conditions, the reduction of some hydrazones to methylenes can even be performed at ambient temperature. Me O Me Me

H

H HO

H H

O

TBS Me

H

H N N H TBS, Sc(OTf)3 t-BuOK, t-BuOH, DMSO

Me Me

100 °C 96%

H

O

Me

H HO

H

H H

Me

H

H

Alternate conditions involve the treatment of a tosyl hydrazone with an in situ-generated borohydride.96 This procedure also allows for the reaction to occur at ambient temperature.

N

NHTs

(i) BzOH, BH3·THF CHCl3 (ii) NaOAc·3H2O 82%

t-Bu

9.3.5 9.3.5.1

t-Bu

Reduction of Carbon–Nitrogen Single Bonds Reduction of Benzylic Amines

The most common cleavage of aliphatic carbon–nitrogen bonds involves the reduction of benzylic amines. Palladium-catalyzed hydrogenolysis constitutes the preferred method for this transformation, but each substrate requires screening to identify the optimal conditions. Benzylamines are generally less susceptible to catalytic hydrogenolysis than benzyl ethers (see Section 9.4.4.3), but their cleavage can be facilitated by the addition of acid. Through careful control of the conditions, Merck scientists were able to selectively cleave an exocyclic benzylamine bond in the presence of an endocylic benzylamine and a benzyloxy function.97 94 Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P.; Rosini, G.; Serra, R.; Venturelli, F. Tetrahedron 1994, 50, 3235-3250. 95 Furrow, M. E.; Myers, A. G. Journal of the American Chemical Society 2004, 126, 5436-5445. 96 Kabalka, G. W.; Summers, S. T. The Journal of Organic Chemistry 1981, 46, 1217-1218. 97 Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. The Journal of Organic Chemistry 2002, 67, 6743-6747.

477

478

9 Reductions

CF3

CF3 Me O

CF3

O

Pd/C, H 2 TsOH· H2O EtOH, toluene

O

94%

N Ph

Me

Me

CF3

O

N H

F

F

Alternative hydrogen sources, such as cyclohexene,98 ammonium formate,99 and borane-amines100 have also been used successfully. In addition to palladium on carbon, Pearlman’s catalyst can also be relied on for benzylamine hydrogenolysis.101 OMe

Ph

CO2t-Bu

N

Me

OMe

(i) Pd(OH)2/C, H2 EtOH, HOAc (ii) TsOH

N

N

93%

H2N •TsOH

Ph

CO2t-Bu

Complementary to these palladium-mediated reactions, dissolved metals can also promote the cleavage of benzylic C—N bonds. Although few examples have been reported in the literature, Joshi and coworkers have published a detailed evaluation and successful application of a lithium/ammonia reduction on multi-kilogram scale.102 Me N N Ph

N

9.3.5.2

NHMe

Li, NH3 t-amyl alcohol 84%

O

N H

N

O

Reduction of Aromatic Carbon–Nitrogen Single Bonds

The reduction of aromatic amines is typically carried out via the deamination of diazonium salts. Hypophosphorous acid has been used by Fu and coworkers to effect the clean reduction of a diazonium salt that was generated in situ.103

N

Cl NO2

(i) SnSO4, HBr (ii) NBS

N

Cl Br

NH2

(iii) NaNO2, H3PO2 (iv) aq NaOH 75% over 4 steps

N

Cl Br

Hydrogen peroxide has also been employed as the reducing agent. A rare example of such reactivity is exemplified by the work of Barbero.104 High yields were obtained for a variety of arene diazonium sulfonimidates. It is noteworthy that molecular oxygen is formed as a by-product, raising flammability concerns.

98 Patel, M. K.; Fox, R.; Taylor, P. D. Tetrahedron 1996, 52, 1835-1840. 99 Slade, J.; Bajwa, J.; Liu, H.; Parker, D.; Vivelo, J.; Chen, G.-P.; Calienni, J.; Villhauer, E.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 2007, 11, 825-835. 100 Couturier, M.; Andresen, B. M.; Jorgensen, J. B.; Tucker, J. L.; Busch, F. R.; Brenek, S. J.; Dube, P.; Ende, D. J.; Negri, J. T. Organic Process Research & Development 2002, 6, 42-48. 101 Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.; Volante, R. P.; Hughes, D. L.; Reider, P. J. The Journal of Organic Chemistry 2004, 69, 1959-1966. 102 Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P. Organic Process Research & Development 2005, 9, 997-1002. 103 Fu, X.; McAllister, T. L.; Shi, X.; Thiruvengadam, T. K.; Tann, C.-H.; Lee, J. Organic Process Research & Development 2003, 7, 692-695. 104 Barbero, M.; Degani, I.; Dughera, S.; Fochi, R. Synthesis 2004, 2386-2390.

9.4 Reduction of C—O Bonds

N 2+ O O S – N S O O

Me O

H2O2 THF, reflux

Me O

97%

The reduction can also be carried under metal catalysis, where the hydrogen is abstracted from the solvent. Two of the preferred catalysts are iron(II) sulfate105 and copper metal.106 Br N2+BF 4– Br

Br F

77%

N2+BF 4–

Br

FeSO4 (1 mol%) DMA Br

Br

Cu powder (25 mol%) 18-crown-6, CH2Cl2

F

90%

F

9.3.5.3

F

Reduction of Aliphatic Nitro Groups

Aliphatic nitro groups can be cleaved under a variety of conditions for which the synthetic limitations have been reviewed.107 LAH can affect the reduction of tertiary nitro groups adjacent to tosyl hydrazones.108 N Ph

NHTs Me Me NO2

LiAlH4 THF, reflux 94%

N

NHTs Me

Ph

Me

Tributyltin hydride is a standard reagent for this transformation and is the most versatile, as it can also be applied to the reduction of secondary nitro groups. The latter substrates require more forcing conditions and an excess of tin hydride is typically used.109 O

n-Bu3SnH AIBN, benzene

O O2N

O

OAc

Me O NO2

O O

88%

n-Bu3SnH (5 equiv) AIBN, toluene

OAc

O

Me O

48%

9.4 Reduction of C—O Bonds 9.4.1 9.4.1.1

Reduction of Carboxylic Acid Derivatives Reduction of Esters to Aldehydes

The partial reduction of esters to aldehydes is generally accomplished by addition of DIBAL-H at low temperature. These reaction conditions are often difficult to control as the scale of the reaction is increased, and over-reduction is 105 106 107 108 109

Wassmundt, F. W.; Kiesman, W. F. The Journal of Organic Chemistry 1995, 60, 1713-1719. Hartman, G. D.; Biffar, S. E. The Journal of Organic Chemistry 1977, 42, 1468-1469. Ono, N.; Kaji, A. Synthesis 1986, 693-704. Rosini, G.; Ballini, R.; Zanotti, V. Synthesis 1983, 137-139. Ono, N.; Miyake, H.; Kaji, A. The Journal of Organic Chemistry 1984, 49, 4997-4999.

479

480

9 Reductions

always observed to a certain extent. The example below was successfully conducted on 17.5 kg of starting material and the aldehyde was purified by crystallization of the bisulfite adduct.110 DIBAL-H

NHCbz

NHCbz

toluene –90 °C >85%

CO2Et

CHO

DIBAL-H is also the reagent of choice for the reduction of lactones to lactols without further reduction.111 O

F

DIBAL-H

O

OH

F

O

toluene, CH2Cl2 –78 °C 100%

9.4.1.2

Reduction of Esters to Primary Alcohols

The reduction of esters to primary alcohols is a very common transformation that can be accomplished by a variety of reducing agents. Lithium borohydride112 and sodium borohydride, with or without a Lewis acid additive such as calcium chloride,113 are often utilized and can offer the advantages of chemoselectivity and ease of work up. In the last example shown below, sodium borohydride in toluene offered the lowest level of epimerization of the alkyl side chain, and rapidly reduced the aldehyde intermediate.114 CO2Et

Me

CO2H

LiBH4/THF

Me

OH CO2H

i-PrOH 100%

S t-Bu

O

N

CO2Me

HO t-Bu

O

NaBH 4 CaCl 2 EtOH 98%

S t-Bu

N

O OH

HO t-Bu

OH OH

O NaBH 4

OMe

N Me

Ph

toluene –15 °C >95%

OMe

N Me

Ph

In cases where chemoselectivity is not required, LAH115 and Red-Al116 are very effective reagents for the reduction of esters to alcohols. 110 Yue, T.-Y.; McLeod, D. D.; Albertson, K. B.; Beck, S. R.; Deerberg, J.; Fortunak, J. M.; Nugent, W. A.; Radesca, L. A.; Tang, L.; Xiang, C. D. Organic Process Research & Development 2006, 10, 262-271. 111 Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.; Jauregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Guo, L.; Moriarty, R. M.; Penmasta, R.; Rao, M. S.; Singhal, R. K.; Song, Z.; Staszewski, J. P.; Tuladhar, S. M.; Yang, S. Organic Process Research & Development 1999, 3, 73-76. 112 Hu, B.; Prashad, M.; Har, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Organic Process Research & Development 2007, 11, 90-93. 113 Kato, T.; Ozaki, T.; Tsuzuki, K.; Ohi, N. Organic Process Research & Development 2001, 5, 122-126. 114 Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King, S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.; Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang, W. Organic Process Research & Development 2004, 8, 897-902. 115 Caille, J.-C.; Govindan, C. K.; Junga, H.; Lalonde, J.; Yao, Y. Organic Process Research & Development 2002, 6, 471-476. 116 Srinivas, K.; Srinivasan, N.; Reddy, K. S.; Ramakrishna, M.; Reddy, C. R.; Arunagiri, M.; Kumari, R. L.; Venkataraman, S.; Mathad, V. T. Organic Process Research & Development 2005, 9, 314-318.

9.4 Reduction of C—O Bonds

CO2Me

OBn

OBn

OH

Red-Al

Ph

Ph

THF 97%

Me

CO2Et

Me

LiAlH4

OH O

THF

O

94%

9.4.1.3

Reduction of Carboxylic Acids to Primary Alcohols

LAH is an effective reagent for the reduction of carboxylic acids to primary alcohols. In the example below, both a carboxylic acid and a carbamate are fully reduced to a N-methylamino alcohol in high yield.117 Borane is also a very effective and exhibits chemoselectivity for carboxylic acids. In the example shown, the acid is reduced selectively in the presence of an α,β-unsaturated ester.118 O Ph H

N

Ph

LiAlH4

OH

THF 0 °C to reflux 98%

CO2Et

OH

H

N

SO2Me HO2C

SO2Me HO

BH3·THF THF 0 °C 98%

EtO2C Br

9.4.1.4

Me

EtO2C Br

Reduction of Anhydrides and Mixed Anhydrides to Aldehydes

The reduction of anhydrides or mixed anhydrides to aldehydes is rare, and the full reduction to a primary alcohol followed by an oxidation is usually employed. One exception is the partial reduction of cyclic anhydrides that yield an aldehyde, usually residing in the hydroxylactone form. Lithium tri-tert-butoxyaluminohydride is generally the reagent of choice for this transformation and has proven to be superior to DIBAL-H.119 (t–BuO)3LiAlH O

O

9.4.1.5

O

THF 0 °C to rt 53%

O

O

OH

Reduction of Anhydrides and Mixed Anhydrides to Primary Alcohols

Anhydrides can easily be reduced to diols using a reducing agent such as LAH. In the example below, a cyclic anhydride is reduced to the diol in high yield.120 117 Becker, C. W.; Dembofsky, B. T.; Hall, J. E.; Jacobs, R. T.; Pivonka, D. E.; Ohnmacht, C. J. Synthesis 2005, 2549-2561. 118 Lobben, P. C.; Leung, S. S.-W.; Tummala, S. Organic Process Research & Development 2004, 8, 1072-1075. 119 Ocain, T. D.; Deininger, D. D.; Russo, R.; Senko, N. A.; Katz, A.; Kitzen, J. M.; Mitchell, R.; Oshiro, G.; Russo, A.; et al. Journal of Medicinal Chemistry 1992, 35, 823-832. 120 Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron 2002, 58, 6545-6554.

481

482

9 Reductions

O

HO

O

OBn

O

O Me O

LiAlH4

OBn

HO

O Me O

THF 95%

Me

Me

Carboxylic acids can also be modified in situ to be rendered more reactive toward a milder reducing agent. For example, a mixed anhydride can be easily generated and reacted with sodium borohydride to provide the primary alcohol.121 Similarly, in the second example shown, the acylimidazole can be prepared and selectively reduced in the presence of an N-sulfonylamide.122 HO CO2H

N PNBO

(i) ClCO2Et Et3N, CH2Cl2

MsO (iii) NaBH4

O N

(ii) MsCl Et3N

O

MsO

RO

O

OCO2Et

i-PrOH H2O –45 °C

N RO

O

OH

93% Me

Me

OMe H O S N H O O HO2C

9.4.1.6

N Me

O O

OMe H O S N H O O

(i) CDI, THF (ii) NaBH4 THF, H2O 76%

HO

O O

N Me

Reduction of Amides and Imides to Aldehydes

Amides can be reduced to the corresponding aldehydes with a number of reducing agents that usually require cryogenic conditions to minimize further reduction. Weinreb amides are often selected as a suitable protected form of a carboxylate that can easily provide an aldehyde after a reduction. A tetrahydrofuran (THF) solution of LAH is a convenient reagent choice,123 and Red-Al (bis(2-methoxyethoxy)aluminum hydride) can also be utilized.124 Pseudoephedrine amides that have been used as chiral auxiliaries can be reduced to the aldehyde upon treatment with lithium triethoxyaluminum hydride generated in situ from reduction of ethyl acetate with LAH.125

121 Nishino, Y.; Komurasaki, T.; Yuasa, T.; Kakinuma, M.; Izumi, K.; Kobayashi, M.; Fujiie, S.; Gotoh, T.; Masui, Y.; Hajima, M.; Takahira, M.; Okuyama, A.; Kataoka, T. Organic Process Research & Development 2003, 7, 649-654. 122 Ashcroft, C. P.; Challenger, S.; Clifford, D.; Derrick, A. M.; Hajikarimian, Y.; Slucock, K.; Silk, T. V.; Thomson, N. M.; Williams, J. R. Organic Process Research & Development 2005, 9, 663-669. 123 Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.; Daeffler, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.; Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L. Organic Process Research & Development 2004, 8, 107-112. 124 Loiseleur, O.; Koch, G.; Cercus, J.; Schuerch, F. Organic Process Research & Development 2005, 9, 259-271. 125 Myers, A. G.; Yang, B. H.; Chen, H. Organic Syntheses 2000, 77, 29-44.

9.4 Reduction of C—O Bonds

MeO

Me

Me N

Me

Me LiAlH4

O

O

O

MeO

Me N

Me

Me

Me Ph

O

N OH Me

Me

H

toluene –40 °C >88%

OTBS

O

O

PMP

Me

Red-Al

OTES

O

O

THF –75 to –20 °C 91%

PMP

Me

H

OTES O

Me

LiAlH(OEt)3

Ph

hexanes THF –78 to 0 °C

OTBS

O Me

H

Ph

76%

Lactams, especially imides, can be reduced to hemiaminals, which can easily be converted to aminoaldehydes under mild conditions.126 In cases where the nitrogen is protected as a carbamate, chemoselectivity is observed in the reduction.127 In some instances, the equilibrium favors the aldehyde.128 O N

N

N

Cl

OH KBH4

N

MeCN, H2O >85%

O

TrS

n-Pr

NH O H2N

N

Me DIBAL-H

O N Me Boc OMe

THF –78 °C 87%

TrS

H N

n-Pr

OH N Me Boc OMe O

H N O

N O

N

O

Me H N

Cl

N

H N

LiAlH4 THF –60 °C 89%

H

H N O

N O

H N

HN H2N

NH

126 Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Organic Process Research & Development 2003, 7, 851-855. 127 DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.; Grampovnik, D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. The Journal of Organic Chemistry 2002, 67, 5445-5453. 128 Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith, G. F.; Gifford-Moore, D. S.; Gesellchen, P. D. Journal of Medicinal Chemistry 1993, 36, 314-319.

483

484

9 Reductions

9.4.1.7

Reduction of Amides to Alkylamines

While partial reduction of amides to aldehydes can be achieved by careful control of stoichiometry of the reducing agent and temperature, full reduction to the alkylamine will proceed if the temperature is raised. LAH is often the reducing agent of choice for this reaction either in toluene,129 THF,130 or in toluene using the bis-THF complex.131 In these cases, LAH has proved to be superior to Red-Al, which in the second example below, also resulted in the formation of the isoindole along with significant defluorination. However, in cases where substrate sensitivity might not be an issue, Red-Al represents a good choice of reagent.132 H N

O

H N

LiAlH4 toluene 15–40 °C 84%

F

F

F BnO N

F

O

F

LiAlH4·2THF toluene 0°C 100%

N O

BnO N

F

O N

N

O N

Me Me

Me Me O O

O N Bn

O

O

Red-Al toluene reflux 93%

O N Bn

Borane is also an effective reducing agent, but often results in a borane-amine complex that requires additional manipulation in order to be cleaved.133 This is often practically carried out by distillative removal of trimethylborate after treatment with methanol.134 O

O2N N N

N CH3

(i) BH3·THF; CH3OH (ii) H2, Pd/C, CH3OH

H2N N N

N CH3

98% over 2 steps

9.4.1.8

Reduction of Carbamates to N-Methylamines

Carbamates can be fully reduced to a methyl group upon reaction with an excess of a reducing agent. The reducing agent of choice for this transformation is LAH. The substrate and hydride are combined, generally with controlled cooling, and reaction occurs by increasing the temperature. Methyl and ethyl carbamates both perform equally well.135,136 In the third example below, both a Cbz carbamate and a benzylic ketone are fully reduced.137 129 Yue, T.-Y.; McLeod, D. D.; Albertson, K. B.; Beck, S. R.; Deerberg, J.; Fortunak, J. M.; Nugent, W. A.; Radesca, L. A.; Tang, L.; Xiang, C. D. Organic Process Research & Development 2006, 10, 262-271. 130 Shieh, W.-C.; Chen, G.-P.; Xue, S.; McKenna, J.; Jiang, X.; Prasad, K.; Repic, O.; Straub, C.; Sharma, S. K. Organic Process Research & Development 2007, 11, 711-715. 131 Watson, T. J.; Ayers, T. A.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.; Horgan, S.; Carey, J. P. Organic Process Research & Development 2003, 7, 521-532. 132 Alimardanov, A. R.; Barrila, M. T.; Busch, F. R.; Carey, J. J.; Couturier, M. A.; Cui, C. Organic Process Research & Development 2004, 8, 834-837. 133 Couturier, M.; Andresen, B. M.; Jorgensen, J. B.; Tucker, J. L.; Busch, F. R.; Brenek, S. J.; Dube, P.; Ende, D. J.; Negri, J. T. Organic Process Research & Development 2002, 6, 42-48. 134 Shu, L.; Wang, P.; Gu, C.; Garofalo, L.; Alabanza, L. M.; Dong, Y. Organic Process Research & Development 2012, 16, 1870-1873. 135 Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.; Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.; White, T. D. Organic Process Research & Development 2005, 9, 51-56. 136 Webb, R. R., II; Venuti, M. C.; Eigenbrot, C. The Journal of Organic Chemistry 1991, 56, 4706-4713. 137 Macor, J. E.; Chenard, B. L.; Post, R. J. The Journal of Organic Chemistry 1994, 59, 7496-7498.

9.4 Reduction of C—O Bonds

• HCl

Me MeO2C

N

N H

EtO2C

Me

LiAlH4

Ph

THF –15 to 30 °C 87%

H

N

N

Me Me

THF rt 92%

N H Me Me

N

N H

Me LiAlH4

Me Me

Me

H

N H Me Me

O Me

OBn

N

H O

Me

THF 0 °C to reflux 93%

N H

N

Me

LiAlH4

N

Ph

Me H

N Me

N H

Red-Al in toluene is also an acceptable reagent for this transformation. In the case shown below, it proved to be a superior reducing agent than LAH.138 In the last example below, borane is utilized to cleave an N—O bond, reduce an amide, and also reduce a carbamate to the N-methyl derivative in a single operation.139

MeO2C

H N

N N O

Me

H N

CO2Me

N O OMe

9.4.2 9.4.2.1

Me

Red-Al

H N

toluene 50 °C 81%

N N O

Me

H N

BH3·SMe2 THF 0 °C to reflux 71%

Me

N H

Reduction of Aldehydes and Ketones to Alcohols Reduction with Hydride Donors

One of the most common methods to reduce aldehydes and ketones is with a hydride donor, typically sodium borohydride or a variation thereof. Sodium borohydride offers selectivity toward aldehydes and ketones over acids/amides/esters.140 H

O O

Cl

OH

Me

O

F

N N Me

O

NaBH4 2-MeTHF, MeOH

Cl

Me

O

F

N N Me

138 Hoffmann-Emery, F.; Hilpert, H.; Scalone, M.; Waldmeier, P. The Journal of Organic Chemistry 2006, 71, 2000-2008. 139 Romero, A. G.; Darlington, W. H.; McMillan, M. W. The Journal of Organic Chemistry 1997, 62, 6582-6587. 140 Belecki, K.; Berliner, M.; Bibart, R. T.; Meltz, C.; Ng, K.; Phillips, J.; Brown Ripin, D. H.; Vetelino, M. Organic Process Research & Development 2007, 11, 754-761.

485

486

9 Reductions

Sodium borohydride also can function in a range of solvents and acidities, as seen in the example of a two-step asymmetric Mannich reaction, reduction sequence from Merck.141

MeO

MeO +

N

O

(i) 0.17% L-proline

H Ph

CO2Et

Me

MeO N

THF, –5 °C, 24 hr

H

(ii) HOAc, NaBH4 –5 °C to rt

Me

O

N

Ph

HO

H Me

Ph

72% over 2 steps 96 : 4 syn:anti

When an appropriate neighboring group is present, it is possible to obtain diastereoselectivity using standard hydride reagents. Chemists at SmithKline Beecham have demonstrated that with an appropriately hindered chiral primary amine, derived from l-phenylalanine, sodium borohydride can be used to provide a 27 : 1 ratio of desired S,S-diastereomer relative to the undesired S,R.142 This ratio could be further improved through crystallization.

NaBH4, MeOH, 0 °C

O

95% yield dr: 27 : 1

O

Bn 2N O

O O

Bn 2N OH

This selectivity is largely dependent on the steric bulk of the neighboring groups in the reduction, as demonstrated in the reduction of a similar compound with the smaller Boc-protected amine. In this example, N-selectride (sodium tri-sec-butylborohydride solution) was the most selective for the desired isomer.143 The authors continued screening and found that standard MPV conditions gave even greater selectivity (see Section 9.4.2.2). F

F

O

O O

BocHN

O

BocHN

O

OH

Ratio of diastereomers N-selectride at –78 °C: 4.3 : 1 L-selectride: 1.3 : 1 K-selectride: 2 : 1 NaBH4: 1.3 : 1 DIBAL-H: 1 : 3.35

Chiral hydroxy or alkoxy ketones can in many cases be reduced diastereoselectivity with the appropriate choice of conditions that take into account sterics and conformational effects. In some cases, hindered borohydrides can give high selectivity. In the example below, K-selectride (potassium tri-sec-butylborohydride solution) was used to effect reduction in 85% yield with a 97 : 3 ratio of diastereomers favoring the desired anti product.144 Me TBS O O Me

O

Me OTBS

Me TBS

O Me

NH2 O

Me

Me OTBS

Me

O HO

K-selectride toluene, THF –8 °C 85% 97 : 3

O Me

O

Me

O Me

NH2 O

Me

Me OTBS

Me

O

OTBS

141 Janey, J. M.; Hsiao, Y.; Armstrong, J. D., III The Journal of Organic Chemistry 2006, 71, 390-392. 142 Diederich, A. M.; Ryckman, D. M. Tetrahedron Letters 1993, 34, 6169-6172. 143 Urban, F. J.; Jasys, V. J. Organic Process Research & Development 2004, 8, 169-175. 144 Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.; Kuesters, E.; Schmid, E.; Schaer, K.; Gamboni, R.; Chen, W.; Loeser, E.; Kinder, F. R., Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic, O.; Wang, R.-M.; Florence, G.; Lyothier, I.; Paterson, I. Organic Process Research & Development 2004, 8, 122-130.

9.4 Reduction of C—O Bonds

By modifying the reducing agents and conditions, the syn products can also be produced, as seen in the reduction of a β-hydroxyketone.145 It is important to note, in these cases the reducing agents selected are substrate-dependent. In some cases, the selectride reagents provide formation of the syn isomer, as in the case where a bulky hydride was needed to force equatorial attack on the six-membered ring allowing isolation of the kinetic product. O

Et3B, NaBH4

OH

Me

Me

OH OH

OH MeOH, –70 °C 81% 98 : 2 syn:anti

Me

O

Me

OH

OH

L-Selectride MeO

i-PrOH, –70 °C 92%

O

MeO

O

LAH can also be used to reduce aldehydes146 and ketones but is far less chemoselective toward other carbonyl functionalities. In some cases, stabilized borane complexes can be used in place of borohydride salts or other hydride donors for the reduction of ketones. This method has been most commonly used for the asymmetric reduction of ketones. The Corey group has developed a series of asymmetric oxazaborolidine catalysts, known as CBS catalysts, derived from the reaction of chiral amino alcohols and borane complexes that can be used for the selective reduction of ketones. Only a few select examples will be included here as this method has been reviewed elsewhere.147,148 As CBS catalysts are moisture and air sensitive, a number of in situ-generated oxazaborolidine catalysts have been developed. In these cases, chiral amino alcohols are reacted with a borane-methyl sulfide complex to generate the oxazaborolidines prior to reaction. The exact conditions needed for catalyst formation are ligand dependent. Quallich illustrated that (1S,2R)-2-amino-1,2-diphenylethanol, a commercially available amino alcohol, would complex with borane at room temperature in THF or toluene.149 The catalyst generated in situ could then be used to reduce prochiral ketones selectively in high yield. O

Ph

Ph

BH3·SMe2

H2N

OH

THF, 16 h

Ph HN

Ph B H

Me

OH

MeO

O

Me

THF, 16 h

MeO

>90% yield 94% ee

Researchers at Bayer have scaled a similar in situ-generated oxazaborolidine catalyst that relies on the traditional Corey CBS ligand to synthesize kilograms of a chiral chlorohydrin.150 They found that controlling the ketone addition time and the temperature was crucial for maintaining high enantioselectivity.

O

(i) NEt3, THF, 15 °C (ii) 0.07 equiv B(OMe)3, 0.05 equiv ligand,

2.0 equiv BH3·SMe2, 25 °C, 11 h Cl (iii) MeOH

N Ligand:

Ph Ph OH

OH Cl N

(iv) NH4OH, MeOH 15 °C, 18 h (v) n-BuOH, aq HCl 79% over 2 steps 96% ee

NH

145 146 147 148 149 150

Romeyke, Y.; Keller, M.; Kluge, H.; Grabley, S.; Hammann, P. Tetrahedron 1991, 47, 3335-3346. Aycock, D. F. Organic Process Research & Development 2007, 11, 156-159. Corey, E. J.; Helal, C. J. Angewandte Chemie, International Edition in English 1998, 37, 1986-2012. Cho, B. T. Tetrahedron 2006, 62, 7621-7643. Quallich, G. J.; Woodall, T. M. Synlett 1993, 929-930. Duquette, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Organic Process Research & Development 2003, 7, 285-288.

OH Cl N

487

488

9 Reductions

9.4.2.2

Meerwein–Ponndorf–Verley Reaction

The MPV reaction, originally described in 1925, involves the reduction of a ketone or aldehyde with an aluminum trialkoxide and has been extended to include a number of boron variations.151 When using aluminum triisopropoxide as the reductant, acetone is eliminated as a by-product, making the reaction reversible unless the acetone is removed throughout the reaction. As a result, the aluminum variation of the MPV reaction is typically run at elevated temperatures. Much like the hydride donors above, these reductants are required in equimolar ratios to the molecule being reduced, creating extensive metal waste. Although not as common as the use of hydride donors, the MPV reaction provides unique selectivity in some cases. In the case of the Boc-protected phenylalanine below, reduction with aluminum triisopropoxide provided a ratio of 24 : 1 between the S,R- and S,S-diastereomers.152 Although the S,S diastereomer was originally desired, the enhanced selectivity caused the researchers to redesign the route to include the MPV conditions followed by an alcohol inversion. F

F (i-PrO)3Al, i-PrOH O O

BocHN

O

reflux 88% dr 24 : 1

O

O

BocHN OH

The most common variation of the standard MPV reaction is the use of trialkyl and dialkyl-halo boron reagents. In these cases, the hydride is abstracted from the alkyl groups, generating alkenes incapable of reversing the reaction.153 Dialkylboranes such as 9-BBN can be applied to aldehydes and ketones but are relatively expensive and are pyrophoric, limiting their utility on large scale.154 One of the most common alkyl borane reagents for the asymmetric reduction of ketones is diisopinocampheylchloroborane (DIP-Cl). DIP-Cl was developed by H.C. Brown and coworkers in the 1980s and can reduce a wide range of prochiral ketones with stereoselectivity at or below room temperature.155 The use of DIP-Cl and related species has been extensively reviewed.156,157 The (−)-DIP-Cl method has also been applied to the synthesis of chiral chlorohydrins.158 Both high purity commercial DIP-Cl and DIP-Cl made from lower purity pinene (80% ee) gave reasonable enantioselectivities providing evidence for nonlinear effects (see Chapter 14 on chirality). Cl O

OH (i) (–) -DIP-Cl N

Me

N

Me Me

THF, –25 °C Me

Cl

Me N

N

Me (ii) NaBO3·4H2O, MtBE (iii) NaOH, H2O

Me Complete conversion 93% ee from commercial DIP-Cl 90% ee from 80% ee pinene DIP-Cl

Cl B H Me Me

N Me

O N

No yield provided, contaminated with pinene

Me Me

(–)-DIP-Cl

One complication when using DIP-Cl or similar boron species is the need to safely oxidize the boron carbon bonds after reaction. In this case, the basic oxidation conditions caused partial cyclization to the epoxide; as a result, sodium 151 Cha, J. S. Organic Process Research & Development 2006, 10, 1032-1053. 152 Urban, F. J.; Jasys, V. J. Organic Process Research & Development 2004, 8, 169-175. 153 Cha, J. S. Organic Process Research & Development 2006, 10, 1032-1053. 154 Chidambaram, R.; Kant, J.; Zhu, J.; Lajeunesse, J.; Sirard, P.; Ermann, P.; Schierling, P.; Lee, P.; Kronenthal, D. Organic Process Research & Development 2002, 6, 632-636. 155 Chandrasekharan, J.; Ramachandran, P. V.; Brown, H. C. The Journal of Organic Chemistry 1985, 50, 5446-5448. 156 Brown, H. C.; Ramachandran, P. V.; Chandrasekharan, J. Heteroatom Chemistry 1995, 6, 117-131. 157 Cha, J. S. Organic Process Research & Development 2006, 10, 1032-1053. 158 Scott, R. W.; Fox, D. E.; Wong, J. W.; Burns, M. P. Organic Process Research & Development 2004, 8, 587-592.

9.4 Reduction of C—O Bonds

hydroxide was added to drive the epoxidation to completion. A further complication is the challenge of separating the product and the pinene related byproducts when chromatography is not an option. In the case of this particular chlorohydrin, the authors also explored Quallich’s modified oxazaborolidine catalyst and obtained 95% yield with 84% ee. Although CBS-like catalysis provided slightly lower ee, it allowed the authors to isolate the chlorohydrin and crystallize to 95% ee. 9.4.2.3

Reduction via Catalytic Hydrogenation

Many aldehydes and ketones can be reduced with molecular hydrogen (or under transfer hydrogenation conditions) in the presence of an appropriate catalyst. In the example beneath, Zaidi and coworkers used Pd/C to reduce only one of the two aldehydes of terephthalaldehyde in high yield.159 OH

O H2, 5% Pd/C

H

i-PrOH, H2O 87%

H O

H O

Most of the examples that use catalytic hydrogenation (or transfer hydrogenation) for the reduction of carbonyls demonstrate asymmetric reduction of ketones. Many of these asymmetric reductions grew from the work of Noyori and coworkers who have shown that chiral ruthenium, rhodium, and iridium complexes can be used to successfully reduce both ketones and imines. The ligands for these metals can be chiral diamines, amino alcohols, or amino phosphines. In these cases, it is often possible to use molecular hydrogen, formic acid/triethylamine mixtures, or isopropanol as the stoichiometric reductant.160,161 Researchers at Lilly carried out an asymmetric transfer hydrogenation in lieu of a classical resolution because of the poorly crystalline intermediates.162 For this particular case, the ruthenium catalyzed reduction provided 84% ee and 95% yield. This chemistry was compared directly against an oxazaborolidine catalyst derived from (S)-(−)-diphenylprolinol that provides 93% yield and 76% ee with the opposite selectivity. OH

O Br

CN Me

Catalyst: Ph Ph

Catalyst

Br

HCOOH–TEA 5 : 2 95% CN 84% de

Me SO2 N Ru Cl N H2

Me

Me

As with many enantioselective processes, development of a highly selective asymmetric ketone reduction requires extensive screening of metal-ligand combinations, along with detailed optimization of the reaction conditions. Researchers from Merck demonstrated excellent selectivity in the synthesis of a drug candidate, controlling not only the stereochemistry of the carbonyl reduction but also the neighboring asymmetric center through kinetic dynamic resolution.163 159 Zaidi, S. H. H.; Loewe, R. S.; Clark, B. A.; Jacob, M. J.; Lindsey, J. S. Organic Process Research & Development 2006, 10, 304-314. 160 Ikariya, T.; Murata, K.; Noyori, R. Organic & Biomolecular Chemistry 2006, 4, 393-406. 161 Miyagi, M.; Takehara, J.; Collet, S.; Okano, K. Organic Process Research & Development 2000, 4, 346-348. 162 Merschaert, A.; Boquel, P.; Van Hoeck, J.-P.; Gorissen, H.; Borghese, A.; Bonnier, B.; Mockel, A.; Napora, F. Organic Process Research & Development 2006, 10, 776-783. 163 Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Organic Process Research & Development 2012, 16, 1832-1845.

489

490

9 Reductions

Cl

Cl O

O Ot-Bu

O

H2, catalyst KOt-Bu, IPA

Ot-Bu HO

CH3

CH3 O

Ar2 P

O O

P Ar2

O

Cl Ru Cl

H2 iPr N

>90% yield >99% dr, ≥98.5% ee

OCH3

N H2 OCH3

Ar = 3,5-dimethylphenyl

9.4.2.4

Biocatalytic Routes to Reduction of Aldehydes and Ketones

Asymmetric reduction of ketones can in some cases be carried out in the presence of an appropriate enzyme. Similar to the chiral organometallic catalysts, biocatalytic routes often require extensive screening and optimization to identify the best enzyme, host, medium, loading, and work-up conditions for the reaction. Once developed, biocatalysis benefits can include high enantioselectivity, low catalyst cost, and mild reaction conditions.164 Disadvantages can include relatively large volumes needed for these reactions and the potential for poor product recovery. Further discussion and examples of biocatalysis can be found in Chapter 15. 9.4.2.5

Aldol–Tishchenko Reaction

The Tishchenko reaction involves the combination of two equivalents of aldehyde in the presence of a Lewis acid catalyst, such as aluminum, to form an ester. One equivalent of aldehyde is reduced while one equivalent is oxidized.165 O H

Catalyst :

O

0.5% catalyst Toluene, 21 °C, 15 min 99%

(iPrO)2Al Me

O

O

O

Al(OiPr)2 Me

Often times, the Tishchenko reaction is not run as a stand-alone reaction but in combination with an aldol condensation, providing a diastereoselective route to a monoprotected diol. This can be carried out as a one166 or two step process.167 To carry out this reaction, especially as a one-pot process, the catalyst needs to be sufficiently basic to catalyze the aldol condensation as well as providing a sufficiently Lewis acidic cation for the reduction reaction. Woerpel and coworkers developed a one-pot approach that relies on lithium diisopropylamide (LDA) to form the desired enolate; the lithium cations catalyze the reduction step.168 This method provides good yields and very high diastereoselectivity arising from the cyclic transition states formed during the reduction portion of the reaction.

164 165 166 167 168

Scott, R. W.; Fox, D. E.; Wong, J. W.; Burns, M. P. Organic Process Research & Development 2004, 8, 587-592. Ooi, T.; Miura, T.; Takaya, K.; Maruoka, K. Tetrahedron Letters 1999, 40, 7695-7698. Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. The Journal of Organic Chemistry 1997, 62, 5674-5675. Toermaekangas, O. P.; Koskinen, A. M. P. Organic Process Research & Development 2001, 5, 421-425. Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. The Journal of Organic Chemistry 1997, 62, 5674-5675.

9.4 Reduction of C—O Bonds

O

O 2

Et

O

OH O

LDA, THF

H

–78 to 22 °C

Et

Me

O

O

OLi Me

9.4.2.6

Me

Et

O

H

Ph Me

Et

Li

OH OH

Et NaOH, MeOH 64% Et 99 : 1

Et O

Et

Reduction of Acetals and Ketals

Acetals and ketals are commonly used as protecting groups for aldehydes, ketones, and diols. Reductive cleavage of acetals can be used to prepare alcohols, diols, or ethers depending on the conditions chosen. Most commonly, ketals and acetals are reduced using hydride reagents in the presence of a Brønstead or Lewis acid. When reducing a cyclic ketal to a hydroxyether, the less hindered ether is typically favored.169 This is demonstrated in the deprotection of a chiral diol by scientists at Gilead.170 In this case, trimethylsilyl triflate was used as the activating acid with borane⋅methyl sulfide acting as the reductant. When rapidly quenched, this reaction was found to provide the desired 3-pentyl ether in a 10 : 1 : 1 ratio relative to the undesired ether and the fully deprotected diol.

CO2Et

O

Et Et

Et

TMSOTf BH3·Me2S

O

CH2Cl2, –20 °C

O

Et CO2Et

aq EtOH

HO

OMs

KHCO3

OMs

CO2Et

O

Et Et

O

60% over 2 steps

There are cases where the more hindered ether can be formed selectively through formation of cyclic intermediates. Soderquist and coworkers have shown by using 9-BBN, a Lewis acidic reducing agent, they could selectively form hindered benzyl ethers when deprotecting unsymmetrical diols.171 Ph O

(i) (9-BBN–H)2 toluene, 110 °C

O Me Me

Me

Me HO

(ii) HO(CH2)2NH2

O

Ph Me Me

67%

These methods can also be applied to the reduction of hemi-acetals, as seen below in the reduction of a lactol to the cyclic ether using triethylsilane under acidic conditions.172 Me F3C

O

Me

OH Et3SiH, TFA

F3C

O

CH2Cl2 OMe

88%

OMe

169 Soderquist, J. A.; Kock, I.; Estrella, M. E. Organic Process Research & Development 2006, 10, 1076-1079. 170 Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. The Journal of Organic Chemistry 1998, 63, 4545-4550. 171 Soderquist, J. A.; Kock, I.; Estrella, M. E. Organic Process Research & Development 2006, 10, 1076-1079. 172 Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Organic Process Research & Development 2007, 11, 1015-1024.

491

492

9 Reductions

9.4.3

Reduction of Ketones to Alkanes

9.4.3.1

Wolff–Kishner Reduction

One of the oldest and still most common methods for the reduction of an aldehyde or ketone to the corresponding alkane is with the Wolff–Kishner reduction. In this reaction, the aldehyde or ketone is reacted with hydrazine to form a hydrazone which can then be reduced, leaving behind the alkane. This reaction is discussed in more detail in the section on the reduction of C—N bonds (see Section 9.3.3).

9.4.3.2

Clemmensen Reduction

The Clemmensen reduction uses activated zinc and acid to reduce an aldehyde or ketone to the corresponding alkane. Although the original conditions required zinc amalgam in refluxing aqueous hydrochloric acid, gentler variations have been developed that use powdered zinc under anhydrous conditions.173 These anhydrous conditions are exemplified in the reduction of a tricyclic ketone to an alkane in the preparation of an anti-cancer agent.174 Cl

Br N

9.4.3.3

THF, –28 °C

O Br

Cl

Br

Zn, Ac2O, TFA

N Br

80%

Silane-Mediated Reduction

A number of other methods have been developed that use silanes, both small molecule and solid supported, to reduce specific classes of ketones or aldehydes. In the following example, a benzylic ketone was selectively reduced in the presence of an acid by using a combination of triethylsilane and trifluoroacetic acid.175 O O

Me

9.4.4

Et3SiH, TFA

OH

Me

86%

O OH

Reduction of Alcohols to Alkanes

9.4.4.1

Reduction of Aliphatic Alcohols

The most common method for the reduction of unhindered alcohols is the Barton deoxygenation reaction (see Section 11.1.1), which is a two-step process involving the activation of the alcohol as a xanthate, followed by treatment with a tin or silyl hydride to complete the reduction (see Section 9.5.1). Although originally developed with stoichiometric tin hydride, it has been modified to require only catalytic tin with a more innocuous stoichiometric reductant. The Fu group has successfully reduced a number of xanthates using a tributyltin hydride/olymethylhydrosiloxane (PMHS) combination that compared favorably with the standard Barton conditions.176 OMe Ph

O Ph

OPh S

15 mol% Bu3SnH 5 equiv PMHS, AIBN n-BuOH, 80 °C 70%

OMe Ph Ph

In a similar fashion, unhindered alcohols can be reduced in a single step via Mitsunobu replacement of the hydroxyl with o-nitrobenzenesulfonylhydrazide (NBSH) which may be reduced in situ.177

173 174 175 176 177

Vedejs, E. Organic Reactions (New York) 1975, 22, 401-422. Kuo, S.-C.; Chen, F.; Hou, D.; Kim-Meade, A.; Bernard, C.; Liu, J.; Levy, S.; Wu, G. G. The Journal of Organic Chemistry 2003, 68, 4984-4987. Ashcroft, C. P.; Challenger, S.; Derrick, A. M.; Storey, R.; Thomson, N. M. Organic Process Research & Development 2003, 7, 362-368. Lopez, R. M.; Hays, D. S.; Fu, G. C. Journal of the American Chemical Society 1997, 119, 6949-6950. Myers, A. G.; Movassaghi, M.; Zheng, B. Journal of the American Chemical Society 1997, 119, 8572-8573.

9.4 Reduction of C—O Bonds

OH MeO N

Me

PPh3, DEAD, NBSH THF, –15 °C

Me

MeO N

87%

O

O

Cl

Me Cl

SO2NHNH2

NBSH:

NO2

9.4.4.2

Reduction of Benzylic Alcohols

Unlike aliphatic hydroxyl groups and phenols,178 benzylic hydroxyl groups can in some cases be reduced to the alkane under hydrogenation conditions. The selectivity of this method is illustrated in the example from Storz and coworkers where the benzylic hydroxyl could be removed in the presence of both an ester and an aliphatic alcohol.179 OH O OMe OH

O

5% Pd/C, H2

OMe

HCl, MeOH, 67 °C 90% 96.4% ee

OH

In some cases, the benzylic hydroxyl needs to be further activated to prevent reduction of other functional groups. In the following example, the benzylic alcohol is acetylated and then reduced along with the nitro functionality, without reduction of the ketone.180 OH O

Me

O2N

9.4.4.3

Me

O

(i) Ac2O, pyridine (ii) H2, Pd(OH)2

Me Me

H2N

Reduction of Benzylic Ethers

Benzylic ethers, like their alcohol counterparts, can be reduced to the alkane and free alcohol under hydrogenation conditions. Because of their susceptibility to reductive cleavage, benzylic functionalities are commonly used to protect free alcohols. They are stable under many organic reaction conditions, but may be removed easily in the presence of a catalyst and hydrogen (see Section 9.3.5.1 for cleavage of benzylic amines).181 Many catalysts can be used but palladium on carbon is the most common. As with many other organometallic catalyzed transformations, some catalyst screening is needed when a specific solvent is required or there are other reducible groups in the molecule. In the following case, the authors chose to use palladium hydroxide on carbon because it allowed for hydrogenolysis of the benzyl group without reducing the indazole ring.182 BnO

N N

CO2Et

H2, Pd(OH)2/C MTBE >70%

HO

N N

CO2Et

A special case arises when the bond being reduced is at an anomeric center of a carbohydrate, where activation by the neighboring oxygen will facilitate the reaction using hydride conditions.183 178 Ujvary, I.; Mikite, G. Organic Process Research & Development 2003, 7, 585-587. 179 Storz, T.; Dittmar, P.; Fauquex, P. F.; Marschal, P.; Lottenbach, W. U.; Steiner, H. Organic Process Research & Development 2003, 7, 559-570. 180 Deering, C. F.; Huckabee, B. K.; Lin, S.; Porter, K. T.; Rossman, C. A.; Wemple, J. Organic Process Research & Development 2000, 4, 596-600. 181 Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 3rd ed.; John Wiley & Sons, Inc. : New York, 1999. 182 Saenz, J.; Mitchell, M.; Bahmanyar, S.; Stankovic, N.; Perry, M.; Craig-Woods, B.; Kline, B.; Yu, S.; Albizati, K. Organic Process Research & Development 2007, 11, 30-38. 183 Deshpande, P. P.; Singh, J.; Pullockaran, A.; Kissick, T.; Ellsworth, B. A.; Gougoutas, J. Z.; Dimarco, J.; Fakes, M.; Reyes, M.; Lai, C.; Lobinger, H.; Denzel, T.; Ermann, P.; Crispino, G.; Randazzo, M.; Gao, Z.; Randazzo, R.; Lindrud, M.; Rosso, V.; Buono, F.; Doubleday, W. W.; Leung, S.; Richberg, P.; Hughes, D.; Washburn, W. N.; Meng, W.; Volk, K. J.; Mueller, R. H. Organic Process Research & Development 2012, 16, 577-585.

493

494

9 Reductions

(i) Et3SiH, BF3·OEt2 H2O, CH3CN

O

AcO

OCH3 OAc

AcO

AcO

(ii) 2,2-dimethoxypropane (iii) EtOH

OAc

AcO

OAc OAc

>74%

Et

O

Et

9.5 Reduction of C—S Bonds The reduction of carbon–sulfur bonds is well precedented for sulfides, sulfoxides, sulfones, and other sulfur functional groups and can be carried out with a variety of reagents. Although other reagents can be very useful for specific functional groups, nickel-based reagents have unique reactivity in reducing almost all carbon–sulfur bonds. The classic reagent is Raney nickel, and more recently, nickel boride has been used. Nickel complex reducing agents (NiCRAs) have also been used, but are not generally recommended as they use NaH in their preparation. Nickel metal is carcinogenic, and reagents based on it are usually assumed to be the same. Raney nickel is pyrophoric, has widely varying reactivity depending on how it is prepared, and is deactivated with aging; large excesses are usually required to get good conversion. It can also reduce other types of functional groups, such as amides or olefins, but can be deactivated with reagents like acetone to increase selectivity. Nickel boride,184 prepared from a nickel salt and sodium borohydride, is more reproducible and its stoichiometry is more easily controlled, but large excesses of it are still required for reduction since it has reduced reactivity. Despite these drawbacks, these reagents are a staple for reducing carbon–sulfur bonds, and must be considered when such a transformation is desired. Another classic reagent is a metal amalgam, but it is not recommended because of the issues associated with mercury. Few of the examples discussed below have been executed on very large scale. This is due in part to the perceived inelegance in utilizing functional groups that are not part of the final molecule, and in part because of the stench associated with lower oxidation state analogues. These groups can have a strong directing effect, however, either in reactivity or selectivity, and have found use as control elements in synthesis. Another general issue arises in substrates where a carbon–sulfur double bond is reduced without cleavage: the primary thiol produced is extremely prone to oxidative dimerization, and prevention of disulfide formation can be very challenging. For this reason, thioesters are often cleaved under reducing, rather than hydrolytic conditions.

9.5.1

Reduction of Alkyl Sulfides, Sulfoxides, and Sulfones

Alkyl sulfides are reduced under dissolving metal conditions, most mildly by zinc in acid.185 In the example below, ammonium chloride was sufficiently acidic to effect the desired reduction without hydrolysis of the acetonide.

O

SPh O

OH

Me Me O

Zn, THF aq NH4Cl

n-hex

87%

O

O

OH

Me Me O n-hex

Other electron transfer conditions are also effective, and a wide variety of conditions have been employed. The most commonly used reagent is sodium amalgam, but less offensive alternatives, such as magnesium in methanol186 or samarium diiodide187 can be used to achieve the desulfurization. 184 Back, T. G.; Baron, D. L.; Yang, K. The Journal of Organic Chemistry 1993, 58, 2407-2413. 185 Liu, G.; Wang, Z. Synthesis 2001, 119-127. 186 Porta, A.; Vidari, G.; Zanoni, G. The Journal of Organic Chemistry 2005, 70, 4876-4878. 187 Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. The Journal of Organic Chemistry 2005, 70, 5449-5460.

9.5 Reduction of C—S Bonds

OMe

OMe (i) n-BuLi, THF; ClCO2Me

O

O

(ii) Mg, MeOH SO2Ph R Me Me

Me

O

BPSO

CO2Me

85%

SmI2, THF MeOH, –78 °C

OPMB

Me Me

Me

93%

O

BPSO

OPMB

R = SO2Ph

These reductions can also be carried out by Raney nickel, which is effective for alkyl sulfides,188 sulfoxides,189 and sulfones.190 O PhS

Me Me

O O

O

O Ra-Ni, EtOH

O O

O

Me Me

76%

HO Me

MeO

HO Me

Me

Ra-Ni, EtOH

SOp-tol

65%

CO2Et

(i) Ra-Ni, EtOH (ii) aq NaOH

Et

N PhO 2S

MeO

CO2Et Et

N H

85%

SO2Ph

Me

Nickel boride can be used in place of Raney nickel, and usually reacts in a very similar fashion.191 Me SMe SMe N O Bn

NiCl2·H2O, NaBH4 THF, H2O

BnO

Me BnO O

70%

N

Bn

Tin hydrides are also effective reducing agents, although less preferred, but may be used in situations where the other functional groups present are sensitive to the conditions above.192 OAc O

OMe

N

O MeO

O

O

SMe Me Bn

188 189 190 191 192

O

95%

OAc O

OMe

n-Bu3SnH, AIBN PhH, 80 °C

N

O MeO

O

O

O

Me Bn

Inomata, K.; Barrague, M.; Paquette, L. A. The Journal of Organic Chemistry 2005, 70, 533-539. Garcia Ruano, J. L.; Rodriguez-Fernandez, M. M.; Maestro, M. C. Tetrahedron 2004, 60, 5701-5710. Sadanandan, E. V.; Srinivasan, P. C. Synthesis 1992, 648-650. Alcaide, B.; Casarrubios, L.; Dominguez, G.; Sierra, M. A. The Journal of Organic Chemistry 1994, 59, 7934-7936. Liang, Q.; Zhang, J.; Quan, W.; Sun, Y.; She, X.; Pan, X. The Journal of Organic Chemistry 2007, 72, 2694-2697.

495

496

9 Reductions

Tin hydrides have been the reagents of choice for most Barton reductions. Although this is usually carried out as a deoxygenation procedure (see Section 9.4.4.1), it is also effective in achieving desulfurization.193 The xanthate reduction has also been carried out using lauroyl peroxide (DLP) to initiate the radical mechanism.194 Although this reagent has environmental advantages over tin-containing reagents, reductions using it are typically slower than those using tin hydride, and the peroxide has to be added in small portions at reflux, creating additional handling problems. If reaction pathways other than quenching are possible once the carbon radical has been generated, they occur more frequently under these conditions, and have been purposefully used to create more complex molecules. OEt

O

OEt OEt

S

OEt

70%

S

F3C

OEt

O

n-Bu3SnH, AIBN toluene, reflux

F3C

NHAc

O

DLP, i-PrOH

N

S

O

S

NHAc

O N

78%

OEt

O

A special case exists where the sulfoxide is part of a thioaminal. In this instance, sodium borohydride in pyridine has been found to be very effective for selective cleavage of the C—S bond.195 OH

OH CF3

CF3

NaBH4, pyridine

HN SOp-tol Cbz

HN H Cbz

70%

12 : 1

9.5.2

Reduction of Vinyl Sulfides, Sulfoxides, and Sulfones

Not many practical examples of the reduction of vinyl sulfides exist that do not also result in the reduction of the alkene. The reduction has been achieved with a catalytic amount of a nickel complex in the presence of a stoichiometric Grignard.196 SPh (Ph3P)2NiCl2, THF

MeO OMe

Ph

MeO

i-PrMgBr, Et2O

OMe

76%

Ph

One special case is the example shown below, in which a dithioketene acetal was mono-reduced under electron transfer conditions.197 SMe

O Me

SMe Et

193 194 195 196 197

Zn, ZnCl2–TMEDA EtOH, reflux 95%

O Me

SMe Et

Alameda-Angulo, C.; Quiclet-Sire, B.; Schmidt, E.; Zard, S. Z. Organic Letters 2005, 7, 3489-3492. Gagosz, F.; Zard, S. Z. Organic Letters 2003, 5, 2655-2657. Volonterio, A.; Vergani, B.; Crucianelli, M.; Zanda, M.; Bravo, P. The Journal of Organic Chemistry 1998, 63, 7236-7243. Trost, B. M.; Ornstein, P. L. Tetrahedron Letters 1981, 22, 3463-3466. Yadav, K. M.; Suresh, J. R.; Patro, B.; Ila, H.; Junjappa, H. Tetrahedron 1996, 52, 4679-4686.

9.5 Reduction of C—S Bonds

Vinylic sulfoxides can be reduced with samarium iodide.198 The drawbacks to its use are cost and relative unavailability on large scale. OMOM

OMOM

SmI2 MeOH, THF

SOp-tol

84%

MeO2C

MeO2C

The cleavage of vinylic sulfone bonds is fairly well precedented in the literature. While sodium amalgam has classically been used for the reduction, it is not preferred due to the toxic nature of the reagent and the occasional weak control of the double bond geometry. A preferred method employs dithionite as the reducing agent under very mild conditions.199 It has been touted as an alternative to the usual Julia olefination procedure, since the vinyl sulfone can be generated by base-induced cleavage of the precursor acetate. OMe

OMe Na2S2O4, NaHCO3 EtOH, H2O, reflux

O SO2Ph

O

76%

Me

Me

A secondary, much less preferred, method that may be used involves metal exchange with the sulfone followed by protonation.200 Ph

(i) Cp2ZrCl2, n-BuLi THF, –78 °C (ii) aq HCl

SO2Ph

9.5.3

Ph

95 : 5

73%

Reduction of Aryl Sulfides, Sulfoxides, and Sulfones

Aryl sulfides201 and sulfoxides202 are readily reduced with Raney nickel. Note that in the second example below, the thioester was also reduced. Aryl sulfones are relatively inert to these conditions. O

Ra-Ni, EtOH aq NH4OH

HN MeS

N

N H

OTIPS COSt-Bu SOp-tol

54%

H2, Ra-Ni EtOH

O HN N

N H

OTIPS OH

91%

Aryl sulfoxides can also be reductively cleaved with Grignard reagents, as impressively demonstrated in the example below, where the aryl chloride bond remained untouched.203 198 199 200 201 202 203

Paley, R. S.; Estroff, L. A.; Gauguet, J.-M.; Hunt, D. K.; Newlin, R. C. Organic Letters 2000, 2, 365-368. Porta, A.; Re, S.; Zanoni, G.; Vidari, G. Tetrahedron 2007, 63, 3989-3994. Chinkov, N.; Majumdar, S.; Marek, I. Synthesis 2004, 2411-2417. Gerster, J. F.; Hinshaw, B. C.; Robins, R. K.; Townsend, L. B. Journal of Heterocyclic Chemistry 1969, 6, 207-213. Garcia Ruano, J. L.; Fernandez-Ibanez, M. A.; Maestro, M. C. Tetrahedron 2006, 62, 12297-12305. Ogawa, S.; Furukawa, N. The Journal of Organic Chemistry 1991, 56, 5723-5726.

497

498

9 Reductions

Cl SOp-tol

Cl

(i) EtMgBr, THF, 0 °C (ii) H2O

OH

OH

91%

Me

Me

Few examples for the reduction of aryl sulfones exist. One option is the use of LAH,204 but it will not be compatible with other easily reduced functional groups. SO2Ph O

O

LAH, THF, reflux

Me

81%

N

9.5.4

Me

N

Reduction of Thioketones

Thioketones are readily reduced by mild agents such as sodium borohydride.205 Me

Me

Me

Me NaBH4, i-PrOH

9.5.5

SH

91%

S SO2Ni-Pr2

SO2Ni-Pr2

Reduction of Thioesters and Thioamides

The reduction of mono-thioesters is accomplished with many of the same reducing agents as the all-oxygen analogues. LAH is one of the most frequently used and successful reagents for the transformation.206 SH

S Me

O

Me

LAH, Et2O

Me

OH Me

71%

Me Me

Me Me

This reaction has been used many times for the conversion of an alcohol to a thiol, since the intermediate thioester can be readily formed by a Mitsunobu reaction of the starting alcohol with thioacetic acid.207 S

Me

100%

O

Me

SH

LAH, THF Me

A special case of thioester reduction occurs when a palladium catalyst is used with a silane. In these reactions, an aldehyde is obtained as the product, and other potentially reactive functional groups are not touched.208 O

Ph O

N S

SEt

Pd/C, Et3SiH THF 90%

O

Ph O

N

H

S

204 Ghera, E.; Ben-David, Y.; Rapoport, H. The Journal of Organic Chemistry 1983, 48, 774-779. 205 Barrett, A. G. M.; Braddock, D. C.; Christian, P. W. N.; Pilipauskas, D.; White, A. J. P.; Williams, D. J. The Journal of Organic Chemistry 1998, 63, 5818-5823. 206 Costa, M. d. C.; Teixeira, S. G.; Rodrigues, C. B.; Ryberg Figueiredo, P.; Marcelo Curto, M. J. Tetrahedron 2005, 61, 4403-4407. 207 Yang, X.-F.; Mague, J. T.; Li, C.-J. The Journal of Organic Chemistry 2001, 66, 739-747. 208 Kimura, M.; Seki, M. Tetrahedron Letters 2004, 45, 3219-3223.

9.5 Reduction of C—S Bonds

The reduction of dithioesters can be accomplished with hydride reagents such as LAH. As with the corresponding oxygen analogs, it is extremely difficult to stop the reduction at the thioaldehyde stage, and the primary sulfide is almost inevitably the product.209 PhS

OH

S

PhS

LAH, Et2O, 0 °C

SEt

OH SH

83%

Thioamides are reduced under a variety of conditions. They can be directly reduced by Raney nickel210 or nickel boride,211 as shown below. O

S

t-BuO2C

Ot-Bu S

N

CO2t-Bu

N H

NHBoc

BocHN H S

Ra-Ni, THF

Me

CO2t-Bu

t-BuO2C

75%

N

BocHN H

NiCl2·H2O, NaBH4 aq NaOH, THF, MeOH 62–80%

N H

N H

CO2t-Bu NHBoc

Me

N H

Thioamides are also frequently reduced by formation of a thioimidate derivative and treatment with a reducing agent such as nickel boride. The thioimidate can be formed discretely212 or generated in situ213 prior to reduction. NHBoc

OTBS

NHBoc

Boc N

N

NHBoc

NiCl2, NaBH4

OTBS H N

MeOH, THF 63%

SEt

NHBoc

Boc N

S N N Ts

9.5.6

CO2Me

Et CO2Me

N

(i) Et3OBF4, CH2Cl2 (ii) NaBH4, MeOH N Ts

52% over 3 steps

CO2Me

Et CO2Me

Reduction of Miscellaneous Thiocarbonyls

Thiocarbonyls that are part of complex moieties can be selectively reduced under many of the same conditions under which other carbon–sulfur bonds are cleaved. In the example below, a 2-thioxo-4-thiazolidinone was reduced with zinc in acetic acid to cleanly give the des-thio product.214 O

t-Bu S

HO t-Bu

209 210 211 212 213 214

NH S

Zn, HOAc reflux 80–85%

O

t-Bu S

HO

N H

t-Bu

Eames, J.; Jones, R. V. H.; Warren, S. Tetrahedron Letters 1996, 37, 707-710. Miyakoshi, K.; Oshita, J.; Kitahara, T. Tetrahedron 2001, 57, 3355-3360. Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.; Parlett, R. V. I. V.; Vrieze, D. Organic Process Research & Development 2007, 11, 441-449. Jean, M.; Le Roch, M.; Renault, J.; Uriac, P. Organic Letters 2005, 7, 2663-2665. Raucher, S.; Klein, P. The Journal of Organic Chemistry 1986, 51, 123-130. Hansen, M. M.; Grutsch, J. L., Jr. Organic Process Research & Development 1997, 1, 168-171.

499

500

9 Reductions

Similarly, 2-thioxo-4-quinazolinones can be reduced with nickel boride. The reduction can be stopped at the mono-reduced product or more fully reduced depending on the ratio of hydride to nickel. The authors propose the mono-reduced product as an intermediate.215 Cl

O

10 equiv NiCl2, MeOH 10 equiv NaBH4

N N H

S

Cl

O N N

85%

Cl

O

4 equiv NiCl2, MeOH 12 equiv NaBH4

N

82%

N H

9.6 Reduction of C—X Bonds The reduction of carbon–halogen bonds is a fundamental reaction of organic chemistry,216 and is relatively straightforward to carry out when the halide is iodide, bromide, or chloride (I > Br > Cl). A wide variety of reagents have been used for these transformations, most typically hydrogen gas or hydride sources. The choice of reagent is often dependent on a consideration of other functional groups in the molecule. When the halide is fluoride, the reduction is much more difficult to achieve, and is not synthetically practical at an sp3 carbon without some form of neighboring activation. Vinyl or aryl fluorides are more easily reduced, but are still more challenging than the other halogen analogues. For all the halides, neighboring group activation, such as an electron-withdrawing group or 𝜋 system, facilitates the reduction. 9.6.1

Alkyl Halide Reductions

The reduction of alkyl halides (I, Br, Cl) can be carried out under catalytic hydrogenation conditions. The reactivity generally follows the order of tertiary halides > secondary > primary. A base is often added to the reaction to neutralize the acid generated, which may act as a catalyst poison. The reduction is usually stereospecific, giving the product consistent with retention of configuration of the starting halide. As shown by the penem example below, hydrogenolysis under catalytic palladium gave a good yield of the desired product with reasonable control of the stereoisomers.217 The use of germanium hydride (posited to be a less toxic alternative to tin hydride218 ) was shown to be stereoselective,219 and presumably arises from hydrogen atom transfer to the sterically less hindered face of the molecule. Br HO O

H O O S Me N

Me CO 2Bn H

H2, Pd/C DIPEA EtOAc i-PrOH

H HO O

H O O S Me N

Me CO 2Bn H

H2, Pd/C 86%

H HO O

H O O S Me N

Me CO 2H H

β : α = 90 : 10 Either diastereomer

n-Bu3GeH AIBN CH3CN, 80 °C

β only

53–72% 215 Khurana, J. M.; Kukreja, G. Journal of Heterocyclic Chemistry 2003, 40, 677-679. 216 Pinder, A. R. Synthesis 1980, 425-452. 217 Norris, T.; Ripin, D. H. B.; Ahlijanian, P.; Andresen, B. M.; Barrila, M. T.; Colon-Cruz, R.; Couturier, M.; Hawkins, J. M.; Loubkina, I. V.; Rutherford, J.; Stickley, K.; Wei, L.; Vollinga, R.; de Pater, R.; Maas, P.; de Lang, B.; Callant, D.; Konings, J.; Andrien, J.; Versleijen, J.; Hulshof, J.; Daia, E.; Johnson, N.; Sung, D. W. L. Organic Process Research & Development 2005, 9, 432-439. 218 Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Organic & Biomolecular Chemistry 2004, 2, 585-592. 219 Norris, T.; Dowdeswell, C.; Johnson, N.; Daia, D. Organic Process Research & Development 2005, 9, 792-799.

9.6 Reduction of C—X Bonds

The hydrogenolysis of alkyl halide bonds can also be carried out with hydride reagents. Not surprisingly, the order of reactivity is inverse to the palladium-mediated reduction, and follows the pattern primary halide > secondary > tertiary. Sodium borohydride in aprotic polar solvents220 is the mildest reagent of this type that has been employed, and tolerates a wide variety of functional groups, including other halides. Modifiers such as ZnCl2 221 or other Lewis acids may also be added to the reaction. Stronger hydride donors such as LAH222 or its modified versions may be needed for less reactive substrates. Br TMS

NaBH4, DMSO

CF2Br

80–90 °C

TMS

CF2Br

72% OH

O

O

Me

SOCl2 cat. DMF

O

Me

ZnCl2, NaBH4 THF, heptane

O

O Me

10–70 °C

heptane 0–10 °C

Br

Cl

O

Br

Cl Cl

70% over 2 steps

Br

LAH, Et2O 75%

Cl

Tributyltin hydride is a standard reagent for these transformations, and is usually the reagent of choice for tertiary halides.223 Its use should be avoided whenever possible on large scale because of its toxicity. If it must be used, methods have been developed to minimize the amount of tin required, such as employing catalytic n-Bu3 SnH with NaBH4 as a stoichiometric reductant.224 A variety of tricks can be employed to separate the tin-containing residues from the product while avoiding chromatography, including selective extractions225 and immobilization of the stannane. Samarium iodide can also be used for tertiary halide reductions, and in the presence of a chiral proton source, has been shown to proceed with reasonable stereoinduction.226 n-Bu3SnH, AIBN toluene, 130 °C

Br O

O

O

O

72%

Me

O Br

SmI2, THF (R,S)-DHPEB

O

O O

O

O

Me

–45 °C 84%

92% ee

As mentioned previously, alkyl fluorides are not reduced easily, and on a practical level only in substrates in which the fluoride is activated, such as allylic fluorides227 or α-fluoroketones.228 For some substrates, a net dehydrofluorination can be effected via an elimination mechanism followed by reduction.229 Although not mentioned by the authors, it 220 Gonzalez, J.; Foti, M. J.; Elsheimer, S. Organic Syntheses 1995, 72, 225-231. 221 Jacks, T. E.; Belmont, D. T.; Briggs, C. A.; Horne, N. M.; Kanter, G. D.; Karrick, G. L.; Krikke, J. J.; McCabe, R. J.; Mustakis, J. G.; Nanninga, T. N.; Risedorph, G. S.; Seamans, R. E.; Skeean, R.; Winkle, D. D.; Zennie, T. M. Organic Process Research & Development 2004, 8, 201-212. 222 Jefford, C. W.; Gunsher, J.; Hill, D. T.; Brun, P.; Le Gras, J.; Waegell, B. Organic Syntheses 1971, 51, 60-65. 223 Vijgen, S.; Nauwelaerts, K.; Wang, J.; Van Aerschot, A.; Lagoja, I.; Herdewijn, P. The Journal of Organic Chemistry 2005, 70, 4591-4597. 224 Attrill, R. P.; Blower, M. A.; Mulholland, K. R.; Roberts, J. K.; Richardson, J. E.; Teasdale, M. J.; Wanders, A. Organic Process Research & Development 2000, 4, 98-101. 225 Berge, J. M.; Roberts, S. M. Synthesis 1979, 471-472. 226 Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.; Mikami, K. Tetrahedron 1999, 55, 4595-4620. 227 Yamazaki, T.; Hiraoka, S.; Sakamoto, J.; Kitazume, T. Organic Letters 2001, 3, 743-746. 228 Chikashita, H.; Ide, H.; Itoh, K. The Journal of Organic Chemistry 1986, 51, 5400-5405. 229 Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 5201-5206.

501

502

9 Reductions

seems likely that in the final example below, the fluoride is displaced by the neighboring alcohol and the resulting epoxide is reduced by LiAlH4 .230 Me Me

Me

EtOH 95%

F F F2HC

Me

NaBH 4

OMs

OMs

Me

F

O

CO2t-Bu N Boc

TEA

CO2t-Bu N Boc

O

CH3CN 90% OH FH2C

9.6.2

MeOH 96%

O

CO2t-Bu N Boc

OH

LiAlH4

SPh

Ra-Ni

SPh

Me

THF

Acid Halides to Aldehydes

The reduction of acid halides, usually acid chlorides, to their corresponding aldehydes is known as the Rosenmund reduction, and is a classical method for converting carboxylic acids to aldehydes without having to reoxidize the over-reduction product. It is best carried out under hydrogenolysis conditions. In most cases, a catalyst poison or a deactivated catalyst may be needed to prevent over-reduction.231 O

OH

O

(i) (COCl)2, DMF toluene

H

(ii) H2, Pd–C, DIPEA cat. thioanisole

N Cbz

N Cbz

94%

Hydride reagents have also been used for the reduction and should be considered when the substrate possesses functionality incompatible with hydrogenation conditions.232 O

O2 N

Cl

O

LiAlH(O-t-Bu)3 diglyme, –78 °C 60%

NO2

H

O2 N

NO2

In an analogous fashion, iminoyl halides can also be reduced to their corresponding imines; hydrolysis then provides the aldehyde,233 or the imine derivative can be isolated.234 CN

(i) HCl, SnCl2 Et2O

CHO

(ii) H2O, Δ 93–95%

Br MeO

OMe N

H2, Pd–C TEA, t-BuOH 85%

MeO

OMe N

230 Yamazaki, T.; Asai, M.; Onogi, T.; Lin, J. T.; Kitazume, T. Journal of Fluorine Chemistry 1987, 35, 537-555. 231 Maligres, P. E.; Houpis, I.; Rossen, K.; Molina, A.; Sager, J.; Upadhyay, V.; Wells, K. M.; Reamer, R. A.; Lynch, J. E.; Askin, D.; Volante, R. P.; Reider, P. J.; Houghton, P. Tetrahedron 1997, 53, 10983-10992. 232 Siggins, J. E.; Larsen, A. A.; Ackerman, J. H.; Carabateas, C. D. Organic Syntheses 1973, 53, 52-55. 233 Williams, J. W. Organic Syntheses 1943, 23, 63-65. 234 Sakamoto, T.; Okamoto, K.; Kikugawa, Y. The Journal of Organic Chemistry 1992, 57, 3245-3248.

9.6 Reduction of C—X Bonds

9.6.3

Vinyl Halide Reductions

Vinyl halides are most easily reduced with zinc in acid.235,236,237 For many substrates, the control of double bond geometry is good to excellent and occurs with retention. N O

N O Zn, HOAc

N

F

F

I

N

80%

PhO 2S

H

Cl

PhO 2S

Zn, HOAc

Ph

H

86%

F

F

H Ph

The reduction can also be carried out with palladium catalysis, and for gem-bromides, the regiochemical control can be high. The drawback in the use of palladium is the need for strong hydride sources to reduce the Pd—C bond; tributyltin hydride is the reagent most commonly used for this purpose.238 Hydrogen gas can be used to effect the reduction, but over-reduction to the saturated product can be difficult to stop, especially for vinylic chlorides and fluorides. An interesting complementary method for the mono-reduction of gem-dibromides is that of Hirao,239 that uses basic dialkylphosphite for the debromination, and gives the opposite regioisomer to the palladium process. Unfortunately, this procedure seems to be limited to this type of substrate, and has not been shown to have wider applicability. Br S

Br

Br

60%

Br Cl

Pd(OAc)2, PPh3 n-Bu3SnH, toluene

Br

S

Br

Br

(EtO)2POH EtONa, EtOH

Br Cl

94%

Vinyl halides can also be reduced by metal-halogen exchange followed by quenching,240 which is often a side-process when trapping with more complex electrophiles. This method is less preferred because of the high reactivity of reagents such as n-BuLi, which often react with other functional groups, and the instability of the lithiated species. Me H

SeTIPP

(i) n-BuLi, hexanes THF, –78 °C

I

(ii) NH4Cl

Me H

SeTIPP H

91% TIPP = 2,4,6-triisopropylphenyl

9.6.4

Aryl Halide Reductions

Aryl halides can be readily reduced under hydrogenolysis conditions,241 often at very low pressures of hydrogen.242 Hydrogen sources other than hydrogen gas, such as dimethylformamide (DMF), have also been shown to be effective for these reactions.243 235 236 237 238 239 240 241 242 243

Yang, X.; Wang, Z.; Fang, X.; Yang, X.; Wu, F.; Shen, Y. Synthesis 2007, 1768-1778. Yamamoto, I.; Sakai, T.; Yamamoto, S.; Ohta, K.; Matsuzaki, K. Synthesis 1985, 676-677. Viger, A.; Coustal, S.; Schambel, P.; Marquet, A. Tetrahedron 1991, 47, 7309-7322. Rahman, S. M. A.; Sonoda, M.; Ono, M.; Miki, K.; Tobe, Y. Organic Letters 2006, 8, 1197-1200. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. The Journal of Organic Chemistry 1981, 46, 3745-3747. Perez-Balado, C.; Marko, I. E. Tetrahedron 2006, 62, 2331-2349. Neumann, F. W.; Sommer, N. B.; Kaslow, C. E.; Shriner, R. L. Organic Syntheses 1946, 26, 45-49. Arcadi, A.; Cerichelli, G.; Chiarini, M.; Vico, R.; Zorzan, D. European Journal of Organic Chemistry 2004, 3404-3407. Zawisza, A. M.; Muzart, J. Tetrahedron Letters 2007, 48, 6738-6742.

503

504

9 Reductions

Me

Me

H2, Pd–C NaOAc, HOAc 55–70 °C

Cl

N

N

81–87% Pd/C, HCO2Na H2O, rt

NH2 Cl

NH2

89%

The reduction can also be carried out under dissolving metal conditions, such as zinc in acetic acid.244 Br Br

89–90%

Br

S

Br

Zn, HOAc H2O, Δ S

As with the vinyl halides, metal-halogen exchange and quench may be a viable option for some substrates,245 although less preferred for the same reasons. In addition, the potential for a “hydrogen dance” to occur can be a complicating factor.246 Br (i) n-BuLi, hexanes THF, –78 °C

OR OR

Br

OR OR

(ii) H2O 97%

Me O

R=

O Me

Me

As with the alkyl fluorides, aryl fluorides are less readily reduced, and in many cases, the apparent reduction occurs by a prior elimination, such as benzyne or quinide-type formation, followed by reduction.247 It is not practical to design these elimination-reduction reactions into a synthetic scheme, since it can be difficult to carry out cleanly, but these are side-processes that should be considered when carrying out reductions. F

NHNH2 F

F

F F

NaOH, H2O Δ 90%

F

F

F

F

9.7 Reduction of Heteroatom–Heteroatom Bonds 9.7.1

Reduction of Nitrogen–Nitrogen Bonds

The reduction of nitrogen–nitrogen bonds is often an important step in synthetic sequences that utilize azides, hydrazones, and diazo compounds. Aminations and cycloadditions that involve diazodicarboxylates are often followed by 244 245 246 247

Gronowitz, S.; Raznikiewicz, T. Organic Syntheses 1964, 44, 9-11. Li, Z.; Liang, X.; Wan, B.; Wu, F. Synthesis 2004, 2805-2808. Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Organic Letters 2002, 4, 2385-2388. Holland, D. G.; Moore, G. J.; Tamborski, C. The Journal of Organic Chemistry 1964, 29, 3042-3046.

9.7 Reduction of Heteroatom–Heteroatom Bonds

nitrogen–nitrogen bond reductions, in order to reveal the desired amine or diamine functionality. Hydrogenolysis is typically the most practical approach for these types of reductions.248,249 NH2

HO MeO

OH O

Boc OEt

Me

NCBz NCBz

NH2

OH O

LDA

OH

MeO

95%

Boc N N Me

63%

9.7.1.1

H2, PtO 2

BocHN

OEt NHBoc

TFA H2, PtO 2 80%

OH O OEt

Me NH2

Reduction of Azides

Azides are a versatile functional group that can serve as protected amines. Conversion of azides to the corresponding amines can be readily accomplished by reduction. The most practical azide reductions for larger scale reactions and/or simple substrates typically involve hydrogenolysis.250 H2 Pd/C

OH O N3

OH O NH2

94%

In cases where existing functionality precludes the use of hydrogenolysis, zinc in ammonium chloride may be a practical alternative.251 N3

NH2 Zn, NH4Cl

S

i-PrO H

N

S

N

80%

O

O

Reactions requiring the selective reduction of an azide in the presence of other reducible functionality can also be accomplished via Staudinger reduction with a phosphine as the reducing agent. This approach is also particularly convenient for small-scale reactions. Using triphenylphosphine, Mapp and coworkers were able to selectively reduce an azide in the presence of a benzylamine, an olefin, and a nitrogen–oxygen bond.252 All of these groups would likely be reduced under hydrogenation conditions. While this azide reduction was performed on a small scale (15 mg), it showcases the outstanding chemoselectivity that phosphines can provide for azide reductions. Bn

Me

9.7.2

N O

Me

Bn N3

PPh 3 THF H 2O 92%

Me

N O

NH2

Me

Reduction of Nitrogen–Oxygen Bonds

The efficient reduction of nitrogen–oxygen bonds is a critical transformation in many synthetic sequences that involve oximes, nitrones, nitroso, and nitro compounds. In most cases, the reduction method of choice would be catalytic 248 249 250 251 252

Bournaud, C.; Bonin, M.; Micouin, L. Organic Letters 2006, 8, 3041-3043. Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron 1988, 44, 5553-5562. Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. Journal of the American Chemical Society 2007, 129, 12084-12085. Li, C.; Li, B.-F.; Chen, J.-G.; Sun, T.; Chen, Z. Organic Process Research & Development 2012, 16, 2021-2024. Rowe, S. P.; Casey, R. J.; Brennan, B. B.; Buhrlage, S. J.; Mapp, A. K. Journal of the American Chemical Society 2007, 129, 10654-10655.

505

506

9 Reductions

hydrogenation, but functional group compatibility might force an alternative reagent choice. Additionally, many of these functional groups can undergo multiple stages of reduction, and effective partial reduction can call for more specialized conditions. Various cycloaddition strategies, including those that involve nitrones and nitroalkenes, require reduction of the cycloadduct nitrogen–oxygen bonds. Gallos and coworkers developed an intramolecular nitrone cycloaddition and reduction sequence during their development of synthetic strategies for the total synthesis of pentenomycin I and naplanocin A.253 The product of the nitrone [3+2] cycloaddition could be reduced with zinc and acetic acid or via catalytic hydrogenolysis with palladium on carbon. The benzylamine was untouched in the reaction with zinc and acetic acid, while hydrogenolysis resulted in complete debenzylation. BnHN

OH

Zn Bn Bn +N – O

AcOH

O

O

91%

Me

Me

N O

PhCl 135 °C

O

O

Me

Me

62%

O

O

Me

Me

H2N

H2

OH

Pd/C 98%

O

O

Me

Me

Another synthetic sequence that often requires the reduction of a nitrogen–oxygen bond is the organocatalytic asymmetric α-oxidation of ketones and aldehydes. This approach can be an effective method for the enantioselective installation of a hydroxyl group, but these reactions typically utilize nitroso compounds as oxidants, and thus a reduction must be performed in order to reveal the desired hydroxyl group. Hayashi and coworkers utilized an l-proline catalyzed α-aminoxylation/hydrogenolysis sequence in their synthesis of fumagillol and several related angiogenesis inhibitors.254 O

NHPh

O

L-proline

O

PhNO O

O

9.7.2.1

93% 99% ee

O

O

O

H2 Pd/C 90%

O

OH

O

Reduction of Nitro Groups to Amines

The reduction of nitro compounds to the corresponding amines is typically straightforward, and it can be accomplished with a variety of reagents. Catalytic hydrogenation, either under hydrogen atmosphere255 or via transfer hydrogenation,256 is often the most practical method for this transformation. When a nitro group must be selectively reduced in the presence of other reducible functional groups, sodium dithionite,257 and iron with acetic acid258 can be highly effective reagents.

253 Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis, A. E. The Journal of Organic Chemistry 2005, 70, 6884-6890. 254 Yamaguchi, J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.; Hayashi, Y. Angewandte Chemie, International Edition in English 2006, 45, 789-793. 255 Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.; Mauragis, M. A.; McGhee, W. E.; Moeslein, J. A.; Strohbach, J. W.; Veley, M. F. Organic Process Research & Development 2006, 10, 493-499. 256 Walz, A. J.; Sundberg, R. J. The Journal of Organic Chemistry 2000, 65, 8001-8010. 257 Chandregowda, V.; Rao, G. V.; Reddy, G. C. Organic Process Research & Development 2007, 11, 813-816. 258 Huelgas, G.; Bernes, S.; Sanchez, M.; Quintero, L.; Juaristi, E.; de Parrodi, C. A.; Walsh, P. J. Tetrahedron 2007, 63, 12655-12664.

9.7 Reduction of Heteroatom–Heteroatom Bonds

H2 Pt/C

N O

NO2

OTBS NO2

O2N MeO

N O

91%

NH2

HCO2NH4 Pd/C

H 2N

100%

MeO

OTBS NH2

OMe

MeO MeO

OMe

O

CN

O

NO2

Na2S2O4 H2O

MeO MeO

50 °C

O

CN

O

NH2

95% Me

Ph

Me

Fe, AcOH

N

EtOH, H 2O reflux

O2N

Ph N

NH2

95%

9.7.2.2

Partial Reduction of Aromatic Nitro Compounds

The nitrogen–oxygen bonds of aromatic nitro compounds can be partially or fully reduced, depending on the reaction conditions. Reduction of nitro compounds to the corresponding hydroxylamines is relatively straightforward with zinc and ammonium chloride.259 The reduction can be carried out under carefully controlled conditions to generate the nitroso product.260 However, it is typically more practical to reduce the nitro derivative to the hydroxylamine with zinc and ammonium chloride, followed by partial oxidation up to the nitroso derivative using iron trichloride.261 NO2

Zn

H N

NH4Cl

OH

90% H N

NO2

N

OH

Zn NH4Cl

O

FeCl 3 86%

CO2t-Bu

9.7.2.3

CO2t-Bu

CO2t-Bu

Partial Reduction of Aliphatic Nitro Compounds

The partial reduction of aliphatic nitro compounds is also possible, but the initial reduction generates an oxime instead of the tautomeric nitroso derivative, unless tautomerization is impossible due to substitution α to the nitro group. The preferred method for the partial reduction of aliphatic nitro compounds to the corresponding oxime is the 259 Evans, D. A.; Song, H.-J.; Fandrick, K. R. Organic Letters 2006, 8, 3351-3354. 260 Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807-8815. 261 Standaert, R. F.; Park, S. B. The Journal of Organic Chemistry 2006, 71, 7952-7966.

507

508

9 Reductions

benzylation/elimination protocol developed by Czekelius and Carreira.262 In this approach, the nitro group is alkylated with benzyl bromide, followed by a base-induced elimination to generate the oxime and benzaldehyde. BnBr Bu 4NI KOH

NO2 Me

N O Me

Me

Me

PhCHO

H

H

OBn

N 81%

Me

OH

Me

Analogous to the transformation with aromatic nitro compounds, the partial reduction of aliphatic nitro compounds to the corresponding hydroxylamines can be accomplished with zinc and ammonium chloride.263 F

F

F

Me NO2

Zn NH4Cl 100%

O O

O O

OH

9.7.3

HO Me NH

F

OH

Reduction of Oxygen–Oxygen Bonds

The reduction of oxygen–oxygen bonds is not a particularly common process in organic synthesis, but it is a critical reaction in many sequences that involve singlet oxygen, ozone, or peroxides. 9.7.3.1

Reduction of Peroxides

Reactions with singlet oxygen, including ene reactions and cycloadditions, generate peroxide products that often require reduction. Additionally, nucleophilic additions of peroxides can be useful for the installation of hydroxyl groups, but a reduction is required to convert the peroxide intermediates to the corresponding hydroxyl products. The preferred methods for the reduction of peroxides are hydrogenolysis or zinc and acetic acid.264 Wood and coworkers utilized a Diels–Alder reaction with singlet oxygen and a reduction of the resulting peroxide in their synthesis of the BCE ring system of ryanodine.265 H2 Me

O O

HO

Pd/C

Me

Zn AcOH

OH

O

O O

Me

1

Br

Me

OH

O

O O O O

O2

95%

9.7.3.2

Me HO OH

HO

84%

O

Me

Me

72%

Br

Me

H2, Pd/C 90%

O O OH Me Me HO Br

Reduction of Ozonides

The reaction of ozone with alkenes results in the formation of ozonides. The oxygen–oxygen bonds of these ozonides can be reduced with various reagents, such as trimethyl phosphite,266 to provide carbonyl compounds. Alternatively, 262 263 264 265 266

Czekelius, C.; Carreira, E. M. Angewandte Chemie, International Edition in English 2005, 44, 612-615, S612/611-S612/620. Jin, C.; Burgess, J. P.; Kepler, J. A.; Cook, C. E. Organic Letters 2007, 9, 1887-1890. Robinson, T. V.; Taylor, D. K.; Tiekink, E. R. T. The Journal of Organic Chemistry 2006, 71, 7236-7244. Wood, J. L.; Graeber, J. K.; Njardarson, J. T. Tetrahedron 2003, 59, 8855-8858. Bernasconi, E.; Lee, J.; Sogli, L.; Walker, D. Organic Process Research & Development 2002, 6, 169-177.

9.7 Reduction of Heteroatom–Heteroatom Bonds

when ozonolysis reactions are performed in methanol, the ozonides react with methanol to generate peroxyaldehydes, which can be converted to the corresponding diols with sodium borohydride.267 Many other reducing agents can be used to reduce ozonides (or methoxy-hydroperoxides if executed in methanol), such as dimethylsulfide, triphenylphosphine, or zinc in acetic acid. Dimethylsulfide is convenient at a laboratory scale, but is not preferred on larger scale due to the stench associated with this reagent. Sodium bisulfite has also been used, which delivers the bisulfite adduct of the aldehyde.268 CO2DPM H N O

CO2DPM S

CO2DPM

H N

O3 O

N O DPMO2C

H N

P(OMe)3

S

N O O DPMO2C

O

O

85%

O

S

N O DPMO2C

OH

DPM = diphenylmethyl

O

CHO

MeO +

OOH

TrO O3

O

TrO

MeOH CH2Cl 2

100%

OOH

O TrO

NaBH 4

O TrO

OH OH

OMe CHO

9.7.4

Reduction of Oxygen–Sulfur Bonds

While the reduction of sulfoxides and sulfones to the corresponding sulfides is not a particularly common reaction in organic synthesis, these transformations can be successfully completed. The partial reduction of sulfones to sulfoxides, however, is not usually possible. 9.7.4.1

Reduction of Sulfones to Sulfides

The two most practical approaches for the reduction of sulfones to sulfides are magnesium/methanol,269 and aluminum hydride reagents.270 O O S

Mg, I 2 MeOH Me

H H S O O S O H H O

S

82%

Me

H H

LiAlH4 66%

S

H H

S

267 Caille, J.-C.; Govindan, C. K.; Junga, H.; Lalonde, J.; Yao, Y. Organic Process Research & Development 2002, 6, 471-476. 268 Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.; Singer, R. A.; Tickner, D. L.; Teixeira, J. J., Jr.; Vanderplas, B. C.; Weston, N. Organic Process Research & Development 2003, 7, 155-160. 269 Khurana, J. M.; Sharma, V.; Chacko, S. A. Tetrahedron 2006, 63, 966-969. 270 Harpp, D. N.; Heitner, C. The Journal of Organic Chemistry 1970, 35, 3256-3259.

509

510

9 Reductions

9.7.4.2

Reduction of Sulfoxides to Sulfides

There are many methods for the reduction of sulfoxides to sulfides, and the best method will be highly dependent upon the scale of the reaction and compatibility with other functional groups on the molecule. One of the preferred methods for this transformation, developed by Drabowicz and Oae, utilizes trifluoroacetic anhydride (TFAA) and sodium iodide.271,272 A green approach for the reduction of sulfoxides to sulfides using a molybdenum catalyst and PMHS in water has been reported by Fernandes and Romão.273 Borane,274 phosphorus pentasulfide,275 and phosphorus trichloride276 are also effective reagents for converting sulfoxides to sulfides. O

TFAA NaI

O S Me

O

95%

Me

MoO 2Cl 2(H2O)2

O S

S

S

PMHS H2O 92%

S O

BH 3

S O

O S H

100%

Me

C

S

P2 S5 pyridine

S

90%

Et

H

O BnN

PCl 3 Me

9.7.5

C

Me Et

O

NBn S O

S

( )4

BnN

NBn

100% S

Me ( )4

Reduction of Disulfides to Thiols

Disulfides are often used as a protected form of the more oxidatively unstable thiol group and can be readily reduced to the corresponding thiols under a variety of conditions. While disulfide reductions are often accomplished in biochemical research by the addition of thiols, sodium borohydride is typically used for this transformation in organic synthesis.277 N

N

N

O2 N

NO2 S

S

S

S

N

NaBH 4 79%

HS

SH

271 Drabowicz, J.; Oae, S. Synthesis 1977, 404-405. 272 Cho, B. T.; Shin, S. H. Tetrahedron 2005, 61, 6959-6966. 273 Fernandes, A. C.; Romao, C. C. Tetrahedron 2006, 62, 9650-9654. 274 Madec, D.; Mingoia, F.; Macovei, C.; Maitro, G.; Giambastiani, G.; Poli, G. European Journal of Organic Chemistry 2005, 552-557. 275 Ma, S.; Hao, X.; Meng, X.; Huang, X. The Journal of Organic Chemistry 2004, 69, 5720-5724. 276 Oh, K. Organic Letters 2007, 9, 2973-2975. 277 Wheelhouse, R. T.; Jennings, S. A.; Phillips, V. A.; Pletsas, D.; Murphy, P. M.; Garbett, N. C.; Chaires, J. B.; Jenkins, T. C. Journal of Medicinal Chemistry 2006, 49, 5187-5198.

9.7 Reduction of Heteroatom–Heteroatom Bonds

9.7.6

Reduction of Phosphine Oxides to Phosphines

The reduction of phosphine oxides to phosphines is an important step in the synthesis of many chiral and achiral phosphine ligands. There are multiple reagents that can reduce phosphine oxides, but trichlorosilane is typically used. In this reaction, the trichlorosilane deoxygenates the phosphine oxide to provide trichlorosilanol and the phosphine. This method is particularly useful because the reduction occurs with retention of configuration at phosphorus.278,279,280 P-chirogenic phosphine oxides can also be reduced to the corresponding phosphines with inversion of configuration at phosphorus. This is accomplished by alkylation with methyl triflate, followed by reduction with LAH.281 Ph

Ph HSiCl 3 90 °C

P Ph Ph O

90%

Ph

P

Ph

Me

Me Cl Cl

Me

HSiCl 3 P

O

0 °C 100%

Cl

Me P

Cl

278 Wu, H.-C.; Yu, J.-Q.; Spencer, J. B. Organic Letters 2004, 6, 4675-4678. 279 Piras, E.; Lang, F.; Ruegger, H.; Stein, D.; Worle, M.; Grutzmacher, H. Chemistry-A European Journal 2006, 12, 5849-5858. 280 Odinets, I. L.; Vinogradova, N. M.; Matveeva, E. V.; Golovanov, D. D.; Lyssenko, K. A.; Keglevich, G.; Kollar, L.; Roeschenthaler, G.-V.; Mastryukova, T. A. Journal of Organometallic Chemistry 2005, 690, 2559-2570. 281 Imamoto, T.; Kikuchi, S.-i.; Miura, T.; Wada, Y. Organic Letters 2001, 3, 87-90.

511

513

10 Oxidations Eric C. Hansen 1 , Robert Perkins 2 , and David H. Brown Ripin 3 1

Pfizer Worldwide R&D, Groton, CT, USA

2 St. Louis University, St. Louis, MO 3

Clinton Health Access Initiative, Boston, MA, USA

CHAPTER MENU Introduction, 513 Oxidation of C—C Single and Double Bonds, 514 Oxidation of C—H Bonds, 520 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent, 536 Oxidation of Aldehydes to Carboxylic Acids and Derivatives, 543 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent, 546 Oxidation of Nitrogen Functionalities, 548 Oxidation of Sulfur and at Carbon Adjacent to Sulfur, 555 Oxidation of Other Functionality, 561

10.1 Introduction The oxidation of organic compounds generally refers to the replacement of a functional group (or atom) with a more electronegative functional group, or the conversion of a lone pair of electrons to the N–O, S–O, N–X, or S–X. Most commonly oxidized are C—H, C—C, C—O, and C—N bonds, and lone pairs on nitrogen and sulfur. Oxidation reactions are powerful tools to convert a position that is protected in a lower oxidation state to the desired functionality, and for the activation of otherwise unfunctionalized positions. A wide variety of reagents have been developed over the years for the oxidation of various functional groups, with varying reactivity, stability, ease of preparation and use, and waste products. Yet despite their power as a synthetic tool and abundant use in academic research, oxidation reactions as a whole tend to be avoided in commercial processes.1 This disparity is likely due to a mixture of factors including the exothermicity of the reactions, stability of reagents, toxic waste products, and general preference not to adjust oxidation state. While the use of stable, easily prepared reagents that generate minimal amounts of waste is obviously preferred, this is frequently not an option in the course of a synthesis. This said, there are a number of oxidation reactions that are safe, produce innocuous by-products, and are amenable to large-scale execution. The examples selected provide practical experimental details for the oxidations depicted. Examples of the use of a variety of reagents are provided when available; the selection of the appropriate method requires consideration of the reactivity of the substrate, the scale of the reaction, and the resultant safety and waste disposal issues. Excluded from discussion are biotransformations and oxidative aromatic substitution reactions (see Chapter 5). This chapter is organized by the oxidized functionality for ease in looking up specific transformations. Caution: Many of the oxidants, oxidation reactions, and products described herein have the potential to release large amounts of energy in an uncontrolled fashion. Investigators considering conducting a large-scale oxidation reaction

1 Oxidation reactions as a whole comprise as little as 3% of the reactions used on a preparative scale in the pharmaceutical industry. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

514

10 Oxidations

should consult the literature, appropriate evaluate/characterize the safety of the reaction, and take proper precautions when performing the oxidation.

10.2 Oxidation of C—C Single and Double Bonds The oxidation of carbon–carbon bonds encompasses a number of transformations. Many of the reactions of olefins are formally oxidations, but are covered in Chapter 3, on the electrophilic substitution of olefins. This section will primarily focus on the oxidative cleavage of C—C double and single bonds, and on the oxidation of double and triple bonds to the corresponding ketones or diketones. Not included in this section are rearrangement reactions that result in the oxidative cleavage of a C—C bond such as the Baeyer–Villiger, Beckmann, Hoffman, and other rearrangements (Chapter 7). 10.2.1 Oxidative Cleavage of Glycols 𝛃-Aminoalcohols, 𝛂-Hydroxyaldehydes and Ketones, and Related Compounds Periodates are the reagent of choice to achieve the oxidative cleavage of vicinal diols to produce aldehydes and ketones, as exemplified in the preparation of 2,3-O-isopropylidene-d-glyceraldehyde from a d-mannitol derivative.2 Me

Me

O

NaIO4 aq NaHCO3

OH

O

OH

O

O

Me

Me

Me

Me

O

67%

O H O

Periodates are also useful for the oxidative cleavage of vicinal aminoalcohols. The sequence shown below,3 in which oxidative cleavage of the aminoalcohol to the imine, was executed on 150 kg scale. Sodium periodate was preferred over lead tetraacetate for this oxidation due to the less hazardous waste products and significantly lower toxicity of the reagent. Ph

Ph

OH

HN

CO2t-Bu OMEM

NaIO4 MeOH

p-TsOH •

N

Br

Cl

H CO2t-Bu OMEM Br

Cl

H2N

p-TsOH 48–57% overall

CO2t-Bu OMEM Br

Cl

Hydrogen peroxide-mediated oxidation can also be utilized to effect oxidative cleavage in some cases.4

HO

HO H

NaO

O

O OH

H 2 O2 Na2CO3

HO H

HO

84% HO

−

O

HO

O

O HO O

OH

OH

O

−OH

HO

HO H NaO2C

O

O HCl

O CO2Na

−(CO2Na)2

HO

HO H

OH

NaO2C

2 Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. The Journal of Organic Chemistry 1991, 56, 4056–4058. 3 Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable, C. M.; Lantz, M. K.; Moore, C. M. V.; Murphy, J. B.; Rogers, T. E.; Ruminski, P. G.; Shah, A. S.; Storer, N.; Wise, B. E. Organic Process Research & Development 2004, 8, 51–61. 4 Dunigan, J.; Weigel, L. O. The Journal of Organic Chemistry 1991, 56, 6225–6227.

10.2 Oxidation of C—C Single and Double Bonds

10.2.2

Ozonolysis

The ozonolytic cleavage of olefins5 is followed by a variety of workups to convert the intermediate ozonide into alcohols, amines, esters, aldehydes, and other functionalities. While ozonolysis is a very powerful process for the oxidative cleavage of olefins, the intermediate ozonides, and ozone itself dissolved in organic solvents, are highly hazardous and should be handled with extreme care, even on research scale. Complete decomposition of intermediate ozonides should be confirmed by a test for residual peroxides (such as fresh peroxide test strips), especially prior to heating the material. The reaction is very general, and selectivity for less substituted olefins over more highly substituted olefins can be achieved through the use of the appropriate indicator. Indicators can also be used to determine reaction completion before the concentration of dissolved ozone in solution rises to a hazardous level. On a large scale, a number of factors need to be considered in designing a process, including the flammability of the solvent being used, whether to dilute the ozone stream with nitrogen to lower the flammability of the gas phase in the reactor, and the nature of the intermediates. Use of a protic solvent leads to the formation of alkoxy or acyloxy hydroperoxides, rather than the primary ozonide, which can improve the safety factor of the reaction. 10.2.2.1

Ozonolysis Followed by Reduction to the Alcohol

Alcohols can be prepared by ozonolysis followed by work-up with a reducing agent such as NaBH4 . The 100 g preparation depicted below details the care that should be employed in the sodium borohydride quench of the ozonide; in this case, the addition of the ozonide to the reducing agent was carried out over 45 minutes.6 (i) O3 (ii) NaBH4

O Ph3CO

OH

O Ph3CO

85%

OH OH

Although typically carried out in alcohols or CH2 Cl2 , ozonolysis has been reported using water as the solvent.7 Other reducing agents that will convert an aldehyde to an alcohol can be used in the workup in place of sodium borohydride. 10.2.2.2

Ozonolysis to the Ketone or Aldehyde Oxidation State

Ozonolysis of the bicyclic carbamate shown to generate the bis-aldehyde was followed by a treatment with benzylamine and sodium cyanoborohydride to generate the bicyclic amine.8 Dimethylsulfide (DMS) was utilized to reduce the intermediate ozonide to the corresponding bis-aldehyde. Triphenylphosphine and trimethylphosphite are other reagents commonly used to reduce ozonides to the corresponding aldehyde or ketone. NCO2Et

(i) O3 (ii) DMS

O

NCO2Et

BnNH2 NaCNBH3 33% overall

O

Bn

N

NCO2Et

An alternative ozonolysis sequence on the above substrate was described in which the methoxyhydroperoxide is reduced by hydrogenation over Pt/C to generate the bis-aldehyde equivalent, and benzylamine and HCO2 H are added to affect reductive amination after further hydrogenation over the same catalyst.9 The ozonolytic cleavage of a cyclopenene to a keto-aldehyde, and its subsequent aldol condensation has been described, using DMS to reduce the intermediate ozonide.10 NC

(i) O3 (ii) DMS

O NC

85%

5 Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chemical Reviews 2006, 106, 2990–3001. 6 Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. The Journal of Organic Chemistry 1998, 63, 1961–1973. 7 Fleck, T. J.; McWhorter, W. W., Jr.; DeKam, R. N.; Pearlman, B. A. The Journal of Organic Chemistry 2003, 68, 9612–9617. 8 Fray, A. H.; Augeri, D. J.; Kleinman, E. F. The Journal of Organic Chemistry 1988, 53, 896–899. 9 Brooks, P. R.; Caron, S.; Coe, J. W.; Ng, K. K.; Singer, R. A.; Vazquez, E.; Vetelino, M. G.; Watson, H. H., Jr.; Whritenour, D. C.; Wirtz, M. C. Synthesis 2004, 1755–1758. 10 Fleming, F. F.; Shook, B. C. Organic Syntheses 2002, 78, 254–264.

515

516

10 Oxidations

A commonly used method for the ozonolysis of cyclic olefins reported in Organic Syntheses results in a dialdehyde product with one end differentiated from the other as an acetal.11 It should be noted that this procedure works well for acyclic olefins and six-membered rings, but other ring sizes do not behave well in this reaction due to the formation of cyclic acetals. (i) O3, MeOH (ii) TsOH (iii) NaHCO3 (iv) DMS

CHO

68–70%

MeO

OMe

The scale-up of the ozonolysis of the olefin below has been described.12 The primary ozonide was trapped by methanol to generate the methoxy-hydroperoxide, which was treated with aqueous sodium bisulfite to effect simultaneous peroxide reduction and bisulfite adduct formation in 57% yield on 2.3 kg scale. OH

(i) O3, −60 °C (ii) aq NaHSO3

OH

57%

10.2.2.3

HO

SO3Na

Ozonolysis Resulting in Carboxylic Acids or Esters

The electron-rich furan ring is readily oxidized and can serve as a masked carboxylic acid or as a precursor to other heterocycles. A two-substituted furan was utilized as a masked carboxylic acid in the synthesis of a cephalosporin.13 Ozonolysis of the furan below and oxidative work-up provided the acid in 77% yield. OPh O

O

H N

(i) O3 (ii) H2O2 77%

NH

O

OPh O

H N O

CO2H NH

The ozonolysis of simple olefins can be followed by an oxidative workup to produce the carboxylic acid directly. The most common methods for oxidative workup are hydrogen peroxide in formic acid (performic acid is most likely the oxidant)14 or oxygen in the presence of a carbocylic acid.15

O

(i) O3 (ii) H2O2, HCO2H 90%

HO2C HO2C

O

Methods for the ozonolysis of cyclic olefins to the aldehyde/acid oxidation state have also been published and widely used.16 (i) O3, MeOH (ii) Ac2O, Et3N 65–72%

CHO

O

OMe

11 Claus, R. E.; Schreiber, S. L. Organic Syntheses 1986, 64, 150–156. 12 Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.; Singer, R. A.; Tickner, D. L.; Teixeira, J. J., Jr.; Vanderplas, B. C.; Weston, N. Organic Process Research & Development 2003, 7, 155–160. 13 Bodurow, C. C.; Boyer, B. D.; Brennan, J.; Bunnell, C. A.; Burks, J. E.; Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J. W.; et al. Tetrahedron Letters 1989, 30, 2321–2324. 14 Baraldi, P. G.; Pollini, G. P.; Simoni, D.; Barco, A.; Benetti, S. Tetrahedron 1984, 40, 761–764. 15 Habib, R. M.; Chiang, C. Y.; Bailey, P. S. The Journal of Organic Chemistry 1984, 49, 2780–2784. 16 See Note 11.

10.2 Oxidation of C—C Single and Double Bonds

(i) O3, MeOH (ii) TsOH iii) Ac2O, Et3N

OMe OMe

78–83% O

10.2.2.4

OMe

Ozonolysis Followed by Criegee Rearrangement

The Criegee rearrangement is reminiscent of the Baeyer–Villiger oxidation and proceeds through a similar mechanism. The propenyl side chain below was cleaved by ozonolysis followed by Criegee rearrangement of the intermediate methoxy-hydroperoxide to generate the acetate of the desired alcohol.17,18 This procedure allows the use of an olefin as a masked alcohol. Me

(i) O3 (ii) Ac2O, DMAP

OTBS

Me OTBS

(iii) NaOH 73%

Me

(i) O3 (ii) Ac2O, Et3N

O Me

10.2.3

OH

Me O

(iii) Δ

>82%

O Me O HO

Oxidative Cleavage of Double Bonds and Aromatic Rings

Double bonds can be cleaved with a variety of inorganic reagents, with potassium permanganate being preferred.19 If the intermediacy of a diol is employed, periodate reagents are also preferred reagents.20 Permanganate is preferred over catalytic OsO4 with either N-methylmorpholine-N-oxide or sodium chlorite as stoichiometric oxidants (for dihydroxylation methods, see Section 3.10.1). Oxidative cleavage with NaIO4 in aqueous dichloromethane generated a solution of the bis-aldehyde, which was condensed with benzylamine and reduced with NaBH(OAc)3 directly.21 OH F

KMnO4 BnEt3NCl 42–67%

F

OH

F

(i) NaIO4 (ii) BnNH2, NaBH(OAc)3 73%

NBn F F

F

Electron-rich olefins such as enamines can be oxidatively cleaved directly by treatment with periodate reagents. A strategy based on this oxidation was developed for oxidation of activated aromatic methyl groups.22 MeO2C

Me NO2

(MeO)2CHNMe2 140 °C

NMe2

MeO2C NO2

NaIO4 95%

MeO2C

CHO NO2

17 Varie, D. L.; Brennan, J.; Briggs, B.; Cronin, J. S.; Hay, D. A.; Rieck, J. A., III; Zmijewski, M. J. Tetrahedron Letters 1998, 39, 8405–8408. 18 Schreiber, S. L.; Liew, W. F. Tetrahedron Letters 1983, 24, 2363–2366. 19 Frost, H. N. Presented at the Northeast Regional Meeting of the American Chemical Society, Fairfield, CT, July, 2005. 20 See Note 9. 21 Bashore, C. G.; Vetelino, M. G.; Wirtz, M. C.; Brooks, P. R.; Frost, H. N.; McDermott, R. E.; Whritenour, D. C.; Ragan, J. A.; Rutherford, J. L.; Makowski, T. W.; Brenek, S. J.; Coe, J. W. Organic Letters 2006, 8, 5947–5950. 22 Vetelino, M. G.; Coe, J. W. Tetrahedron Letters 1994, 35, 219–222.

517

518

10 Oxidations

Noyori and coworkers have reported the oxidative cleavage of cyclohexene to adipic acid (HO2 C(CH2 )4 CO2 H) with 30% hydrogen peroxide and catalytic Na2 WO4 ⋅2H2 O and a phase-transfer catalyst (Me(n-octyl)3 NHSO4 ), both at 1 mol% loading.23 H2O2, H2WO4

HO2C

CO2H

87%

Oxidative cleavage of a highly conjugated aromatic system was accomplished with hydrogen peroxide and catalytic WO4 to provide phenanthrenedicarboxylic acid.24 WO4, Aliquat 336 H3PO4, H2O2

CO2H CO2H

91%

10.2.4

Oxidative Cleavage of Alkyl Groups from Rings

Oxidative loss of alkyl groups from phenyl ethers can be accomplished via oxidation to the quinone oxidation state, followed by loss of an alkyl cation. For alkyl groups that will not form stable cations, the dienone–phenol rearrangement is an alternative reaction pathway for the rearomatization of the ring system (Section 7.2.1.5). The di-t-butylphenol below was oxidized using MnO2 and the resulting intermediate was trapped the intermediate para to the phenol. Following loss of the t-butyl group affected with TiCl4 , the depicted product was obtained in 55% yield.25 OH

OH t-Bu Cl

N

t-Bu

(i) MnO2 (ii) TiCl4

N

Cl

Br

t-Bu

CO2Me NHCOCF3

HO

N

N

Br O Br MeO2C

Br

NHCOCF3

55%

The Baeyer–Villiger reaction (Section 7.2.4.1) is a common method for the cleavage of aryl-carbon bonds.

10.2.5

Oxidative Decarboxylation

Dimethyl-1,3-acetonedicarboxylate has been prepared by oxidative decarboxylation of citric acid.26 This procedure is a modification of an Organic Syntheses procedure that utilized fuming H2 SO4 .27 OH HO2C

CO2H CO2H

H2SO4 52%

MeO2C

CO2Me O

23 Sato, K.; Aoki, M.; Noyori, R. Science 1998, 281, 1646–1647. 24 Young, E. R. R.; Funk, R. L. The Journal of Organic Chemistry 1998, 63, 9995–9996. 25 Hickey, D. M. B.; Leeson, P. D.; Carter, S. D.; Goodyear, M. D.; Jones, S. J.; Lewis, N. J.; Morgan, I. T.; Mullane, M. V.; Tricker, J. Y. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1988, 3097–3102. 26 Kotha, S.; Joseph, A.; Sivakumar, R.; Manivannan, E. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1998, 37B, 397–398. 27 Adams, R.; Chiles, H. M. Organic Syntheses 1925, V , 53–54.

10.2 Oxidation of C—C Single and Double Bonds

The use of catalytic amounts of AgNO3 with stoichiometric Na2 S2 O8 , and the use of CuCl2 with oxygen have also been reported for oxidative decarboxylations.28 Decarboxylations of unactivated carboxylic acids (not adjacent to an oxygen substituent) generally proceed through radical intermediates, limiting their synthetic utility. In one process, a carboxylic acid is decarboxylated with elimination to produce the olefin. Although usually accomplished with Pb(OAc)4 and a copper catalyst,29 more appealing conditions have been published, including PdCl2 and pivaloyl anhydride30 or iodobenzene diacetate and a copper catalyst.31 CO2H

Ph

PdCl2 (t-BuCO)2O Ph

80%

Oxidative replacement of a carboxylic acid with a halide, known as the Hunsdiecker reaction, can be accomplished under fairly mild conditions.32 S

CO2H

Oxone NaBr

S

Br

93%

More commonly, this reaction is run using N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS) as the oxidant and halide source, along with a catalyst such as PhIO33 or Bu4 NOCOCF3 .34 Oxidative decarboxylation can also be achieved electrochemically in a process known as the Kolbe decarboxylation, as demonstrated by the example below from Organic Syntheses.35 t-Bu HN

t-Bu CO2Me

N

O

[O], MeOH

CO2H

10.2.6

HN O

N

t-Bu CO2Me OMe

HCl >60%

HN

N

CO2Me

O

Oxidative Decyanation

The oxidative conversion of arylacetonitriles into the corresponding acetophenone is accomplished by deprotonation followed by trapping with oxygen and expulsion of cyanide anion. As such, the acidity of the benzylic proton dictates the strength of base needed to accomplish the transformation. In the case of benzophenones, aqueous potassium carbonate is a strong enough base.36 Care must be taken when working with oxygen in the presence of a flammable solvent, particularly on a large scale, to avoid undesired combustion. CN

K2CO3, O2 DMSO

O

95%

For substrates with a lower acidity, such as acetophenone, sodium hydroxide is a suitable base37 ; with hydrolysis-prone substrates lithium diisopropylamide (LDA) can be employed.38 28 29 30 31 32 33 34 35 36 37 38

Bjorsvik, H.-R.; Liguori, L.; Minisci, F. Organic Process Research & Development 2000, 4, 534–543. Hanessian, S.; Sahoo, S. P. Tetrahedron Letters 1984, 25, 1425–1428. Goossen, L. J.; Rodriguez, N. Chemical Communications 2004, 724–725. Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.; Salazar, J. A.; Suarez, E. The Journal of Organic Chemistry 1986, 51, 402–404. You, H.-W.; Lee, K.-J. Synlett 2001, 105–107. Graven, A.; Joergensen, K. A.; Dahl, S.; Stanczak, A. The Journal of Organic Chemistry 1994, 59, 3543–3546. Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369–1377. Lakner, F. J.; Chu, K. S.; Negrete, G. R.; Konopelski, J. P. Organic Syntheses 1996, 73, 201–214. Kulp, S. S.; McGee, M. J. The Journal of Organic Chemistry 1983, 48, 4097–4098. Donetti, A.; Boniardi, O.; Ezhaya, A. Synthesis 1980, 1009–1011. Parker, K. A.; Kallmerten, J. The Journal of Organic Chemistry 1980, 45, 2614–2620.

519

520

10 Oxidations

10.2.7

Oxidation of Olefins to Aldehydes and Ketones

The Wacker process converts olefins to the corresponding aldehyde or ketone. The carbonyl is selectively installed at the internal position of a terminal olefin to make the ketone rather than at the primary position to make the aldehyde. The process uses a palladium catalyst, a copper cooxidant, and oxygen as the stoichiometric oxidant.39 PdCl2, CuCl, O2 DMF, H2O C8H17

O C8H17

65–73%

Me

10.3 Oxidation of C—H Bonds 10.3.1

Aromatization of Six-Membered Rings

The aromatization of six-membered rings can be accomplished in a number of ways. The most practical method is dehydrogenation using a metal catalyst, although other reagents can be useful for this transformation as well. Generally, some level of unsaturation must exist in the ring as a handle for aromatization. Aromatization of cyclic enamines can be accomplished using Pd/C, with nitrobenzene as the hydrogen scavenger.40 This procedure has been applied to cyclohexanone oximes41 and to dihydropyridines.42

N

5% Pd/C, 4 Å MS PhNO2, PhCH3

O

N

O

86%

Another common reagent used for the aromatization of six-membered rings is 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).43 Ph

Ph

DDQ, CH2Cl2 88%

CHO

CHO

Aromatization of the dihydropyridine below with sulfur was exploited in a regiospecific synthesis of the product depicted.44 EtO2C

N

N N

S

N

S8

S

85% F

F

In the synthesis of a serotonin receptor agonist, aromatization was accomplished by treatment with MnO2 .45 An interesting solvent effect was noted; HOAc greatly accelerated the reaction such that only 2 equiv of MnO2 were required.

39 40 41 42 43 44 45

Tsuji, J.; Nagashima, H.; Nemoto, H. Organic Syntheses 1984, 62, 9–13. Cossy, J.; Belotti, D. Organic Letters 2002, 4, 2557–2559. Matsumoto, M.; Tomizuka, J.; Suzuki, M. Synthetic Communications 1994, 24, 1441–1446. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Organic Letters 2002, 4, 3955–3957. Adams, J.; Belley, M. The Journal of Organic Chemistry 1986, 51, 3878–3881. Lantos, I.; Gombatz, K.; McGuire, M.; Pridgen, L.; Remich, J.; Shilcrat, S. The Journal of Organic Chemistry 1988, 53, 4223–4227. Martinelli, M. J. The Journal of Organic Chemistry 1990, 55, 5065–5073.

10.3 Oxidation of C—H Bonds

CN

CN NPr2

83%

H

HN

NPr2

AcOH, MnO2

HN

In the synthesis of voriconazole, a key ethylpyrimidine was prepared by addition of ethyl Grignard to a pyrimidine followed by in situ oxidation with iodine.46 Cl

Cl F

EtMgBr

N N

F Et

Cl

Cl F

N

I2

N Cl MgBr

Et3N

N

Et

75%

N

Cl

Another interesting aromatization is found in the synthesis of 10-hydroxycamptothecin.47 The reaction actually proceeds by oxidation para to the aniline nitrogen followed by a rapid aromatization. Oxygenation of the fully aromatized substrate does not work, lending evidence that the oxygenation reaction proceeds first. The desired product can also be further oxidized, but the authors found that by careful selection of solvent, the product would precipitate from the reaction mixture as it was formed, protecting it from further oxidation.

O Me HO

O

N

PhI(OAc)2

N H

10.3.2

HO

O

N

N

91%

O

O

Me HO

O

Dehydrogenations Yielding Carbon–Carbon Bonds

A few methods have been developed to directly introduce α,β-unsaturation from the corresponding saturated carbonyl. Saegusa’s method is to treat a silyl enol ether with palladium to effect dehydrogenation.48 Me Me

O

H

Me Me OMOM

Me Me

(i) LDA, TMSCl (ii) Pd(OAc)2

H

94%

H

O

Me Me OMOM

H

Using DDQ in conjunction with bis(trimethylsilyl)trifluoroacetamide (BSTFA) accomplishes the direct oxidation of the amide below to produce finasteride in high yield.49 This reagent mixture provided a nice alternative to the more commonly employed reagent phenylselenic anhydride, which is not attractive due to the toxicity of the reagent and waste streams produced. O Me Me

O Me

NHt-Bu BSTFA, DDQ 110 °C

NHt-Bu

Me

85%

O

N H H

O

N H H

46 Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Organic Process Research & Development 2001, 5, 28–36. 47 Lipshutz, B. H.; Wood, M. R. Journal of the American Chemical Society 1994, 116, 11689–11702. 48 Torneiro, M.; Fall, Y.; Castedo, L.; Mourino, A. Tetrahedron 1997, 53, 10851–10870. 49 Bhattacharya, A.; DiMichele, L. M.; Dolling, U. H.; Douglas, A. W.; Grabowski, E. J. J. Journal of the American Chemical Society 1988, 110, 3318–3319.

521

522

10 Oxidations

Another reagent for introducing unsaturation proximal to a ketone is o-iodoxybenzoic acid (IBX).50 As an alternative, HIO3 and I2 O5 have also been reported to work well for this transformation.51 Me O

Me O IBX, NMO DMSO

Me

92%

O

H

Me O

H

Halogenation 𝛂 to a Ketone or Aldehyde, or Carboxylic Acid

10.3.3

The halogenation of enolizable carbons α to a carbonyl is a widely utilized reaction, and a wide variety of reagents can be used for this transformation. Acidic, basic, and radical reaction mechanisms often achieve different levels of selectivity and reactivity. 10.3.3.1

Chlorination

Chlorination is most often achieved using NCS or sulfuryl chloride, although chlorine and chlorophosphorus reagents can also be used. Other useful reagents include trichloroisocyanuric acid (TCCA)52 and N,N ′ -dichlorodimethyl hydantoin (NDDH). TCCA is worth considering as a replacement for NCS due to its relatively low-cost, high-organic solubility, and the active chlorine content is 92%, as all three chlorines are active. If the chlorinated product contains additional hydrogen atoms, the higher acidity of the product frequently results in polyhalogenated products. Avoiding over-reaction is the greatest challenge in this type of reaction. In the example below, 3-acetylpyridine can be chlorinated with NCS, under acidic conditions which protect the pyridine nitrogen from oxidation, on a large scale in 83% yield.53 O Me

O

(i) HCl, HOAc (ii) NCS 83%

N

Cl • HCl

N

Chlorination of ketones can also be accomplished with sulfuryl chloride as exemplified below.54,55,56 In the second example, chlorination of the more highly substituted position, resulting from the more stable enol, is noteworthy. O

O Me

F3C

SO2Cl2 73%

O

F3C O

Me

SO2Cl2 83–85%

50 51 52 53 54 55 56

Cl

Me Cl

Davies, H. M. L.; Long, M. S. Angewandte Chemie, International Edition 2005, 44, 3518–3520. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angewandte Chemie, International Edition 2002, 41, 993–996. Tilstam, U.; Weinmann, H. Organic Process Research & Development 2002, 6, 384–393. Duquette, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Organic Process Research & Development 2003, 7, 285–288. Masilamani, D.; Rogic, M. M. The Journal of Organic Chemistry 1981, 46, 4486–4489. Ikemoto, N.; Liu, J.; Brands, K. M. J.; McNamara, J. M.; Reider, P. J. Tetrahedron 2003, 59, 1317–1325. Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. Organic Syntheses 1957, 37, 8–12.

10.3 Oxidation of C—H Bonds

The chlorination of acids and esters requires more forcing conditions. A strong oxidant that can be generated in situ is OCl2 , but this requires not only the use of chlorine gas but mixing in a second gas as well.57 The reaction can also be accomplished using PCl5 ,58 or Cl2 and PCl3 (known as the Hell–Volhard–Zelinskii reaction). H N

Ph

CO2H

Cl2, O2 ClSO3H 48–52%

O

Me

H N

Ph

CO2H CO2H

CO2H

O

Me

Me Me

Cl

Me Me

PCl5 90%

Cl

O

O

O

In the case of an ester, enolate formation with a strong base can be followed by chlorination with a wide variety of chlorinating agents, including hexachloroethane.59 Me

Me

O

O

Me

(i) LDA (ii) Cl3CCCl3 O

10.3.3.2

63–65%

Me

Me

O

O

Cl

O

Bromination

Bromination is more common than chlorination, and a wider variety of reagents are useful for this transformation. Particularly useful brominating agents are Br2 , NBS, dibromodimethylhydantoin (DBDMH), pyridinium hydrobromide perbromide (PHP), and phenyltrimethylammonium perbromide (PTAB). The simplest and least expensive brominating agent is Br2 , which is more easily handled than chlorine.60 In some cases, an acid such as HBr61 or PBr3 62 is added to catalyze the reaction. O Me

Me Me O

Me

Br2, MeOH 74%

Br2, HBr Me

50–58%

O Me

Br Me O

Me

Br Br

In cases where selectivity is an issue, bromine may not be the optimal choice of reagent. Bromine in methanol produced a 63 : 37 ratio of bromoketones below.63 The authors took advantage of the large rate difference of the subsequent reaction with PPh3 . The primary bromoketone reacts much faster with PPh3, allowing the isolation of the primary phosphonium salt in 57% overall yield (115 kg).

57 Ogata, Y.; Sugimoto, T.; Inaishi, M. Organic Syntheses 1980, 59, 20–26. 58 Gerlach, H.; Kappes, D.; Boeckman, R. K., Jr.; Maw, G. N. Organic Syntheses 1993, 71, 48–55. 59 Boeckman, R. K., Jr.; Perni, R. B.; Macdonald, J. E.; Thomas, A. J. Organic Syntheses 1988, 66, 194–202. 60 Rappe, C. Organic Syntheses 1973, 53, 123–127. 61 Gaudry, M.; Marquet, A. Organic Syntheses 1976, 55, 24–27. 62 Ashcroft, M. R.; Hoffmann, H. M. R. Organic Syntheses 1978, 58, 17–24. 63 Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Organic Process Research & Development 2003, 7, 851–855.

523

524

10 Oxidations

O

Br2 MeOH

Me

Me

O

O Br

+

i-Pr

Me

Br

Fast

Slow

PPh3

O BrPh3P

i-Pr

Me

i-Pr

OPPh3Br

+

i-Pr

Me

57% overall

Cupric bromide (CuBr2 ) is known to be a mild brominating agent for ketones.64 Treatment of the ketone with CuBr2 in EtOAc results in 85% conversion to the bromoketone.65 Although CuBr2 often demonstrates useful selectivity differences over Br2 , a major detriment is that it requires the use of 2 equiv of CuBr2 , generating a large amount of metal-containing waste. CO2Ph

CO2Ph N

CuBr2

N Br

EtOAc O

O

Although rare, aldehydes can also be α-brominated. The aldehyde shown was brominated with dibromobarbituric acid.66 The bromide was not isolated but carried into the next step as a crude solution. CO2Me

CH2Cl2, cat. HBr, >67%

CO2Me

O

OHC

N O

N

OHC

Br

Br

O

Br

Other reagents that are often used to brominate ketones are PHP and PTAB. Unlike Br2 , PHP and PTAB are stable crystalline solids, which increase the ease of handling. They act like Br2 and in some cases, offer superior results; for example the methylketones below was brominated with PHP67 and PTAB,68 respectively. O

O Me

Cl

S

SO2NH2 O Me

MeO

Br

PHP 72%

Cl

SO2NH2 O

PTAB 79%

S

Br MeO

64 Kochi, J. K. Journal of the American Chemical Society 1955, 77, 5274–5278. 65 Bai, D.; Xu, R.; Chu, G.; Zhu, X. The Journal of Organic Chemistry 1996, 61, 4600–4606. 66 Barnett, C. J.; Wilson, T. M.; Kobierski, M. E. Organic Process Research & Development 1999, 3, 184–188. 67 Conrow, R. E.; Dean, W. D.; Zinke, P. W.; Deason, M. E.; Sproull, S. J.; Dantanarayana, A. P.; DuPriest, M. T. Organic Process Research & Development 1999, 3, 114–120. 68 Jacques, J.; Marquet, A. Organic Syntheses 1973, 53, 111–115.

10.3 Oxidation of C—H Bonds

The bromination of acids and esters requires the use of more powerful oxidants. Bromine with phosphorus69 or PCl3 70 (Hell–Volhard–Zelinskii reaction) can be used. In the case of an acid chloride, NBS alone can be employed,71 but in the case of the less acidic ester, NBS requires conditions which initiate radical formation.72 O O

Ph

Br

55% Br2, PCl3

CO2H

n-Bu

O

Br2, P(0)

CO2H

O

Ph

CO2H

60–62% (i) SOCl2 (ii) NBS, HBr

BocHN

CO2t-Bu

10.3.3.3

Iodination

Br

n-Bu

69–74% NBS, hv

COCl Br

BocHN

>33%

CO2t-Bu Br

Iodination is employed less frequently than chlorination and bromination and is most commonly accomplished with I2 or NIS.73 Ph

Ph O

I2, NaOH 23–26%

O

I Ph

Ph O

Ph

Ph O

O

O

α-Halogenation of amides is not as common as the corresponding reaction of ketones. A general procedure for α-iodination or α-bromination of secondary amides was applied to the steroid below.74 Treatment with trimethylsilyl iodide (TMSI) and I2 produces the α-iodoamide in 98% yield. O Me

O Me

NHt-Bu

Me

TMSI, I2 TMEDA

I

NHt-Bu

Me

98%

O

N H H

10.3.3.4

O

N H H

Fluorination

Electrophilic introduction of fluorine is the most difficult halogenation to run, and the reagents employed generally pose safety hazards. Nevertheless, the importance of fluorine in biologically active compounds has driven the development of a number of methods for its introduction. The most widely known reagent for this task is

69 70 71 72 73 74

Price, C. C.; Judge, J. M. Organic Syntheses 1965, 45, 22–24. Carpino, L. A.; McAdams, L. V., III. Organic Syntheses 1970, 50, 31–35. Harpp, D. N.; Bao, L. Q.; Coyle, C.; Gleason, J. G.; Horovitch, S. Organic Syntheses 1976, 55, 27–31. Muehlemann, C.; Hartmann, P.; Obrecht, J. P. Organic Syntheses 1993, 71, 200–206. Colon, I.; Griffin, G. W.; O’Connell, E. J., Jr. Organic Syntheses 1972, 52, 33–35. King, A. O.; Anderson, R. K.; Shuman, R. F.; Karady, S.; Abramson, N. L.; Douglas, A. W. The Journal of Organic Chemistry 1993, 58, 3384–3386.

525

526

10 Oxidations

1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor); and in the example below, treatment of the in situ-generated enol ether of the steroidal ketone produces the fluoroketone in 93% yield.75 COOH

Me Me

(i) TMSCl, TEA

Me HO

(ii) Selectfluor 93%

O

H

Me Me

R

Me HO

H

N+ N+

O

F

F

Cl 2BF4 −

Selectfluor

A comparison of the reaction of several fluorinating agents (N-fluorobenzenesulfonimide [NFSI], N-fluoropyridinium pyridine heptafluorodiborate [NFPy], and Selectfluor) with three key steroidal 3,5-dienol acetates to produce the fluorinated products has been reported.76 In general, Selectfluor had the best combination of reactivity and minimal byproduct formation, but procedures for using all three are provided. Me O

Me OAc

Me O

Me

Me

Me

O

O

O F

F

F

Another reagent reported in an Organic Syntheses preparation is N-fluoropyridinium triflate.77 Me OTMS

− +

Me O

OTf

N F

F

66% MeO

MeO

10.3.3.5

Haloform Reaction

The haloform reaction, the solvolysis of a trihalomethyl ketone to the ester or acid, is a useful procedure for the cleavage of methyl ketones.78,79,80 Sodium hydroxide in water is most commonly used for this transformation, in the presence of a hypochlorite or hypobromite if the halogenation runs concurrently with the cleavage reaction. The cleavage is facile and does not require heat to proceed. O EtO

CCl3 Me Me

O

OEt O

EtOH, K2CO3 87%

NaOH, NaOCl O

91%

OEt

EtO Me Me HO2C

CO2H

75 Koenigsberger, K.; Chen, G.-P.; Vivelo, J.; Lee, G.; Fitt, J.; McKenna, J.; Jenson, T.; Prasad, K.; Repic, O. Organic Process Research & Development 2002, 6, 665–669. 76 Reydellet-Casey, V.; Knoechel, D. J.; Herrinton, P. M. Organic Process Research & Development 1997, 1, 217–221. 77 Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. Journal of the American Chemical Society 1990, 112, 8563–8575. 78 Tietze, L. F.; Voss, E.; Hartfiel, U. Organic Syntheses 1990, 69, 238–244. 79 Smith, W. T., Jr.; McLeod, G. L. Organic Syntheses 1951, 31, 40–42. 80 Staunton, J.; Eisenbraun, E. J. Organic Syntheses 1962, 42, 4–7.

10.3 Oxidation of C—H Bonds

O Me Me H

O Me

Me NaOH, NaOBr

H

Me

91%

H

H

H

AcO

OH

H

HO

When following a Friedel–Crafts reaction, the haloform reaction essentially allows the electrophilic introduction of a carboxylic acid or ester to an aromatic system.81 CCl3

N H

91%

O

10.3.3.6

NaOEt

OEt N H

O

Cleavage of Ketones with MNH2

Nitrogen nucleophiles can participate in the haloform reaction.82 When following a Friedel–Crafts acylation (Section 5.5.1), the amino variant of the haloform reaction essentially allows the electrophilic introduction of an amide to an aromatic system. The cleavage on an unenolizable ketone with ammonia is known as the Haller–Bauer reaction.

O

O

PhNH2 67%

Cl3C

NHPh

Cl3C

CCl3

10.3.4

Oxygenation 𝛂 to a Ketone, Aldehyde, or Carboxylic Acid

Via the enolate, ketones, aldehydes, and carboxylic acid derivatives can be oxygenated at the α position. Useful reagents for the introduction of oxygen include oxygen, peracids, dimethyldioxirane (DMDO), and oxaziridines. Introduction of oxygen α to a carbonyl is much less common on a large scale than halogenation. This is likely due to the more hazardous nature of common oxygenating agents. One interesting example of a large-scale (10 kg) oxygenation that illustrates some of the safety concerns is the synthesis of 6-hydroxybuspirone from buspirone.83 Treatment with sodium hexamethyldisilazide (NaHMDS) generated the enolate, which was then oxygenated with oxygen in 71% yield. Triethylphosphite had to be present in the reaction mixture before the introduction of O2 so that the intermediate peroxide was reduced and did not build up in the reaction mixture. Additionally, the concentration of oxygen in the headspace of the reactor had to be carefully controlled so as to not reach levels where it would form a combustible mixture with the solvent vapors. OH

O

O N

N N

N N

O

(i) NaHMDS, P(OEt)3 (ii) O2

N N

71%

N

O

N N

The enolate oxygenation with oxygen can be run to produce the alcohol or ketone, depending on the use of a reducing agent under specific conditions.84

81 Bailey, D. M.; Johnson, R. E.; Albertson, N. F. Organic Syntheses 1971, 51, 100–102. 82 Sukornick, B. Organic Syntheses 1960, 40, 103–104. 83 See Note 9. 84 Crocq, V.; Masson, C.; Winter, J.; Richard, C.; Lemaitre, G.; Lenay, J.; Vivat, M.; Buendia, J.; Prat, D. Organic Process Research & Development 1997, 1, 2–13.

527

528

10 Oxidations

t-BuOK P(OEt)3, O2

Me

O Me

O Me

>35%

O O Me

t-BuOK, O2

O

Me

OH

O

Me

O

Me

Me Me

O

88%

O O

The use of DMDO has also been reported to be effective.85 (i) LDA (ii)(i-PrO)3TiCl (iii) DMDO

O Me

Ph

Me

O

45%

Me

Me

Ph

OH Me

(i) LDA (ii) DMDO

Me OH

95% Me

Other oxidants:

Me

O

Ph

O N

O SO2Ph

O

O

O

Mo

O O Pyr O P(NMe2)3

TMSO OTMS

As shown earlier, other reagents are also useful for the latter transformation, and provide varying levels of diastereoselectivity.86 The use of oxaziridines has been described in a diasteroselective and enantioselective process.87 For enantioselective oxygenations of achiral enolates, the most common oxaziridines used are derivatives of camphor.88 Me

Me N

O Ph

Ph

S O O O 84%, 95% ee

O Ph

Ph OH

An alternative strategy is to make an intermediate enol acetate or enol silane and epoxidize or dihydroxylate the olefin (see Section 3.10). 10.3.5 10.3.5.1

Introduction of Nitrogen 𝛂 to a Ketone, Aldehyde, or Carboxylic Acid Aliphatic Diazonium Coupling

The enolates of ethyl 2-methylacetoacetate and methyl 2-methylmalonate were utilized to trap p-methoxyphenyl azide as the diazo intermediates, which after deacetylation and decarboxylation, respectively, resulted in the α-iminoester.89 The overall process is known as the Japp–Klingermann reaction. 85 86 87 88 89

Adam, W.; Mueller, M.; Prechtl, F. The Journal of Organic Chemistry 1994, 59, 2358–2364. Adam, W.; Korb, M. N. Tetrahedron 1996, 52, 5487–5494. Davis, F. A.; Chen, B. C. Chemical Reviews 1992, 92, 919–934. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. Journal of the American Chemical Society 1990, 112, 6679–6690. Bessard, Y. Organic Process Research & Development 1998, 2, 214–220.

10.3 Oxidation of C—H Bonds

O

(i) NaNO 2, HCl (ii) KOAc, NaOAc

O

R

OEt

O

Me

R

MeO

NH2

O OEt

N

MeO

O

N

N

ArHN

Me

OEt Me

R = Me R = OMe

80% 64%

Another example can be found in Organic Syntheses.90 O

O

Me

OH

10.3.5.2

O

PhN2Cl, NaOAc Me

89–95%

N

NHPh

Nitrosation of Activated Carbon–Hydrogen Bonds

Nitrous acid adds to acidic position of organic compounds to make the corresponding oxime.91,92 The same transformation can be accomplished with RONO reagents such as methyl nitrite93 or isoamyl nitrite.94 On compounds with only one acidic proton, the nitrosated product is the final product. NC

CN

Me O

NaNO2 HOAc

NC N

>80%

OH Me O

Isoamyl nitrite t-BuOK

Me

CN

Me

NOH

79% HO

HO

10.3.5.3

Formation of Diazo Compounds

One classic example of the direct introduction of nitrogen can be found in the synthesis of thienamycin.95 The ketoester was converted to the diazo compound in 90% yield. HO2C

OH Me

Et3N

CO2PNB

H

NH

O

SO2N3 Me

90%

O

OH H O

N2 CO2PNB NH

O

Likewise, loracarbef was prepared by a similar strategy.96 Diazotization was accomplished in 85% yield with p-dodecylbenzenesulfonyl azide, a reagent that has been shown to have a better safety profile than other sulfonyl azides.97 PhO O

90 91 92 93 94 95 96 97

O

H N O

CO2PNB NH

p-dodecylPhSO2N3 Et3N 85%

O

H N

PhO O

O

CO2PNB NH

N2

Reynolds, G. A.; Van Allan, J. A. Organic Syntheses 1952, 32, 84–86. Ferris, J. P.; Sanchez, R. A.; Mancuso, R. W. Organic Syntheses 1973, Coll. Vol. V , 32–35. Zambito, A. J.; Howe, E. E. Organic Syntheses 1960, 40, 21–23. Itoh, M.; Hagiwara, D.; Kamiya, T. Organic Syntheses 1980, 59, 95–101. Wheeler, T. N.; Meinwald, J. Organic Syntheses 1972, 52, 53–58. Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. Journal of the American Chemical Society 1980, 102, 6161–6163. See Note 13. Hazen, G. G.; Weinstock, L. M.; Connell, R.; Bollinger, F. W. Synthetic Communications 1981, 11, 947–956.

529

530

10 Oxidations

Two preparations for the “diazo transfer reaction” are shown below. The first reaction can be achieved using triethylamine98 or with NaOH and a phase transfer catalyst.99 The second example demonstrates a diazo transfer with deacylation.100 O

p-MePhSO2N3 Et 3N

O

O

OH

O Me

t-BuO

94–98%

Me

t-BuO

O N2 O

p-MePhSO2N3 Et 3N

N2

83–95%

10.3.5.4

Amination 𝛂 to a Carbonyl

The Neber rearrangement (Section 7.2.2.2) is an effective method for the introduction of an amine next to a ketone.101,102,103 N

OTs

EtO

EtOK

Me

75%

N

N

OEt NH2

Common reagents for the trapping of an enolate to introduce nitrogen are diazocarboxylates. These lead to the carboxyhydrazino derivatives, which can be difficult to reduce to the amine or carbamate.104,105 Trisyl azide is an electrophilic source of nitrogen that can be trapped by an enolate,106,107 leading to the alkyl azide intermediate. These are more easily reduced to the amine. This type of amination reaction can be done asymmetrically using chiral auxiliaries. O O

N

O O

N

F (i) KHMDS, THF, −45 °C (ii) Trisyl azide

CF3

(iii) AcOH, H 2O

O i-Pr

Bn Trisyl azide = i-Pr

O

N3

N

F

F H2, Pd/C HCl, EtOH

O CF3

N Bn

O BocN NHBoc Bn

DBAD: BocN=NBoc

F

O

O

94%

Bn

F

O

(i) LDA (ii) DBAD

O

N3

63% (2 steps)

O O

F

O N Bn

CF3 NH2 HCl

S O O i-Pr

98 Regitz, M.; Hocker, J.; Liedhegener, A. Organic Syntheses 1973, Coll. Vol. V , 179–183. 99 Ledon, H. J. Organic Syntheses 1980, 59, 66–71. 100 Regitz, M.; Rueter, J.; Liedhegener, A. Organic Syntheses 1971, 51, 86–89. 101 Chung, J. Y. L.; Ho, G.-J.; Chartrain, M.; Roberge, C.; Zhao, D.; Leazer, J.; Farr, R.; Robbins, M.; Emerson, K.; Mathre, D. J.; McNamara, J. M.; Hughes, D. L.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Letters 1999, 40, 6739–6743. 102 LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. 103 LaMattina, J. L.; Suleske, R. T. Organic Syntheses 1986, 64, 19–26. 104 Evans, D. A.; Britton, T. C.; Dellaria, J. F., Jr. Tetrahedron 1988, 44, 5525–5540. 105 Evans, D. A.; Nelson, S. G. Journal of the American Chemical Society 1997, 119, 6452–6453. 106 Evans, D. A.; Britton, T. C. Journal of the American Chemical Society 1987, 109, 6881–6883. 107 Alimardanov, A.; Nikitenko, A.; Connolly, T. J.; Feigelson, G.; Chan, A. W.; Ding, Z.; Ghosh, M.; Shi, X.; Ren, J.; Hansen, E.; Farr, R.; MacEwan, M.; Tadayon, S.; Springer, D. M.; Kreft, A. F.; Ho, D. M.; Potoski, J. R. Organic Process Research & Development 2009, 13, 1161–1168.

10.3 Oxidation of C—H Bonds

Oxaziridines can also be used to transfer nitrogen to an enolate, as shown below. This methodology introduces a single nitrogen to the substrate, obviating the need for a hydrazine or azide reduction, but suffers from the disadvantage that the reagents are more expensive and less readily available.108 O Me

Ph

O

(i) LDA (ii)

O N

NC

Me

Ph

NHBoc Boc

38%

O-Nitroarylhydroxylamines can also be used as an electrophilic nitrogen source with enolates.109 O Me

EtO

Ph

O

(i) LDA

EtO

NO2

(ii)

O

Me Ph NH2

NH2

O 2N 35%

10.3.6

Sulfenation and Selenylation of Ketones, Aldehydes, and Esters

Enolates can be sulfenated and selenated using electrophilic sulfur or selenium reagents. The selenation is frequently followed by selenoxide elimination to form the α,β-unsaturated compound. Phenylselenic anhydride accomplishes both of these transformations.110,111 Me CO2H Me

O−

(PhSeO)2O

Ph

O

N H H

O

Se+

O

Me CO2H Me

Me

N H H

O

O

O NaH, PhSeCl

Me

Me CO2H

>80%

N H H

O Me SePh

Disulfides and PhSCl are the most frequently employed reagents for electrophilic sulfination.112 n-BuLi, MeSSMe

S Ph

S

10.3.7

72–77%

Ph

S

MeS

S

Sulfonylation of Aldehydes, Ketones, and Acids

Sulfur trioxide reacts α to carbonyl compounds containing an acidic proton to produce the sulfonic acid.113 Solvents other than carbon tetrachloride should be selected if utilizing this transformation. 108 109 110 111 112 113

Vidal, J.; Guy, L.; Sterin, S.; Collet, A. The Journal of Organic Chemistry 1993, 58, 4791–4793. Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. The Journal of Organic Chemistry 1979, 44, 4836–4841. See Note 49. Renga, J. M.; Reich, H. J. Organic Syntheses 1980, 59, 58–65. Stuetz, P.; Stadler, P. A. Organic Syntheses 1977, 56, 8–14. Weil, J. K.; Bistline, R. G., Jr.; Stirton, A. J. Organic Syntheses 1956, 36, 83–86.

531

532

10 Oxidations

O C14H29

10.3.8

O

SO3, CCl4

C14H29

68–75%

OH

OH SO3H

Allylic and Benzylic Halogenation

For the halogenation of allylic or benzylic positions, different halogen sources can be used including Cl2 , Br2 , or N-halo amides or imides (NBS, 1,3-dibromo-5,5-dimethylhydantoin, etc.).114,115,116,117,118,119,120 Free radical initiation is generally accomplished by azo derivatives or photochemically. DuPont has developed a number of azo derivatives (including VAZO-52) that offer different stabilities so one can tailor the reaction to different solvent and temperature combinations.121 O

O DBDMH, AcOH

O

Me Me Me

B O

VAZO-52 PhCl, 40 °C

Me

Me Me

89%

Me CO2Me

DBDMH AIBN

Me

CHCl3

OMe

Me

O

B O

Br

Me CO2Me

Br

81%

OMe

PhCF3, Cl2 N

Me

Na2CO3, NaHCO3

N

Cl

59% Me Me TBSO

Me

O

Me OH Me

NBS, AIBN

Me Me TBSO

Heptanes >43%

TBSO

OR

Me Br

TBSO

Br2, hv O

O

46% Br

114 Yasuda, N.; Huffman, M. A.; Ho, G.-J.; Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M. H.; Rieger, D. L.; Karady, S.; Sohar, P.; Abramson, N. L.; DeCamp, A. E.; Mathre, D. J.; Douglas, A. W.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. The Journal of Organic Chemistry 1998, 63, 5438–5446. 115 Srinivas, K.; Srinivasan, N.; Krishna, M. R.; Reddy, C. R.; Arunagiri, M.; Lalitha, R.; Reddy, K. S. R.; Reddy, B. S.; Reddy, G. M.; Reddy, P. P.; Kumar, M. K.; Reddy, M. S. Organic Process Research & Development 2004, 8, 952–954. 116 Shimizu, H.; Shimizu, K.; Kubodera, N.; Mikami, T.; Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.; Shimizu, M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.; Kobayashi, M.; Kigawa, M.; Kato, M.; Kozono, T.; Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M. Organic Process Research & Development 2005, 9, 278–287. 117 Hayler, J. D.; Howie, S. L. B.; Giles, R. G.; Negus, A.; Oxley, P. W.; Walsgrove, T. C.; Whiter, M. Organic Process Research & Development 1998, 2, 3–9. 118 Larsen, R. D.; Corley, E. G.; King, A. O.; Carroll, J. D.; Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y. B.; Zamboni, R. J. The Journal of Organic Chemistry 1996, 61, 3398–3405. 119 Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.; Hoveyda, A. H.; Schrock, R. R. Angewandte Chemie, International Edition 2001, 40, 1452–1456. 120 Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.; McNamara, J. M.; Shi, Y.-J.; Williams, J. M.; Macdonald, D.; Deschenes, D.; Gallant, M.; Mastracchio, A.; Roy, B.; Scheigetz, J. Organic Process Research & Development 2006, 10, 36–45. 121 http://www.dupont.com/vazo/.

10.3 Oxidation of C—H Bonds

In one noteworthy example, free radical bromination of a benzylic position required the photochemical initiation of an ordinary light bulb.122 CO2Me Me

CO2Me Br2, (PhCO2)2, hv

NO2

10.3.8.1

Br

96%

NO2

Oxygenations

Many allylic oxygenations are metal catalyzed. A variety of metals are known to afford this transformation including, chromium, manganese, ruthenium, rhodium, iron, cobalt, palladium, and copper.123 A ruthenium catalyzed t-butylhydroperoxide oxidation that produced the enone below in 75% yield was developed and could be performed on kilogram scale.124 Me Me

Me Me

Me Me

Me

0.7 mol% RuCl3 t-BuOOH

R

Me

75%

AcO

AcO

O

A copper-catalyzed oxidation using peroxyesters known as the Kharasch–Sosnovsky reaction is useful for installing allylic esters.125 O Ph Me Me

O

BzO

Ot-Bu

CuCl, DBU CH3CN, 25 oC

Me

Me Me

Me

The relatively high acidity of the benzylic proton below allowed for its easy ionization. Oxidation with the O2 in air yielded the hemiketal.126 Me

O O

O

NaOH, air DMSO 95%

NO2

Me

O O

O OH

NO2

A classic example of benzylic oxidation is the removal of p-methoxybenzyl (PMB) ethers by oxidation, often with DDQ. Two interesting large-scale examples of this reaction can be found in the synthesis of discodermolide by Novartis. A DDQ oxidation that was performed under anhydrous conditions resulted in the adjacent alcohol adding to the inter-

122 Soederberg, B. C.; Shriver, J. A.; Wallace, J. M. Organic Syntheses 2003, 80, 75–84. 123 Weidmann, V.; Maison, W. Synthesis 2013, 45, 2201–2221. 124 Miller, R. A.; Li, W.; Humphrey, G. R. Tetrahedron Letters 1996, 37, 3429–3432. 125 García-Cabeza, A. L.; Ray, L. P.; Marín-Barrios, R.; Ortega, M. J.; Moreno-Dorado, F. J.; Guerra, F. M.; Massanet, G. M. Organic Process Research & Development 2015, 19, 1662–1666. 126 Anderson, B. A.; Hansen, M. M.; Harkness, A. R.; Henry, C. L.; Vicenzi, J. T.; Zmijewski, M. J. Journal of the American Chemical Society 1995, 117, 12358–12359.

533

534

10 Oxidations

mediate benzylic cation to form a PMB acetal in 50% yield. In a later stage of the synthesis, two PMB protecting groups were removed simultaneously.127 Me

OMe

Me

N

Me

OMe N

Me

DDQ

OH O

O

Me

O

O

Me

O

PhMe 50% OMe

OMe

Me PMBO

Me

Me

Me

Me OR OPMB Me

Me OTBS

DDQ

HO

CH2Cl2 88%

Me

Me

Me

Me OR OH Me OTBS

The oxidation of ethylbenzene to benzoic acid using oxygen and a manganese catalyst was reported.128,129 Me R

O or

Me

O

O2, Mn(OAc)3

R

OH R

R = H, NO2

Potassium permanganate was utilized to produce the triacid below following complete oxidation of all carbon substituents on the aryl ring.130 In cases where overoxidation is not going to be an issue, this is the reagent of choice for this transformation due to its effectiveness in this transformation and low cost. Cl

Cl Me O

Me Cl

CO2H

KMnO4, K2CO3 44%

HO2C

Me

CO2H Cl

The classic method for the hydroxylation of allylic positions is through the use of SeO2 and hydrogen peroxide.131 The requirement for stoichiometric quantities of selenium in this process is a drawback to the method. OH

SeO2, H2O2 Me Me

10.3.8.2

49–55%

Me Me

Allylic Amination

The allylic position of olefins can be aminated with reagents of the structure RN=Se=NR or RN=S=NR in direct analogy to the allylic oxidation using selenium dioxide.132,133 127 Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.; Daeffler, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.; Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L. Organic Process Research & Development 2004, 8, 107–112. 128 Bukharkina, T. V.; Digurov, N. G.; Mil’ko, S. B.; Shelud’ko, A. B. Organic Process Research & Development 1999, 3, 404–408. 129 Bukharkina, T. V.; Grechishkina, O. S.; Digurov, N. G.; Krukovskaya, N. V. Organic Process Research & Development 2003, 7, 148–154. 130 Lyttle, M. H.; Carter, T. G.; Cook, R. M. Organic Process Research & Development 2001, 5, 45–49. 131 Coxon, J. M.; Dansted, E.; Hartshorn, M. P. Organic Syntheses 1977, 56, 25–27. 132 Kresze, G.; Braxmeier, H.; Muensterer, H. Organic Syntheses 1987, 65, 159–165. 133 Katz, T. J.; Shi, S. The Journal of Organic Chemistry 1994, 59, 8297–8298.

10.3 Oxidation of C—H Bonds

(i) MeO2CN=S=NCO2Me (ii) KOH

Me Me

Me

Me Me

43–52% based on thioimide

NHCO2Me

This reaction proceeds through an ene reaction followed by [2,3] sigmatropic rearrangement (Section 7.3.2) and reduction of the N—S or N—Se bond. This mechanism, which involves the olefin moving back and forth, results in an overall amination of the allylic position. Less preferable, but also useful, is the selenium analog of the above reaction.134 Reaction with an azodicarboxylate and a Lewis acid results in an ene reaction with the olefin, in this case the final product has the olefin transposed one carbon from its origination.135 CO2Me

DEAD, SnCl4

Me

N

Me

87%

NHCO2Me

Allylic amination with transposition of the olefin can also be achieved using a hydroxylamine and an iron catalyst.136 Me

PhNHOH, Fe(Pc) 60%

Ph

NHPh

Ph

Pc = Phthalocyanin

Another methodology for the introduction of an allylic nitrogen is through the use of π-allyl chemistry.137 OTBS

OTBS TBSO

OAc

92%

NHTs

10.3.9

TBSO

Pd(dba)2, Bu3P

N Ts

Nitrene Insertion into Carbon–Hydrogen Bonds

Nitrenes are known to insert into unactivated C—H bonds. The nitrene is typically generated from the thermolysis of an azide and is most frequently trapped intramolecularly. Two examples are shown below. Caution should be exercised when considering thermolyzing an azide.138,139 OMe

OMe CO2Et

O O Me

Me

67%

N3

N

O OO

O

N3

150 °C

Me Me O

N H

N

CO2Et

O 150 °C 55%

O Me

Me

O OO

O HN

Me Me

O

Nitrenes can also be generated by the oxidation of amide and sulfonamide nitrogens with PhI(OAc)2 and a metal catalyst.140,141 134 135 136 137 138 139 140 141

Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angewandte Chemie, International Edition in English 1996, 35, 454–456. Brimble, M. A.; Heathcock, C. H. The Journal of Organic Chemistry 1993, 58, 5261–5263. Johannsen, M.; Joergensen, K. A. The Journal of Organic Chemistry 1994, 59, 214–216. Hara, O.; Sugimoto, K.; Hamada, Y. Tetrahedron 2004, 60, 9381–9390. Molina, P.; Fresneda, P. M.; Delgado, S. The Journal of Organic Chemistry 2003, 68, 489–499. Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Gould, R. O.; Hodgson, P. K. G.; McDougall, D. Tetrahedron 1998, 54, 9765–9784. Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. Journal of the American Chemical Society 2001, 123, 6935–6936. See Note 50.

535

536

10 Oxidations

O O S H2N O

Rh2(oct)4 PhI(OAc)2 MgO

O O S HN O

84%

Ph

Ph

Intermolecular versions have more recently been developed. The combination of a chiral rhodium catalyst and a chiral sulfonimidamide gives the corresponding product in high diastereoselectivity.142 This methodology works for allylic, benzylic, and even unactivated C–H functionalization. The resulting products can by hydrolyzed to generate the corresponding amine. TsN O HN S

3 mol% cat. 1.2 equiv "amine" 1.4 equiv PhI(OCOtBu)2 DCM/MeOH 3: 1 88% yield 99% de

Me

O N H Me Cat. = Rh2{(S)-nta}4 =

O

"amine" = O O Rh Rh

O NTs S NH2

Me

10.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent 10.4.1

Oxidation of Alcohols to Aldehydes and Ketones

The oxidation of alcohols to the corresponding aldehydes, ketones, or carboxylic acid derivatives is one of the most commonly utilized chemical transformations in organic synthesis and remains an active research area for the identification of more effective and practical methods.143,144,145,146 This is due in part to the development and availability of a plethora of orthogonal protecting groups for alcohols that often allow for chemoselective deprotection

Table 10.1 Preferred methods for oxidation of alcohols.

Preference

Primary alcohol to aldehyde

Primary alcohol to acid

Secondary alcohol to ketone

1

TEMPO

TEMPO/NaClO2

Moffat

2

SO3 ⋅pyridine

Catalytic metal mediated

TEMPO

3

Moffatt

Stoichiometric metal

SO3 ⋅pyridine

4

Catalytic metal mediated

Catalytic metal mediated

5

Stoichiometric metal

Stoichiometric metal

142 143 144 145 146

Liang, C.; Collet, F.; Robert-Peillard, F.; Müller, P.; Dodd, R. H.; Dauban, P. Journal of the American Chemical Society 2008, 130, 343–350. Kwon, M. S.; Kim, N.; Park, C. M.; Lee, J. S.; Kang, K. Y.; Park, J. Organic Letters 2005, 7, 1077–1079. Matano, Y.; Hisanaga, T.; Yamada, H.; Kusakabe, S.; Nomura, H.; Imahori, H. The Journal of Organic Chemistry 2004, 69, 8676–8680. Mori, K.; Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Journal of the American Chemical Society 2004, 126, 10657–10666. See Note 52.

10.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent

of the desired alcohol prior to its oxidation to the required derivative.147 For the oxidation of primary alcohols, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) has become the reagent of choice in industry. Moffatt and modified Moffatt processes are also very useful for the oxidation of primary alcohols and are the method of choice for secondary alcohols. It is rarely necessary to resort to stoichiometric metal oxidations with the wide range of oxidants available, but there are a number of effective catalytic metal reagents available for alcohol oxidation if necessary (Table 10.1). 10.4.1.1

TEMPO-Mediated Processes

TEMPO148 is a hydroxyl radical catalyst that is successful under mild conditions, generally at room temperature, using inexpensive co-oxidants such as bleach (NaOCl). It can be chemoselective for a primary alcohols149 and is not prone to over-oxidation under the appropriate conditions. TEMPO is particularly effective for the preparation of chiral α-amino and α-alkoxy aldehydes.150 CbzHN

OH

TEMPO NaBr, NaOCl NaHCO3 Several examples

Ph

CbzHN

CHO

Ph

51–96% yield >95% ee

Because the oxidation is significantly slower on secondary alcohols, TEMPO-mediated oxidations do not have the same frequency of use for large-scale preparation of ketones from secondary alcohols as do Moffatt-type oxidations.151 While NaOCl has been the most utilized co-oxidant in the industry, other alternatives such as CuCl in the presence of oxygen152 and iodine153 have also been employed. 10.4.1.2

Moffatt and Modified-Moffatt Processes

The Moffatt oxidation, originally introduced in 1965,154 has proven to be one of the methods of choice for the preparation of ketones from secondary alcohols. Conditions are listed in Table 10.2. This procedure has the advantage of generating an oxosulfenium ion that is deprotonated under mild conditions. A unique feature to these procedures is that the oxidation occurs in a stepwise manner, and the aldehyde or ketone products are not produced until the second stage of the process when excess oxidant is not present to further oxidize the substrate. For primary alcohols particularly, the SO3 ⋅pyridine activating agent is the easiest and most practical to use, as cryogenic temperatures are not needed and additional reagent can be used to push the reaction to completion. In cases where a more reactive oxidant is needed, such as secondary alcohols, the most practical method experimentally is to premix the alcohol and dimethyl sulfoxide (DMSO) in solvent, and add the activating agent to the cooled solution: a “reverse addition order” Moffatt. Trifluoroacetic anhydride (TFAA) is the best-activating agent in this case as gaseous byproducts are not produced in the reaction. If off-gassing is not a concern, oxalyl chloride and thionyl chloride also work very well. In some cases, substrates prone to side reactions require a screen of activating agents. Some useful ones are shown in Table 10.2. The Swern modification,155 utilizing oxalyl chloride as the activating agent, has been used extensively in the pharmaceutical industry.156

HO

147 148 149 150 151 152 153 154 155 156

OBn

(i) (COCl)2, DMSO (ii) Et 3N 90%

OHC

OBn

Greene, T. W.; Wuts, P. G. M. 1991, 10–175. De Nooy, A. E. J.; Besemer, A. C.; Van Bekkum, H. Synthesis 1996, 1153–1174. Semmelhack, M. F.; Chou, C. S.; Cortes, D. A. Journal of the American Chemical Society 1983, 105, 4492–4494. Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Letters 1992, 33, 5029–5032. Urban, F. J.; Anderson, B. G.; Orrill, S. L.; Daniels, P. J. Organic Process Research & Development 2001, 5, 575–580. Ernst, H. Pure and Applied Chemistry 2002, 74, 2213–2226. Miller, R. A.; Hoerrner, R. S. Organic Letters 2003, 5, 285–287. Pfitzner, K. E.; Moffatt, J. G. Journal of the American Chemical Society 1965, 87, 5661–5670. Mancuso, A. J.; Huang, S.-L.; Swern, D. The Journal of Organic Chemistry 1978, 43, 2480–2482. See Note 45.

537

538

10 Oxidations

Table 10.2 Activating agents used in Moffat processes. Activating agent DCC

PhPCl2

Advantage

Product

O H NHAc

Chemoselective oxidation of an alcohol in the presence of a thioether

S

Yield (%)

157

60

158

>82

159

78

160

75

161

52

H

O

Me

Oxidation of a very sensitive substrate

References

OMe

O O

OMe

Me

Me

O

Me

O

O H

Me

O

O

Me

Me

O

OH O H

Me O

O O

Acetic anhydride

α-Chloroketone was the sole product when using oxalyl chloride

Ms N

MeO

N

O

N

NO2 P2 O5

Inexpensive reagent, cryogenic conditions not required, MTM ether formation minimized

HN O Et

O S

O N O

Trifluoroacetic anhydride

By-products observed with oxalyl chloride

CHO CHO OHC Me Me Me 157 Confalone, P. N.; Baggiolini, E.; Hennessy, B.; Pizzolato, G.; Uskokovic, M. R. The Journal of Organic Chemistry 1981, 46, 4923–4927. 158 Cvetovich, R. J.; Leonard, W. R.; Amato, J. S.; DiMichele, L. M.; Reamer, R. A.; Shuman, R. F.; Grabowski, E. J. J. The Journal of Organic Chemistry 1994, 59, 5838–5840. 159 See Note 166. 160 Carpenter, D. E.; Imbordino, R. J.; Maloney, M. T.; Moeslein, J. A.; Reeder, M. R.; Scott, A. Organic Process Research & Development 2002, 6, 721–728. 161 Izumi, H.; Futamura, S. The Journal of Organic Chemistry 1999, 64, 4502–4505.

10.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent

A number of activating agents have been used in place of oxalyl chloride to prevent problems such as CO and CO2 formation, and the formation of methylthiomethyl ethers (MTM ethers) (Table 10.2). Operationally, a process in which the activating agent is added to a solution of all of the other reactants at reaction temperature is the simplest to execute. The rate of reaction of the activating agents with DMSO is so much higher than with the alcohols that acylated by-products are not seen. All of the procedures in Table 10.2 require cryogenic temperatures with the exception of the P2 O5 procedure, suggesting that a different mechanistic pathway is operative with this activating agent. This makes the P2 O5 protocol comparable to the Parikh–Doering process described below. One process that has gained popularity in industry is the Parikh–Doering oxidation, which is the use of DMSO activated with the SO3 ⋅pyridine complex.162 This reagent has the practicality of being a solid and offers the advantage that the reaction can be carried out at or near room temperature. This also provides the flexibility to charge additional reagent in the case of an incomplete reaction due to the compatibility of the reactive intermediate with amine bases. For example, phenyl alaninol was oxidized to the corresponding aldehyde on a 190 kg scale without any loss of the chiral purity as part of the synthesis of an HIV protease inhibitor.163 SO3 • pyr, DMSO Et3N

Ph Bn2N

OH

>95% yield 99.9% ee

Ph Bn2N

CHO

This reagent is significantly less reactive than intermediates generated in the examples in Table 10.1, and requires extended reaction times at elevated temperature for the oxidation of secondary alcohols. Its use has been documented by Boehringer Ingelheim as a convenient procedure for the preparation of 2-hydroxy-3-pinanone in two steps from α-pinene.164 OH Me Me

OH

SO3• pyr, DMSO Et3N >76%

Me

O Me Me

OH Me

Another modification of the Moffatt oxidation is the Corey–Kim protocol165 where the chlorosulfenium ion is generated by oxidation of dimethyl sulfide by either chlorine or NCS.166 OH C7H15

10.4.1.3

TMS

(i) NCS, DMS (ii) Et 3N 64%

O C7H15

TMS

Metal-Mediated Processes

Metal-mediated oxidations were of primary importance before 1980, prior to the introduction of more environmentally friendly methods. In recent years, the use of a metal catalyst to promote oxidation has gained in popularity, especially in the case of secondary alcohols that cannot over-oxidize. One such example is tetra-n-propyl ammonium perruthenate (TPAP)167 that is capable of selective oxidation of a very sensitive macrolide using N-methylmorpholine N-oxide (NMO) as the cooxidant.168

162 Parikh, J. R.; Doering, W. v. E. Journal of the American Chemical Society 1967, 89, 5505–5507. 163 Liu, C.; Ng, J. S.; Behling, J. R.; Yen, C. H.; Campbell, A. L.; Fuzail, K. S.; Yonan, E. E.; Mehrotra, D. V. Organic Process Research & Development 1997, 1, 45–54. 164 Krishnamurthy, V.; Landi, J., Jr.; Roth, G. P. Synthetic Communications 1997, 27, 853–860. 165 Corey, E. J.; Kim, C. U. Journal of the American Chemical Society 1972, 94, 7586–7587. 166 Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y. M.; Szczepanski, S. W. The Journal of Organic Chemistry 1985, 50, 5393–5396. 167 Ares, J. J.; Outt, P. E.; Kakodkar, S. V.; Buss, R. C.; Geiger, J. C. The Journal of Organic Chemistry 1993, 58, 7903–7905. 168 Jones, A. B. The Journal of Organic Chemistry 1992, 57, 4361–4367.

539

540

10 Oxidations

Me

Me Me HO

Me OR1

O O

Me OR2 Me

Me O Me

Me O

TPAP NMO

Me OR1

O O

Me OR2 Me

Me

59%

O Me

O

O

Another efficient catalytic reagent is RuO4 , usually generated from RuCl3 and a cooxidant. It is only suitable for oxidation of secondary alcohols, since primary alcohols produce a carboxylic acid. Approximately 1 mol% of ruthenium is employed, usually in aqueous acetonitrile, and the preferred cooxidant is sodium bromate (NaBrO3 ) due to its reactivity, cost, and innocuous side products.169 An acidic buffer such as acetic acid can be employed if the substrate or product is sensitive to the high pH resulting from the cooxidant.170 In another metal-mediated oxidation, catalytic amounts of Na2 WO4 in the presence of H2 O2 have been demonstrated as an effective oxidant of secondary alcohols in the presence of a phase transfer catalyst. It also proved to be chemoselective for secondary over primary alcohols as demonstrated in the oxidation below.171 O

R R

O

RuCl3 NaBrO3 R = Ts 95% R = H 99%

OH

OH Me

O

O

O

Na2WO4, H2O2 R4NHSO4

OH

R R

O

Me

OH

83% 16 examples

Me

Me

Reagents such as chromium trioxide (CrO3 ) in pyridine,172 pyridinum chlorochromate (PCC),173 and pyridinum dichromate (PDC)174 have been used extensively in academia but sparsely in industry. One example of such a process has been demonstrated in the preparation of an α-amino aldehyde using CrO3 in pyridine without loss of chiral purity.175 Me Me

NHBoc OH

CrO3 pyridine 67% >99.5% ee

Me Me

NHBoc CHO

There are few stoichiometric metal-mediated oxidations of secondary alcohols reported from process groups since 1980. A classic example is the oxidation below using CrO3 in the Merck synthesis of cortisone.176 These processes are not recommended. Me OH Me Me EtO2CO

169 170 171 172 173 174 175 176

H

CO2Me

Me O Me CrO3

Me

95% EtO2CO

CO2Me

H

Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D., III; Volante, R. P. Synthetic Communications 2000, 30, 3171–3180. Belyk, K. M.; Leonard, W. R., Jr.; Bender, D. R.; Hughes, D. L. The Journal of Organic Chemistry 2000, 65, 2588–2590. Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. Journal of the American Chemical Society 1997, 119, 12386–12387. Salman, M.; Babu, S. J.; Kaul, V. K.; Ray, P. C.; Kumar, N. Organic Process Research & Development 2005, 9, 302–305. Corey, E. J.; Suggs, J. W. Tetrahedron Letters 1975, 2647–2650. Corey, E. J.; Schmidt, G. Tetrahedron Letters 1979, 399–402. Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.; Evans, B. E. The Journal of Organic Chemistry 1982, 47, 3016–3018. Pines, S. H. Organic Process Research & Development 2004, 8, 708–724.

10.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent

10.4.1.4

Alternative Methods

The Dess–Martin reagent177 is rarely used on a large scale for a variety of reasons, but an example is shown below.178 OBn BnO

OBn

Dess–Martin periodinane

H

BnO

CH2Cl2, rt

OBn

H OBn

77%

OH

O

OBn

OBn

An interesting oxidation of the cholic acid derivative below was accomplished on 17 kg scale by simply using aqueous NaOCl179 in the presence of KBr in a mixture of EtOAc and water. This procedure afforded a 92% yield of the desired ketone.180 Me HO Me

CO2Me

Me

Me O Me

KBr NaOCl

CO2Me

Me

92% AcO

OAc

AcO

OAc

Another oxidation that is seldom used on a large scale is the Oppenauer oxidation. In general, this procedure suffers from the fact that a large excess of a sacrificial ketone must be employed in order to drive the equilibrium toward the substrate oxidation, and that it is difficult to drive the reaction to completion despite long reaction times. A large number of catalysts for the Oppenauer oxidation have been reported; below is an example using potassium t-butoxide as the catalyst and benzophenone as the hydride acceptor. In this case, the reaction is driven to completion following oxidation by retro-aldol reaction to form the relatively stable enolate that does not undergo reduction under the reaction conditions.181 OH HN

MeS

OH O

O

t-BuOK PhCOPh 70%

HN

MeS

Ph

Ph

10.4.1.5

O

Oxidation of Benzylic and Allylic Alcohols

MnO2 Oxidation Manganese dioxide has been used for the preparation of a key intermediate in the synthesis of

isotretinoin at 1 kg scale in >95% yield.182

Me

Me

Me

CH2OH Me

MnO2 >95%

Me

Me

Me

CHO Me

DDQ Oxidation Oxidations using DDQ for the preparation of aldehydes and ketones are rare. One reported example

is the preparation of a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor side-chain through the chemoselective oxidation of an allylic alcohol in the presence of a secondary alcohol in a very sensitive product.183

177 Dess, D. B.; Martin, J. C. The Journal of Organic Chemistry 1983, 48, 4155–4156. 178 Sarma, D. N.; Sharma, R. P. Chemistry & Industry 1984, 712–713. 179 Stevens, R. V.; Chapman, K. T.; Weller, H. N. The Journal of Organic Chemistry 1980, 45, 2030–2032. 180 Arosio, R.; Rossetti, V.; Beratto, S.; Talamona, A.; Crisafulli, E. Process for the production of chenodeoxycholic and ursodeoxycholic acids EP1991 19 pp. 181 Horak, V.; Moezie, F.; Klein, R. F. X.; Giordano, C. Synthesis 1984, 839–840. 182 See Note 172. 183 Tempkin, O.; Abel, S.; Chen, C.-P.; Underwood, R.; Prasad, K.; Chen, K.-M.; Repic, O.; Blacklock, T. J. Tetrahedron 1997, 53, 10659–10670.

541

542

10 Oxidations

i-Pr N R

CO2t-Bu OH OH

R

DDQ

CO2t-Bu O

70%

R=

OH F

10.4.1.6

Oxidation of Diols to Lactones, Selective Oxidation of Primary or Secondary Alcohols

In some cases, diols can be oxidized to the lactone with selectivity for oxidation at primary vs. secondary alcohols. The reaction proceeds via oxidation to the aldehyde, hemiacetal formation, and oxidation of the hemiacetal to the lactone. This transformation can be achieved with a variety of reagents. An example using TEMPO as the oxidant was used in a complex total synthesis.184 Sodium bromite has also been reported as a cooxidant with TEMPO.185 OH Boc Me N Me O

Me

Me OH OH

OH

TEMPO (AcO)2IPh

Boc Me N

95%

Me

Me

Me O

O

Me

Me O

Another oxidant that has been reported to accomplish this type of transformation is TCCA.186 Sodium bromite alone has been reported to oxidize diols to the lactol without further oxidation to the lactone.187 Me

OH OH

10.4.2.1

H

53%

O OH

HOAc

Me Me

10.4.2

Me

NaBrO2

Br

Me Me

Oxidation of Primary Alcohols to Carboxylic Acids TEMPO/Sodium Chlorite Oxidation of Alcohols to Carboxylic Acids and Derivatives

Primary alcohols can be directly oxidized to carboxylic acids in a single operation by tandem oxidation to the aldehyde with TEMPO followed by a second oxidation with NaClO2 .188 O

O TEMPO NaOCl NaH2PO4 NaClO2

O Bu

N

CO2H OH

>90%

O Bu

N

CO2H CO2H

Me OMe

Me OMe

184 Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Letters 2002, 44, 57–59. 185 Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. The Journal of Organic Chemistry 1990, 55, 462–466. 186 Hiegel, G. A.; Gilley, C. B. Synthetic Communications 2003, 33, 2003–2009. 187 See Note 105. 188 Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen, D. M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer, R.; Volante, R.; Grabowski, E. J.; Dolling, U. H.; Reider, P. J.; Okada, S.; Kato, Y.; Mano, E. The Journal of Organic Chemistry 1999, 64, 9658–9667.

10.5 Oxidation of Aldehydes to Carboxylic Acids and Derivatives

10.4.2.2

Metal-Mediated Oxidation of Alcohols to Carboxylic Acids and Derivatives

As stated in previous sections, noncatalytic metal-mediated oxidations have the disadvantage of generating a large waste effluent and often lead to difficult workups that are cumbersome at scale. KMnO4 in the presence of a phase-transfer catalyst proved to be efficient in the preparation of pentafluoropentanoic acid.189 A procedure for the oxidation of primary and secondary alcohols using a catalytic amount of chromium trioxide and 2.5 equiv of periodic acid has also been developed.190 As a last ditch effort, a Jones oxidation protocol can be employed, but this process is not recommended.191

10.5 Oxidation of Aldehydes to Carboxylic Acids and Derivatives 10.5.1

Sodium Chlorite Oxidation of Aldehydes to Carboxylic Acids and Derivatives

Probably the most practical method for the oxidation of an aldehyde to the carboxylic acid is sodium chlorite in the presence of a hypochlorite and chlorine scavenger such as sulfamic acid or an electron-rich olefin or arene. In the example shown, H2 O2 is used as the hypochlorite and chlorine scavenger.192 While it seems counterintuitive to use an oxidant to eliminate hypochlorite and chlorine, H2 O2 reacts with HOCl to produce HCl, H2 O, and O2 , which are innocuous side products. For substrates not prone to chlorination, no chlorine scavenger is necessary.193 Cl CHO

NaClO2 NaH2PO4• 2H2O 30% H2O2

O

CHO O

N

CO2H

>85%

Me

N

Cl

Me

NaClO2 NaH2PO4

N

tBuOH, H2O

O

89%

N

10.5.1.1

N

CO2H O

N

Hydrogen Peroxide Oxidation of Aldehydes to Carboxylic Acids and Derivatives

Hydrogen peroxide has been reported as a safe and effective reagent for the preparation of a benzoic acid intermediate. The benzaldehyde below could be oxidized under a variety of conditions, and NaClO2 proved to be acceptable in the presence of sulfamic acid (NH2 SO3 H). However, chlorination of the aromatic ring was observed and could not be eliminated. In order to circumvent this problem, H2 O2 under basic conditions was identified as an inexpensive alternative for the preparation.194 MeO O

10.5.1.2

CHO

NaOH H2O2

MeO

89%

O

CO2H

Metal-Mediated Oxidations of Aldehydes to Carboxylic Acids and Derivatives

For reasons discussed previously, noncatalytic metal-mediated processes are now used infrequently in oxidations performed on a large scale. These processes are not recommended. Some exceptions are shown.195,196 189 Mahmood, A.; Robinson, G. E.; Powell, L. Organic Process Research & Development 1999, 3, 363–364. 190 Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Letters 1998, 39, 5323–5326. 191 Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. The Journal of Organic Chemistry 1986, 51, 3140–3143. 192 Lopez, F. C.; Shankar, A.; Thompson, M.; Shealy, B.; Locklear, D.; Rawalpally, T.; Cleary, T.; Gagliardi, C. Organic Process Research & Development 2005, 9, 1003–1008. 193 Ruggeri, S. G.; Bill, D. R.; Bourassa, D. E.; Castaldi, M. J.; Houck, T. L.; Ripin, D. H. B.; Wei, L.; Weston, N. Organic Process Research & Development 2003, 7, 1043–1047. 194 Cook, D. C.; Jones, R. H.; Kabir, H.; Lythgoe, D. J.; McFarlane, I. M.; Pemberton, C.; Thatcher, A. A.; Thompson, D. M.; Walton, J. B. Organic Process Research & Development 1998, 2, 157–168. 195 Wuts, P. G. M.; Ritter, A. R. The Journal of Organic Chemistry 1989, 54, 5180–5182. 196 Raggon, J. W.; Welborn, J. M.; Godlewski, J. E.; Kelly, S. E.; LaCour, T. G. Organic Preparations and Procedures International 1995, 27, 233–236.

543

544

10 Oxidations

Cl

Cl

KMnO4, 67% or AgNO3, NaOH, 72%

CHO

S

CO2H

S

O

HO Me O

Me O Me H

O

PDC

H

Me

97%

H

H

H

O

H

O

O

10.5.1.3

Oxidation of Bisulfite Adducts

The bisulfite addition adducts of aldehydes can be oxidized to the carboxylic acid under modified Moffat conditions.197 OH Me

O Me

SO3Na

OH

DMSO, Ac2O 67%

Cl

10.5.2

Cl

Oxidation of Carboxylic Acids to Peroxyacids

The oxidation of carboxylic acids to the peroxyacid is generally accomplished in situ in the course of running oxidation reactions, as the peroxyacids tend to be thermally unstable. Formic acid reacts almost instantly with hydrogen peroxide to generate performic acid; acetic acid requires prolonged heating with hydrogen peroxide to accomplish the same transformation. The reaction of acid chlorides or anhydrides with hydrogen peroxide very quickly generates the peroxyacid. Examples of in situ peroxy acid formation can be found in Sections 10.7.10 (Table 10.3, examples 2 and 3), “Peracid Oxidations”, and “Peroxide-Based Reagents” on the oxidation of nitrogen and sulfur.

10.5.3

Oxidation of Phenols and Anilines to Quinones

Galanthamine was synthesized from a fairly simple substrate via an intramolecular oxidative aromatic coupling reaction on 12 kg scale; the oxidation was achieved using K2 [Fe(CN)6 ].198 OH

O K3[Fe(CN)6] K2CO3

OH MeO

40% N Br

CHO

H O MeO N Br

CHO

197 Wuts, P. G. M.; Bergh, C. L. Tetrahedron Letters 1986, 27, 3995–3998. 198 Kueenburg, B.; Czollner, L.; Froehlich, J.; Jordis, U. Organic Process Research & Development 1999, 3, 425–431.

10.5 Oxidation of Aldehydes to Carboxylic Acids and Derivatives

An oxidation followed by reduction was used to demethylate a methyl phenyl ether.199 Following Cbz deprotection, a second phenol to quinone oxidation was effected with Fremy’s salt [NO(SO3 Na) or NO(SO3 K)] to afford the benzodiazepine. OMe

O

Me N

CbzHN OMe

R

CAN

O

Me

OH

CO2Me

N

Fremy’s salt

56%

Me N

10.5.4

Me N

O

O CO2Me

N H

CO2Me

CbzHN OH

O

HO

O

N

O CO2Me

Oxidation 𝛂 to Oxygen and Nitrogen

Although it is known that simple ethers will oxidize via a radical mechanism to form hazardous peroxides, there are few synthetically useful examples. One such example is the oxidation of an acetal to an ester using ozone.203 Interestingly, if the ozonolysis is prolonged, the primary alcohol will slowly oxidize to the carboxylic acid. F

F OH

O3 O BocHN

O

EtOAc >59%

O

BocHN

O

O

O

Ethers can be oxidized to the corresponding ester using ruthenium tetroxide.204 C9H19

OMe

O

NaIO4, RuCl3 83%

C9H19

OMe

N-acylamines can also be oxidized by the combination of ruthenium tetroxide and sodium periodate.205 Amines can also be oxidized using transition metals including ruthenium206 and iron207 catalysts. A metal-free system uses iodine as the oxidant.208 7.5 equiv I2 NaHCO3 N

199 200 201 202 203 204 205 206 207 208

THF/H2O 96%

N O

Hayes, J. F. Synlett 1999, 865–866. Payack, J. F.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. The Journal of Organic Chemistry 2005, 70, 175–178. Nettekoven, M.; Jenny, C. Organic Process Research & Development 2003, 7, 38–43. Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Letters 2000, 41, 2299–2302. Urban, F. J.; Jasys, V. J. Organic Process Research & Development 2004, 8, 169–175. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. The Journal of Organic Chemistry 1981, 46, 3936–3938. Kaname, M.; Yoshifuji, S.; Sashida, H. Tetrahedron Letters 2008, 49, 2786–2788. Khusnutdinova, J. R.; Ben-David, Y.; Milstein, D. Journal of the American Chemical Society 2014, 136, 2998–3001. Legacy, C. J.; Wang, A.; O’Day, B. J.; Emmert, M. H. Angewandte Chemie International Edition 2015, 54, 14907–14910. Griffiths, R. J.; Burley, G. A.; Talbot, E. P. A. Organic Letters 2017, 19, 870–873.

545

546

10 Oxidations

10.6 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent 10.6.1

Dehydrogenation of Amines to Imines and Nitriles

Oxidation of a hydrazide to the corresponding hydrazone under Swern conditions has been reported.209 Oxidation of a cephalosporin to the 7α-formamido cephalosporin via oxidation of the imine to a quinone210 has been carried out on 1 kg scale. (i) DMSO, TFAA (ii) Et3N

Barium permanganate can also be used.211 O NH2

Ba(MnO4)2 75%

H

Oxidation of primary amines to the corresponding nitrile has been reported under a variety of mild conditions. In the example shown, TCCA with catalytic TEMPO was used to dehydrogenate benzylamine to benzonitrile in 90% yield.212 NH2

TCCA, TEMPO 10 °C

N

90%

Other systems reported to effect the same transformation include catalytic Ru/Al2 O3 213 or Cu214 with O2 as the oxidant, the use of iodosobenzene,215 and electrochemical methods.216,217,218 10.6.1.1

Oxidation 𝛂 to Nitrogen

The Nef reaction is the conversion of a primary or secondary alkylnitro compounds to the corresponding aldehyde or ketone.219 The transformation can be accomplished under oxidative, hydrolytic, or reductive conditions, but regardless of the method, a net oxidation at carbon is achieved.

209 Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185. 210 Berry, P. D.; Brown, A. C.; Hanson, J. C.; Kaura, A. C.; Milner, P. H.; Moores, C. J.; Quick, J. K.; Saunders, R. N.; Southgate, R.; Whittall, N. Tetrahedron Letters 1991, 32, 2683–2686. 211 Firouzabadi, H.; Seddighi, M.; Mottaghinejad, E.; Bolourchian, M. Tetrahedron 1990, 46, 6869–6878. 212 Chen, F.-E.; Kuang, Y.-y.; Dai, H.-f.; Lu, L.; Huo, M. Synthesis 2003, 2629–2631. 213 Yamaguchi, K.; Mizuno, N. Angewandte Chemie, International Edition 2003, 42, 1480–1483. 214 Capdevielle, P.; Lavigne, A.; Maumy, M. Synthesis 1989, 453–454. 215 Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Ochiai, M.; Inenaga, M.; Nagao, Y. Tetrahedron Letters 1988, 29, 6913–6916. 216 Feldhues, U.; Schaefer, H. J. Synthesis 1982, 145–146. 217 See Note 149. 218 Shono, T.; Matsumura, Y.; Inoue, K. Journal of the American Chemical Society 1984, 106, 6075–6076. 219 Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047.

10.6 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent

R

R

NO

NOH

Reduction

R

NO2

R

rol

d Hy

Base N+

R

O−

O

is

ys

Oxidant

OH

O−

R

NO2

The method of choice will depend on functional group compatibility with the various reaction conditions. Hydrolytic conditions are reported with hydroxide base followed by sulfuric acid as the hydrolyzing agent.220 Although significantly slower, the transformation can be accomplished in wet acetonitrile with 8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as the base.221 Reductive conditions typically involve alkoxide base and TiCl3 .222 Oxidative conditions also use strong base, hydroxide or alkoxide, and an oxidant such as KMnO4 ,223 DMDO, Oxone, H2 O2 , and TPAP. NO2 OAc AcO

OH

(i) Ba(OH)2 (ii) H2SO4 OAc

O HO

86%

OH OH

OAc

Carbamates can be oxidized to form the N-acylimminium ion electrochemically,224 or through the use of strong oxidants. The product is the α-alkoxy carbamate in the case of electrochemical oxidation, and the imide in the case of Dess–Martin periodinane.225 −2e, MeOH

N O

OMe

O Ph

N

Me

H

O

Dess–Martin 98%

OMe

N

78–83%

OMe O

Ph

O N

Me

H

1,2,4-Triazenes can be oxidized to 1,2,4-triazoles using hypochlorites, Dess–Martin periodinane, and TPAP.226 PhHN N

N H

Ph N

[O] Ph Reagent NaOCl Ca(OCl)2 Dess-Martin TPAP

220 221 222 223 224 225 226

N Yield 45% 63% 52% 45%

N N Ph

N

Grethe, G.; Mitt, T.; Williams, T. H.; Uskokovic, M. R. The Journal of Organic Chemistry 1983, 48, 5309–5315. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Letters 2002, 43, 5233–5235. Hauser, F. M.; Baghdanov, V. M. The Journal of Organic Chemistry 1988, 53, 4676–4681. Steliou, K.; Poupart, M. A. The Journal of Organic Chemistry 1985, 50, 4971–4973. Shono, T.; Matsumura, Y.; Tsubata, K. Organic Syntheses 1985, 63, 206–213. Nicolaou, K. C.; Mathison, C. J. N. Angewandte Chemie, International Edition 2005, 44, 5992–5997. Paulvannan, K.; Hale, R.; Sedehi, D.; Chen, T. Tetrahedron 2001, 57, 9677–9682.

547

548

10 Oxidations

10.6.1.2

Oxidation of Aldoximes and Hydrazones of Aldehydes

Aldoximes can be oxidized to the corresponding nitrile oxide by chlorination followed by elimination with base. Although the nitrile oxides are unstable, they can be trapped with alkenes or alkynes to form isoxazolines and isoxazoles, respectively. To synthesize isoxazole, the acetaldoxime was oxidized to the corresponding nitrile oxide which then reacted with methyl propiolate.227 HO

Cl2, HCl methyl propiolate

N

H

O

MeO2C

N

70%

Me

Me

Hydrazones of aldehydes can be oxidized using NCS.228 PhHN H

PhHN

NCS, DMS

N Ph

N Ph

Cl

70%

10.7 Oxidation of Nitrogen Functionalities 10.7.1

Diazotization of Amines

The most common nitrogen oxidation run on large scale in the literature is diazotization of an aniline. In general, the diazo compound is not isolated, and reacted in situ, although in a few rare cases isolations were reported. In almost every case, the diazotization is run using NaNO2 in mineral acid as the oxidant. Trifluoroacetic acid (TFA) can be used as the acid as well. A rarely used alternative to NaNO2 is t-amyl nitrite, but stability of the reagent is a concern. Several examples are provided below, categorized by the manner in which the intermediate is trapped. Reaction following diazotization

Scheme

O

H N

HN H2N

O NH2

HN

51%

N

H2N

N

(i) NaNO2 , HCl; (ii) H3 PO2 , CuSO4 or H2 , Ni, HCl

229

Halogenation

NaNO2 , HBr, KBr

230

Cyanation

(i) NaNO2 , H2 SO4 ; (ii) CuCN, NaCN

231

Electrophilic aromatic substitution (Pschorr ring closure)

NaNO2

232

CO2H

O

NH2

Br

N O

O CF3

CF3 50%

H2N

NC

Cl

Cl

O

O Me

Br

Reduction S

CO2H N

References

H N

S O

Reagents used

H2N

Me 73%

Br

H3 PO4

227 Bell, D.; Crowe, E. A.; Dixon, N. J.; Geen, G. R.; Mann, I. S.; Shipton, M. R. Tetrahedron 1994, 50, 6643–6652. 228 Paulvannan, K.; Chen, T.; Hale, R. Tetrahedron 2000, 56, 8071–8076.

10.7 Oxidation of Nitrogen Functionalities

Reaction following diazotization

Scheme

N NH2 O2 N

OMe

O2N

NH2

Beech reaction

OMe

CO2H SO3H

SO3H

Carbonylation 88% OMe

References

(i) NaNO2 , HCl; (ii) NH2 OH⋅HCl, (CH2 O)n , CuSO4 , Na2 SO3 , NaOAc (i) NaNO2 , HCl; (ii) H2 NSO3 H, PdCl2 , CO, H2 O

233

OH H

24%

Reagents used

OMe

234

F3C

F3C

HBr

N

N

93%

O

Me

Me OH

NH2

AcHN

10.7.2

235

Hydroxylation

NaNO2 , H2 SO4

236

Reduction

(i) NaNO2 , HCl; (ii) Na2 SO3

237

SO2Cl

NH2

HO

(i) NaNO2 , HCl, HOAc; (ii) SO2 , CuCl

S

S

Me

Sulfonylation

Cl

Me

56%

OH OH

HO

Cl

O

H2NHN

Cl

Cl

Oxidations of Hydrazines and Hydrazones

The majority of examples of hydrazine oxidation on a large scale are run in the context of Curtius rearrangements (see Section 7.2.3.2) wherein the acyl azide is generated by oxidation of an acyl hydrazine. The ergoline derivative below was synthesized via hydrazine oxidation with sodium nitrite to form the intermediate acyl azide, followed by heating to effect rearrangement.238 O H H

HN

NHNH2

NMe H

H

NaNO2 H2SO4

H

78%

NH2 NMe H

HN

229 De Jong, R. L.; Davidson, J. G.; Dozeman, G. J.; Fiore, P. J.; Giri, P.; Kelly, M. E.; Puls, T. P.; Seamans, R. E. Organic Process Research & Development 2001, 5, 216–225. 230 Bunegar, M. J.; Dyer, U. C.; Green, A. P.; Gott, G. G.; Jaggs, C. M.; Lock, C. J.; Mead, B. J. V.; Spearing, W. R.; Tiffin, P. D.; Tremayne, N.; Woods, M. Organic Process Research & Development 1998, 2, 334–336. 231 Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Organic Process Research & Development 2004, 8, 1059–1064. 232 See Note 114. 233 Herr, R. J.; Fairfax, D. J.; Meckler, H.; Wilson, J. D. Organic Process Research & Development 2002, 6, 677–681. 234 Siegrist, U.; Rapold, T.; Blaser, H.-U. Organic Process Research & Development 2003, 7, 429–431. 235 See Note 55. 236 Storz, T.; Dittmar, P.; Fauquex, P. F.; Marschal, P.; Lottenbach, W. U.; Steiner, H. Organic Process Research & Development 2003, 7, 559–570. 237 Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. The Journal of Organic Chemistry 2001, 66, 5772–5782. 238 Baenziger, M.; Mak, C. P.; Muehle, H.; Nobs, F.; Prikoszovich, W.; Reber, J. L.; Sunay, U. Organic Process Research & Development 1997, 1, 395–406.

549

550

10 Oxidations

Hydrazones can be oxidized to the corresponding azo compound using a variety of oxidants including NaOCl, I2 , H2 O2 , and AcOOH. However, there are few examples of these reagents being used. An oxidation of an N—N bond leading to aromatization was accomplished using bromine or sodium nitrite.239 HN t-Bu

H N N

Br2 or NaNO2

SMe

N

20–30%

N

t-Bu

N N

SMe N

Oximes can be oxidized to the diazo compound with the use of H2 NCl.240 Me O Me

H

H

Me O H2NCl

NOH

Me

55–64%

H

HO

N2

H

H

H

HO

10.7.3

Amination of Nitrogen

Although diazotization is the most common method in the literature for conversion of N—H to N—N bonds, electrophilic sources of nitrogen have also been reported. The O-nitroarylhydroxylamine shown was found to be a useful source of electrophilic nitrogen.241 Several related hydroxylamines were evaluated from a safety and yield perspective. O F

O NH

F

N

F

K2CO3

O

NO2

O H2N

Me

N

F

N

NH2 O

Me

83%

Oxaziridines can also be used to transfer nitrogen to an amine.242 O N H N O

Boc

NC

NHBoc N

Et2O 90%

O

Another reagent that can be used for this transformation is hydroxylamine-O-sulfonic acid.243 (i) H2NOSO3H K2CO3 (ii) HI N

239 240 241 242 243

63–72%

N + I− NH2

Fields, S. C.; Parker, M. H.; Erickson, W. R. The Journal of Organic Chemistry 1994, 59, 8284–8287. See Note 94. Boyles, D. C.; Curran, T. T.; Parlett, R. V. I. V.; Davis, M.; Mauro, F. Organic Process Research & Development 2002, 6, 230–233. See Note 108. Goesl, R.; Meuwsen, A. Organic Syntheses 1963, 43, 1–3.

10.7 Oxidation of Nitrogen Functionalities

10.7.4

Oxidation of Amines to Azo or Azoxy Compounds

Diazo compounds can be trapped by nucleophiles to form azo dyes. The enolate of ethyl 2-methylacetoacetate was utilized to trap p-methoxyphenyl azide as the azo intermediate in the example below.244 (i) NaNO2, HCl (ii) KOAc, NaOAc O Me

Me

NH2

MeO

O

O

OEt

O

Me N N

OEt

81%

Me

OMe

Benzotriazoles can be synthesized from o-diaminobenzenes through generation of the diazo compound followed by intramolecular trapping of the intermediate.245 NHMe NH2

HO2C

Me N

NaNO2

N N

HO2C

62%

Anilines can be converted to the corresponding azo compounds on treatment with oxidants. The dimeric azo compounds are produced when permanganate246 or hydrogen peroxide in acetic acid is used as the oxidant. Me

Ba(MnO4)2 NH2

Me

86%

N

N Me

Mixed azo compounds can be produced by trapping a diazotized aniline with a second aniline. 10.7.5

Oxidation of Primary Amines to Hydroxylamines

When a primary amine is alkylated with bromoacetonitrile, oxidized to the nitrone (as in the previous section), and reacted with hydroxylamine, the primary hydroxylamine is formed.247 Me

Me

NH2

NHOH 86%

BrCH2CN

NH2OH Me

Me N H

10.7.6

CN

m-CPBA

+

N O−

CN

Oxidation of Nitrogen to Nitroso Compounds

244 See Note 89. 245 De Knaep, A. G. M.; Vandendriessche, A. M. J.; Daemen, D. J. E.; Dingenen, J. J.; Laenen, K. D.; Nijs, R. L.; Pauwels, F. L. J.; Van den Heuvel, D. F.; Van der Eycken, F. J.; Vanierschot, R. W. E.; Van Laar, G. M. L. W.; Verstappen, W. L. A.; Willemsens, B. L. A. Organic Process Research & Development 2000, 4, 162–166. 246 See Note 211. 247 Tokuyama, H.; Kuboyama, T.; Fukuyama, T. Organic Syntheses 2003, 80, 207–218.

551

552

10 Oxidations

10.7.6.1

Nitrone Formation

Secondary amines can be converted to the corresponding nitrone using hydrogen peroxide catalyzed by Na2 WO4 248,249 or MeReO3 .250 The same transformation has been reported using meta-chloroperbenzoic acid (m-CPBA).251 NH

O− N+

m-CPBA 95% H2O2, Na2WO4

N H

Ph

N H

Me

Ph

+

N − O

62–70%

MeReO3 (0.5%) urea• H2O2

N+ O−

Ph

MeOH 97%

Me

Ph

Anilines can be oxidized to the corresponding nitroso derivative in a two-stage process using DMS/NBS followed by m-CPBA.252 NH2

(i) DMS, NCS, 71% (ii) m-CPBA, 44%

NO

N

N

10.7.6.2

Oxidation of Hydroxylamine to Nitroso Compounds

Tertiary or aryl hydroxylamines can be oxidized to the nitroso compound using NaOBr.253 Me Me

H N

OH

Me

NaOBr

Me

75–85%

Me

N

O

Me

Me

Me

O− N+ Me

Me Me N+ O−

Me

PCC254 and silver carbonate255 have also been utilized for this oxidation. Benzofurazans can be synthesized by oxidative cyclization from an o-nitroaniline using sodium hypochlorite as the oxidant.256 N

N N

O

N

NaOCl

O

>73% −O

O2N NH2

N+ O N

248 Stappers, F.; Broeckx, R.; Leurs, S.; Van den Bergh, L.; Agten, J.; Lambrechts, A.; Van den Heuvel, D.; De Smaele, D. Organic Process Research & Development 2002, 6, 911–914. 249 Murahashi, S.; Shiota, T.; Imada, Y. Organic Syntheses 1992, 70, 265–271. 250 Goti, A.; Cardona, F.; Soldaini, G. Organic Syntheses 2005, 81, 204–212. 251 See Note 247. 252 Taylor, E. C.; Tseng, C. P.; Rampal, J. B. The Journal of Organic Chemistry 1982, 47, 552–555. 253 Calder, A.; Forrester, A. R.; Hepburn, S. P. Organic Syntheses 1972, 52, 77–82. 254 Wood, W. W.; Wilkin, J. A. Synthetic Communications 1992, 22, 1683–1686. 255 Demeunynck, M.; Tohme, N.; Lhomme, M. F.; Lhomme, J. Journal of Heterocyclic Chemistry 1984, 21, 501–503. 256 See Note 193.

10.7 Oxidation of Nitrogen Functionalities

10.7.7

Nitrosation of Secondary Amines and Amides

Amides can be nitrosated using N2 O4, 257 ClNO,258 or N2 O3 259 (generated from H2 NO3 and NaNO2 ) to make the N-nitrosamide. These nitrosamides are useful in the nitrosamide decomposition (Section 7.3.4.4) to make the corresponding ester, or can be hydrolyzed much more easily than an amide. H N

Ph

NO

N2O4, NaOAc

Ph O

N

Ph

64%

Ph O

Secondary anilines can be converted to the corresponding N-nitrosoaniline using sodium nitrite.260 NaNO2, HCl N H

CO2H

N

80–83%

CO2H

NO

Secondary amines can be nitrosated with alkylnitrites as well. The N-nitrosoamines acidify the hydrogens α to the amine and allow anionic chemistry to be performed.261 EtONO N

N

>60%

H

10.7.8

NO

Oxidation of Primary Amines, Oximes, or Nitroso Compounds to Nitro Compounds

Tertiary or aryl amines can be oxidized to the nitro compound using KMnO4 .262 Me Me

NH2 Me

KMnO4 78%

Me

NO2

Me

Me

Anilines can be oxidized to the nitroaryl compound using DMDO that is generated in situ from acetone and oxone under phase-transfer conditions.263 OMe NH2

Oxone acetone

OMe NO2

100%

10.7.9

Oxidation of Tertiary Amines to Amine Oxides and Elimination to Form Imines

Oxidation of a tertiary amine to the N-oxide followed by elimination of water results in the formation of an imine that can be tautomerized to the enamine, or hydrolyzed to the corresponding carbonyl compound and the N-dealkylated product.264

257 258 259 260 261 262 263 264

White, E. Organic Syntheses 1973, Coll. Vol. V , 336–339. Van Leusen, A. M.; Strating, J. Organic Syntheses 1977, 57, 95–102. Huisgen, R.; Bast, K. Organic Syntheses 1962, 42, 69–72. Thoman, C. J.; Voaden, D. J. Organic Syntheses 1965, 45, 96–99. Enders, D.; Pieter, R.; Renger, B.; Seebach, D. Organic Syntheses 1978, 58, 113–122. See Note 253. Zabrowski, D. L.; Moormann, A. E.; Beck, K. R., Jr. Tetrahedron Letters 1988, 29, 4501–4504. See Note 168.

553

554

10 Oxidations

NMe2

Me O Me HO

Me O

HO

HO Me

Me

O

Me O O Me

O Me O

O Me HO

I2, NaOAc

HO Me O

HO

HO Me

>80%

Me

MeO Me

NHMe

Me

HO

Me O O Me

O Me O

OH

M e

O

Me

MeO Me

OH

Oxidation can also be accomplished with m-CPBA or other peracids, and iron catalysts can be used to facilitate the elimination reaction.265 N MeO

NH

(i) m-CPBA (ii) FeCl2 O

MeO

89%

O

The Polonovski reaction involves the reaction of an N-oxide with an acid anhydride to result in elimination, followed by tautomerization to form an enamine, hydrolytic dealkylation, or addition of nucleophiles such as cyanide to the iminium ion.266 Me

O HO Me Me

O

OH Me

NMe2

Me

O

HO

95%

Me

O

33%

O

OH

HO Me

(i) m-CPBA (ii) TFAA

O OH CHO

HO

Me

O

Me 35%

−O +

10.7.10

HO

NMe2 OH

TFAO

RO

O

Me

RO

NMe2 OTFA O

Me

Oxidation of Pyridines to Pyridine N-Oxides

Pyridine N-oxides are useful intermediates in the synthesis of a number of pharmaceutically active compounds. Table 10.3 summarizes some of the more common oxidants used in this transformation. 10.7.11

Halogenation or Sulfination of Amines and Amides

Aromatization of a 3-carboxytetrahydro-β-carbolines using TCCA267 via chlorination of the nitrogen followed by elimination has been reported.268,269 CO2Me N H

265 266 267 268 269

NH Me

CO2Me

TCCA N H

N Me

Monkovic, I.; Wong, H.; Bachand, C. Synthesis 1985, 770–773. Grieco, P. A.; Inana, J.; Lin, N. H. The Journal of Organic Chemistry 1983, 48, 892–895. See Note 52. Haffer, G.; Nickisch, K.; Tilstam, U. Heterocycles 1998, 48, 993–998. Haffer, G.; Nickisch, K. Preparation of b-carbolines DE1994 5 pp

10.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur

Table 10.3 Methods for pyridine oxidation Reaction

Reagents

Br

Br 81%

N

Br

N

Br

N H Br

80%

F3C

F3C N

O

Br

N+ O−

82%

Cl

N+ O−

(i) MeReO3 , H2 O2 (ii) TsCl, K2 CO3

Cl

References

200

H2 O2 , TFA

201

Urea-H2 O2 , TFAA

202

Morpholine can be chlorinated with bleach to make a useful chlorinating agent.270 O

O

NaOCl 86–88%

N H

N Cl

Methylcarbamate can be chlorinated with chlorine gas in acetic acid.271 O H2N

Cl2, HOAc OMe

O Cl

63–73%

N Cl

OMe

Piperizine can be converted to the N-thiophenyl derivative on treatment with disulfides.272 CN H N N H

S

S

CN DMSO, IPA, 120 °C 89%

H N N S

CN

10.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur 10.8.1

Pummerer Rerrangement

The Pummerer rearrangement is the rearrangement of a sulfoxide to the α-acetoxysulfide. Although not a net oxidation, the carbon atom appended to sulfur undergoes oxidation. This reaction can be employed in the dealkylation of mercaptans.273 S MeO2C

Me

(i) m-CPBA (ii) TFAA (iii) MeOH 97%

SH MeO2C

270 Girard, G. R.; Bondinell, W. E.; Hillegass, L. M.; Holden, K. G.; Pendleton, R. G.; Uzinskas, I. Journal of Medicinal Chemistry 1989, 32, 1566–1571. 271 See Note 132. 272 Walinsky, S. W.; Fox, D. E.; Lambert, J. F.; Sinay, T. G. Organic Process Research & Development 1999, 3, 126–130. 273 Young, R. N.; Gauthier, J. Y.; Coombs, W. Tetrahedron Letters 1984, 25, 1753–1756.

555

556

10 Oxidations

When base is added to the reaction, the intermediate sulfur ylide is deprotonated to produce the vinylsulfide.274 (i) m-CPBA (ii) TFAA, Et 3N

SPh

SPh

97%

Formation of 𝛂-Halosulfides

10.8.2

When a sulfoxide is treated with an activating agent in the presence of halide, a Pummerer-like reaction occurs to form the α-halosulfide. Treating a sulfoxide with diethylaminosulfur trifluoride (DAST) results in the formation of α-fluorosulfides.275 Treating a sulfide with NCS276 or thionyl chloride277 directly results in oxidation of sulfur, elimination, and addition of chloride at the α-carbon. DAST SbCl3

O S

Ph

Me

O Me

O

NCS, CCl4

Me

Me Cl

100%

SEt

F

S

Ph

>80%

Me SEt

Mono- or di-chlorination or bromination can be achieved using sulfuryl chloride or NBS, respectively.278 SO2Tol

MeS Cl

10.8.3

SO2Cl2

MeS

73%

NBS

SO2Tol

SO2Tol

MeS

58%

Br

Halogenation of Sulfoxides, Sulfones, and Phosphine Oxides

Sulfoxides and sulfones can be halogenated at the α-position in direct analogy to the halogenation α to ketones, aldehydes, and carboxylic acids (Section 10.3.3). Sulfones that are further acidified at the α-position by the presence of an additional electron-withdrawing group can be halogenated under mild conditions.279 O Ph

N Ph

O O

NBS, NaHCO3

SO2Ph

50%

Ph

N Ph

O Br SO2Ph

Deprotonation of a sulfone, a sulfoximine, or a phosphine oxide followed by quenching with iodine results in the iodo derivative.280

R

H

(i) n-BuLi (ii) Et 3Al (iii) I2

R = SO2Ph R = S(O)(NTos)Ph R = P(O)Ph2 274 275 276 277 278 279 280

R

I

89% 72% 75%

Bakuzis, P.; Bakuzis, M. L. F. The Journal of Organic Chemistry 1985, 50, 2569–2573. McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. Organic Syntheses 1995, 72, 209–215. Abbaspour Tehrani, K.; Boeykens, M.; Tyvorskii, V. I.; Kulinkovich, O.; De Kimpe, N. Tetrahedron 2000, 56, 6541–6548. Van der Veen, J. M.; Bari, S. S.; Krishnan, L.; Manhas, M. S.; Bose, A. K. The Journal of Organic Chemistry 1989, 54, 5758–5762. Ogura, K.; Kiuchi, S.; Takahashi, K.; Iida, H. Synthesis 1985, 524–525. Freihammer, P. M.; Detty, M. R. The Journal of Organic Chemistry 2000, 65, 7203–7207. Imamoto, T.; Koto, H. Synthesis 1985, 982–983.

10.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur

10.8.4

Oxidation of Mercaptans and Other Sulfur Compounds to Sulfonic Acids or Sulfonyl Chlorides

10.8.4.1

Peroxide-Based Oxidations

N-Phenylthiourea was oxidized to its corresponding amidine sulfonic acid using hydrogen peroxide as the stoichiometric oxidant with a molybdenum catalyst.281 30% H2O2 Na2MoO4 •2 H2O

S H2N

NHPh

SO3H H2N

NaCl, H2O

NPh

80%

10.8.4.2

Chlorine Oxidations

Oxidation to a sulfonic acid has also been achieved using chlorine as the oxidant. In many cases, the intermediate sulfonyl chloride is trapped with an amine to form the sulfonamide derivative, as shown in the example below.282

Cl2

R2NH

CH2Cl2 MeO2C

MeO2C

SAc

MeO2C

O O S N

56%

SO2Cl

N

Cl

One unusual case of a sulfide oxidation to a sulfonic acid equivalent is shown below.283 Direct chlorine oxidation of the thioether to its corresponding sulfonyl chloride was successful on small scale but erratic during scale-up. Therefore, the two-step procedure to the desired sulfonamide was further broken down into three steps in order to better control the chemistry: oxidation to the sulfenyl chloride, amination, and oxidation to sulfonamide. O

Cl

S

Me

O Cl2

SBn PhMe

Cl

S

O

Me

Me

RNH2

SOCl

Cl

S

SONHR

O

m-CPBA NaHCO3 78%

Cl

S

Me SO2NHR

R = (CH2)2OMe

10.8.5

Oxidation of Sulfides to Sulfoxides and Sulfones

10.8.5.1

Oxidation of a Sulfide to a Sulfoxide

Peroxide-Based Reagents One of the most common sulfur oxidations found in pharmaceutical research and produc-

tion is the oxidation of a sulfide to a sulfoxide. The oxidation occurs with a very wide variety of reagents, with the main issue for the reaction being limiting the amount of overoxidation to the sulfone, usually controlled by the stoichiometry of the oxidant. Historically, hydrogen peroxide has been the most commonly used stoichiometric oxidant to achieve the desired transformation. This transformation can be catalyzed by a large number of catalysts.284,285 Using trifluoroethanol as the solvent can reduce the level of overoxidation seen in this process, but is not required. S

Me

H2O2 CF3CH2OH

O S

Me

91% 281 Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. The Journal of Organic Chemistry 1986, 51, 1882–1884. 282 Atkins, R. J.; Banks, A.; Bellingham, R. K.; Breen, G. F.; Carey, J. S.; Etridge, S. K.; Hayes, J. F.; Hussain, N.; Morgan, D. O.; Oxley, P.; Passey, S. C.; Walsgrove, T. C.; Wells, A. S. Organic Process Research & Development 2003, 7, 663–675. 283 See Note 67. 284 Kaczorowska, K.; Kolarska, Z.; Mitka, K.; Kowalski, P. Tetrahedron 2005, 61, 8315–8327. 285 Ravikumar, K. S.; Kesavan, V.; Crousse, B.; Bonnet-Delpon, D.; Begue, J.-P. Organic Syntheses 2003, 80, 184–189.

557

558

10 Oxidations

Peracid Oxidations Another common class of reagents for the oxidation of sulfide to sulfoxide is organic peracids, such

as peracetic acid, 6-phthalimidohexanoic peracid or m-CPBA. Pantoprazole was synthesized (50 kg) by oxidation with peracetic acid in a mixture of dichloromethane, water, and methanol to allow the reaction temperature to be lowered, minimizing the production of sulfone.286 MeO

MeO MeCO3H

H N

N

S

N

F2HCO

OMe H N

86%

S O

N

F2HCO

OMe

N

The use of peracids has also been demonstrated for other structural classes, such as cephalosporins, as shown in the synthesis below (37 kg).287 The peracid reagents are usually inexpensive and readily available. The major detraction from their use, aside from the usual safety issues, is the need to purge the resulting organic acid, which can be a much more difficult task than with inorganic reagents. HO2C

H N

H

O

N

O

R

S OAc

MeCO3H

CO2H

H N

O O

95%

O S

H N

OAc CO2H

In some cases, the exact nature of the oxidizing species is not clear, especially when hydrogen peroxide is used as the oxidant in acidic media.288 For example, the conversion of acetic acid to peracetic acid with hydrogen peroxide is reported to be slow in the absence of a stronger acid catalyst,289 but some of the oxidations carried out in such a system occur at elevated temperatures for prolonged reaction times. In these instances, the reaction rate may be dependent on the conversion of the acid to the peracid, but this issue is not usually discussed in the publications reviewed. For example, the reaction below required refluxing temperatures for 17 hours.290 S N

O S

30% H2O2 HOAc, MeOH

Cl

N

46%

N N

Cl N N

Me

Me

Inorganic Oxidants Inorganic oxidants have also been used to oxidize sulfides to sulfoxides. These reagents are relatively

inexpensive and generate byproducts that are often more readily purged from the product than organic-based oxidants; some are also nonhazardous and/or environmentally benign. Oxone is effective at oxidizing sulfides to the sulfoxide or sulfone depending on reaction temperature and time.291 Other useful oxidants include sodium perborate292 and sodium hypochlorite.293 S

CO2H

Oxone acetone

O S

CO2H

98%

286 287 288 289 290 291 292 293

Mathad, V. T.; Govindan, S.; Kolla, N. K.; Maddipatla, M.; Sajja, E.; Sundaram, V. Organic Process Research & Development 2004, 8, 266–270. Bernasconi, E.; Lee, J.; Roletto, J.; Sogli, L.; Walker, D. Organic Process Research & Development 2002, 6, 152–157. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1967. Sawaki, Y.; Ogata, Y. Bulletin of the Chemical Society of Japan 1965, 38, 2103–2106. Anderson, E. L.; Post, A.; Staiger, D. S.; Warren, R. Journal of Heterocyclic Chemistry 1980, 17, 597–598. Webb, K. S. Tetrahedron Letters 1994, 35, 3457–3460. McKillop, A.; Tarbin, J. A. Tetrahedron 1987, 43, 1753–1758. See Note 284.

10.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur

Stereoselective Oxidations In systems where the oxidation of a sulfide to a sulfoxide can lead to the formation of a new

chiral center, stereoselective oxidation of the sulfur may be achieved by either substrate or reagent control. Oxone has been successfully utilized to control the relative stereochemistry of a sulfide oxidation, presumably due to the steric bulk of the inorganic complex, in the synthesis of a penem sidechain.294 Oxone TsO

S

−

S O +

TsO

90% >10:1 trans:cis

The Kagan modification295 of the Sharpless reagent has been successfully scaled up for a number of substrates. In these cases, alkyl peroxides give the best stereoselectivity. Conveniently, they can be purchased in anhydrous form or with low water content, since the water level is often critical to the success of the asymmetric induction. The enantioselectivity is highest for rigid substrates or those in which there is a large disparity in size between the two substituents on sulfur, such as the substrate below.296,297 MeO

SMe

Cumene peroxide D-DET, Ti(OiPr)4

O S

MeO

Me

91%, 94% ee

NCbz

NCbz

D-DET = D-diethyl tartrate

10.8.5.2

Oxidation of a Sulfide to a Sulfone

Peroxide-Based Reagents Sulfones are another form of oxidized sulfur commonly found in pharmaceuticals. As men-

tioned previously, in many cases, the sulfone can be installed at the correct oxidation state by direct sulfonylation, but in some cases, it has been formed by oxidation of the corresponding sulfide. Once again, hydrogen peroxide is the most commonly utilized stoichiometric oxidant, and has been demonstrated for a wide range of substrates. In the past 15 years, its use with catalytic sodium tungstate has been particularly exploited, since the reaction is usually carried out under phase transfer conditions, and the byproducts are water-soluble. These conditions have been used in the reaction below.298 HO

S

O

Ph

30% H2O2 cat. Na2WO4

HO

O O S

O

Ph

As with the sulfoxides, there are some cases where the actual oxidizing species is ambiguous, since hydrogen peroxide in an organic acid is a commonly used system. For example, in the conversion below, hydrogen peroxide is reported to be the oxidant, but residual TFA/TFAA from the previous step is not removed prior to addition of the peroxide, making it unclear whether peroxide or trifluoroperacetic acid is the oxidant.299

Me

O

O

HO2C S

S

30% H2O2

TFAA Toluene

Me

S

S

>55%

Me

S O O

S

294 Quallich, G. J.; Lackey, J. W. Tetrahedron Letters 1990, 31, 3685–3686. 295 Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43, 5135–5144. 296 Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Organic Process Research & Development 2004, 8, 33–44. 297 Zhao, S. H.; Samuel, O.; Kagan, H. B. Organic Syntheses 1990, 68, 49–55. 298 Giles, M. E.; Thomson, C.; Eyley, S. C.; Cole, A. J.; Goodwin, C. J.; Hurved, P. A.; Morlin, A. J. G.; Tornos, J.; Atkinson, S.; Just, C.; Dean, J. C.; Singleton, J. T.; Longton, A. J.; Woodland, I.; Teasdale, A.; Gregertsen, B.; Else, H.; Athwal, M. S.; Tatterton, S.; Knott, J. M.; Thompson, N.; Smith, S. J. Organic Process Research & Development 2004, 8, 628–642. 299 Tempkin, O.; Blacklock, T. J.; Burke, J. A.; Anastasia, M. Tetrahedron: Asymmetry 1996, 7, 2721–2724.

559

560

10 Oxidations

Peracid Oxidations Peracids have also been employed to achieve the oxidation to sulfones. The reaction below was run on 100 kg scale using peracetic acid oxidation of the protected amino-alcohol.300 Other simple sulfone building blocks have been synthesized by oxidation using both m-CPBA301 and magnesium monoperoxyphthalate (MMPP).302 MeS

OH

OH

MeO2S

PhCN, K2CO3 MeCO3H, HOAc

NH2

N O

93%

OH

Ph

Inorganic Oxidants Inorganic oxidants have been used to effect large-scale oxidations to sulfones, as shown below.303 Br

Br H

O

N

S

Me Me

KMnO4, H3PO4 90%

CO2H

Br H O O S Me

Br O

N

Me CO2H

One special inorganic oxidant that is more commonly used in this situation than in other sulfide oxidations is Oxone, since it readily gives the sulfone oxidation state with little contamination from the corresponding sulfoxide, and tolerates a wide variety of functional groups. In the synthesis of a cyclooxygenase (COX)-2 inhibitor, the sulfone was cleanly formed in high yield, and that residual palladium from a previous step was also purged during the oxidation.304 Oxone is inexpensive, and the resulting salts are easily separated from most products; however, its greatest drawback is its high molecular weight relative to the amount of oxygen it delivers, which requires large mass charges relative to most substrates. F

F

O

O Oxone

F

F

95%

MeO2S

MeS

Although rare, the sulfide can be oxidized to a sulfilimine. Treatment of the sulfide with an amine in the presence of a hypervalent iodine reagent will generate the sulfilimine. This was further oxidized with catalytic ruthenium chloride and sodium periodate to give the crop protection agent, Isoclast .305 TM

Me S F3C

N

10.8.5.3

Me

Me

H2NCN PhI(OAc)2 CH3CN

S F3C

N

N

Me Me CN

RuCl3, NaIO4 CH2Cl2/H2O 75% two steps

S

F3 C

N

Me

O NCN

IsoclastTM

Oxidation of Selenides

The oxidation of a selenide is usually followed by elimination or rearrangement.306,307 300 Schumacher, D. P.; Clark, J. E.; Murphy, B. L.; Fischer, P. A. The Journal of Organic Chemistry 1990, 55, 5291–5294. 301 Kaptein, B.; van Dooren, T. J. G. M.; Boesten, W. H. J.; Sonke, T.; Duchateau, A. L. L.; Broxterman, Q. B.; Kamphuis, J. Organic Process Research & Development 1998, 2, 10–17. 302 Therien, M.; Gauthier, J. Y.; Leblanc, Y.; Leger, S.; Perrier, H.; Prasit, P.; Wang, Z. Synthesis 2001, 1778–1779. 303 Volkmann, R. A.; Carroll, R. D.; Drolet, R. B.; Elliott, M. L.; Moore, B. S. The Journal of Organic Chemistry 1982, 47, 3344–3345. 304 See Note 101. 305 Arndt, K. E.; Bland, D. C.; Irvine, N. M.; Powers, S. L.; Martin, T. P.; McConnell, J. R.; Podhorez, D. E.; Renga, J. M.; Ross, R.; Roth, G. A.; Scherzer, B. D.; Toyzan, T. W. Organic Process Research & Development 2015, 19, 454–462. 306 Kshirsagar, T. A.; Moe, S. T.; Portoghese, P. S. The Journal of Organic Chemistry 1998, 63, 1704–1705. 307 Zanoni, G.; Porta, A.; Castronovo, F.; Vidari, G. The Journal of Organic Chemistry 2003, 68, 6005–6010.

10.9 Oxidation of Other Functionality

NMe

NMe (i) H2O2 (ii) KOH

O

MeO

60%

SePh

O2NC6H5Se

CO2Me

H2O2 60%

n-Pent

n-Pent HO

TBSO

10.8.6

O

MeO

CO2Me

OH

TBSO

Oxidation of Mercaptans to Disulfides

The oxidation of a mercaptan to a disulfide can be accomplished with a wide array of oxidants. The most common choices are halides,308 peroxides,309 hypochlorites,310 and even sulfoxides.311 CHO

CHO

I2 EtOAc

S

Hexanes

SH

CHO

S

90%

10.9 Oxidation of Other Functionality 10.9.1

Oxidation of Primary Halides

The Sommelet reaction is the oxidation of an alkyl chloride with hexamethylenetetramine (HMTA). The reaction proceeds through alkylation at nitrogen, elimination of the quaternary amine salt to form an imine, and intramolecular hydride transfer.312 N N

OBz Cl

N N

N+

N+ N N

O

65–70%

N R

OBz

H R

N

N N

H

N

H N+ R

N N

Barium permanganate can also be used to achieve this transformation, although overoxidation to the carboxylic acid is a problem with this reagent.313 308 309 310 311 312 313

Basha, A.; Brooks, D. W. The Journal of Organic Chemistry 1993, 58, 1293–1294. See Note 285. Ramadas, K.; Srinivasan, N. Synthetic Communications 1995, 25, 227–234. See Note 272. See Note 117. See Note 211.

561

562

10 Oxidations

H Ba(MnO4)2

Cl

O

75% +10% acid

Oxidation of primary halides by displacement with DMSO and base-mediated elimination of DMS (similar to a Swern oxidation) is known as a Kornblum oxidation. Hydrolysis to the corresponding alcohol is a common competing reaction, but can be minimized. Other leaving groups, such as sulfonate esters can also be used.314 Silver-mediated variants can be quite efficient.315 O

S

Cl

O

O

O

Me

HO

Cl OMe OH

H

DMSO iPr2EtN

O

o

130 C

Cl

Cl

O

Cl OMe OH

HO

OH

+

O

HO HO

OH

Cl OMe OH

OH 93 : 6

10.9.2

Oxidation of C—Si Bonds: The Tamao Oxidation

The Tamao oxidation is the formation of an alcohol via the oxidative cleavage of a C—Si bond. Oxidation of the silicon center induces a rearrangement, facilitated by fluoride ion, whereby oxygen is stereospecifically transferred to the carbon substituent. Cleavage of the silicon oxygen bond liberates the free alcohol.316,317

O

Si

O

H2O2, NaHCO3

Me Me i-PrOMe2Si

MeOH KF, H2O2 NaHCO3

OH OBn O N OBn OBn OBn

N

MeOH Me

OH OH OH Me Me HO

OH OBn O N OBn OBn OBn

N

Me

314 Bernhardson, D.; Brandt, T. A.; Hulford, C. A.; Lehner, R. S.; Preston, B. R.; Price, K.; Sagal, J. F.; St. Pierre, M. J.; Thompson, P. H.; Thuma, B. Organic Process Research & Development 2014, 18, 57–65. 315 Ganem, B.; Boeckman, R. K., Jr. Tetrahedron Letters 1974, 917–920. 316 Zacuto, M. J.; Leighton, J. L. Journal of the American Chemical Society 2000, 122, 8587–8588. 317 Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E. C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.; Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C. L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Organic Process Research & Development 2014, 18, 66–81.

563

11 Selected Free Radical Reactions Christophe Allais 1 , Eric C. Hansen 1 , Nathan D. Ide 2 , Robert J. Perkins 3 , and Elizabeth C. Swift 2 1

Pfizer Worldwide R&D, Groton, CT, USA

2 Abbvie Inc., North Chicago, IL, USA 3

St. Louis University, St. Loius, MO.

CHAPTER MENU Introduction, 563 Radical Reactions via Chemical Initiation, 563 Photoredox Catalysis, 575 Electrochemical Methods, 583

11.1 Introduction Many useful bond-forming reactions and functional group manipulations involve free radicals. Because this class of reactions includes oxidations, reductions, and bond-forming reactions, a number of free radical reactions are best discussed in other chapters. This chapter was envisioned as a place to discuss selected radical reactions that do not fit elsewhere in this book. Additionally, photo redox and electrochemical methods, which inherently involve 1 electron oxidations and reductions to form radical intermediates, have come to the forefront of synthetic chemistry. These methods will also be summarized here. This chapter is divided into three sections: Section 11.2 will cover radical reaction initiated by chemical means; Section 11.3 will cover radical reactions initiated by photoredox catalysts; and Section 11.4 will cover electrochemical methods. 11.1.1

Radical Reactions Discussed in Other Chapters

Radical reductions (dehalogenations, decarboxylations, deoxygenations, reactions involving radical anions, etc.) are discussed in the context of reductions (Chapter 9). Radical oxidations (halogenations, hydroxylations, reactions involving radical cations, etc.) are discussed in the context of oxidations (Chapter 10). Reactions involving aromatic diazonium salts (Sandmeyer reaction, Meerwein arylation, etc.) are discussed in the context of nucleophilic aromatic substitution (Chapter 4). Some radical reactions that involve addition across double bonds are discussed in Chapter 3.

11.2 Radical Reactions via Chemical Initiation 11.2.1

Radical Cyclizations

Radical cyclizations are a broad class of reactions that are useful in organic synthesis, largely due to their functional group tolerance. These reactions typically involve a radical and a carbon–carbon multiple bond or a carbon–heteroatom multiple bond. Because of the huge variety of reactions in this class, a full discussion is beyond the scope of this book.

Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

564

11 Selected Free Radical Reactions

11.2.2

Atom Transfer Radical Cyclizations

While many radical cyclizations depend upon tributyltin hydride for the reduction of the cyclized radical intermediate (see Section 3.5.8), the avoidance of tin is highly desirable from a practical standpoint. For this reason, atom transfer radical cyclizations stand out as one of the most practical radical cyclization protocols. During the course of their formal synthesis of stemoamide, Cossy and coworkers converted an iodoester to the corresponding lactone (1 : 1 mixture of iodide epimers) by treatment with 0.30 equiv of dilauroyl peroxide (DLP) in refluxing benzene.1 The DLP presumably homolyzes to initiate the radical reaction, followed by abstraction of iodine from the starting material and 5-exo-trig radical cyclization. The cyclized radical intermediate could then abstract the iodine from a molecule of starting material to generate product and propagate the chain reaction. O

I O

OEt

H

DLP O

O

64% OTHF

O

I

OEt O OTHF

H

O DLP =

Me

( )10 O

O O

Me ( )9

In the absence of overwhelming steric bias, reactions of this type will proceed via 5-exo-trig cyclization rather than 6-endo-trig cyclization.2 Atom transfer radical cyclizations can also be promoted by transition metal catalysts, such as copper(I) complexes.3 Speckamp and coworkers have utilized catalytic amounts of copper(I) chloride 2,2′ -bipyridine (bpy) complexes as promoters for chlorine transfer radical cyclizations.4 In these reactions, the chlorine in the starting material is transferred to the copper(I) complex, to generate a radical and a copper(II) complex. The radical intermediate undergoes cyclization, and the copper(II) complex transfers a chlorine back to the cyclized radical intermediate, thus generating product and regenerating the copper(I) complex. The reaction shown below was slow (two days in refluxing 1,2-dichloroethane), but the yield is impressive. Cl OMe

O O

11.2.3

H

30 mol% CuCl 30 mol% bpy 95% α/β = 82 : 12

O Cl

H O

OMe

Radical Allylation

Radical allylation is a powerful method for forming carbon–carbon bonds and has been successfully utilized in the synthesis of several complex molecules.5 This reaction is particularly useful because it not only forms a carbon–carbon bond but also allows for additional functionalization via manipulation of the alkene portion of the allyl unit. 11.2.3.1

Keck Radical Allylation

The traditional method for radical allylation, sometimes referred to as the Keck radical allylation,6 involves allyltributyltin, a radical initiator and an alkyl halide, a starting material.7 This process proceeds via a radical chain reaction. The reaction scope is quite broad, as the transformation can be accomplished with various alkyl halides in the presence of a wide variety of functional groups. The use of organotin compounds is a concern from an environmental and safety 1 2 3 4 5 6 7

Bogliotti, N.; Dalko, P. I.; Cossy, J. The Journal of Organic Chemistry 2006, 71, 9528–9531. Baldwin, J. E. Journal of the Chemical Society, Chemical Communications 1976, 734–736. Clark, A. J. Chemical Society Reviews 2002, 31, 1–11. Udding, J. H.; Tuijp, K. C. J. M.; van Zanden, M. N. A.; Hiemstra, H.; Speckamp, W. N. The Journal of Organic Chemistry 1994, 59, 1993–2003. Jarosz, S.; Kozlowska, E. Polish Journal of Chemistry 1998, 72, 815–831. Keck, G. E.; Yates, J. B. Journal of the American Chemical Society 1982, 104, 5829–5831. Kurti, L.; Czako, B.; Editors Strategic Applications of Named Reactions in Organic Synthesis; Academic Press: Burlington, MA, 2005.

11.2 Radical Reactions via Chemical Initiation

perspective, so the most practical radical allylations use the smallest possible amount of allyltributyltin. While many examples in the literature use a large excess of this reagent, the reaction can be accomplished in high yield with only a slight excess of allyltributyltin. This was shown to be the case by Raman et al. during their synthesis of carba-sugars.8 They were able to conduct a radical allylation with a secondary alkyl chloride, allyltributyltin (1.1 equiv), and azobisisobutyronitrile (AIBN) as an initiator. This process allowed for the isolation of a 92% yield of the allylated product, as a single diastereomer, on multigram scale. Cl O

H

O

O

H

11.2.3.2

SnBu3 O

H

AIBN

Me

O

92%

O Me

O

O H

O

Me O Me

Tin-Free Radical Allylations

While radical allylations with allyltributyltin have proven to be robust and effective reactions for the synthesis of complex molecules, the practicality of this methodology is significantly diminished by the use of allyltributyltin. Tin reagents not only represent a hazard to workers and the environment, but they can also cause problems when they contaminate compounds that are being evaluated for toxicity and/or biological activity.9 In an effort to obviate the need for organotin reagents, several tin-free radical allylation methods have been developed. While none of these methods have yet been shown to have the substrate scope of the Keck radical allylation, it is likely that these methods could be advantageous in certain circumstances. SO2Et

I O

AIBN

OH O

OH

O

71%

O

Zard and coworkers have developed a strategy that allows for the replacement of allyltin reagents with allyl sulfones.9 This methodology allows for the conversion of a variety of alkyl iodides to the corresponding allyl substituted compounds. In the example shown above, a secondary alkyl iodide is converted (71% yield) to the corresponding allyl compound in the presence of allylethylsulfone and AIBN. Analogous to the Keck radical allylation, the reaction is broad in scope and tolerant of many functional groups. Unfortunately, the requisite allylsulfones are not as readily available, from commercial sources, as the corresponding allyltin reagents. Despite this drawback, the benefits of performing radical allylations without tin are significant and would suggest that this methodology could indeed provide the most practical radical allylation for applications where tin byproducts would be undesirable. While the approach of Zard and coworkers utilizes alkyliodides and allyl sulfones, an alternative strategy developed by Renaud and coworkers involves boronates and allyl sulfones.10 In this approach, an alkene undergoes dimethylacetamide-promoted hydroboration and the resulting boronate is subjected to oxygen-initiated radical allylation. This reaction provides products that have undergone a net hydroallylation. This approach is highlighted in the following figure, which depicts the hydroallylation of α-pinene, a process that proceeds in 80% yield. This strategy is desirable because it allows for the use of alkenes as starting materials and obviates the need for tin reagents. In situations where an alkene is a more logical intermediate than an alkyl halide, this technique could be the most practical approach for radical allylation.

Me Me Me

H B

O

Me

O

DMAc

Me Me

O B

CO2Et SO2Ph O

Me

O2 80%

Me Me

CO2Et

8 Ramana, C. V.; Chaudhuri, S. R.; Gurjar, M. K. Synthesis 2007, 523–528. 9 Le Guyader, F.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Journal of the American Chemical Society 1997, 119, 7410–7411. 10 Darmency, V.; Scanlan, E. M.; Schaffner, A. P.; Renaud, P.; Sui, B.; Curran, D. P. Organic Syntheses 2006, 83, 24–30.

565

566

11 Selected Free Radical Reactions

11.2.4

Remote Functionalization Reactions

Radical remote functionalization reactions are a powerful set of methods for the functionalization of complex molecules.11,12 These reactions typically involve the generation of a heteroatom-centered radical, which proceeds to abstract a pendant hydrogen atom, typically via a six-membered ring that incorporates the abstracted hydrogen atom (hydrogen abstraction at the 𝛿-position). The generation of the carbon-centered radical allows for functionalization at that position. Depending on many factors, including the number of positions with accessible hydrogen atoms and their relative reactivities, these remote functionalization reactions can vary from poorly selective and low yielding to exquisitely selective and high yielding. While the conditions and reagents required for remote radical functionalization may not be the most practical, the transformations accomplished via these methods would be difficult or even impossible to accomplish using alternative methods.

11.2.5

Barton Nitrite Ester Reaction

The Barton nitrite ester reaction involves the photolytic homolysis of a nitrite ester.13,14,15 This homolysis results in the formation of an alkoxyl radical, which abstracts a remote hydrogen via a six-membered ring transition state. The resulting carbon-centered radical then recombines with the NO radical that was generated by photolysis. Tautomerization then leads to the desired oxime product. This reaction was utilized by Hakimelahi et al. in the preparation of a carbacephem antibiotic.16 In this case, which is shown below, the captodative carbon-centered radical is stabilized by the adjacent nitrogen atom and ester group. Stabilization of the carbon-centered radical by an adjacent heteroatom is not a requirement for a successful remote radical functionalization, but it is often highly beneficial. In this reaction, the oxime was formed in a 7 : 5 ratio favoring the anti-product. N3

ONO

N O MeO2C

N3 hv

N3

O

N H O H MeO2C NO

N3

OH

N O MeO2C

H NO

60%

N O MeO2C

OH NOH

Konoike et al. were able to utilize a Barton nitrite ester reaction for the preparation of an oxime intermediate in 85% yield.17 This transformation, which is depicted below, required exclusion of oxygen to prevent formation of nitrate products. While the concentration of the photolytic reaction was low by industrial standards (67 mM, 30 l/kg), the reaction was still practical enough to allow for the production of 237 g of product from 14 batches in the photoreactor. This reaction has also been carried out using a flow microreactor.18

ONO Me

Me Me O

Me Me

O

Me Me

HO

O Me

hv 85% O

Me Me O O

Me NOH

Me Me

11 Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095–7129. 12 Reese, P. B. Steroids 2001, 66, 481–497. 13 Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. Journal of the American Chemical Society 1960, 82, 2640–2641. 14 Robinson, C. H.; Gnoj, O.; Mitchell, A.; Wayne, R.; Townley, E.; Kabasakalian, P.; Oliveto, E. P.; Barton, D. H. R. Journal of the American Chemical Society 1961, 83, 1771–1772. 15 See Note 7. 16 Hakimelahi, G. H.; Li, P.-C.; Moosavi-Movahedi, A. A.; Chamani, J.; Khodarahmi, G. A.; Ly, T. W.; Valiyev, F.; Leong, M. K.; Hakimelahi, S.; Shia, K.-S.; Chao, I. Organic & Biomolecular Chemistry 2003, 1, 2461–2467. 17 Konoike, T.; Takahashi, K.; Araki, Y.; Horibe, I. The Journal of Organic Chemistry 1997, 62, 960–966. 18 Sugimoto, A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I. Tetrahedron Letters 2006, 47, 6197–6200.

11.2 Radical Reactions via Chemical Initiation

11.2.5.1

Hofmann–Löffler–Freytag Reaction

The Hofmann–Löffler–Freytag reaction is a method for remote radical functionalization that is related to the Barton nitrite ester reaction, but involves the homolytic cleavage of a nitrogen–halogen bond, rather than a nitrite ester.19 This transformation was used by Ban and coworker in their synthesis of various 1,3-diaza heterocycles.20 Their method, which is shown below, involves treatment of a diamine starting material with N-chlorosuccinimide and triethylamine. The resulting chloroamine is directly irradiated with ultraviolet light, which results in homolysis of the nitrogen–chlorine bond. The nitrogen-centered radical then abstracts the adjacent hydrogen atom via a seven-membered ring transition state. Recombination of the carbon-centered radical with the chlorine radical and displacement of the resulting chloride by the secondary nitrogen gives the tricyclic product in high yield. The tertiary nitrogen of the starting material likely plays a key role in this reaction. It stabilizes the carbon-centered radical and also assists with the displacement of the chloride, by allowing the displacement to proceed via an iminium intermediate. While this example showcases a reaction that is highly efficient, generating product in quantitative yield, the Hofmann–Löffler–Freytag reaction is clearly not a widely applicable reaction. As reported by Ban and coworker,20 seemingly minor changes in substrate structure can result in dramatic changes in the efficiency of this reaction. This is not surprising, when one considers the complex sequence of events that must occur in order to generate product via this transformation.

NH

N

(i) NCS (ii) Et3N

N

hv

N

H

N H

Cl

N

Cl

N

N

NH Cl

H

N

NH

H

N

Cl

As shown subsequently, the Hofmann–Löffler–Freytag reaction can also be used to generate alkyl chlorides, if the reaction halts prior to intramolecular alkylation of the secondary nitrogen. This variation of the reaction was used by Uskokovi´c et al. during the course of their synthesis of meroquinene.21 In this case, the alkylation step is disfavored because the alkylation would have to proceed via an unactivated (no adjacent heteroatoms) primary alkyl chloride to generate a bridged bicyclic product. CO2Me

CO2Me

CO2Me

Me

Cl

hv

N Cl

BzCl K2CO3

Cl N

84%

N H

O

Ph

A useful variation of the Hofmann–Löffler–Freytag reaction, which uses iodine and either (diacetoxyiodo)benzene (DIB) or iodosylbenzene, has been developed by Suárez and coworkers.22 While most Hofmann–Löffler–Freytag reactions are initiated by ultraviolet light, the Suárez modification proceeds under irradiation with visible light. NHBoc Me

O

MeO

OMe OMe

19 20 21 22

DIB I2 hv 87%

BocN Me O MeO

OMe OMe

See Note 7. Kimura, M.; Ban, Y. Synthesis 1976, 201–202. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. Journal of the American Chemical Society 1978, 100, 571–576. Francisco, C. G.; Herrera, A. J.; Suarez, E. The Journal of Organic Chemistry 2003, 68, 1012–1017.

567

568

11 Selected Free Radical Reactions

11.2.6

Hypohalite Reaction

The hypohalite reaction is analogous to the Hofmann–Löffler–Freytag reaction, except for the involvement of an oxygen-centered radical rather than a nitrogen-centered radical. This reaction has traditionally been accomplished using lead tetraacetate and iodine under photolytic conditions. The reaction typically requires a large excess of lead tetraacetate, which is undesirable. The reaction can also be promoted by mercury and selenium derived reagents,23 but these are also undesirable due to their toxicity. Suárez and coworkers have developed a convenient protocol for the hypoiodite reaction, which utilizes hypervalent iodine reagents.24 When dihydrotigogenin 3-acetate was irradiated in the presence of DIB and iodine, a 92% yield of tigogenin acetate was obtained. This reaction is particularly interesting because it forms the six-membered ring preferentially over a five-membered ring, which suggests a seven-membered ring transition state for the abstraction of hydrogen by the alkoxyl radical. This preferential reactivity is likely due to the tendency to form carbon-centered radicals adjacent to oxygen and other radical-stabilizing heteroatoms. HO Me

Me Me

O

Me AcO

Me Me

DIB I2 , hv

O

Me

O

Me

92% AcO

H

H

During their efforts toward the synthesis of calcitriol analogues, Mouriño and coworkers investigated conditions and reagents for a key hypoiodite reaction.25 They found that DIB was at least as effective as lead tetraacetate and that reactions promoted by DIB proceeded under more practical conditions. While the lead tetraacetate reactions required high dilution in benzene, the DIB-promoted reactions proceeded efficiently at much higher concentrations in cyclohexane. Additionally, the DIB-promoted reactions required less reagent (1.5 equiv DIB vs. 4.5 equiv lead tetraacetate) and could be initiated by either irradiation or sonication. When using DIB, sonication allowed for higher reaction concentrations than were possible with the photoinitiated reactions. Me O H OH

H

Conditions

Yield

DIB, I2, hv DIB, I2, ))))

93% 96% 92%

Pb(OAc)4, hv )))) = sonication

11.2.7

The Hunsdiecker Reaction

The Hunsdiecker reaction is a method for the conversion of carboxylic acids to the corresponding decarboxylated aryl, alkyl, or vinyl halides.26 The original conditions for this transformation, as developed by Borodin and Hunsdiecker, utilized silver carboxylates and elemental bromine.27 The mechanism of this reaction is shown below. The silver carboxylate is converted to the corresponding acyl hypobromite, which can undergo homolysis either thermally or photolytically. The resulting carboxyl radical can decarboxylate to reveal a carbon-centered radical, which then 23 See Note 11. 24 De Armas, P.; Concepcion, J. I.; Francisco, C. G.; Hernandez, R.; Salazar, J. A.; Suarez, E. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1989, 405–411. 25 Moman, E.; Nicoletti, D.; Mourino, A. The Journal of Organic Chemistry 2004, 69, 4615–4625. 26 See Note 7. 27 Li, J. J. In Name Reactions for Functional Group Transformations; John Wiley & Sons, Inc: Hoboken, NJ, 2007, 623–629.

11.2 Radical Reactions via Chemical Initiation

abstracts a bromine atom from elemental bromine. The carbon-centered radical could, alternatively, recombine with the previously generated bromine radical or abstract bromine from another acyl hypobromite molecule. O R

O

O

Br2

R

OAg

O

R

Br

AgBr

+ Br

CO2 O

Br2

R•

RBr Br

The original Hunsdiecker reaction is not very practical because it requires isolation and drying of the thermally sensitive silver carboxylates. For this reason, a number of modifications have been developed, including approaches with other metals (Hg, Tl, Mn, Pb, etc.),27 but most of these variations lack the functional group compatibility observed for the more practical Barton et al.28 and Suárez and coworkers29 modifications. 11.2.7.1

Barton Modification of the Hunsdiecker Reaction

An example of the Barton modification of the Hunsdiecker reaction is shown below.30 In this reaction, the carboxylic acid is converted to the acid chloride, which is treated with sodium 2-thioxopyridin-1(2H)-olate, 4-dimethylaminopyridine (DMAP), and iodoform in refluxing cyclohexane. This procedure results in the formation and thermolysis of the corresponding thiohydroxamic ester. Homolysis of the nitrogen–oxygen bond of the thiohydroxamic ester results in a carboxylate radical, which decarboxylates to provide a carbon-centered radical, followed by abstraction of iodine from iodoform. This process converts the carboxylic acid to the corresponding iodide in 65% yield. Even better yields have been observed with simpler starting materials, but this example showcases the most significant feature of this approach, which is the observed functional group tolerance. O Me O Me

O OH

Me AcO

Me O Me

(COCl)2 DMF

Me AcO

H

Cl

NaO

H

DMAP CHI3

N S

Δ O

Me O Me Me AcO

11.2.7.2

H

Me O Me

I

O

N S

Me

65% AcO

H

Suárez Modification of the Hunsdiecker Reaction

The Suárez modification of the Hunsdiecker reaction relies upon irradiation of a carboxylic acid with DIB and iodine in refluxing cyclohexane.31 Mechanistically, it has been proposed that the carboxylic acid displaces an acetate from the DIB, and reaction of the resulting adduct with iodine results in acyl hypoiodite formation. The intermediate acyl hypoiodite then undergoes a decarboxylative iodination to provide the alkyl iodide, as a 3 : 2 mixture of epimers. It is 28 29 30 31

Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Letters 1983, 24, 4979–4982. Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.; Salazar, J. A.; Suarez, E. The Journal of Organic Chemistry 1986, 51, 402–404. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901–3924. See Note 29.

569

570

11 Selected Free Radical Reactions

significant that the reaction proceeds in high yield with only 1.1 equiv of DIB and 1.0 equiv of I2 . Similar conditions have also been reported for decarboxylative bromination.32 It should also be noted that this reaction proceeds efficiently for primary and secondary carboxylic acids, but tertiary carboxylic acids tend to form olefins via oxidation of the tertiary radical intermediate to the corresponding carbocation, followed by elimination. O Me Me

O Me Me

OH DIB I2 hv, Δ

Me AcO

OI

Me

Me Me

CO2

I

Me

89% AcO

AcO

Interestingly, the oxidative olefin formation can be encouraged with primary and secondary carboxylic acids, if excess DIB and catalytic cupric acetate (without iodine) are utilized, but this procedure is not particularly practical, as it requires 5.0 equiv of DIB.33 O Me Me

OH

Me AcO

Me Me

DIB I2 hv, Δ

Me

80% AcO

H

I

H

DIB Cu(OAc)2 80% Δ Me Me Me AcO

11.2.7.3

H

Catalytic Hunsdiecker Reaction with 𝛂,𝛃-Unsaturated Carboxylic Acids

A catalytic variant of the Hunsdiecker reaction has been developed by Roy and coworker for use with α,β-unsaturated carboxylic acids.34 This reaction utilizes catalytic lithium acetate and stoichiometric N-bromosuccinimide (NBS). O OH MeO

NBS LiOAc 92%

Br MeO

This reaction works best for electron-rich α,β-unsaturated carboxylic acids and it typically provides the (E)-bromoalkenes with good stereoselectivity. Useful modifications include the use of microwave heating35 and alternative bases, such as triethylamine.36 It is important to note that this reaction most likely does not proceed via a radical pathway. An ionic mechanism has been proposed,37 and is shown below.

32 33 34 35 36 37

Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron 2000, 56, 2703–2707. See Note 29. Chowdhury, S.; Roy, S. The Journal of Organic Chemistry 1997, 62, 199–200. Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M. Synthesis 2005, 1319–1325. Das, J. P.; Roy, S. The Journal of Organic Chemistry 2002, 67, 7861–7864. Naskar, D.; Roy, S. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1999, 2435–2436.

11.2 Radical Reactions via Chemical Initiation

O OH

Li

O

LiOAc

O

MeO

+

−

+

NBS

MeO

Br

O O

−

MeO

O

Br

O

+

MeO

MeO

−

Br

In this proposed mechanism, the base deprotonates the α,β-unsaturated carboxylic acid, and the olefin then reacts with NBS to generate a bromonium carboxylate (which can also be drawn as a benzylic carbocation), followed by decarboxylative elimination to generate the bromoalkene. 11.2.7.4

Nitro-Hunsdiecker Reaction

Roy and coworkers have also developed a nitro-Hunsdiecker reaction, which uses nitric acid and substoichiometric AIBN to convert electron-rich α,β-unsaturated carboxylic acids and aromatic acids to the corresponding nitro derivatives.38 CO2H

HNO3 AIBN

MeO

75%

MeO

CO2H

MeO

NO2 MeO

HNO3 AIBN

MeO

78%

MeO

OMe

NO2

OMe

The conversion of electron-rich benzoic acid derivatives to the mono-nitro products is significant because other approaches to these products, via nitration of the appropriate benzene derivative, often suffer from competitive oxidation reactions.39 The mechanism of this reaction is not well understood at this time, but the requirement of a substoichiometric amount of AIBN strongly suggests a radical mechanism.

11.2.8

The Minisci Reaction

The Minisci reaction involves the reaction of nucleophilic carbon-centered radicals with heteroaromatic systems, typically under acidic conditions.40,41,42 The acidic conditions, although not a strict requirement, result in protonation of the heteroaromatic system and thereby activate the system for reaction with nucleophilic radicals. The power of the Minisci reaction, and the reason that it has seen use in organic synthesis, is that the selectivity of the reaction is complementary to that observed with electrophilic aromatic functionalization reactions, such as Friedel–Crafts acylations/alkylations. Minisci and coworkers developed the reaction shown below, which allows for the conversion of iodo sugars to the corresponding heterocycle-bound derivatives.43 In this case, a nucleophilic carbon-centered radical is generated from 38 39 40 41 42 43

Das, J. P.; Sinha, P.; Roy, S. Organic Letters 2002, 4, 3055–3058. Dwyer, C. L.; Holzapfel, C. W. Tetrahedron 1998, 54, 7843–7848. Minisci, F.; Fontana, F.; Vismara, E. Journal of Heterocyclic Chemistry 1990, 27, 79–96. See Note 7. Punta, C.; Minisci, F. Trends in Heterocyclic Chemistry 2008, 13, 1–68. Vismara, E.; Donna, A.; Minisci, F.; Naggi, A.; Pastori, N.; Torri, G. The Journal of Organic Chemistry 1993, 58, 959–963.

571

572

11 Selected Free Radical Reactions

the iodo sugar using benzoyl peroxide. The radical adds to the quinolinium ring, and the resulting stabilized radical is oxidized to the corresponding cation. Deprotonation provides the product in high yield. Me

N

I O

O O

O Me Me

Me Me Me +

(PhCO2)2 TFA

N

O

O

90%

O

O

O Me Me

Me Me

O

PhCO2

Me

N

Me

O

O O

O Me Me

H Me Me

O O

O

Me

N

Me Me

O O

Me Me

PhCO2

N H

O O

O

Me Me

O O

Me Me

O

As is the case for many radical reactions, the Minisci reaction can be performed using radicals generated under a wide variety of conditions. Cowden has developed a Minisci reaction that relies upon radical decarboxylation of amino acids and subsequent reaction with dihalopyridazines.44 This reaction utilizes catalytic silver with stoichiometric ammonium persulfate and provides a variety of useful products in moderate to high yields. It is worth noting that the dihalopyridazine products of this methodology are functionalized appropriately to undergo a variety of nucleophilic aromatic substitutions and/or transition metal promoted cross-coupling reactions. (NH4)2S2O8 AgNO3 TFA

Cl O BzHN

OH

N N

+

88%

Cl N N

BzHN

Cl

Cl

Baran and coworkers have developed a variation of the Minisci reaction that couples arylboronic acids to electron-deficient heterocycles using catalytic silver nitrate and excess potassium persulfate.45 As with most Minisci reaction variants, the transformations are of high synthetic utility, but the yields are substrate dependent. CF3 + N

11.2.9

K2S2O8 AgNO3 TFA

(HO)2B Me

DCM:H2O 81%

CF3

N Me

Radical Conjugate Additions

Radical conjugate additions involve the reaction of a nucleophilic radical with an electron-deficient olefin (α,β-unsaturated amides, esters, ketones, sulfones, sulfoxides, etc.). Unlike ionic conjugate additions, which are readily reversible and often suffer from unfavorable equilibria, most radical conjugate additions are essentially irreversible. Additionally, radical conjugate additions typically react exclusively via 1,4-addition, without competitive 44 Cowden, C. J. Organic Letters 2003, 5, 4497–4499. 45 Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. Journal of the American Chemical Society 2010, 132, 13194–13196.

11.2 Radical Reactions via Chemical Initiation

1,2-addition. Finally, radical reaction conditions are typically mild, which results in good functional group tolerance and minimal need for protecting groups.46,47 11.2.9.1

Intramolecular Radical Conjugate Additions

In this book, intramolecular radical conjugate additions will be considered a subset of radical cyclizations (see Sections 3.5.8 and 11.2). 11.2.9.2

Intermolecular Radical Conjugate Additions

Intermolecular radical conjugate additions have proven to be a useful method for carbon–carbon bond formation and for the establishment of chiral centers.47,48,49,50,51 Sibi and Chen have developed a catalytic asymmetric variant of this reaction, which is capable of generating two new stereocenters.52 Radical initiation by triethylborane and oxygen results in the formation of the t-butyl radical, which undergoes a conjugate addition to the alkene. The resulting radical is then trapped by the allyltributyltin, providing the second stereocenter and a tin radical for chain propagation. The reaction is enantioselective because the radical conjugate addition is accelerated by complexation of the acyloxazolidinone to the chiral Lewis acid. High enantioselectivities require bulky radicals in the addition step and the radical trapping occurs with anti diastereoselectivity. It is interesting to note that the use of copper(II) triflate, instead of magnesium(II) iodide, resulted in enantiomeric products, even though the same ligand was used. This reversal of enantioselectivity is likely due to different coordination geometries with copper and magnesium. O

O N

O

O O

N

Ph

N

MgI2 t-BuI (n-Bu)3SnAllyl Et3B/O2

Me O

O O

84% 99 : 1 dr 97% ee

N

Me

Me Ph

Renaud and coworker have developed a tin-free radical conjugate addition, which relies upon the hydroboration of olefins with catecholborane, followed by oxygen initiated radical conjugate addition into unsaturated ketones and aldehydes.53 As shown below, an alkene can be treated with catecholborane to provide the hydroboration product. Treatment of this intermediate with oxygen (air) generates the corresponding alkyl radical, which can add in a conjugate fashion to the enone. The authors have proposed that the conjugate addition results in the formation of a boron enolate intermediate, which could form via radical recombination or via a chain propagating reaction with another equivalent of alkylcatecholborane. Quenching of the boron enolate results in formation of the conjugate addition product in good yield.

O

Me

H B

O

DMAc

O O B O

Me

Air

Me

DMPU

O Me

B O

O

H2O 84%

Me

Me O

Me

46 47 48 49 50 51 52 53

Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377–10441. Zhang, W. Tetrahedron 2001, 57, 7237–7262. See Note 46. Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–8061. Sibi, M. P.; Manyem, S.; Zimmerman, J. Chemical Reviews 2003, 103, 3263–3295. Sibi, M. P.; Porter, N. A. Accounts of Chemical Research 1999, 32, 163–171. Sibi, M. P.; Chen, J. Journal of the American Chemical Society 2001, 123, 9472–9473. Ollivier, C.; Renaud, P. Chemistry - A European Journal 1999, 5, 1468–1473.

573

574

11 Selected Free Radical Reactions

11.2.10

𝛃-Scission Reactions

In addition to their utility for the formation of carbon–carbon bonds, radical reactions can be effective for the selective fragmentation of carbon–carbon bonds, typically via β-scission reactions. One of the most commonly employed β-scission approaches involves the generation of an alkoxy radical, which then undergoes fragmentation. Macdonald and O’Dell used this approach for the β-scission of 9-decalinol.54 Treatment with mercuric oxide and iodine results in the formation of the corresponding hypoiodite, followed by homolysis to give the alkoxy radical and scission of the adjacent carbon–carbon bond. Finally, the primary radical is trapped with iodine to give a 68% yield of 2-(4-iodobutyl)cyclohexanone. The iodine source for the trapping of the primary radical could be elemental iodine, an iodine radical, or another hypoiodite molecule. HgO I2 Δ

OH

O

68%

O

I

I

A similar approach was used by Cairns and Englund for the synthesis of 𝜔-haloketones.55,56 Conversion of 1-methylcyclopentanol to the corresponding hypochlorite was completed using chlorine and aqueous sodium hydroxide. Gentle heating (40 ∘ C) resulted in rearrangement to the 𝜔-chloroketone. This reaction probably proceeds in a similar fashion to the above reaction of 9-decalinol.

Me OH

Cl2 NaOH 74%

Me OCl

Me Δ 90%

O Cl

Samarium diiodide can also be used to promote β-scission reactions, and although samarium diiodide-mediated β-scissions are reduction reactions, they will be discussed in the context of radical reactions. One of the main advantages of samarium diiodide is its tendency to react in a highly chemoselective fashion. The resulting functional group compatibility has made it a useful reagent for the synthesis of complex molecules. Baran and coworkers utilized a key samarium diiodide-induced radical cleavage during their synthesis of (+)-cortistatin A.57 In this reaction, samarium diiodide reacts with the ketone to generate a ketyl radical, which results in cyclopropyl ring opening and radical debromination. The resulting samarium enolate is selectively trapped with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCHD), an electrophilic bromination reagent, to provide the desired α-bromoketone. The α-bromoketone was not isolated, but the isolation of an intermediate in 58% yield after two additional steps is indicative of a highly efficient radical cascade sequence.

54 55 56 57

Macdonald, T. L.; O’Dell, D. E. The Journal of Organic Chemistry 1981, 46, 1501–1503. Cairns, T. L.; Englund, B. E. The Journal of Organic Chemistry 1956, 21, 140. Englund, B. E. Preparing w-halo ketones by rearrangement of tertiary cycloaliphatic hypohalites US2691682 1954 Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. Journal of the American Chemical Society 2008, 130, 7241–7243.

11.3 Photoredox Catalysis

O

Br TMSO

H Me

OHCN

H

TMSO

SmI2 TBCHD

O

O O

>58%

O

OHCN

H

TMSO

OHCN

O

H

O O

I2SmO

OSmI2

TMSO O

H

Me O

H

TBCHD

H Me O O

O

H

SmI2

Br

Br

OHCN

O

H

Me O O

H

O O H

H I2SmO Br

TMSO

OHCN

O O H

H H

Me O O

O Br

Br

TBCHD = Br Br

11.2.11

Free Radical Polymerization

While a discussion of free-radical polymerization is well beyond the scope of this book, it is worth noting that radical chemistry finds far more use in the industrial manufacturing of polymers than it does in the manufacturing of small molecules.58,59,60 In fact, radical polymerization is the most commonly employed method for synthesis of polymers on an industrial scale.

11.3 Photoredox Catalysis Photoredox catalysis emerged in the last decade as a powerful tool to induce or accelerate chemical transformations via single-electron transfer events. The introduction of iridium- and ruthenium-based photoredox catalysts61 has opened up new pathways into radical formation from visible light. Photoexcitation of these catalysts creates a species that is both a strong 1-electron oxidant and reductant, which offers both pathways for interaction with organic substrates. Several families of organic photocatalysts are also known and offer a rich array of chemistry without the need for precious metal catalysts.62 58 59 60 61 62

Kamigaito, M.; Ando, T.; Sawamoto, M. Chemical Reviews 2001, 101, 3689–3745. Matyjaszewski, K.; Braunecker, W. A. Radical Polymerization; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2007; Vol. 1. Matyjaszewski, K.; Xia, J. Chemical Reviews 2001, 101, 2921–2990. Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chemical Reviews 2016, 116, 10035–10074. Romero, N. A.; Nicewicz, D. A. Chemical Reviews 2016, 116, 10075–10166.

575

576

11 Selected Free Radical Reactions

CF3

F

F F

Ir

Me

tBu

N N

+

N

PF6 −

N N

Ru2+

N

N 2 Cl

−

CF3 Ru(bpy)3Cl2

Ir[dFCF3(CF3)ppy]2(dtbbpy)PF6

Me Me

N N

tBu

F

N

Ph

N+

−

ClO4

10-Phenyl-9mesitylacridinium chlorate

Photochemical processes are associated with scalability issues due to difficulty of photons to travel through large reaction mixtures. However, recent use of continuous flow technology is enabling preparative use of this technology.

11.3.1

Dual Catalytic Cross-coupling Reactions

The combination of photoredox catalysis with other transition metals has generated many new reactions in recent years. These reactions utilize power of photoredox catalysis to generate radical intermediates and modulate oxidation states of transition metal catalysts to expand traditional cross-coupling reactions into new chemical space. In 2014, Doyle and coworkers first published the use of an iridium-based photoredox catalyst in combination with a nickel catalyst to drive a dual catalytic cycle capable of achieving Csp3 − Csp2 cross-coupling reactions between alkyl carboxylic acids and aryl halides.63 These reactions have also more recently been expanded to vinyl halides,64 and alkyl halides.65 For industrial applications, chemists at Merck described the use of a microslug reactor to optimize this transformation in flow.66 From this data, they were able to demonstrate the scale up of a typical cross-coupling reaction using a Vapourtec flow reactor, achieving 88% yield and throughput of up to 710 mg/h.

CO2H N CBz

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) NiCl2(dtbbpy) (10 mol%) tBu-TMG (1.5 equiv)

Br +

Ac

DMF, Vapourtec UV-150 10 mL reactor 50 °C, 12 min, 0.83 ml/min 88% (0.5 mmol scale) 710 mg/h

N CBz

Ac

More recently, in a collaboration between the Fu and coworkers labs, the coupling of alkyl carboxylic acids was reported in an enantioselective manifold.67 The combination of a nickel catalyst with a chiral ligand was capable of rendering the C—C bond formation between the intermediate alkyl radical and aryl halide enantioselective to yield products in high ee. This method was demonstrated on Boc-leucine to produce the polyethylene glycol (PEG2) receptor antagonist

63 64 65 66 67

Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Science (Washington, DC, U. S.) 2014, 345, 437–440. Noble, A.; McCarver, S. J.; MacMillan, D. W. C. Journal of the American Chemical Society 2015, 137, 624–627. Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature (London, U. K.) 2016, 536, 322–325. Hsieh, H.-W.; Coley, C. W.; Baumgartner, L. M.; Jensen, K. F.; Robinson, R. I. Organic Process Research & Development 2018, 22, 542–550. Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillan, D. W. C. Journal of the American Chemical Society 2016, 138, 1832–1835.

11.3 Photoredox Catalysis

shown below. Since the coupling proceeds through a radical intermediate, the configuration of the stereogenic center in the product is controlled entirely by the choice of chiral ligand. CF3 CF3

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%) NiCl2-glyme (2 mol%) CO2H ligand (2.2 mol%), TBAI Me

Me Me HN

Cs2CO3, blue LEDs DME/toluene, RT

Boc

Me CF3 Me HN

76%, 96% ee

PhO PEG2 receptor antagonist

O NH

Ligand =

O CO2H

Boc

CN O

CF3 Me HN

N

tBu

tBu

In 2015, Molander and coworkers showed the coupling of aryl bromides with alkyl potassium trifluoroborates could be promoted by visible light in the presence of nickel and iridium catalysts.68 Under photoredox conditions, the trifluoroborate is reduced to the alkyl radical that can then be intercepted by the nickel catalyst to undergo C—C bond formation. This reaction has provided mild reaction conditions for coupling an array of alkyl trifluoroborates with aryl halides and avoids deleterious side pathways, such as β-hydride elimination, typical of Pd-catalyzed reactions. For application to pharmaceutically relevant compounds, chemists at Vertex sought to further improve this useful transformation.69 By making a selected number of changes to the initial conditions reported by Molander and coworkers, they were able to obtain a homogeneous reaction mixture that could be subjected to continuous flow processing. The main hurdle to flow processing was the use of the heterogeneous base, cesium carbonate. Switching to 2,6-lutidine and adjusting the solvent system to a mixture of dimethyl acetamide (DMA) and dioxane gave homogeneous reaction mixtures as well as simplifying reaction set-up. Furthermore, they found that irradiation in flow not only gave improved yields but was capable of rescuing reactions that gave trace product to synthetically useful yields of the desired cross-coupled material, as shown in the example below. O Br OMe N Me

N

O +

O

BF3K

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mol%) NiCl2dme/dtbbpy (10 mol%) 2,6-lutidine (1.6 equiv) 1 : 4 DMA : dioxane, blue LEDs Batch: trace Flow: 46% (40 min)

OMe N

N O

Me

Dual catalytic cycles have also been shown to enable coupling through C–H activation modes. In 2018, chemists at Merck in collaboration with the MacMillan lab showed the coupling of benzylic alcohols in the α-position.70 This reactivity was facilitated through the use of a hydrogen atom transfer (HAT) catalyst and a Lewis acid activator. Traditional C—O bond formation is avoided by the addition of a zinc Lewis acid that actives the α-hydroxy C–H, while also preventing the formation of nickel alkoxide species. They demonstrated the utility of this method through selective

68 Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander, G. A. Journal of the American Chemical Society 2015, 137, 2195–2198. 69 DeLano, T. J.; Bandarage, U. K.; Palaychuk, N.; Green, J.; Boyd, M. J. The Journal of Organic Chemistry 2016, 81, 12525–12531. 70 Twilton, J.; Christensen, M.; DiRocco, D. A.; Ruck, R. T.; Davies, I. W.; MacMillan, D. W. C. Angewandte Chemie International Edition 2018, 57, 5369–5373.

577

578

11 Selected Free Radical Reactions

arylation of N-(3-hydroxypropyl)-N-methylbenzamide. This intermediate was then taken on to a dual catalytic Ir/Ni cross-coupling to forge the C—O bond and lead to the preparation of Prozac in three steps. OH Me

N Bz

Ir[FCF3(CF3)ppy]2(dtbbpy)PF6 (1 mol%) NiBr2-glyme (2 mol%), ligand (2 mol%), quinuclidine (30 mol%) Me

+

ZnCl2 (1.5 equiv), K3PO4 (1 equiv) DMSO, blue LEDs, 24 h then NaBH4 54%

Br

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%) NiBr2-glyme/dtbbpy (10 mol%) quinuclidine (10 mol%) K2CO3 (1 equiv), MeCN blue LEDs Br

OH

Me

N Bz

Me

Me

CF3

CF3 O Me

Me

N N Ligand

O

HF-pyr

Me

N Bz

N H

Prozac 50% yield over 3 steps

CF3 95%

A key ability of photocatalysts to be both strong oxidants or reductants in their excited state was also employed to modulate the oxidation state of nickel complexes on the catalytic cycle. This was first demonstrated for the formation of challenging C—O bonds (vide infra). It has also enabled the development of a general, ligand-free C—N bond formation. In their report, the Buchwald and coworkers labs, in collaboration with chemists at Merck, showed a screen of 18 complex, pharmaceutically relevant coupling partners proceeded with a high degree of success.71 Selected examples of the drug-like structures that underwent successful coupling with piperidine are shown below.

Ar

X

+

HN

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.02 mol%) NiCl2 • glyme (5 mol%) DABCO (1.8 equiv)

Examples of complex substrates with 18–60% yield in screen: O N I CO2Et N N N

Br O

11.3.2

Ar N

DMSO, blue LEDs, HTE platform

N Me

nPr HN S tBu O O

Br

S

H N

Me

N N

Boc

Me

O

Photoredox Minisci Reactions

The Minisci reaction is a regioselective insertion of alkyl radicals onto electron-deficient arenes, mostly N-containing heterocycles. From a chemical perspective, its selectivity is complementary to the Friedel–Crafts reaction, which made this transformation appealing to the pharmaceutical industry. While initial reports in the 1970s employed strong oxidants and acids, along with elevated temperatures, the recent development of photoredox Minisci reactions enabled milder conditions. Only nucleophilic carbon-centered radicals are reactive due to the electron-deficient nature of the protonated heterocycles. Depending on the degree of substitution of the desired radical (e.g. primary, secondary, or tertiary), various radical precursors have successfully been utilized. For instance, MacMillan and coworker developed a C–H functionalization of heteroarenes using primary alcohols as the radical source.72 The mechanism relies on a synergistic 71 Corcoran, E. B.; Pirnot, M. T.; Lin, S.; Dreher, S. D.; DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C. Science (Washington, DC, U. S.) 2016, 353, 279–283. 72 Jin, J.; MacMillan, D. W. C. Nature (London, U. K.) 2015, 525, 87–90.

11.3 Photoredox Catalysis

photoredox catalytic cycle using an iridium catalyst, and an organocatalytic cycle using a thiol to ensure radical formation via HAT. The scope is quite broad in terms of six-membered heterocycles, with selectivity for either 2- or 4-position. O EtO

N

+

OH

Me Ir(ppy)2(dtbbpy)PF6 (1 mol%)

Me

HO 10 equiv

H

SH (50 mol%) N

TsOH (2 equiv), DMSO blue LEDs, 23 °C, 72 h

OH Me

81%

Other approaches have been developed to introduce secondary as well as tertiary radicals onto protonated heterocycles. Merck researchers reported in 2014 the use of alkyl tert-butylperacetate in combination with an iridium catalyst in a late-stage functionalization of drugs via photoredox Minisci reaction.73 More recently, Pfizer scientists published a nonprecious metal method using a Mn-based catalyst to alkylate a wide range of heteroarenes with unactivated iodoalkanes.74 The low price of the catalyst combined with the commercial availability of many alkyliodides made this transformation attractive when considering large-scale synthesis. R-I (2 equiv)

R-I (2 equiv)

Me

Mn2(CO)10 (15 mol%) TFA (1.0 equiv)

N NBoc Via secondary radical

MeOH (0.5 M) 36 W blue LED, 18 h

Me

Mn2(CO)10 (15 mol%) TFA (0.1 equiv)

Me

MeOH (0.5 M) 36 W blue LED, 18 h

N

80%

98%

N

Via tertiary radical

Interestingly enough, a catalytic enantioselective photoredox Minisci reaction has also been reported by Phipps and coworkers in 2018.75 An α-nitrogen radical was generated via Ir-catalyzed photochemistry from activated amino-acids, while the enantioselectivity was ensured by the chiral environment provided by a binol-derived phosphoric acid. In 2016, Stephenson and coworkers reported a regioselective trifluoromethylation of arenes using inexpensive reagents and mild conditions.76 The ruthenium-catalyzed approach was performed by irradiating an acetonitrile solution of the arene with trifluoroacetic anhydride (TFAA) and 4-phenyl-pyridine-N-oxide under blue LEDs. The N-oxide first activated TFAA, and then a succession of single-electron bond cleavage events generated 4-phenyl-pyridine, carbon dioxide, and nucleophilic CF3 radical. The method was adapted to perfluoroalkylation of arenes as well, and a kilogram-scale demonstration was performed in a simple custom-made reactor to process 1.2 kg of 2-methylester-boc-pyrrole in 48 hours (25 g/h). The corresponding trifluoromethyl pyrrole was obtained in 50% corrected yield (0.95 kg, 20 g/h). O MeO

Boc N

Ru(bpy)3Cl2 (0.1 mol%) TFAA (2.1 equiv) pyridine-N-oxide (2.0 equiv) MeCN, 45 °C blue LEDs residence time: 30 min 50%

O MeO

Boc N

CF3

0.95 kg

73 Di Rocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Angewandte Chemie International Edition 2014, 53, 4802–4806. 74 Nuhant, P.; Oderinde, M. S.; Genovino, J.; Juneau, A.; Gagne, Y.; Allais, C.; Chinigo, G. M.; Choi, C.; Sach, N. W.; Bernier, L.; Fobian, Y. M.; Bundesmann, M. W.; Khunte, B.; Frenette, M.; Fadeyi, O. O. Angewandte Chemie International Edition 2017, 56, 15309–15313. 75 Proctor, R. S. J.; Davis, H. J.; Phipps, R. J. Science (Washington, DC, U. S.) 2018, 360, 419–422. 76 Beatty, J. W.; Douglas, J. J.; Miller, R.; McAtee, R. C.; Cole, K. P.; Stephenson, C. R. J. Chem 2016, 1, 456–472.

579

580

11 Selected Free Radical Reactions

11.3.3

Photoredox Conjugate Addition

The inorganic photocatalyst tetrabutylammonium decatungstate (TBADT) was used to functionalize electron–poor olefins with a variety of acyl and alkyl groups.77 The photocatalyst was able to selectively activate C—H bonds in organic molecules including aldehydes, amides, ethers, and even unactivated alkanes, leading to reactive radical intermediates that underwent conjugate addition reactions with a variety of olefins and diazocarboxylates. The authors showed this reaction could be done in a flow reactor constructed of UV-transparent fluorinated ethylene propylene (FEP) tubing wrapped around a water-cooled 500 W medium pressure Hg vapor lamp to achieve up to 73 g/d productivity. O H

C6H13

CO2Me CO2Me

+

O

TBADT (0.4 mol%)

C6H13

Flow, 0.5 ml/min 500 W Hg-vapor lamp

CO2Me CO2Me

Throughput = 73 g/d

79%

In 2017, Overman and coworkers reported the photoredox-catalyzed C—C bond formation to construct quaternary stereocenters. The method, developed in collaboration with the MacMillan group, relies on the addition of a tertiary radical, generated from deoxygenation of a tertiary alcohol via a lithium oxalate intermediate, onto electron-poor olefins.78 Thus, cedrol-derived oxalate salt was coupled with benzyl acrylate when irradiated under blue LEDs in presence of an iridium photocatalyst. Six vials were exposed in parallel and combined for the work-up to isolate 1.04 g (78% yield) of desired product as a single epimer after column chromatography. OBn

Me

O

Me

H Me Me

O

O

O BnO

H2O, DME:DMF 34 W blue LEDs

OLi

11.3.4

Me

O [Ir{dF(CF3)ppy]2(dtbbpy)]PF6 (1 mol%)

Me

78%

H Me Me

Photoredox Rearrangements

Thermally initiated rearrangements have the potential to be performed at ambient temperature when subjected to visible light, which usually enhance functional groups tolerance. The following two examples were developed in flow to generate multigrams of rearranged products. First, Nicewicz and coworkers demonstrated that a C—S bond could be efficiently formed via a pyrylium-catalyzed Newman–Kwart rearrangement under blue LEDs irradiation.79 Commercially available triphenylpyrylium tetrafluoroborate (TPT, 1 mol%) was used to produce the corresponding S-thiocarbamate (19.7 g, 91% yield) in 82 hours using a flow reactor (with recirculation). Me

Me S O Me

N Me

Me

TPT (1 mol%) MeCN (0.12 M) Blue LEDs, air 82 h, flow (recirculation)

Me

Me O S Me

N Me

Me

91%

Collaboration between Eli Lilly and Stephenson resulted in the development of a visible light-mediated Smiles rearrangement to create a new C—C bond while installing a —CF2 — moiety under mild conditions.80 A ruthenium-based catalyst was necessary for generality purposes and several multigram experiments were conducted. Authors also 77 78 79 80

Bonassi, F.; Ravelli, D.; Protti, S.; Fagnoni, M. Advanced Synthesis and Catalysis 2015, 357, 3687–3695. Jamison, C. R.; Slutskyy, Y.; Overman, L. E. Organic Syntheses 2017, 94, 167–183. Perkowski, A. J.; Cruz, C. L.; Nicewicz, D. A. Journal of the American Chemical Society 2015, 137, 15684–15687. Douglas, J. J.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J. Organic Process Research & Development 2016, 20, 1148–1155.

11.3 Photoredox Catalysis

focused on a thiophene core to demonstrate the application of the Smiles rearrangement on scale with or without any catalyst in batch mode, as well as in continuous flow. F

F

S

Et3N (1.5 equiv) formic acid (1.5 equiv) DMSO (0.25 M)

OH

Blue LEDs, Ru(bpy)3Cl2

CO2Me

F

69%

9.8 g

S F

F

F Br

Et3N (1.5 equiv) formic acid (1.5 equiv) DMSO (0.25 M)

CO2Me

300 W white LEDs, 10 min residence time

O O S O

S 43.4 g

OH

CO2Me

5.4 g 2.4 g/h Continuous flow mode

300 W white LEDs, 64%

CO2Me

F

S

65%

Et3N (1.5 equiv) formic acid (1.5 equiv) DMSO (0.25 M)

OH

F

Batch mode

11.3.5

Photoredox Cycloadditions

Cycloaddition transformations have also been studied under photoredox catalysis. Classical cycloadditions, such as the Diels–Alder reaction, are driven by electronic considerations. This observation prevents, for example the reaction of electron-rich dienes and dienophiles together. Photoredox-catalyzed cycloaddition can sometimes overcome this limitation because the mechanism here is different and usually involves radical cation intermediates. Thus, Yoon and coworkers described in 2016 a cationic ruthenium-catalyzed formal [4+2] cycloaddition using white bulbs.81 The catalyst loading was as low as 0.1 mol%, and the reaction was complete within 6 hours to generate 6.7 g of cycloadduct in 92% yield. OMe

OMe Ru(bpz)3(BArF)2 (0.1 mol%)

+ Me

Visible light (white bulb) DCM, air, 6 h

Me

Me

Me

92% N N

N N

Ru2+

N N

F3C N

CF3

F3C

CF3

N

B−

N

F3C

CF3

N

N

N

Ru(bpz)3(BArF)2

F3C

CF3

2

A metal-free approach was also developed by Nicewicz and coworkers to access substituted tetralines via [4+2] reactions of styrenes. An acridinium-type organic photosensitizer was used as catalyst along with diphenyl disulfide as

81 Lies, S. D.; Lin, S.; Yoon, T. P. Organic Syntheses 2016, 93, 178–199.

581

582

11 Selected Free Radical Reactions

the HAT co-catalyst. The key to limit formation of the [2+2] cycloadduct was to switch to dichloroethane, a nonpolar solvent.82 Cat. (5 mol%) PhSSPh (20 mol%)

MeO

DCE, blue LED

MeO

MeO

77%

OMe Br > Cl >> F. Mechanistically, such reductions can proceed through several different mechanisms depending on the nature of the substrate, solvent, electrolyte, cathode material, and other conditions. The reaction can proceed through a radical anion of the alkyl halide followed by hemolytic cleavage to the alkyl radical or through a single concerted reduction-cleavage step. The radical may or may not then be further reduced rapidly to an anion, again depending on a variety of factors. Regardless of mechanism, electrochemistry can be a viable means for reagentless reduction of organic halides. This point is illustrated well in an example by Waldvogel and coworkers.96 In this example, the geminal dibromide remaining after a cyclopropanation reaction were reduced to the saturated cyclopropyl in a divided cell. In this case, a divided rather than undivided cell was necessary to avoid substrate oxidation (likely leading to a non-Kolbe 93 Mazurkiewicz, R.; Adamek, J.; Pazdzierniok-Holewa, A.; Zielinska, K.; Simka, W.; Gajos, A.; Szymura, K. The Journal of Organic Chemistry 2012, 77, 1952–1960. 94 Jones, A. M.; Banks, C. E. Beilstein Journal of Organic Chemistry 2014, 10, 3056–3072, 3017 pp. 95 Danielmeier, K.; Schierle, K.; Steckhan, E. Tetrahedron 1996, 52, 9743–9754. 96 Guetz, C.; Baenziger, M.; Bucher, C.; Galvao, T. R.; Waldvogel, S. R. Organic Process Research & Development 2015, 19, 1428–1433.

585

586

11 Selected Free Radical Reactions

or Shono-like reaction pathways). The cathodic and anodic chambers of the cell were divided by a porous ceramic membrane, with substrate in dimethylformamide (DMF), triethylmethylammonium methyl sulfate supporting electrolyte, and a leaded bronze pipe in the anodic chamber and DMF, methanol, supporting electrolyte, and a platinum mesh electrode. Oxidation of methanol was the complimentary anodic oxidation to the cathodic dibromide reduction. Under these conditions, 25.9 g (93% yield) of product of fully de-brominated product could be obtained. This result is in contrast to lesser yields for attempted Birch-like reduction (65%) and hydrogenation reactions (48%) on the same substrate which led to significant amounts of by-products resulting from cyclopropyl ring opening. Br Br BocN

COOH

DMF/MeOH (Et3NMe)O3SOMe 10 mA/cm2 Pt anode CuSn7Pb15 cathode divided cell 93%

BocN

COOH

In another example, Lu and coworkers electrochemically reduced allylic alkyl chlorides under a stream of CO2 in acetonitrile solvent with tetraethylammonium chloride as the supporting electrolyte to afford carboxylic acid products.97 As previously mentioned, activation of the alkyl chloride by virtue of being at an allylic position allows for its reduction at less negative (i.e. less reducing) potentials. Additionally, in this case it was found that surface interactions of the alkyl chloride with a silver cathode led to requiring even less reducing potentials for the alkyl chloride (−1.6 V vs. Ag/AgCl reference electrode) as compared to other electrode materials, which in turn gave better selectivity for alkyl chloride reduction over competing direct CO2 reduction. As for the anode, magnesium metal was used as a “sacrificial anode,” where the complementary anodic oxidation to the cathodic reduction is oxidation of the metal anode itself. The use of a sacrificial anode is a common technique for avoiding oxidation of substrate or product in the reaction solution without the need for a divided cell due to the ease at which the metal anode oxidizes compared to such organic compounds. In this case, an undivided cell is used without oxidation of the chloride ion or Kolbe oxidation of the carboxylate product of the reaction (see Section 11.4.1), though with the trade-off of introducing a stoichiometric quantity magnesium salts into the final reaction mixture.

Me

11.4.4

Cl

CO2 (1 atm) MeCN, Et4NCl 0 °C −1.6 V vs. Ag/AgCl Mg anode, Ag cathode undivided cell 89%

Me

CO2–

Indirect Electrolysis Reactions

All of the electrochemical reactions discussed thus far occur via direct oxidation or reduction of an organic substrate directly near the surface of an electrode, referred to as “direct electrolysis” reactions. Alternatively, a species aside from the substrate can be oxidized or reduced at an electrode, and that species, now in its redox active form, can proceed to react with the desired substrate away from the electrode surface in bulk solution. These reactions are referred to as “indirect electrolysis” or “mediated electrolysis” reactions.98 Such reactions can be useful for taking advantage of particular properties of a redox catalyst (such as steric bulk or electronic properties) that are not available during direct electrolysis while still avoiding use of stoichiometric amounts of chemical oxidant or reductant to turn over the catalyst. For example, in the case illustrated below, 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) is used as an oxidation catalyst with its reduced form being reoxidized at the anode following substrate oxidation. Using TEMPO as a mediator allowed for selective oxidation of the primary alcohol of methyl-α-d-glucopyranoside to a carboxylic acid using an 97 Niu, D.-F.; Xiao, L.-P.; Zhang, A.-J.; Zhang, G.-R.; Tan, Q.-Y.; Lu, J.-X. Tetrahedron 2008, 64, 10517–10520. 98 Francke, R.; Little, R. D. Chemical Society Reviews 2014, 43, 2492–2521.

11.4 Electrochemical Methods

aqueous sodium carbonate/sodium bicarbonate buffer as the electrolyte with water reduction to hydrogen and hydroxide as the complimentary cathodic reduction to the anodic oxidation of the reduced TEMPO catalyst. This reaction was initially demonstrated on gram scale by Schäfer and coworker under constant potential conditions, using an undivided cell with a saturated calomel reference electrode (SCE) to control the potential at the anode throughout the course of the reaction.99 Moeller and coworkers more recently performed the same transformation using a simpler constant current setup while achieving similar yield.100 OH O HO

OMe

20 mol% TEMPO H2O Na2CO3/NaHCO3

O HO

Pt anode carbon cathode undivided cell

OH OH

O

HO

OMe OH

OH

Constant potential: 96% Constant current: 98%

Organometallic catalysts can also be used in a mediated electrolysis, using an anode or a cathode to oxidize or reduce the catalyst after one catalytic cycle back to its active redox state. For example, catalytic amounts of nickel(II) precatalysts can be cathodically reduced to give active Ni(0) species which, after reaction is reduced again from the Ni(II) or Ni(I) oxidation by the cathode to again produce active Ni(0). Condon et al. demonstrated such a reaction for the arylation of activated olefins with aryl bromides and chlorides via the reduction of a NiBr2 ⋅H2 O precatalyst in DMF/pyridine under constant current conditions in an undivided cell with a sacrificial iron anode. It was found that the iron salts produced via the oxidation of the sacrificial iron anode actually improved the reaction, with a short pre-electrolysis of the anode prior to addition of substrates and nickel precatalyst to introduce a starting amount of iron cations into solution being beneficial.101 Br EtO2C

+ O

10 mol% NiBr2·3H2O Me DMF:pyridine (9 : 1) Bu4NBr/Bu4NI 0.3 A/dm2 Fe anode Ni grid cathode undivided cell 88%

O Me EtO2C

Doubly mediated electrochemical systems are also possible, where a redox mediator is oxidized or reduced at an electrode and that redox active species then proceeds to oxidize or reduce a separate mediator catalyst in bulk solution which, finally, reacts with the substrate. Such systems are useful when the heterogeneous electron transfer to the desired redox catalyst is inefficient or leads to catalyst degradation. For example, electrochemical reactions that require oxidation of catalytic palladium(0) to palladium(II) often proceed better with the use of a second mediator to oxidize the palladium in bulk solution away from the electrode rather than at the anode surface directly. Triarylamines, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and TEMPO are all common secondary mediators for such reactions.102 Torii an coworkers used such a double mediatory system to perform a series of Wacker oxidations (Section 10.2.7), such as the example below, using tris(4-bromophenyl)amine as a secondary redox mediator under constant current conditions. In this system, the triarylamine mediator is oxidized at the anode to a radical cation, which in turn oxidized Pd(0) to the catalytically relevant Pd(II) which reacts with substrate

99 Schnatbaum, K.; Schafer, H. J. Synthesis 1999, 864–872. 100 Nguyen, B. H.; Redden, A.; Moeller, K. D. Green Chemistry 2014, 16, 69–72. 101 Condon, S.; Dupre, D.; Falgayrac, G.; Nedelec, J.-Y. European Journal of Organic Chemistry 2002, 105–111. 102 Inokuchi, T.; Ping, L.; Hamaue, F.; Izawa, M.; Torii, S. Chemistry Letters 1994, 121–124.

587

588

11 Selected Free Radical Reactions

to give the Wacker oxidation product, Pd(0), and the neutral triarylamine thus completing one catalytic cycle. At the cathode, water is reduced to hydrogen gas and hydroxide. 5 mol% PdCl2 7 : 1 MeCN : H2O 0.5 M Et4NOTs

O CO2Me

O CO2Me

2–3 mA Pt anode Pt cathode undivided cell

Me

O

90%

Anode

2Ar3N

Pd(II)

R +H2O

−2e−

O

•+

2Ar3N

11.4.5

Pd(0)

R

Me

Oxidation and Reduction at Sulfur

The sulfur atom is particularly susceptible to electrochemical transformations due to the low redox potentials of many organosulfur functional groups. The disulfide bond is easily reduced electrochemically and eliminates the need for stoichiometric reductants. A process for the reduction of d,l-homocystine was described using a batch recirculation cell to generate d,l-homocysteine, which cyclized under the reaction conditions for form the thiolactone.103 Disulfide reductions are typically done in a divided cell to prevent the thiol products from reoxidation at the anode. O H2N

2HCl

•

OH S S HO

O

aq HCl NH2

Carbon felt cathode divided cell

O

H2N

2

HCl

•

H2N

OH SH

•

HCl

O S

93%

Oxidation at sulfur is also a facile process. Thioethers can be oxidized to the corresponding sulfoxides and sulfones. Noel and coworkers were able to access either product selectively by varying the applied potential and the residence time (t r ) in a microflow reactor.104 S

Me

TBAClO4 (10 mol%) MeCN, H2O/HCl (0.1 M) Fe anode undivided cell

O− + S Me

65%, tr = 5 min

O +

S

O Me

92%, tr = 10 min

Sulfinic acid salts are also readily oxidized to generate sulfur centered radicals. Aryl sulfinates, upon oxidation, can undergo addition reactions with styrene derivatives to generate vinyl sulfones. Oxidation in the presence of amines leads to the formation of sulfonamides. These reactions are mediated by the sodium iodide electrolyte.105

103 Galia, A. Industrial and Engineering Chemistry Research 2007, 46, 2360–2366. 104 Laudadio, G.; Straathof, N. J. W.; Lanting, M. D.; Knoops, B.; Hessel, V.; Noel, T. Green Chemistry 2017, 19, 4061–4066. 105 Zhang, C.; Chen, Y.; Yuan, G. Chinese Journal of Chemistry 2016, 34, 1277–1282.

11.4 Electrochemical Methods

NaI, DMSO carbon anode Ni cathode

O S

ONa + Cl

O O S

84%

Cl

Alkyl sulfinic acid salts can undergo a different reaction pathway. If the corresponding alkyl group is sufficient to stabilize the radical center, the intermediate sulfur radical can undergo extrusion of sulfur dioxide resulting in a carbon-centered radical. Baran and coworkers utilized this reactivity to generate fluoroalkyl radicals, which they used to functionalize heteroarenes via the Minici reaction.106 Me N Zn(SO2CF3)2

+

MeO

N O

Carbon anode 60 °C 53%

F3C MeO

Me N N

O

106 O’Brien, A. G.; Maruyama, A.; Inokuma, Y.; Fujita, M.; Baran, P. S.; Blackmond, D. G. Angewandte Chemie International Edition 2014, 53, 11868–11871.

589

591

12 Synthesis of “Nucleophilic” Organometallic Reagents David H. Brown Ripin 1 and Adam R. Brown 2 1

Clinton Health Access, Boston, MA, USA

2 Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 591 Synthesis of “Nucleophilic” Organometallic Reagents, 592 Strategies for Metalating Heterocycles, 615 Reactions of “Nucleophilic” Organometallic Reagents, 618

12.1 Introduction The synthesis of organometallic reagents is a large topic that is the subject of many books and reviews.1,2,3,4 This chapter covers useful methods for the synthesis of nucleophilic reagents commonly used in synthesis and is in no way meant to be comprehensive. For a very thorough treatment of this subject, see Schlosser’s treatise.1 The following table lists the metals discussed in this chapter, the common methods of synthesis of the active species, and their uses. Included in the category of “nucleophilic” organometallic reagents are the metalated reagents used in cross-coupling reactions. The subset of metalated heterocycles has been reviewed.2 Not included are transition-metal catalysts; these are discussed in the appropriate chapters on transformations.

Metal

Methods of synthesis

Transmetalation precursors

Lithium

M–X exchange

Sn, Te

Deprotonations, metal–halogen exchange, addition to electrophiles, 1,2 addition to conjugated systems, transmetalation precursor

Li, Mg, Zr

Cross-couplings, oxidation of C—B bond to alcohol

Deprotonation

Common uses

M–M exchange Boron

Hydrometalation M–M exchange M–X exchange C–H functionalization

1 Schlosser, M.; Editor Organometallics in Synthesis: A Manual; 2nd ed.; John Wiley & Sons Ltd: West Sussex, England, 2002. 2 Chinchilla, R.; Najera, C.; Yus, M. Chemical Reviews 2004, 104, 2667–2722. 3 Crabtree, R.; Mongos, M. Comprehensive Organometallic Chemistry III, 13 Volume Set; Elsevier: Oxford, UK, 2006. 4 Abel, E. W.; Stone, F. G. A.; Wilkinson, G.; Editors Comprehensive Organometallic Chemistry II: A Review of the Literature 1982–1994, 14 Volume Set; Pergamon: Oxford, UK, 1995. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

592

12 Synthesis of “Nucleophilic” Organometallic Reagents

Metal

Methods of synthesis

Transmetalation precursors

Magnesium

M–X exchange

Li, Zr

Deprotonation of kinetically acidic protons, addition to electrophiles, 1,2 addition to conjugated systems

Li, Zr

Reaction with acid chlorides, protonation or halogenation, cross-couplings

Li, Mg

Allylations, protonation, cross-coupling

Li, Mg, Sn

Addition to carbonyls

Li, Mg

Selective additions to carbonyls

M–M exchange

Common uses

Carbometalation Hydrometalation Aluminum

M–X exchange Carbometalation Hydrometalation

Silicon

M–M exchange M–X exchange Hydrosilation C–H functionalization

Titanium

M–M exchange Homoenolate form

Chromium

M–M exchange M–X exchange

Manganese

M–M exchange

Iron

M–X exchange

Li, Mg

Conjugate additions Carbonylations

Copper

M–M exchange

Li, Mg, Zn, Zr, Mn

Conjugate additions

Zinc

M–X exchange

Li, Mg, Zr

Carbonyl additions

M–M exchange Homoenolate form Zirconium

Hydrometalation

Indium

M–M exchange

Transmetalation precursor, cross-couplings Sn

Allylations, cross-coupling

Li, Mg

Cross-coupling, allylations, transmetalation precursor

M–X exchange Tin

M–M exchange SN 2 Hydrometalation M–X exchange

Cerium

M–M exchange

Li, Mg

Addition to carbonyl with minimization of enolate formation

Bismuth

M–M exchange

Li, Mg

Cross-coupling

12.2 Synthesis of “Nucleophilic” Organometallic Reagents 12.2.1 12.2.1.1

Lithium Deprotonation

Directed lithiation is a powerful method for accessing organolithium reagents from substrates with Lewis basic moieties that can direct lithiation, such as amines, amides, or carbamates.5,6,7 See Section 12.3 for a discussion of strategies for metalating heterocyclic compounds. 5 Snieckus, V. Chem. Rev. 1990, 90, 879–933. 6 Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376–393. 7 Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. J. Am. Chem. Soc. 2006, 128, 3538–3539.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.1.2

Metal–Halogen Exchange

Perhaps the most common method for generating aryllithium reagents is through a metal–halogen exchange reaction of an iodide or bromide with an alkyllithium reagent (e.g. n-BuLi or t-BuLi).8 This method allows for the generation of an aryllithium with predictable regiochemistry. Useful solvents for the generation of organolithium reagents include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers. THF can undergo ring opening if exposed to an organolithium for a prolonged period of time at ambient temperature, and toluene can be deprotonated at the benzylic position in the absence of more facile reaction pathways. When t-BuLi is employed, 2 equiv of the reagent must be utilized: the first for metal–halogen exchange and the second for elimination of the resulting t-BuX.9 The use of n-BuLi is highly preferred over s-BuLi and t-BuLi due to the relative ease and safety of handling. If the generation of butane is a concern in a large scale process, n-HexLi is a very useful replacement. Br

n-BuLi/hexanes MTBE, –40 °C >75%

N TBS N

Li

t-BuLi/hexane THF –78 °C

N TBS N

TBS N

EtI 96%

Br

Li

Et

Despite the fact that cryogenic temperatures are often necessary, this class of transformation is commonly utilized in large scale synthesis. Some recent examples applied toward synthesis of SGLT2 inhibitors are shown below.10,11 HO

O

HO

O

TMSCl/NMM toluene/THF

TMSO

OH

TMSO

OH

O

O

OTMS OTMS

Et Toluene, –78 °C >70%

n-BuLi Et toluene/THF –78 °C

Br

OEt n-HexLi toluene/THF –15 °C

OBn

OTMS OTMS

Li Me O

Br

OH

TMSO

Et

O

Cl

O

TMSO

Cl Li OBn

OEt

Me OBn O N

OBn OBn OBn

N

Me

O

Me O

Me OBn O

OBn

75% OBn OBn OBn

Cl

OEt

Metal–halogen exchange with lithium is a diffusion controlled reaction that occurs faster than nucleophilic addition and at a competitive rate with deprotonation. This rate allows for the Barbier reaction wherein the organolithium reagent is generated in the presence of an electrophile.12 8 Lipton, M. F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor, D. W.; Newby, J. J.; Appell, R. B.; Daugs, E. D. Organic Process Research & Development 2003, 7, 385–392. 9 Bryce-Smith, D.; Blues, E. T. Organic Syntheses 1973, Coll. Vol. V , 1141–1145. 10 Deshpande, P. P.; Singh, J.; Pullockaran, A.; Kissick, T.; Ellsworth, B. A.; Gougoutas, J. Z.; Dimarco, J.; Fakes, M.; Reyes, M.; Lai, C.; Lobinger, H.; Denzel, T.; Ermann, P.; Crispino, G.; Randazzo, M.; Gao, Z.; Randazzo, R.; Lindrud, M.; Rosso, V.; Buono, F.; Doubleday, W. W.; Leung, S.; Richberg, P.; Hughes, D.; Washburn, W. N.; Meng, W.; Volk, K. J.; Mueller, R. H. Organic Process Research & Development 2012, 16, 577–585. 11 Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E. C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.; Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C. L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Organic Process Research & Development 2014, 18, 66–81. 12 Ennis, D. S.; Lathbury, D. C.; Wanders, A.; Watts, D. Organic Process Research & Development 1998, 2, 287–289.

593

594

12 Synthesis of “Nucleophilic” Organometallic Reagents

I

O

Ph

Cl

Et

O

Ph

I n-BuLi, –60 °C toluene

Et

Cl

OH

75%

O

I

A less common method for the generation of organolithium reagents is the treatment of a halide with Li(0).13 Phenyllithium can also be prepared by this method, although reflux is required.14 Li(0), Et2O 0 °C

Cl

Cl

12.2.1.3

Li

Li

>74%

Metal–Metal Exchange

Organostannanes can be transmetalated to organolithium reagents on treatment with n-BuLi. This is not a desirable method as toxic stannanes need to be prepared and used in the process.15

Bu3Sn

O

12.2.2

Boron

12.2.2.1

OMe

n-BuLi/hexanes THF –78 °C

Li

O

OMe

OH

Cycloheptanone

O

OMe

91–95%

Hydroboration

One of the most common methods for the preparation of alkyl and vinyl boranes is through the hydroboration reaction (see section “hydroboration” for a detailed discussion). An example is shown below.16

H B

(9-BBN) O

O MeO

MeO

N H

N BR2

THF, 30 °C

H Me O

I

A, Pd2(dba)3 K2CO3 H2O 55%

N

HN

Me N

BR2

A

Me O

N HN

O MeO

N H

N Me

N N

13 14 15 16

Wender, P. A.; White, A. W.; McDonald, F. E. Organic Syntheses 1992, 70, 204–214. Woodward, R. B.; Kornfeld, E. C. Organic Syntheses 1949, 29, 44–46. Greco, M. N.; Rasmussen, C. R. The Journal of Organic Chemistry 1992, 57, 5532–5535. Dugger, R. W.; Ragan, J. A.; Brown Ripin, D. H. Organic Process Research & Development 2005, 9, 253–258.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

This method can be used to synthesize allyl boranes as well.17 (Ipc)2BH Et2O, 0 °C

O B

O

•

>42% Me Ipc =

12.2.2.2

Me Me

O

O B

B(Ipc)2

Metal–Metal Exchange

Boronic acid derivatives can be generated by treating an organolithium or Grignard reagent with a trialkylborate. This is the most common method for the preparation of boronic acids to be used in a Suzuki coupling.18,19,20 t-Bu

O

(i) (i-PrO)3B, LDA THF, 0 °C (ii) aq HCl (iii) HN(CH2CH2OH)2

O

t-Bu

O

O O

74% CF3

N

H

CF3

Me BrMg Me

O

O

B O

Me

(i) B(Oi-Pr)3, THF –5 °C to rt (ii) aq HCl 42% isolated >79% in situ

HO B Me

Me

Me Me

(i) n-BuLi/hexane THF, –65 °C (ii) B(Oi-Pr)3 –65 to –10 °C (iii) aq HOAc

O

O Me

95% B(OH)2

Br

Heterocycles containing nitrogen can be derivatized to stable boranes such as the pyridylborane shown below. A 200 kg21 preparation using the organolithium reagent is depicted; the organolithium will “walk,” resulting in a mixture of products if the temperature rises much above −78 ∘ C. The same transformation can be accomplished through the Grignard reagent generated by metalation of the bromide with i-PrMgCl at 0 ∘ C; the Grignard reagent is stable up to 15 ∘ C.22

Br N

(i) n-BuLi/hexanes MTBE, –40 °C (ii) Et 2 BOMe 75% or (i) EtMgCl/ THF, 0 °C (ii) Et 2BOMe 78%

BEt2 N

17 Flamme, E. M.; Roush, W. R. Journal of the American Chemical Society 2002, 124, 13644–13645. 18 Caron, S.; Hawkins, J. M. The Journal of Organic Chemistry 1998, 63, 2054–2055. 19 Winkle, D. D.; Schaab, K. M. Organic Process Research & Development 2001, 5, 450–451. 20 Jacks, T. E.; Belmont, D. T.; Briggs, C. A.; Horne, N. M.; Kanter, G. D.; Karrick, G. L.; Krikke, J. J.; McCabe, R. J.; Mustakis, J. G.; Nanninga, T. N.; Risedorph, G. S.; Seamans, R. E.; Skeean, R.; Winkle, D. D.; Zennie, T. M. Organic Process Research & Development 2004, 8, 201–212. 21 See Note 5. 22 Cai, W.; Ripin, D. H. B. Synlett 2002, 273–274.

595

596

12 Synthesis of “Nucleophilic” Organometallic Reagents

Vinylboranes can also be prepared using a transmetalation, as demonstrated by the 2.3 kg preparation below.23 The vinylborane was used directly in a Suzuki coupling reaction. PMBO

Me

Me

t-BuLi/hexanes 9-MeOBBN, THF −80 °C

I

PMBO

Me

Me

BR2

Me

Me

OTBS

OTBS Me

Me

Me

PdCl2(dppf), Cs2CO3 H2O, 25 °C 73%

I TBSO

O

O PMP

Me PMBO

Me

Me

Me OR O Me

Me OTBS

O PMP

The zirconium-catalyzed hydroboration of acetylenes with pinacol borane can arguably be considered a transmetalation from Zr to B following hydrozirconation and is an effective method for the hydroboration of acetylenes.24 Cp2ZrHCl pinacolborane CH2Cl2

THPO

THPO

B O O

Me Me Me Me

63%

12.2.2.3

Cross-coupling with R2 B–BR2

A mild method for the formation of boronic acids is via the Pd-catalyzed coupling of an aryl halide and bis(pinacolato)diborane. The cost of the reagent and potential for dimerization (through a Suzuki coupling) are issues to consider when selecting this methodology.25 Only one of the two borons in the reagent is transferred. Me Me Me Me

OMe O

MeO

O

I OMe

Me Me B B Me O O Me O

O

KOAc, PdCl2(dppf) DMF, 80 °C 60%

OMe O

MeO

O

Me O B

O

Me Me Me

OMe

Bis-boronic acid has emerged as a more atom-economical alternative to bis(pinacolato)diboron for this class of transformation.26,27 An application in large-scale synthesis (27.5 kg) is shown below.28 The comparatively small size of bis-boronic acid was also advantageous in this case, as the transformation was carried out at a congested site. Appropriate care must be taken when using bis-boronic acid, however, as it has been shown to decompose at 85 ∘ C via polymerization and can also decompose in the presence of protic solvents to evolve hydrogen gas.29 23 Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.; Daeffler, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.; Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L. Organic Process Research & Development 2004, 8, 107–112. 24 Batt, D. G.; Houghton, G. C.; Daneker, W. F.; Jadhav, P. K. The Journal of Organic Chemistry 2000, 65, 8100–8104. 25 Zembower, D. E.; Zhang, H. The Journal of Organic Chemistry 1998, 63, 9300–9305. 26 Molander, G. A.; Trice, S. L. J.; Kennedy, S. M. The Journal of Organic Chemistry 2012, 77, 8678–8688. 27 Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. Journal of the American Chemical Society 2012, 134, 11667–11673. 28 Williams, M. J.; Chen, Q.; Codan, L.; Dermenjian, R. K.; Dreher, S.; Gibson, A. W.; He, X.; Jin, Y.; Keen, S. P.; Lee, A. Y.; Lieberman, D. R.; Lin, W.; Liu, G.; McLaughlin, M.; Reibarkh, M.; Scott, J. P.; Strickfuss, S.; Tan, L.; Varsolona, R. J.; Wen, F. Organic Process Research & Development 2016, 20, 1227–1238. 29 Gurung, S. R.; Mitchell, C.; Huang, J.; Jonas, M.; Strawser, J. D.; Daia, E.; Hardy, A.; O’Brien, E.; Hicks, F.; Papageorgiou, C. D. Organic Process Research & Development 2017, 21, 65–74.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

0.5 mol%

Pd NH2 Cy3P Cl

CO2NHMe

Br Ms

F

O

N

1.5 equiv HO OH B B HO OH

Me

12.2.2.4

OH HO Ms

3.0 equiv DIPEA 0.25 mol% Cy3P MeOH, reflux 88%

CO2NHMe

B

F

O

N Me

C–H Borylation

Metal-catalyzed C–H borylation is an efficient way to prepare organoboron intermediates at sp2 and sp3 hybridized carbons.30,31 These processes are typically catalyzed by iridium, rhodium, or ruthenium and often proceed with high regioselectivity in the presence of multiple C—H bonds. For aryl C—H bonds, this selectivity is typically governed by the steric accessibility of the C—H bond. The following are two examples of selective meta C–H borylation that were carried out on large scale by scientists at Merck and Pfizer, respectively.32,33 1 mol% [Ir(COD)OMe]2 4 mol% 2,2-bpy B2Pin2, CyH, 50 °C

I

Cl

I

Cl

O Me Me

N

12.2.2.5

N Me

B

Me Me

Me

1 mol% [Ir(COD)Cl]2 tmphen, B2Pin2 heptane

94% (2 steps)

O

Me Me

96%

I

Cl

Oxone acetone

OH

Me O

O B N

N Me

Other

Potassium trifluoroborates can be generated either from boronic acids34 or from some hydroboration products35 using KHF2 .

B(OH)2

KHF2, MeOH, rt 82%

−

F F B F + K

30 Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chemical Reviews 2010, 110, 890–931. 31 Hartwig, J. F. Accounts of Chemical Research 2012, 45, 864–873. 32 Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk, K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. Organic Process Research & Development 2016, 20, 1476–1481. 33 Sieser, J. E.; Maloney, M. T.; Chisowa, E.; Brenek, S. J.; Monfette, S.; Salisbury, J. J.; Do, N. M.; Singer, R. A. Organic Process Research & Development 2018, 22, 527–534. 34 Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. The Journal of Organic Chemistry 1995, 60, 3020–3027. 35 Clay, J. M.; Vedejs, E. Journal of the American Chemical Society 2005, 127, 5766–5767.

597

598

12 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.3

Magnesium

12.2.3.1

Metal–Halogen Exchange

The classical method for generating a Grignard reagent is the reaction of Mg(0) with a halide. The reaction is highly exothermic and requires elevated temperatures to proceed. The major difficulty with this process is initiating the reaction, with a hazardous situation arising if too much halide is added prior to initiation. Some useful procedures are referenced here, with a variety of initiators including phenyl Grignard formation with no initiator,36 with iodine,37 and with DIBAL-H activation.38,39 Other useful initiators are TMSCl,40 bromine, diiodoethane, dibromoethane,41 or a Grignard reagent itself such as MeMgCl. A procedure for preparing an unsolvated Grignard reagent, n-BuMgCl, in methylcyclohexane with Mg(0) powder has also been reported.42 Typically, 10% or so of the halide is premixed with the Mg(0), and the reaction is initiated with heat and an added initiator if needed, followed by slow addition of the remaining halide. Ethereal solvents such as THF are most commonly employed in the process and will not react with the Grignard reagent; unlike the case of organolithium reagents. An alternative method for the generation of aryl Grignard reagents is metal–halogen exchange with an alkyl Grignard.43 This method has the advantage of improved functional group compatibility during Grignard formation due to low reaction temperatures (0–25 ∘ C) and circumvents the initiation problems of the reaction with Mg(0).44 These advantages have made metal–halogen exchange with an alkyl Grignard a preferred method for Grignard formation in the context of complex molecule synthesis and large-scale pharmaceutical synthesis, an example of which is illustrated below.45 O I N

N Me

i-PrMgCl THF, –19 °C

MgCl N

N Me

MeO N Me

N N

O

O

N

Me

THF, –9 °C to rt 87%

N

N

N Me

O Me

The synthesis of aryl Grignards bearing trifluoromethyl groups from their corresponding aryl halide and Mg(0) has significant safety concerns that can be overcome through the use of magnesium–halogen exchange.46,47 This technology was used in a key step of the synthesis of a sodium–hydrogen exchange type I inhibitor.48 O

CF3 Br

i-PrMgBr THF, 25 °C

CF3 MgBr

1.5 equiv pyridine 1.1 equiv AcCl

CF3

N

0.1 mol% CuI THF 76%

36 Brenner, M.; la Vecchia, L.; Leutert, T.; Seebach, D. Organic Syntheses 2003, 80, 57–65. 37 Braun, M.; Graf, S.; Herzog, S. Organic Syntheses 1995, 72, 32–37. 38 Tilstam, U.; Weinmann, H. Organic Process Research & Development 2002, 6, 384–393. 39 Slattery, C. N.; Deasy, R. E.; Maguire, A. R.; Kopach, M. E.; Singh, U. K.; Argentine, M. D.; Trankle, W. G.; Scherer, R. B.; Moynihan, H. The Journal of Organic Chemistry 2013, 78, 5955–5963. 40 Ace, K. W.; Armitage, M. A.; Bellingham, R. K.; Blackler, P. D.; Ennis, D. S.; Hussain, N.; Lathbury, D. C.; Morgan, D. O.; O’Connor, N.; Oakes, G. H.; Passey, S. C.; Powling, L. C. Organic Process Research & Development 2001, 5, 479–490. 41 Aki, S.; Haraguchi, Y.; Sakikawa, H.; Ishigami, M.; Fujioka, T.; Furuta, T.; Minamikawa, J.-I. Organic Process Research & Development 2001, 5, 535–538. 42 See Note 6. 43 Leazer, J. L., Jr.; Cvetovich, R.; Maloney, K. M.; Danheiser, R. L. Organic Syntheses 2005, 82, 115–119. 44 Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angewandte Chemie International Edition 2003, 42, 4302–4320. 45 Ruck, R. T.; Huffman, M. A.; Stewart, G. W.; Cleator, E.; Kandur, W. V.; Kim, M. M.; Zhao, D. Organic Process Research & Development 2012, 16, 1329–1337. 46 Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery, T.; Bachert, D. The Journal of Organic Chemistry 2003, 68, 3695–3698. 47 Tang, W.; Sarvestani, M.; Wei, X.; Nummy, L. J.; Patel, N.; Narayanan, B.; Byrne, D.; Lee, H.; Yee, N. K.; Senanayake, C. H. Organic Process Research & Development 2009, 13, 1426–1430. 48 Tang, W.; Patel, N. D.; Wei, X.; Byrne, D.; Chitroda, A.; Narayanan, B.; Sienkiewicz, A.; Nummy, L. J.; Sarvestani, M.; Ma, S.; Grinberg, N.; Lee, H.; Kim, S.; Li, Z.; Spinelli, E.; Yang, B.-S.; Yee, N.; Senanayake, C. H. Organic Process Research & Development 2013, 17, 382–389.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

Pioneering studies by Knochel indicated that i-PrMgCl⋅LiCl has increased reactivity compared to i-PrMgCl in magnesium–halogen exchange reactions and is therefore an option for substrates resistant to magnesium–halogen exchange or in cases when lower reaction temperatures are required.49,50 Using this method, Grignard reagents can be formed and reacted in the presence of nitriles or esters (see below).51 I

i-PrMgCl•LiC l

CO2Me

CO2Me

−40 °C, 12 h

Me Me

OH

MgCl•LiCl

EtCHO

Et

−40 °C to rt 82%

Me Me

CO2Me Me Me

Magnesium-ates are another class of reagents that can be employed for challenging magnesium–halogen exchange reactions (or direct deprotonations). These species have reactivity and stability properties between organolithium reagents and Grignard reagents and are generated by mixing a ∼1 : 2 ratio of i-PrMgCl and n-BuLi.52,53,54

N

(i) 0.33 equiv i-PrMgCl (ii) 0.67 equiv n-BuLi

F

O

O N

F

1.0 equiv

–10 to 0 °C, THF Br

3

MgLi

O

HO

OiPr

OiPr F

–30 °C 65%

N

0.33 equiv

12.2.3.2

Metal–Metal Exchange

A vinyl Grignard reagent can be generated by hydrozirconation followed by transmetalation with an alkyl Grignard reagent.55 OTBS O

OTBS

Cp2ZrHCl t-BuMgCl Toluene 50 °C

CF3

OTBS

O

O

Zr(Cp)2Cl

MgCl

>72% CF3

CF3

Organolithium reagents can also be transmetalated to the Grignard reagent on treatment with a Mg(II) salt, most commonly MgCl2 or MgBr2 .56 Me N

O

Me n-BuLi/hexanes THF, –78 °C Me

Me N H

N

O

Me Me

N

Li

MgCl2, 0 °C Me N H Ph

N OH

O

Me Me

Me

PhCHO, –65 °C 50%

N H Cl

Mg

O

Me Me

N

49 Krasovskiy, A.; Knochel, P. Angewandte Chemie International Edition 2004, 43, 3333–3336. 50 Li-Yuan Bao, R.; Zhao, R.; Shi, L. Chemical Communications 2015, 51, 6884–6900. 51 Ren, H.; Krasovskiy, A.; Knochel, P. Organic Letters 2004, 6, 4215–4217. 52 Hawkins, J. M.; Dubé, P.; Maloney, M. T.; Wei, L.; Ewing, M.; Chesnut, S. M.; Denette, J. R.; Lillie, B. M.; Vaidyanathan, R. Organic Process Research & Development 2012, 16, 1393–1403. 53 Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Angewandte Chemie International Edition 2000, 39, 2481–2483. 54 Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Letters 2001, 42, 4841–4844. 55 Boulton, L. T.; Brick, D.; Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.; Parkin, N.; Rhodes, D.; Ruecroft, G. Organic Process Research & Development 2002, 6, 138–145. 56 Gawley, R. E.; Zhang, P. The Journal of Organic Chemistry 1996, 61, 8103–8112.

599

600

12 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.3.3

Hydromagnesiation

Although rare, propargylic alcohols can be directly hydromagnesiated in the presence of a catalyst, rather than hydrozirconating followed by transmetalation.57 i-PrCH2MgCl Cp2TiCl2, Et2O, rt

Me OH

12.2.3.4

Me

OMgCl MgCl

>60%

Carbomagnesiation

Propargylic alcohols can be carbomagnesiated in a process that can be used as a fragment coupling reaction.58 Me

Me Me

MgBr Et2O, 35 °C Me

OMgBr

Me

Me Me

MgBr

85% Me

Bu2N

NBu2

OMgBr

Carbomagnesiation reaction can also be accomplished in the presence of a Ti catalyst.59

Me

Me Me

n-BuMgCl Cp2TiCl2, THF 0 °C

Cl

Me

Me Me MgCl Me Me

Me

Me Me COPh

PhCOCl 93%

Me Me

12.2.4

Me

Me Me MgCl Me Me

Aluminum

12.2.4.1

Metal–Halogen Exchange

Direct insertion of aluminum into aryl or alkenyl halides has been reported using aluminum powder, lithium chloride, and a catalytic additive such as indium chloride.60 A variety of functionalized organoaluminum species can be generated under these conditions that participate in cross-coupling reactions.

Me

I

3 equiv Al 1.5 equiv LiCl 3 mol% InCl3 THF, 50 °C, 24 h

(i) Zn(OAc)2 (ii) Me

Al2/3X

Br

S

Me

Me O

1.4 mol% PEPPSI 75% (2 steps)

S O

Me

57 Ogasa, T.; Ikeda, S.; Sato, M.; Tamaoki, K. Preparation of N-(2,2,5,5-tetramethylcyclopentanecarbonyl)-(S)-1,1-diaminoethane p-toluenesulfonate as a sweetener intermediate JP02233651 1990 5 pp. 58 Bury, P.; Hareau, G.; Kocienski, P.; Dhanak, D. Tetrahedron 1994, 50, 8793–8808. 59 Nii, S.; Terao, J.; Kambe, N. The Journal of Organic Chemistry 2004, 69, 573–576. 60 Blümke, T.; Chen, Y.-H.; Peng, Z.; Knochel, P. Nature Chemistry 2010, 2, 313.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.4.2

Carboalumination

The carboalumination of acetylenes to vinylalanes is a common method for the preparation of complex metalated olefin species to be used in cross-coupling reactions and other processes. The process is generally conducted using a zirconium catalyst.61 Interestingly, this process can be accelerated by the addition of water.62 The reaction is highly regioselective in the case of terminal acetylenes and can show useful levels of regioselectivity with sterically unsymmetrical internal alkynes (e.g. methyl vs. α-branched alkyl). AlMe3, Cp2ZrCl2 DCE, 0 °C to rt

TBSO

TBSO

>87%

AlMe2 Me

Treating the vinylalane with an organolithium reagent produces the more nucleophilic alanate.63 AlMe3, Cp2ZrCl2 CH2Cl2, hexanes 0 °C

Me Me

Me

Me Me

Me

AlMe2 Me n-BuLi, hexanes THF, –80 to –30 °C

Me

Me Me

OH

Oxirane –30 °C to rt 63%

Me

12.2.4.3

Me

Me Me

Me

Al− Me2Bu Li+

Hydroalumination

Acetylenes can be hydroaluminated using DIBAL-H and LAH in a process analogous to the carboalumination reaction. Selectivity is seen in the case of terminal olefins or olefins with directing groups such as propargylic alcohols.64,65

C8H17

Me OH

DIBAL-H, hexanes rt to 60 °C >66% LAH, NaOMe THF, rt >78%

i-Bu2Al

C8H17

Me MeO Al− Li+ MeO O

Red-Al is generally employed in the trans reduction of acetylenes to olefins and proceeds via a vinyl aluminate.66,67

61 Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. The Journal of Organic Chemistry 1981, 46, 4093–4096. 62 Wipf, P.; Waller, D. L.; Reeves, J. T. The Journal of Organic Chemistry 2005, 70, 8096–8102. 63 See Note 55. 64 Negishi, E.; Takahashi, T.; Baba, S. Organic Syntheses 1988, 66, 60–66. 65 Havranek, M.; Dvorak, D. The Journal of Organic Chemistry 2002, 67, 2125–2130. 66 Jones, A. B. The Journal of Organic Chemistry 1992, 57, 4361–4367. 67 Ripin, D. H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M., III; Vetelino, M. G.; Wei, L. Organic Process Research & Development 2005, 9, 440–450.

601

602

12 Synthesis of “Nucleophilic” Organometallic Reagents

Red-Al, Et2O PhMe, rt

TMS

OH

68–71%

TMS

OH

Me

Me O

N

NHBoc HN

Me N

Red-Al THF, 0 °C

O

NHBoc

N

HN

83%

Me N

N

N

The premixing of DIBAL-H with triethylamine results in deprotonation of the acetylenic proton to generate the alkynyl alane.68 C5H11

12.2.4.4

DIBAL-H, TEA toluene, 0 °C to rt >81%

i-Bu2Al

C5H11

Metal–Metal Exchange

Organoaluminum reagents can be produced by transmetalation of an organozirconium or organolithium species.69,70 The arylaluminum reagents of the type shown below can participate in cross-coupling reactions with aryl and alkenyl halides in the absence of an external catalyst.71

n-C7H15

Zr(Cp)2Cl

AlCl3, CH2Cl2 0 °C

Li

12.2.5

n-C7H15

AlCl2

AcCl –30 °C 98%

Me2AlCl

LiCl

–30 °C, 30 min

AlMe2

Me

n-C7H15 O

Silicon

Organosilicon reagents have found extensive use in organic synthesis. This is likely due to the large supply of silicon-containing starting materials, the relatively high stability of the organosilanes, and the diversity of reactions in which they can participate. Due to the high stability of these reagents, the derivitization of an organosilicon reagent into another organosilicon reagent is a common preparation in the literature. For the sake of brevity, this chapter will only focus on methods that generate the C—Si bond directly. 12.2.5.1

Metal–Metal Exchange

Arylsilanes can be generated from aryllithium or arylmagnesium reagents and a silyl chloride.72,73 This represents the most common way to generate aryl,74 allyl, vinyl,75 and alkyl silanes. Silyl imidazoles, siloxanes, and silyl triflates can also be used as the electrophilic silicon source in these processes. 68 69 70 71 72 73 74 75

Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H. P. The Journal of Organic Chemistry 2000, 65, 6423–6426. Carr, D. B.; Schwartz, J. Journal of the American Chemical Society 1979, 101, 3521–3531. Hawner, C.; Müller, D.; Gremaud, L.; Felouat, A.; Woodward, S.; Alexakis, A. Angewandte Chemie International Edition 2010, 49, 7769–7772. Minami, H.; Saito, T.; Wang, C.; Uchiyama, M. Angewandte Chemie International Edition 2015, 54, 4665–4668. Dondoni, A.; Merino, P. Organic Syntheses 1995, 72, 21–31. Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. Journal of the American Chemical Society 1994, 116, 3231–3239. Haebich, D.; Effenberger, F. Synthesis 1979, 841–876. Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75–85.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

S N

Br

NBoc

(i) n-BuLi/hexanes Et2O, –78 °C (ii) TMSCl

S

85%

N

(i) s-BuLi, (–)-sparteine Et2O, –78 °C (ii) TMSCl 87%, 96% er

TMS H N NBoc

N H

(–)-sparteine

TMS

12.2.5.2

Hydrosilylation

Acetylenes and olefins can be hydrosilylated in the presence of a catalyst, often with high levels of selectivity, as in the example below.76 In this case, the vinylsilane intermediate is utilized in a cross-coupling reaction in situ. [RhCl2 (p-cymene)]2 has also been reported for this transformation.77 Pt Me Si Si Me O Me Me t-Bu3P xylene 65 °C n-Bu

(HSiMe2)2O THF, 30 °C

12.2.5.3

n-Bu

SiMe2OR

TBAF Pd2(dba)3 4-iodoanisole 83%

OMe n-Bu

Metal–Halogen Exchange

Arylsiloxanes can be generated from the aryl halide by treatment with a palladium catalyst in the presence of HSi(OMe)3 .78 This process, coupled with a copper-mediated amination of the siloxane, offers a mild, room temperature alternative to the widely used Pd-catalyzed amination processes. I

Pd2(dba)3, P(o-Tol)3 HSi(OMe)3, i-Pr2NEt DMF, rt

Si(OMe)3

TBAF, Cu(OAc)2 benzimidazole, air, rt

N N

40%

12.2.5.4

C–H Silylation

The direct functionalization of alkenyl, aryl, and aliphatic C—H bonds under iridium or rhodium catalysis is an efficient method for the synthesis of organosilanes.79,80,81,82 Sterics governs the regioselectivity in the case of aryl substrates, while aliphatic substrates typically require a directing group for efficient silylation and react preferentially at primary alkyl C—H bonds. 76 77 78 79 80 81 82

Denmark, S. E.; Wang, Z. Organic Syntheses 2005, 81, 54–62. Angle, S. R.; Neitzel, M. L. The Journal of Organic Chemistry 2000, 65, 6458–6461. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Letters 2000, 41, 5291–5293. Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70. Cheng, C.; Simmons, E. M.; Hartwig, J. F. Angewandte Chemie International Edition 2013, 52, 8984–8989. Li, B.; Driess, M.; Hartwig, J. F. Journal of the American Chemical Society 2014, 136, 6586–6589. Cheng, C.; Hartwig, J. F. Journal of the American Chemical Society 2015, 137, 592–595.

603

604

12 Synthesis of “Nucleophilic” Organometallic Reagents

1.5 mol% [Ir(cod)OMe]2 3.1 mol% Me Me

Me

CN

N

Me

N

Me

HSiMe(OTMS)2 cyclohexene THF, 80–100 °C, 1–2 d 77%

12.2.5.5

CN

Me Si OTMS OTMS

Use of Nucleophilic Silicon Reagents

Reagents featuring a metalated carbon substituted with silicon or featuring metalated silicon have been demonstrated to be useful for the synthesis of organosilanes. The example under shows a readily available nucleophilic silicon-containing reagent being utilized in a cross-coupling reaction.83 O

PO(OEt)2

TMS

MgCl

TMS

Ni(acac)2, Et2O, rt 81%

12.2.6 12.2.6.1

Titanium Metal–Metal Exchange

Metal–metal exchange is the primary method for the synthesis of alkyl or aryl titanium reagents. Some organolithium and organomagnesium reagents can be reacted directly with TiCl4 , although in many cases, this results in the reduction of titanium. The use of an organozinc reagent avoids this reduction. An example is the preparation of MeTiCl3 , which can be preferred over MeLi or MeMgX due to its attenuated basicity compared to these reagents. When synthesizing the etherate of the titanium reagent, MeLi can be employed.84 In the absence of an ethereal solvent, Me2 Zn must be used.85 Chlorotitanium alkoxides can be used in place of TiCl4 . In the example below, MeTiCl3 was found to participate in a significantly cleaner reaction than MeMgBr, which caused incomplete reaction and by-product formation due to enolization of the ketone electrophile. MeTiCl3 was therefore used on scale to access the desired tertiary carbinol.86 CN Me TiCl4

MeLi

MeTiCl3

CN O

Anisole, –5 °C 84%

Me Me OH

A common reagent used in the preparation of olefins is dimethyl titanocene. This reagent is prepared by the treatment of Cp2 TiCl2 with 2 equiv of MeMgCl.87 This is an alternative to the Tebbe reagent.88 83 Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M. Synthesis 1981, 1001–1003. 84 Reetz, M. T.; Kyung, S. H.; Huellmann, M. Tetrahedron 1986, 42, 2931–2935. 85 Reetz, M. T.; Westermann, J.; Steinbach, R. Angewandte Chemie, International Edition in English 1980, 19, 900. 86 Weiberth, F. J.; Gill, H. S.; Lee, G. E.; Ngo, D. P.; Shrimp, F. L.; Chen, X.; D’Netto, G.; Jackson, B. R.; Jiang, Y.; Kumar, N.; Roberts, F.; Zlotnikov, E. Organic Process Research & Development 2015, 19, 806–811. 87 Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Candelario, A.; Huffman, M. A.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. J.; Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.; Reamer, R. A.; Welch, C. J.; Mathre, D. J.; Tsou, N. N.; McNamara, J. M.; Reider, P. J. Journal of the American Chemical Society 2003, 125, 2129–2135. 88 Paquette, L. A.; McLaughlin, M. L. Organic Syntheses 1990, 68, 220–226.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

MeMgBr THF, toluene, 0 °C

Cp2TiCl2

Cp2TiMe2

85% Cp2TiCl2 toluene, rt

AlMe3

Me2Al

>70%

Cl TiCp2

Tebbe reagent

Titanium tetrachloride can also exchange with tin in allylstannanes. The exchange occurs with retention of stereochemistry and transfer of allylic regiochemistry.89 Me

TiCl4, CH2Cl2 –78 °C

Me3Sn

CONi-Pr2

>85%

12.2.6.2

Other

Me

TiCl3 Me

Me

CONi-Pr2

A useful method for the generation of a titanium homoenolate is shown below.90 TiCl4, hexane, rt

Oi-Pr OTMS

12.2.7

i-PrO

89%

O

TiCl3

Chromium

12.2.7.1

Metal–Halogen and Metal–Metal Exchange

In the presence of a nickel(II) catalyst, vinyl or aryl halides and triflates can be converted to the organochromium species via the organonickel intermediate. Two examples are shown below.91,92 Catalysts that are useful include Ni(II) salts such as NiCl2 and Ni(acac)2 ; palladium catalysts are less effective in this transformation, particularly in the case of the triflate. Nickel is converted to Ni(0) as the chromium goes from Cr(II) to Cr(III). CrCl2, NiCl2 DMF, 25 °C n-Hex

Me H

Me

H Me

OTf

OTBDPS Br O

PhCH2CH2CHO n-Hex

CrCl

Me H

CrCl2, NiCl2 DMF, –60 °C to rt

CHO Me

H Me

82–94%

Ph

n-Hex OH

OTBDPS CrCl O CHO

Me H 74% 15:1 dr

OTBDPS O

Me

H Me

OH

Allylic chromium reagents, generated in situ with an excess of Cr(II) and an allylic bromide, can be used in allylic addition reactions with aldehydes. The process suffers from the drawback that a large amount of chromium is required. Allylic chromium reagents can equilibrate olefin geometry and typically result in anti-addition products in cases where selectivity is an issue.93 89 Kraemer, T.; Schwark, J. R.; Hoppe, D. Tetrahedron Letters 1989, 30, 7037–7040. 90 Nakamura, E.; Oshino, H.; Kuwajima, I. Journal of the American Chemical Society 1986, 108, 3745–3755. 91 Takai, K.; Sakogawa, K.; Kataoka, Y.; Oshima, K.; Utimoto, K. Organic Syntheses 1995, 72, 180–188. 92 Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J. Journal of the American Chemical Society 1999, 121, 6563–6579. 93 Nowotny, S.; Tucker, C. E.; Jubert, C.; Knochel, P. The Journal of Organic Chemistry 1995, 60, 2762–2772.

605

606

12 Synthesis of “Nucleophilic” Organometallic Reagents

Me

O Me

PO(OEt)2

Me

LiI, CrCl2 PhCHO, DMPU 25 °C

Ph CrCl

Me

Me

OH Me

98%

Me

Me

Me

The Fischer-type carbenes of chromium can be generated by the reaction of an organolithium or Grignard reagent with Cr(CO)6 followed by alkylation.94 Cr(CO)6

(i) MeLi, Et2O, reflux (ii) Me3O+ BF4−, H2O, rt 83%

12.2.8

(OC)5Cr

OMe Me

Manganese

Organomanganese reagents are rarely used in synthesis, but do provide interesting selectivity in some additions. These relatively unreactive organometallic reagents can add in a 1,4-manner to alkylidene malonates and can even add to an acid chloride in the presence of an aldehyde. The large quantities of manganese required are a significant drawback to these reagents. One example of a useful organomanganese reagent is shown in the example below. This method is very practical, catalytic in copper, and does not require cryogenic conditions. The process is described as a copper-catalyzed addition rather than addition of a cuprate.95 MnCl2, LiCl, THF, rt

n-BuMgCl, 30% MnCl4Li2

Me

n-BuMnCl + LiCl 3% CuCl, 0 °C

O

Me

94%

n-Bu Me

Me

Me

12.2.8.1

O

Me

Metal–Metal Exchange

The primary method for the synthesis of organomanganese reagents is via the addition of an organolithium or Grignard reagent to MnX2 , where MnCl2 is the most convenient due to its commercial availability.96 By increasing the ratio of organolithium to MnX2 , dialkyl organomanganese reagents R2 Mn, and organomanganates R3 MnLi can be generated. The reactivity of these reagents varies.97 Li

Me

MnCl2, hexane THF, 0 °C to rt

Me

MnCl

69%

12.2.9 12.2.9.1

Iron Metal–Halogen Exchange

The addition of Na2 Fe(CO)4 to an alkyl halide or acid chloride can be followed by alkylation, protonation, or oxidation of the acyl-iron intermediate to make ketones, aldehydes, or esters, respectively. A representative procedure published in Organic Syntheses is depicted below.98 The same acyl-iron intermediate can be generated through the addition of an alkyllithium to Fe(CO)5 . 94 95 96 97 98

Hegedus, L. S.; McGuire, M. A.; Schultze, L. M. Organic Syntheses 1987, 65, 140–145. Alami, M.; Marquais, S.; Cahiez, G. Organic Syntheses 1995, 72, 135–146. Friour, G.; Cahiez, G.; Normant, J. F. Synthesis 1984, 37–40. Cahiez, G.; Alami, M. Tetrahedron 1989, 45, 4163–4176. Finke, R. G.; Sorrell, T. N. Organic Syntheses 1980, 59, 102–112.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

CO2Me

Na2Fe(CO)4 DMF, rt

CO2Me

CO2Me

Br

MeI

Fe(CO)2Na

70% Me

12.2.10

O

Copper

Cuprates are unique organometallic reagents that are useful in 1,4-addition reactions and displacement reactions. The primary method of synthesis of cuprates is via a transmetalation reaction. 12.2.10.1

Metal–Metal Exchange

A method for the generation of a catalytically-active cuprate reagent from an aryl Grignard at 0 ∘ C is depicted below and was demonstrated on 11 kg scale.99 (i) Mg(0), 10 mol% CuCl, THF, 0 °C Me OTMS

(ii)

N

O

N

H

O

O Br

O

Me OTMS

O (iii) HCl, H2O, CH2Cl2, 0 °C

O

>82%

One example of a useful cuprate generated from an organomanganese reagent is shown in Section 12.2.8. This method is very practical, catalytic in copper, and does not require cryogenic conditions. The process is described as a copper-catalyzed addition rather than addition of a cuprate.100 A complex method for the generation of higher-order cuprates described in Organic Syntheses is depicted below. Formation of a dialkylzincate followed by addition of Me2 Cu(CN)Li generates the cuprate, which adds in a 1,4-manner to an enone, with the enolate trapped as the silyl enol ether to free copper to act in the catalytic cycle.101 I

CO2Et

Zn(0), THF 35 °C

IZn

R

MeLi, Et2O –78 °C

MeZn

R

Me2Cu(CN)Li2 –78 °C 73%

Li(NC)Cu

R

A powerful method for the generation of vinyl cuprates is hydrozirconation followed by transmetalation with copper. This method has proven very useful in the synthesis of prostaglandins.102 O Me OTMS

>71%

Me

CO2Me TESO

Me HO

O Cp2ZrHCl THF, RT

A

CO2Me

Me

A, −50 °C

TESO (i) CuCN, −50 °C 2− (ii) MeLi, −50 °C Me(NC) Cu

Cl(Cp)2Zr Me TMSO

Me

2Li+

Me TMSO

Me

99 Larkin, J. P.; Wehrey, C.; Boffelli, P.; Lagraulet, H.; Lemaitre, G.; Nedelec, A.; Prat, D. Organic Process Research & Development 2002, 6, 20–27. 100 See Note 92. 101 Lipshutz, B. H.; Wood, M. R.; Tirado, R. Organic Syntheses 1999, 76, 252–262. 102 Dygos, J. H.; Adamek, J. P.; Babiak, K. A.; Behling, J. R.; Medich, J. R.; Ng, J. S.; Wieczorek, J. J. The Journal of Organic Chemistry 1991, 56, 2549–2552.

607

608

12 Synthesis of “Nucleophilic” Organometallic Reagents

A method for the transmetalation of zirconates in the presence of catalytic quantities of copper has been developed. The cuprates are useful for 1,4-additions, additions to acid chlorides, allylic substitution, and epoxide openings.103 (i) Cp2ZrClH, THF, 40 °C (ii) Cyclohexanone, CuBr • DMS, 40 °C

OTBS

O OTBS

76%

Finally, in a transmetalation bonanza, the addition of Me3 ZnLi allows for the transmetalation of the copper enolate that results from 1,4-addition. This frees the copper to participate in the catalytic cycle and generates a more reactive enolate that can be alkylated more readily than the copper enolate.104 (i) Cp2ZrHCl, THF (ii) CuCN, Me2Zn, MeLi, THF, –78 °C (iii) A, –78 °C (iv) B, THF, –78 °C

C5H11

O

TBSO

74%

OBn

TMS C5H11 BnO B

Cp2ZrHCl LiMe2ZnO Cl(Cp)2Zr

C5H11

TBSO

BnO

Li+

Me(NC) − CuO C5H11

Li+

A

BnO

TBSO

O

TBSO A

12.2.11

BnO Me3Zn−Li+

CuCN, MeLi Me(NC) − Cu

C5H11

C5H11 BnO

OTf TMS B

Zinc

The most practical methods for the production of alkylzinc reagents are through metal–halogen exchange using Zn(0) or metal–metal exchange from the reaction of organolithium, magnesium, or zirconium reagents. A number of particularly mild but less practical methods are available for the generation of organozinc reagents of varying reactivity in the presence of a wide variety of functional groups. Zincates are very useful reagents for use in catalyzed cross-coupling reactions and mild additions to carbonyls and are particularly attractive due to the wide functional group tolerance of these compounds. 103 Wipf, P.; Xu, W.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50, 1935–1954. 104 Lipshutz, B. H.; Wood, M. R. Journal of the American Chemical Society 1994, 116, 11689–11702.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.11.1

Metal–Halogen Exchange

The simplest method for the generation of alkylzincs is from Zn(0) and an iodide. These reactions are exothermic and suffer from the same initiation difficulties as Grignard reagents. Activated zinc, such as zinc–copper couple (Zn(Cu)), or the use of activating agents such as dibromoethane, TMSCl, and MsOH are useful to avoid these difficulties.105,106 The middle reaction is an example of a Blaise reaction, the nitrile equivalent of a Reformatsky reaction, and demonstrates the ability to generate a zincate in the presence of an electrophile.107 O N

O

Zn(0), THF 30–40 °C

I

N

O

ZnI

O

I

CO2Et

Zn(0), THF reflux

Zn(Cu), 80 °C benzene

CO2Et

CO2Et

IZn

CO2Et

Cu(CN)ZnI

O

CN

Cl BrZn

N

>50%

F

Br

O

CuCN, LiCl –40 °C

O

Cl 0 °C

F

72%

Cl

Pd(PPh3)4, methacrolyl chloride rt

CO2Et Cl

O Me

CO2Et

87%

The Simmons–Smith reagent, utilized in cyclopropanation reactions, can be generated by the reaction of diiodomethane with either zinc(0)108 or diethyl zinc.109 A highly efficient cyclopropanation of this type that was carried out on plant-scale (34 kg) is shown below.110

Cl

B O

O

Me

12.2.11.2

Me Me Me

Et2Zn, TFA CH2I2, DCM 96%

Cl

B O

O

Me

Me Me Me

Metal–Metal Exchange

Organolithium reagents will transmetalate to the zincate on treatment with ZnCl2 or ZnBr2 . This method is not tolerant of reactive functional groups.111,112 The use of an alkylzinc chloride in the third example is noteworthy, as the 2-lithiooxazole is known to ring open at temperatures much higher than −78 ∘ C, but the zinc reagent is stable at the 60 ∘ C reaction temperature.113

105 Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Organic Syntheses 1989, 67, 98–104. 106 Yeh, M. C. P.; Chen, H. G.; Knochel, P. Organic Syntheses 1992, 70, 195–203. 107 Choi, B. S.; Chang, J. H.; Choi, H.-W.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; Nam, D. H.; Shin, H. Organic Process Research & Development 2005, 9, 311–313. 108 Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Poindexter, G. S. Organic Syntheses 1980, 59, 85–94. 109 Charette, A. B.; Lebel, H. Organic Syntheses 1999, 76, 86–100. 110 Bassan, E. M.; Baxter, C. A.; Beutner, G. L.; Emerson, K. M.; Fleitz, F. J.; Johnson, S.; Keen, S.; Kim, M. M.; Kuethe, J. T.; Leonard, W. R.; Mullens, P. R.; Muzzio, D. J.; Roberge, C.; Yasuda, N. Organic Process Research & Development 2012, 16, 87–95. 111 Jensen, A. E.; Kneisel, F.; Knochel, P. Organic Syntheses 2003, 79, 35–42. 112 Smith, A. P.; Savage, S. A.; Love, J. C.; Fraser, C. L. Organic Syntheses 2002, 78, 51–62. 113 Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.; Pangborn, J. J. Organic Process Research & Development 2003, 7, 696–699.

609

610

12 Synthesis of “Nucleophilic” Organometallic Reagents

Br

N

ZnBr

(ii) ZnBr2, –78 to 0 °C

NC

Br

(i) n-BuLi/hexane, THF, –100 to –78 °C

(i) t-BuLi/pentane THF, –78 °C (ii) ZnCl2 –78 °C to rt

ZnCl

(i) n-BuLi/hexane THF –60 °C

O

N

(ii) ZnCl 2, –60 °C to rt

N

Me

LiCl, Pd(PPh3)4, ArOTf, reflux

N

O

NC

N

94%

ZnCl

N

1-bromonaphthalene Pd(PPh3)4, 60 °C 73%

O N

Acetylenes can be hydrozirconated and transmetalated to zinc to generate the vinyl zinc species.114

TBSO

Cp2ZrHCl CH2Cl2 0 °C to rt

Me2Zn –60 to 0 °C

TBSO Zr(Cp)2Cl

12.2.11.3

>66%

TBSO ZnMe

Other

A method for the generation of the zinc homoenolate below is described in Organic Syntheses.115

OEt OTMS

12.2.12

ZnCl2, Et2O rt to 0 °C >70%

Zn

EtO O

OEt O

Zirconium

Alkylzirconium reagents can be transmetalated to aluminum, boron, copper, nickel, palladium, tin, and zinc. When combined with the powerful hydrozirconation reaction, this is a very effective method for the synthesis of a variety of substituted olefins. 12.2.12.1

Hydrozirconation

By far the most common method for the creation of a carbon–zirconium bond is via the hydrozirconation process.116 Acetylenes can be hydrozirconated followed by transmetalation, direct cross-coupling, or conversion to oxidized products.117,118 The reaction conditions are strongly reducing; therefore, ketones, aldehydes, esters, nitriles, and epoxides are generally not tolerated. 114 115 116 117 118

Wipf, P.; Xu, W. Organic Syntheses 1997, 74, 205–211. Nakamura, E.; Kuwajima, I. Organic Syntheses 1988, 66, 43–51. Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910. See Note 111. See Note 52.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

Cp2ZrHCl CH2Cl2 0 °C to rt

TBSO

TBSO Zr(Cp)2Cl

>66% OTBS O

Cp2ZrHCl t-BuMgCl PhMe, 50 °C

OTBS O

Zr(Cp)2Cl

>72% CF3

CF3

The hydrozirconation of internal alkynes results in metalation at the less sterically hindered position. In the presence of a sub-stoichiometric amount of zirconium hydride, the product ratio is a result of the kinetic selectivity between the two positions. In the presence of excess reagent, the products will equilibrate to the thermodynamically dictated ratio, generally with higher selectivity for the less-hindered position. The exception to this generalization occurs when isomerization to the end of the carbon chain is possible (see below). Hydrozirconation can also be accomplished using Cp2 Zr(Cl)i-Bu, generated in situ by the reaction of t-BuMgCl with Cp2 ZrCl2 .119 Cp2ZrCl2, t-BuMgCl Et2O, PhH 50 °C Cp2Zr(Cl)i-Bu,TMSI 50 °C

BnO

BnO

Zr(Cp)2Cl

9

9

I2, THF 0 °C to rt

I

BnO 9

76%

The hydrozirconation of olefins results in an alkylzirconium intermediate in which the zirconium can freely migrate and will isomerizes to the end of a chain, limiting its synthetic utility.120 Me Me 10

12.2.13

(i) Cp2ZrHCl, THF, 40 °C (ii) I2, 0 °C to rt

10

75%

I Me 10

10

Indium

Allylindium reagents, generated from an allylic mesylate, can be added to aldehydes in the presence of a palladium catalyst. The example below is representative.121 OMs

PdCl2(dppf), InI THF, HMPA, rt

Me

Me TBDPSO Me

•

In

Me

CHO

Me

TBDPSO OH

76%

Allyl stannanes can be transmetalated using InCl3 . This can occur in allylic systems via an anti-SE 2′ mechanism as shown below, leading to a regioselectivity and diastereoselectivity unique from the originating allylstannane.122 OMOM TBSO

119 120 121 122

SnBu3

InCl3, EtOAc –78 °C

OHC ODPS –78 °C to rt TBSO

InCl2 TBSO

OMOM

82%

Makabe, H.; Negishi, E. European Journal of Organic Chemistry 1999, 969–971. Gibson, T.; Tulich, L. The Journal of Organic Chemistry 1981, 46, 1821–1823. Johns, B. A.; Grant, C. M.; Marshall, J. A. Organic Syntheses 2003, 79, 59–71. Marshall, J. A.; Garofalo, A. W. The Journal of Organic Chemistry 1996, 61, 8732–8738.

OMOM ODPS OH

611

612

12 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.14

Tin

12.2.14.1

Metal–Metal Exchange

Grignard reagents and organolithium reagents react with tin chlorides to make organostannanes.123,124 PhSnCl3

MgI

C6F13

(i) Mg(0), Br2 init. (ii) SnCl 4

Br

Me

12.2.14.2

)3SnPh

C6F13

93%

Et4Sn

89–96%

Nucleophilic Sn

Metalated stannanes (e.g. Me3 SnLi, Bu3 SnLi) can be prepared from the tin hydride and LDA, LiHMDS, NaHMDS, or KHMDS or by treating the tin chloride or bromide with lithium or sodium. They can displace leaving groups or add to electrophilic functionality to generate a variety of organostannanes. Some displacement reactions are shown below.125,126 The procedure in the second example is a simpler preparation of the metalated tin species. In the case of the chiral propargylic mesylate, the stereochemistry of the starting material dictates the stereochemistry of the product, with the mesylate leaving anti-periplanar to the incoming tin nucleophiles. Me3SnLi, THF, 0 °C

MsO

Me3Sn

62% (i) LDA, THF, 0 °C (ii) CuBr • SMe2, –78 °C (iii) A, –78 °C

Bu3SnH

64% Me A

Me •

Bu3Sn

C7H15

OMs C7H15

Metalated stannanes can participate in a 1,4-addition to an unsaturated ketone, as shown below.127 In the case of aldehydes, 1,2-addition is observed.128 O

O

Me3SnCl, Li(0), THF, rt 94%

H

TBSO

SnMe3

n-Bu3SnLi, THF, –78 °C 45%

O

TBSO

SnBu3 OH

Acyl stannanes can be prepared via the addition of a metalated stannane to an ester or thioester.129 O

CO2Et

n-Bu3SnLi, BF3 • OEt 2 THF, –78 °C 73%

O

O SnBu3

123 Crombie, A.; Kim, S.-Y.; Hadida, S.; Curran, D. P. Organic Syntheses 2003, 79, 1–10. 124 Van Der Kerk, G. J. M.; Luijten, J. G. A. Organic Syntheses 1963, Coll. Voll. V , 881–883. 125 Newcomb, M.; Courtney, A. R. The Journal of Organic Chemistry 1980, 45, 1707–1708. 126 Fields, S. C.; Parker, M. H.; Erickson, W. R. The Journal of Organic Chemistry 1994, 59, 8284–8287. 127 Wickham, G.; Olszowy, H. A.; Kitching, W. The Journal of Organic Chemistry 1982, 47, 3788–3793. 128 See Note 119. 129 Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Reginato, G.; Ricci, A.; Dembech, P.; Seconi, G. The Journal of Organic Chemistry 1989, 54, 2966–2968.

12.2 Synthesis of “Nucleophilic” Organometallic Reagents

12.2.14.3

Cross-coupling with R3 Sn–SnR3

A mild method for the formation of stannanes is via the Pd-catalyzed coupling of an aryl halide and distannane. This transformation may be better achieved via a Suzuki coupling (Section 6.2). The cost of the reagent and potential for dimerization (through a Stille coupling) are issues to consider when selecting this methodology.130 OMe O

MeO

I

O

OMe O

Me3SnSnMe3, Pd(PPh3)4 toluene, reflux

SnMe3

O

MeO

57%

OMe

12.2.14.4

OMe

Hydrostannation

Hydrostannation is an effective method for the synthesis of cross-coupling components and has been well reviewed.131 The uncatalyzed free-radical hydrostannation of acetylenes frequently results in a mixture of olefin isomers due to the isomerization of olefins under the reaction conditions. In some cases, a directing group can lead to useful selectivity in the reaction. The use of a Pd catalyst in the process can also lead to clean production of the E-olefin.132,133 Bu3SnH AIBN CO2Me toluene, rt

O O

SnBu3

H

79%

CO2Me O

Bu3SnH Pd(PPh3)4 THF, rt

O

61%

O

O

C11H23

Bu3SnH PdCl2(PPh3)2 THF, rt

Bu3Sn

90%

SnBu3 CO2Me

C11H23

Employing a molybdenum catalyst gives access to the α-stannylated product.134

H

Bu3SnH MoBI3 toluene, 50 °C OAc

91%

SnBu3 OAc

Hydrostannylation of terminal acetylenes in the presence of a Lewis acid results in the Z-olefin.135

H

OTBS

(i) Bu 3SnH, 20 mol% ZrCl4 toluene, 0 °C (ii) Et 3N, 0 °C to rt 87%

OTBS SnBu3

The hydrostannation reaction can be combined with a Pd-mediated cross-coupling that is catalytic in tin. The tin chloride that is generated as a by-product of the cross-coupling reaction is reduced with polymethylhydrosiloxane (PMHS) to regenerate the tin hydride for the hydrostannylation process.136 130 See Note 22. 131 Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure; 5th ed.; John Wiley & Sons, Ltd.: Chichester, UK, 2000. 132 Sai, H.; Ogiku, T.; Nishitani, T.; Hiramatsu, H.; Horikawa, H.; Iwasaki, T. Synthesis 1995, 582–586. 133 Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T. Y.; Satish, A. V.; Whang, Y. E. The Journal of Organic Chemistry 1990, 55, 3330–3336. 134 Kazmaier, U.; Schauss, D.; Pohlman, M.; Raddatz, S. Synthesis 2000, 914–916. 135 Asao, N.; Liu, J.-X.; Sudoh, T.; Yamamoto, Y. The Journal of Organic Chemistry 1996, 61, 4568–4571. 136 Gallagher, W. P.; Maleczka, R. E., Jr. The Journal of Organic Chemistry 2005, 70, 841–846.

613

614

12 Synthesis of “Nucleophilic” Organometallic Reagents

Br

Ph Me Me

H

6 mol% Bu3SnCl aq KF, 1 mol% TBAF Pd2dba3, (2-Fur)3P PHMS, PdCl2(PPh3)2 Et2O, reflux

Me

87%

HO

Me Ph

OH

Bu3SnH

Bu3SnX aq KF, 1% TBAF PHMS Me Me HO

Bu3SnX

SnBu3

PHMS = polyhydroxymethylsilane

Olefins can also be hydrostannylated in the presence of a Pd catalyst.137 Bu3SnH, Pd(OH)2/C THF, rt

OH Ph

Ph

96%

12.2.14.5

OH SnBu3

Electrophilic Tin

Allylic stannanes and silanes can be converted to allylic stannanes via an SE 2′ mechanism. In this process, a relatively simple stannane or silane can be converted to a significantly more complex one.138 Me

Bu3Sn

SnCl4, CH2Cl2 –78 °C

OBn

12.2.15

Me

PhCHO, –78 °C

Cl3Sn OBn

90%

Me Ph

OBn OH

Cerium

Organocerium reagents are soft nucleophiles that are frequently employed in the addition of nucleophiles to enolizable carbonyls. The reagents are prepared by transmetalation from magnesium or lithium and cerium trichloride. The cerium salt is available as the hydrate and must be rigorously dried prior to use. Two large-scale preparations are shown below.139,140

N

MeMgCl, CeCl3 THF, 20 °C

O H

Me O

N

O H

MeCeCl2, 20 °C

MeOH Me

>82% HO

n-BuLi, CeCl3 –78 °C O

n-BuCeCl2 –78 °C

HO

n-Bu OH

92–97%

137 138 139 140

Lautens, M.; Kumanovic, S.; Meyer, C. Angewandte Chemie, International Edition in English 1996, 35, 1329–1330. McNeill, A. H.; Thomas, E. J. Synthesis 1994, 322–334. See Note 96. Takeda, N.; Imamoto, T. Organic Syntheses 1999, 76, 228–238.

12.3 Strategies for Metalating Heterocycles

12.2.16

Bismuth

Organobismuth reagents can be produced by the transmetalation of an organolithium reagent with BiCl3 .141 The organobismuth reagents can be stable and isolable. (i) n-BuLi/hexane THF, –65 °C (ii) BiCl 3, –60 °C R N

N TBSO

Br

80%

PhCO3H PhMe, 70 °C 3 Bi

69%

R N 3 Bi

OCOPh OCOPh

12.3 Strategies for Metalating Heterocycles Strategies for the metalation of heterocycles have been reviewed.142 A variety of strategies exist for the metalation of heterocycles at different positions; selection of the appropriate method is frequently dictated by the availability of starting materials. There are strategies, pitfalls, and common methods for the metalation of some heterocycles with specific substitution patterns. Deprotonation or metal–halogen exchange to make the aryllithium or aryl Grignard reagent is frequently the first or only step used in the metalation of a heterocycle. Tables with pK a values for the various positions of heterocycles are not generally available, but the order in which protons will be abstracted by base is well known for many ring systems. In many cases, the lithiated heterocycle can undergo a lithium migration to form a more stable aryllithium, so careful control of temperature may be necessary to prevent this unwanted side-reaction. The use of a metal–halogen exchange reaction with an alkyl Grignard reagent to form a positionally stable anion is often a more practical method than lithium–halogen exchange to prevent anion “walking.” This method does require higher temperatures and times than the very fast lithium–halogen exchange reaction. Metal–halogen exchange processes catalyzed by palladium have also allowed for the direct substitution of a halogen with boron or tin.

12.3.1

Strategies for Metalating Five-Membered Heterocycles

For pyrroles, furans, and thiophenes, the C-2 position can be deprotonated preferentially over the C-3 position.139 Metalation at C-3 is usually accomplished with a metal–halogen exchange reaction.143,144,145 Bases employed for C-2 deprotonation are LDA146,147 or, more commonly, n-, s-, and t-BuLi.148 The presence of directing substituents can change the selectivity of deprotonation.149 1

X

5 4

2 3

X = NR, O, S

Deprotonate Metal halogen exchange

141 Brands, K. M. J.; Dolling, U.-H.; Jobson, R. B.; Marchesini, G.; Reamer, R. A.; Williams, J. M. The Journal of Organic Chemistry 1998, 63, 6721–6726. 142 See Note 2. 143 Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J. Organic Syntheses 1997, 74, 248–256. 144 See Note 5. 145 See Note 19. 146 Alvarez-Ibarra, C.; Quiroga, M. L.; Toledano, E. Tetrahedron 1996, 52, 4065–4078. 147 Pomerantz, M.; Amarasekara, A. S.; Dias, H. V. R. The Journal of Organic Chemistry 2002, 67, 6931–6937. 148 Rewcastle, G. W.; Janosik, T.; Bergman, J. Tetrahedron 2001, 57, 7185–7189. 149 Grimaldi, T.; Romero, M.; Pujol, M. D. Synlett 2000, 1788–1792.

615

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12 Synthesis of “Nucleophilic” Organometallic Reagents

In the case of indoles, benzo(b)furans, and benzothiophenes, again the C-2 position can be deprotonated139,143,145 ; the remaining positions are best selectively metalated using metal–halogen exchange.150,151,152 The presence of a large group on nitrogen, such as a triisopropylsilyl (TIPS) group, can drive the deprotonation to C-3.153 R 1 N

6 4

3

2

Deprotonate Metal halogen exchange

In the case of imidazoles, the C-2 proton is the first to deprotonate,154 followed by the C-5 position if C-2 does not bear a proton.155 A common strategy is to deprotonate C-2, protect it with a silyl group, and then deprotonate at C-5.156 C-4 is generally metalated with a metal–halogen exchange reaction. If the C-2 position bears a substituent with protons, competitive deprotonation of the C-2 substituent151 can compete with deprotonation at C-5, and the choice of base can shift the selectivity.157 Deprotonate if C-2 substituent is not H Metal halogen exchange

R 1 N

First to deprotonate Frequently protected with silyl to access C-5 anion

N

3

The strategy for metalation of oxazoles and thiazoles is similar to that for imidazoles.158 In the case of oxazoles, deprotonation at the 2-position generates an anion that will exist in equilibrium with a ring-opened isonitrile anion at low temperatures.159 This anion will react at C-4, resulting in low selectivity. Thiazoles do not suffer from the same problem.160 C-5 can be directly deprotonated if C-2 is substituted.161 C-4 is generally metalated with a metal–halogen exchange reaction. If the C-2 position bears a substituent with protons, competitive deprotonation of the C-2 substituent162 can compete with deprotonation at C-5, and the choice of base can shift the selectivity.163 Deprotonate if C-2 substituent is not H Metal halogen exchange

1

First to deprotonate Frequently protected with silyl to access C-5 anion

X N 3

X = O will ring-open to enolate and alkylate at C-4

X = O, S

Pyrazoles can be deprotonated at the C-5 position using n-BuLi164 or LDA in the case of N-alkyl or N-aryl pyrazoles, and at the C-3 position in the case of N-alkoxy Pyrazoles using n-BuLi165 or LDA.166 C-4 can be metalated through metal–halogen exchange. A selective electrophilic halogenation is often possible at C-4 to access the substrate for metal–halogen exchange.163

150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166

See Note 140. See Note 5. See Note 19. Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Letters 2001, 42, 7621–7623. Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Tetrahedron 2002, 58, 4669–4673. See Note 2. Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1986, 42, 2351–2358. Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Organic Letters 1999, 1, 87–90. See Note 2. Vedejs, E.; Monahan, S. D. The Journal of Organic Chemistry 1996, 61, 5192–5193. See Note 69. Marcantonio, K. M.; Frey, L. F.; Murry, J. A.; Chen, C.-Y. Tetrahedron Letters 2002, 43, 8845–8848. See Note 151. See Note 154. Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner, M. A. Tetrahedron Letters 2006, 47, 3727–3731. Cali, P.; Begtrup, M. Tetrahedron 2002, 58, 1595–1605. Balle, T.; Vedso, P.; Begtrup, M. The Journal of Organic Chemistry 1999, 64, 5366–5370.

12.3 Strategies for Metalating Heterocycles

When R = alkyl or aryl, first to deprotonate n-BuLi

R 1 N 2 N

Metal halogen exchange

When R = OR, first to deprotonate n-BuLi

Isoxazoles and isothiazoles can also be deprotonated at C-3, but in these cases, rapid ring opening through cleavage of the N—X bond occurs.167 Metalation at C-4 and C-5 can be accomplished through metal–halogen exchange. 1

X Deprotonate when C-3 blocked n-BuLi

12.3.2

N

X = O, S

2

First to deprotonate ring opens rapidly n-BuLi

Strategies for Metalating Six-Membered Heterocycles

Electron-deficient aromatic rings such as pyridines can be deprotonated, although the choice of base becomes critical in these processes. Uncomplexed alkyllithium reagents tend to add to the ring rather than deprotonating; the addition of a complexing agent such as lithium diethylamino ethoxide can change the balance in favor of deprotonation. Lithium amides such as LDA and LTMP can also be used for deprotonation. The aryllithiums are prone to migration of the anion (“walking”) and self-reaction to give coupled products. Different bases may be affected differently by directing groups present on the ring, allowing various modes of deprotonation to be employed by appropriate selection of base.164 Because of these issues, metal–halogen exchange is most commonly employed to generate metalated pyridines168,169,170 unless an ortho-directing group is present.171,172 Deprotonation is also the method of choice if the metalation must be accomplished in the presence of an exchangeable halide.173 Deprotonation can be achieved at C-2 using combinations of alkyl lithium reagents and an aminoalkoxy lithium reagent.174 DG Metal–halogen exchange N

DG = directing group Directed deprotonation

N

Metal–halogen exchange

Selective metal–halogen exchange reactions have been explored on polyhalogenated pyridines, and in some cases very good selectivity for one position over the other can be achieved in the exchange process. In the case of magnesium–halogen exchange, selectivity for the C-3 bromide and C-5 bromide can be achieved over the C-2 bromide, and the C-3 position can be exchanged in the presence of the C-4 bromide.169,175 For example, the 2-lithio or 5-lithio species from 2,5-dibromopyridine can be generated and reacted selectively depending on solvent selection and temperature, essentially determining whether the kinetic or thermodynamic anion will react.176 Another way to ensure selective reaction is to use a pyridine substituted with different halogens, such as 2-iodo-5-bromopyridine.177 167 See Note 2. 168 See Note 140. 169 See Note 5. 170 See Note 19. 171 Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059–4090. 172 Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron Letters 1999, 40, 5483–5486. 173 Fort, Y.; Gros, P.; Rodriguez, A. L. Tetrahedron: Asymmetry 2001, 12, 2631–2635. 174 Gros, P.; Ben Younes-Millot, C.; Fort, Y. Tetrahedron Letters 2000, 41, 303–306. 175 See Note 6. 176 Lee, J. C.; Lee, K.; Cha, J. K. The Journal of Organic Chemistry 2000, 65, 4773–4775. 177 Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Seger, M.; Schreiner, K.; Daeffler, R.; Osmani, A.; Bixel, D.; Loiseleur, O.; Cercus, J.; Stettler, H.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, G.-P.; Chen, W.; Geng, P.; Lee, G. T.; Loeser, E.; McKenna, J.; Kinder, F. R., Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Reel, N.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L.; Xue, S.; Florence, G.; Paterson, I. Organic Process Research & Development 2004, 8, 113–121.

617

618

12 Synthesis of “Nucleophilic” Organometallic Reagents

More stable anion forms here

Br Br

N

Kinetically fastest bromide in exchange reaction

Diazenes and triazenes can be deprotonated adjacent to nitrogen using amide bases; other positions can be metalated using directed metalation178 or metal–halogen exchange. The anions become less stable as electrophilicity increases along with the number of nitrogens in the ring. Triazene anions are quite unstable and difficult to utilize.175 Metal–halogen exchange or directed deprotonation N

Deprotonate or metal–halogen exchange 3 vs. 6 selectivity influenced by directing group

N1

2

Metal–halogen exchange or directed deprotonation First site of deprotonation

N1 N

N Metal–halogen exchange N 2 R 1

2

Deprotonate if C-4 is substituted

Deprotonate or metal–halogen exchange selectivity influenced by nature of R (directing or bulky)

1

First site of deprotonation

N 2 N

Metal–halogen exchange or directed deprotonation

N

Deprotonate if C-6 is substituted, or metal–halogen exchange

12.4 Reactions of “Nucleophilic” Organometallic Reagents In this section, the introduction of a heteroatom at a metalated position is summarized. An excellent overview of this topic has been published.179 12.4.1

Uncatalyzed C–M to C–O

Converting a carbon–metal bond to a carbon–oxygen bond is a difficult transformation. Some special cases are discussed elsewhere in this book – the oxidation of a carbon–boron bond resulting from hydroboration in section “Hydroboration”, the Tamao oxidation (C–Si to C–O) in Section 10.9.2, the Sommelet reaction (benzylic halide to aldehyde) in Section 10.9.1, and the introduction of an oxygen α– to a carbonyl via the enolate in Section 10.3.4. The oxidation of a carbon–metal bond to a carbon–oxygen bond is frequently employed in the process of converting an aryl halide to a phenol. One method is to proceed via the intermediacy of a borate, as shown below.180 Br MeO

(i) Mg(0), I2 init., THF, reflux (ii) (MeO)3B, −10 °C (iii) H2O2, HOAc, −10 °C 73–81%

OH MeO

Alternatively, a more reactive organometallic species such as a Grignard reagent can be reacted directly with a peroxide as shown below.181 178 Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489–4505. 179 Atkins, R. J.; Banks, A.; Bellingham, R. K.; Breen, G. F.; Carey, J. S.; Etridge, S. K.; Hayes, J. F.; Hussain, N.; Morgan, D. O.; Oxley, P.; Passey, S. C.; Walsgrove, T. C.; Wells, A. S. Organic Process Research & Development 2003, 7, 663–675. 180 Kidwell, R. L.; Murphy, M.; Darling, S. D. Organic Syntheses 1969, 49, 90–93. 181 See Note 121.

12.4 Reactions of “Nucleophilic” Organometallic Reagents

S

(i) Mg(0), Et2O, reflux (ii) PhCO3 t-Bu, 0 °C

Br

12.4.2

S

Ot-Bu

70–76%

Uncatalyzed C–M to C–S or C–Se

The conversion of a carbon–metal bond to a carbon–selenium bond or a carbon–sulfur bond can be achieved using a number of reagents. Selenium(0) or sulfur(0) can be used as the trapping agent, in combination with an organolithium or Grignard reagent, as shown in the two Organic Syntheses preparations below.182,183 (i) Mg(0), Et2O, reflux (ii) Se(0), reflux (iii) Br 2, 35 °C

Br

Se

64%

(i) n-BuLi/pentane THF, −20 °C (ii) S(0), −70 to 0 °C

S

S

65%

Se

SH

Alternatively, disulfides, diselenides, selenylchlorides, sulfur chlorides, and reagents of the structure RS–SO2 R′ can be used as trapping agents as shown in the 3 kg preparation below.184 STs TMSO Br

i-PrMgCl, THF BrMg 0 °C

S

N Me PhMe, –20 °C

S

Br

Br

32%

S TMSO

N Me

S Br

Organozirconium reagents can be reacted with diselenides, selenyl chlorides, or selenyl phthalimides to produce the selenated product.185 O PhSe N

Zr(Cp)2Cl

12.4.3

O PhMe, −20 °C 95%

SePh

Uncatalyzed C–M to C–X

Most organometallic species can be converted to the corresponding halide after treatment with the elemental halide, or with reagents such as NCS, NBS, and NIS, as exemplified by the reaction of the Grignard reagent with iodine below.186 182 Reich, H. J.; Cohen, M. L.; Clark, P. S. Organic Syntheses 1980, 59, 141–147. 183 Jones, E.; Moodie, I. M. Organic Syntheses 1970, 50, 979–980. 184 Alcaraz, M.-L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Organic Process Research & Development 2005, 9, 555–569. 185 Fryzuk, M. D.; Bates, G. S.; Stone, C. The Journal of Organic Chemistry 1991, 56, 7201–7211. 186 See Note 52.

619

620

12 Synthesis of “Nucleophilic” Organometallic Reagents

OTBS O

OTBS MgCl

O

I2, THF, –40 °C

I

>72% CF3

CF3

Carboalumination or hydroalumination of acetylenes can be followed by treatment with a halide such as iodine to make the vinyl halide product.187 (i) AlMe3, Cp2ZrCl2 DCE, 0 °C (ii) I2, THF, –30 °C

TBSO

TBSO

I Me

87%

Hydrozirconation products can be directly converted to the halide on treatment with I2 , Br2 , NBS, PhICl2 , or NCS. The stereochemistry of the C—Zr bond is retained in these processes. This is one of the most utilized methods for the conversion of acetylenes into vinyl halides.188,189 OTBS

Cp2Zr(Cl)H PhH, 40 °C

OTBS Zr(Cl)Cp2

n-Bu

12.4.4

I2, 40 °C

n-Bu

OTBS I

91%

n-Bu

Uncatalyzed C–M to C–N

The conversion of a C—M bond to a C—N bond is a much less common process than the conversion of a C—X bond to a C—N bond as in SN Ar reactions and transition-metal catalyzed or uncatalyzed aryl aminations. Some examples do exist and are synthetically useful, such as the case below, where an organozirconium reagent was reacted with an O-sulfonylated amine to produce an amine product, as shown below.190 Me

n-Hex

187 188 189 190

(Cp)2Zr(Cl)H THF, rt

Me O NH2 S Me O O

n-Hex

Zr(Cp)2Cl

0 °C 77%

n-Hex

NH2

See Note 58. See Note 113. Treilhou, M.; Fauve, A.; Pougny, J. R.; Prome, J. C.; Veschambre, H. The Journal of Organic Chemistry 1992, 57, 3203–3208. Zheng, B.; Srebnik, M. The Journal of Organic Chemistry 1995, 60, 1912–1913.

621

13 Synthesis of Common Aromatic Heterocycles Stéphane Caron Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 621 Pyrroles, 623 Indoles, 624 2-Indolinones (Oxindoles), 626 Isatins (2,3-Indolindiones), 628 Carbazoles, 628 Pyrazoles, 629 Indazoles, 630 Imidazoles and Benzimidazoles, 631 1,2,3-Triazoles and Benzotriazole, 633 1,2,4-Triazoles, 635 Tetrazoles, 635 Dihydropyridines, 637 Pyridines, 637 Quinolines, 639 Quinolinones and 2-Hydroxyquinolines, 641 Isoquinolines, 642 Isoquinolinones, 643 Quinolones (4-Hydroxyquinolines), 644 Pyrimidines and Pyrimidones, 645 Quinazolines and Quinazolinones, 647 Pyrazines and Quinoxalines, 648 Pyridazines, Phtalazines, and Cinnolines, 650 1,2,4-Triazines, 651 Furans and Benzofurans, 652 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone, 653 Coumarins, 655 Thiophenes and Benzothiophenes, 656 Isoxazoles and Benzisoxazoles, 657 Oxazoles and Benzoxazoles, 659 Isothiazoles and Benzisothiazoles, 660 Thiazoles and Benzothiazoles, 661 1,2,4-Oxadiazoles, 662 1,3,4-Oxadiazoles, 663

13.1 Introduction While heterocyclic chemistry was a significant focus of organic chemistry in the early part of the twentieth century, the emphasis in current organic chemistry research is on catalytic stereocontrolled synthesis of acyclic compounds or the development of synthetic methodologies for cross-coupling of already constructed reactants. However, much of the chemical industry continues to rely on the efficient preparation of heterocycles. This chapter will focus on the preferred methods for the preparation of several common aromatic heterocyclic ring systems. Specifically, only Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

622

13 Synthesis of Common Aromatic Heterocycles

the heterocyclic ring formation reactions will be discussed and not the synthesis of complex molecules containing one or many heterocycles. In this context, the chapters on metalation of heterocycles (see Section 12.3) and metal-mediated cross couplings (Chapter 6) might provide additional useful information. Methods relying on either the oxidation or reduction of a heterocycle in the final steps are generally not covered. This chapter focuses predominantly on ring heterocycles where all heteroatoms are part of a single ring rather than multiple heteroatoms across several rings. It is organized first by the atom included in the heterocyclic (N, O, S, mixed), ring size, number of heteroatoms, and position of the heteroatom as shown in the table below.

Heteroatom

Five-member

N1

Pyrroles

N1

Indoles

H N

H N

Heteroatom

Six-membered

N1

Dihydropyridines

N1

Pyridines

H N

N

N1

N1

H N

2-Indolinones

Quinolines

N

N1

Quinolinones

H N

N1

Isoquinolines

N1

Isoquinolinones

O

H N

Isatins

N1

O

O

O

N1

Carbazoles

N2

Pyrazoles

N2

H N

H N

N

O

N

NH H N

Indazoles

N1

H N

Quinolones

N

O

N2

H N

Imidazoles and benzimidazoles

N2

Pyrimidines

N2

Quinazolines

N

N

N

N3

H N

1,2,3-triazoles and benzotriazoles

N

N3

1,2,4-triazoles

N

N

NH

N

N2

N

N4

Tetrazoles

O1

Furans and benzofurans

N N NH N O

N

N

Pyrazines and Quinoxalines

N

N2

Pyridazines, Phtalazines and Cinnolines

N3

1,2,4-Triazine

N N N N

N

13.2 Pyrroles

Heteroatom

Five-member

S1

Thiophenes and benzothiophenes

S

Heteroatom

Six-membered

O1

Benzopyran-4-one

O

O

N1, O1

O

Isoxazoles and benzisoxazoles

N

O1

Coumarins O

N1, O1

O

O

Oxazoles and benzoxazoles

N

N1,S1

Isothiazoles and benzisothiazoles

S

N1, S1

Thiazoles and benzothiazoles

S

N

N

N2, O1

O

1,2,4-Oxadiazoles N

N2, O1

N

O

1,3,4-Oxadiazoles

N N

13.2 Pyrroles The pyrrole ring system has been widely studied since it is a common fragment in several naturally occurring molecules, including porphyrins. This heterocycle is a core found in several active pharmaceutical ingredients such as the lipid-lowering agent atorvastatin. While several methods exist for the preparation of pyrroles, the reaction of a 1,4-dicarbonyl with an amine has been the most widely utilized. 13.2.1

Condensation of 1,4-Dicarbonyls with a Primary Amine

The preferred method for the preparation of a pyrrole ring is the Paal–Knorr reaction as it requires two generally cheap starting materials and is operationally simple. In this synthetic method, a 1,4-dicarbonyl starting material is treated with a primary amine under dehydrating conditions. The reaction is generally high yielding1 and is an effective way to protect anilines as the corresponding dimethyl pyrroles.2 O NH2 Br

Ph

Ph

Ph

N

O p-TsOH, toluene

Br

93% O NH2 I

F

Me

Me

Me

O p-TsOH, toluene 100%

Ph

N I

F

Me

1 Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis 2003, 1727–1731. 2 Ragan, J. A.; Jones, B. P.; Castaldi, M. J.; Hill, P. D.; Makowski, T. W. Organic Syntheses 2002, 78, 63–72.

623

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13 Synthesis of Common Aromatic Heterocycles

Condensation of 1,3-Dicarbonyls with an 𝛂-Aminocarbonyl Compound

13.2.2

One of the best-known procedures for the preparation of highly substituted pyrroles is the Knorr reaction, where an α-aminocarbonyl compound is condensed with a 1,3-dicarbonyl to provide the pyrrole, often in a modest yield.3 For this reaction to be productive, it is important that the primary amine reacts selectively with one of the carbonyl moieties to avoid regioselectivity issues. O EtO2C

CO2Et

Me

NH2

Me

CO2Et CO2H

N H

NaOH

O

>53%

13.2.3

Dipolar Cycloaddition

Another popular method for the preparation of pyrroles is the 1,3-dipolar cycloaddition of an azomethine ylide with an alkyne. The dipole can be generated using a number of different methods, such as N-alkylation of an azalalactone4 or through activation of an acylated amino acid in the presence of an alkyne.5 One advantage of this method is the high level of complexity that can be obtained in a single operation. A disadvantage of the method is that it requires far more elaborated starting materials compared to the two previously discussed strategies. MeO2C

O

Ph N

O

CO2Me

MeO2C Ph

Et 3OBF 4 t-Bu

Me

CO2Me N Et

t-Bu

N

Me

80% HO2C N F O

Ph

O

Me

CONHPh

O

Ph

Me

HN Ph

Me

N

F

Me

Ac 2O, 90 °C

O

43%

O

O

13.3 Indoles The indole nucleus has been one of the most studied heterocycles, and several efficient methods have been developed for its preparation. The desired substitution pattern will often dictate the choice of synthetic route. Another key consideration is the availability or ease of preparation of the starting materials. Several active pharmaceutical ingredients contain an indole moiety, most notably in the “triptan” 5-hydroxytriptamine1 receptor agonists family such as eletriptan and sumatriptan, which are for the treatment of migraines. Me N

O O S Ph

Me N H Elitriptan (Relpax)

NMe2

H N

S O O

N H

Sumatriptan (Imitrex)

3 Lancaster, R. E., Jr.; VanderWerf, C. A. The Journal of Organic Chemistry 1958, 23, 1208–1209. 4 Hershenson, F. M.; Pavia, M. R. Synthesis 1988, 999–1001. 5 Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Journal of Medicinal Chemistry 1991, 34, 357–366.

13.3 Indoles

13.3.1

Fisher Indole Synthesis

The Fisher indole synthesis is undeniably the most widely used method for the preparation of indoles, especially in light of the fact that the reaction requires an arylhydrazine and a ketone or aldehyde, two very simple starting materials (see Section 7.3.2.5). A drawback of the reaction is that a mixture of regioisomers can be obtained with meta-substituted hydrazines. Hydrazines also have to be handled with caution as a high-energy functional group. In the first example below, the ammonia generated during the indole synthesis displaces a primary chloride in 88% overall yield.6 A ketohydrazone can be also used for the formation of indoles.7 O

S

O

O

O

Cl

Me N H

NH2

O

NH2 N H

EtOH, H 2O

Me • HCl

88% O N H

N

H2SO4 MeCN

N H

92%

13.3.2

S

O

Intramolecular Condensation of Anilines with Phenacyl Derivatives

Indoles can also be synthesized by the cyclodehydration of phenacyl derivatives with an ortho-substituted aniline. This method is especially attractive for the preparation of two-substituted indoles.8 O EtO

Cl NHBoc

13.3.3

AcCl/MeOH

Cl

EtO

MTBE/THF

N Boc

98%

Cycloelimination of Enamines

An excellent method for the preparation of indoles unsubstituted at the 2- and 3-position is the Batcho–Leimgruber indole synthesis, where an aniline cyclizes onto an enamine under acidic conditions. The substrate for this reaction is easily obtained in a single step from the corresponding nitrotoluene and DMF⋅DMA.9 Very often, the indole formation will proceed during the reduction of the nitro group to the aniline.10 CN NMe2 NO2

13.3.4

Fe, AcOH EtOH

CN

67%

N H

Aldol and Michael Additions

Indoles acylated at the 2-position may be easily accessed via an intramolecular 1,2- or 1,4- nucleophilic addition reaction. In general, a mild base is sufficient to induce the cyclization. In the first example below, a second step was needed 6 Fleck, T. J.; Chen, J. J.; Lu, C. V.; Hanson, K. J. Organic Process Research & Development 2006, 10, 334–338. 7 Hillier, M. C.; Marcoux, J.-F.; Zhao, D.; Grabowski, E. J. J.; McKeown, A. E.; Tillyer, R. D. The Journal of Organic Chemistry 2005, 70, 8385–8394. 8 Peters, R.; Waldmeier, P.; Joncour, A. Organic Process Research & Development 2005, 9, 508–512. 9 Vetelino, M. G.; Coe, J. W. Tetrahedron Letters 1994, 35, 219–222. 10 Ponticello, G. S.; Baldwin, J. J. The Journal of Organic Chemistry 1979, 44, 4003–4005.

625

626

13 Synthesis of Common Aromatic Heterocycles

for the dehydration of the intermediate aldol adduct to generate the indole.11 In the second case, the nitrogen protecting group was eliminated by treatment with NaOH to afford the indole nucleus.12 O Ph

(i) NaOMe (ii) SOCl2

Ph

89%

N Ts

Ph

N Ts

O

Ph O

O CO2H O

Br

CO2Et Cl

NHTs

Cl (i) K2CO3, DMAC

N H

Cl

(ii) NaOH Cl

82%

13.3.5

Alkylation of an Aniline

α-Chloroketones ortho to an aniline can easily be prepared through a number of methods. When placed under reductive conditions, alkylation of the aniline and dehydration occurs to generate the desired indole. Researchers at Merck investigated several synthetic methods and selected this approach for the synthesis of the desired fluoroindole.13 O Cl

Me NH2 F

13.3.6

NaBH4

Me

t-AmOH 96%

F

N H

Addition of Vinyl Grignard Reagents to Nitrobenzene Derivatives

The addition of a vinyl Grignard reagent to a nitrobenzene to generate an indole is known as the Bartoli indole synthesis. While the reaction proceeds in a single step from a nitroarene and is tolerant of some functionality that cannot be present with other methods, the necessity of low temperature renders this reaction less practical. The Bartoli indole synthesis is not the preferred method for preparation of indoles on large scale but can be considered a good alternative for laboratory scale synthesis.14

NO2 TBSO

CH2=CHMgBr –45 °C 56%

TBSO

N H

13.4 2-Indolinones (Oxindoles) Oxindoles are fairly straightforward to prepare and have been widely employed as pharmaceutical agents. For instance, ropinirole is a simple oxindole used for the treatment of Parkinson’s disease and restless leg syndrome, sunitinib is a multi-kinase inhibitor in oncology and ziprasidone is an atypical antipsychotic. Two main methods are reliably utilized for their preparation. 11 Jones, C. D. The Journal of Organic Chemistry 1972, 37, 3624–3625. 12 Caron, S.; Vazquez, E.; Stevens, R. W.; Nakao, K.; Koike, H.; Murata, Y. The Journal of Organic Chemistry 2003, 68, 4104–4107. 13 Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-Y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Organic Process Research & Development 2012, 16, 1832–1845. 14 Faul, M. M.; Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.; Clayton, M. T.; Martinelli, M. J.; Pawlak, J. M.; LeTourneau, M.; Coffey, D. S.; Pedersen, S. W.; Kolis, S. P.; Furness, K.; Malhotra, S.; Al-Awar, R. S.; Ray, J. E. The Journal of Organic Chemistry 2004, 69, 2967–2975.

13.4 2-Indolinones (Oxindoles)

Cl N

N H

N

O

S N Ziprasidone (Geodon)

13.4.1

Lactamization

The most practical method for the preparation of oxindoles is the lactamization of anilines onto a phenylacetic acid derivative.15 The reaction often proceeds directly upon reduction of the corresponding nitroarene.16 MeO

CO2H NH Cl

Cl

HO C5H5N·HCl 170 °C

O

N

Cl

Cl

77%

OH

OMe CO2Me Cl

13.4.2

NO2

Fe AcOH 100 °C 89%

O

N H

Cl

Friedel–Crafts Alkylation

The Friedel–Crafts alkylation of α-chloroacyl anilines is a less common method for the preparation of oxindoles. The advantage of this method is that anilines and α-chloroacetyl chloride derivatives are simple starting materials. Unfortunately, high temperatures in the presence of a Lewis acid is usually required for the cyclization to proceed which can limit functional group compatibility and tends to lead to lower yields.17 Cl Me Me

13.4.3

AlCl3 chlorobenzene

O Cl

N

N

Me

O Cl

Me

47%

C–H Insertion

A much milder method for the synthesis of oxindoles from α-chloroacyl anilines is through the palladium-mediated C–H insertion. The reaction proceeds at much lower temperature under slightly basic conditions affording a higher yield.18 MeO2C

N

N Cbz 15 16 17 18

Pd(OAc) 2 (10 mol%)

Cl

Ph O

(20 mol%) P(t-Bu)2 Et3N, THF, iPrOH 76%

MeO2C N

O

N Cbz

Moser, P.; Sallmann, A.; Wiesenberg, I. Journal of Medicinal Chemistry 1990, 33, 2358–2368. Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51–53. Acemoglu, M.; Allmendinger, T.; Calienni, J.; Cercus, J.; Loiseleur, O.; Sedelmeier, G. H.; Xu, D. Tetrahedron 2004, 60, 11571–11586. Kiser, E. J.; Magano, J.; Shine, R. J.; Chen, M. H. Organic Process Research & Development 2012, 16, 255–259.

627

628

13 Synthesis of Common Aromatic Heterocycles

13.5 Isatins (2,3-Indolindiones) Isatins are very useful synthetic intermediates due to their high reactivity toward nucleophiles. There are two efficient methods for the preparation of these compounds. 13.5.1

Cyclization of Isonitrosoacetanilides

The most common method for the preparation of isatins is the reaction of an aniline with trichloroacetaldehyde (chloral) in the presence of hydroxylamine.19 The resulting isonitroso intermediate undergoes cyclization under acidic conditions.20 OH N

Cl 3CCHO

NH2 CO2Me

13.5.2

NH2OH·HCl 67%

MeO2C

N H

O H2SO4 O

O

N H CO2H

78%

Friedel–Crafts Acylation

Another method for the preparation of isatins is the Friedel–Crafts cyclization of amides of oxalic acid. This method is often higher yielding than the chloral method.21 CO2H MeO Et

N H

O

(i) PCl5, CH2Cl2 (ii) SnCl4

O

MeO

86%

Et

N H

O

13.6 Carbazoles Carbazoles are related to indoles, but the presence of the additional arene makes it such that the majority of the methods to prepare indoles do not apply to carbazoles. 13.6.1

Oxidation of an Indole

The most popular method for the synthesis of a carbazole is to perform a Fisher indole synthesis using a cyclohexanone followed by oxidation of the cyclohexane ring.22 CO2Et

O

13.6.2

F

NHNH2 EtOH 97%

F

CO2Et

F

CO2Et DDQ N H

Xylenes 76%

N H

Reductive Cyclization of a Nitro-Biphenyl Derivative

Another method for the preparation of carbazoles is the reduction of a nitro-biphenyl with a phosphine at elevated temperature.23 This method is fairly general, but the substrates often require a few synthetic steps to be prepared. 19 Marvel, C. S.; Hiers, G. S. Organic Syntheses 1925, V , 71–74. 20 Wakelin, L. P. G.; Bu, X.; Eleftheriou, A.; Parmar, A.; Hayek, C.; Stewart, B. W. Journal of Medicinal Chemistry 2003, 46, 5790–5802. 21 Soll, R. M.; Guinosso, C.; Asselin, A. The Journal of Organic Chemistry 1988, 53, 2844–2847. 22 Block, M. H.; Boyer, S.; Brailsford, W.; Brittain, D. R.; Carroll, D.; Chapman, S.; Clarke, D. S.; Donald, C. S.; Foote, K. M.; Godfrey, L.; Ladner, A.; Marsham, P. R.; Masters, D. J.; Mee, C. D.; O’Donovan, M. R.; Pease, J. E.; Pickup, A. G.; Rayner, J. W.; Roberts, A.; Schofield, P.; Suleman, A.; Turnbull, A. V. Journal of Medicinal Chemistry 2002, 45, 3509–3523. 23 Freeman, A. W.; Urvoy, M.; Criswell, M. E. The Journal of Organic Chemistry 2005, 70, 5014–5019.

13.7 Pyrazoles

t-Bu

PPh 3

t-Bu

t-Bu

o-DCB 180 °C

NO2

t-Bu N H

83%

13.7 Pyrazoles This heterocycle forms the core of several important pharmaceutical drugs, notably celecoxib, a 1,3,5-trisubstituted pyrazole a COX-2 inhibitor and rimonabant, a 1,3,4,5-tetrasubstituted pyrazole CB-1 receptor antagonist. Most syntheses of pyrazoles utilize the addition of a hydrazine to a 1,3-dicarbonyl compound or a Michael acceptor. O

CF3 N

Me

N

N

N

Cl

Cl

SO2NH2

Cl

Celecoxib (Celebrex)

13.7.1

N N H

Me

Rimonabant (Acomplia)

Condensation of a Hydrazine with a 1,3-Dicarbonyl Derivative

The most common method for preparation of a pyrazole is condensation of a hydrazine with a 1,3-dicarbonyl reagent. In the case of a symmetrical diketone24 or when using hydrazine25 the reaction is usually high yielding with no regiochemical issues. In cases where an unsymmetrical diketone or ketoester is treated with a substituted hydrazine, regioisomers of the pyrazole can be obtained.26 Appropriate safety precautions should be taken when working with hydrazines. O Ph

Ph

PhNHNH 2

O Ph

96%

F

F CO2Et

N H

95%

N

MeO2S

MeO2S H N

Ph

OH

NH2NH2·H2O

O

O

N N Ph

Ph

Me NH2

·HCl

O

Ph

N

N

Ph Me

N

N

Me 80%

13%

24 See Note 1. 25 Patel, M. V.; Bell, R.; Majest, S.; Henry, R.; Kolasa, T. The Journal of Organic Chemistry 2004, 69, 7058–7065. 26 Hanefeld, U.; Rees, C. W.; White, A. J. P.; Williams, D. J. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972–1999) 1996, 1545–1552.

629

630

13 Synthesis of Common Aromatic Heterocycles

13.7.2

Condensation of a Hydrazine with a Michael Acceptor

The second method for construction of a pyrazole is the condensation of a hydrazine with a Michael acceptor. The product of the reaction depends on the initial regioselectivity of hydrazine addition (1,2 or 1,4). Michael acceptors27 bearing a leaving group such as an amine28 or an ether29 at the β-position have been used for this transformation. Even when using a very hindered hydrazine, this reaction is operationally simple and proceeds in high yields. OH i-Pr

MeNHNH2

CO2Me

MeOH, H2O

N N Me

i-Pr

48%

MeO2C O N Me OMe O

MeHN

78%

MeO2C

CF3

82%

NH2 CN

Me

N

N Me

4:1

Ph N N

PhNHNH 2·HCl MeOH

S

i-Pr

Ph N N

PhNHNH 2·HCl EtOH OMe

OH

OMe

CF3

S

t-BuNHNH 2·HCl NaOH aq Me

86%

t-Bu N N NH2

13.8 Indazoles Indazoles have been recognized as an important pharmacophore. They are present in a number of drugs such as the tyrosine kinase inhibitor axitinib and the antiemetic granisetron. Three methods are commonly utilized for the preparation of indazoles. The diazotization of ortho-toluidines is straightforward on a small scale but can present safety challenges on scale-up. The nucleophilic aromatic substitution of hydrazone is an efficient method, usually starting from easily obtained reagents. Finally, catalytic metal-mediated cyclization of hydrazones has been demonstrated as a mild and efficient way to access this ring system.

N S CONHMe

N H

N

Axitinib (Intyla)

13.8.1

O

Me

N N

N

Me

N H

Granisetron (Kytril)

Nucleophilic Aromatic Substitution of Arylhydrazones

An efficient method for construction of an indazole is the intramolecular SN Ar reaction of an ortho-activated hydrazone. The hydrazone can be generated in situ from the corresponding ketone and hydrazine, followed by intramolecular cyclization.30 Both cis and trans hydrazones convert to the desired product during the course of the reaction. 27 28 29 30

Hamper, B. C.; Kurtzweil, M. L.; Beck, J. P. The Journal of Organic Chemistry 1992, 57, 5680–5686. Singh, R. K.; Sinha, N.; Jain, S.; Salman, M.; Naqvi, F.; Anand, N. Tetrahedron 2005, 61, 8868–8874. Flores, A. F. C.; Brondani, S.; Pizzuti, L.; Martins, M. A. P.; Zanatta, N.; Bonacorso, H. G.; Flores, D. C. Synthesis 2005, 2744–2750. Caron, S.; Vazquez, E. Synthesis 1999, 588–592; Caron, S.; Vazquez, E. Organic Process Research & Development 2001, 5, 587–592.

13.9 Imidazoles and Benzimidazoles

O

H N O

13.8.2

N N Me

Xylenes 135 °C 91%

Et

F

Me

MeNHNH2 NH4OAc

OMs Me

F

Et NH2 · MsOH

F

N

N

Toluene, reflux 98%

Diazotization of a Toluidine

Another popular method for the preparation of indazoles is the diazotization of ortho-toluidines. Upon generation of the diazonium species, the benzylic proton at the ortho-position is sufficiently acidic to be deprotonated by a mild base. Addition of the resulting anion to the diazonium group leads to the desired indazole.31 Appropriate precautions should be taken when working with diazonium compounds. HO

Me

Ac2O, KOAc n-amyl nitrite

NH2

CHCl3

AcO

N N Ac

58%

13.8.3

Metal-Mediated Cyclization

A more recent method for the generation of indazole is the metal-mediated cyclization of hydrazones onto aryl halides. This transformation has been accomplished using either copper32 or palladium33 catalysts. CO2Et N

CO2Et N N MeO

N

NHSO2Ph

CuI K 2CO3

N

MeO

N N SO2Ph

99%

Br N

NHPh H

Br

Pd(dba) 2 DPEphos K 3PO4 83%

N N Ph

DPEphos: bis[2-(phenylphosphino)phenyl] ether

13.9 Imidazoles and Benzimidazoles Imidazoles and benzimidazoles have been one of the most utilized class of compounds in the pharmaceutical industry. This pharmacophore has led to several gastric-acid pump inhibitors, namely omeprazole and its enantiomer 31 Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A. The Journal of Organic Chemistry 1997, 62, 5627–5629. 32 Watson, T. J.; Ayers, T. A.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.; Horgan, S.; Carey, J. P. Organic Process Research & Development 2003, 7, 521–532. 33 Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z. The Journal of Organic Chemistry 2005, 70, 596–602.

631

632

13 Synthesis of Common Aromatic Heterocycles

esomeprazole. Several excellent synthetic methods exist for the preparation of these heterocycles, generally through the reaction of an amine with a carbonyl derivative. Me H N N

MeO

S O

OMe Me

N

Omeprazole (Prilosec)

13.9.1

Condensation of a 1,2-Diamine with a Carboxylic Acid

Condensation of an ortho-bisaniline with a carboxylic acid derivative is the best method for preparation of benzimidazoles. Carboxylic acids,34 acid chlorides,35 and anhydrides36 have been utilized successfully for this transformation. H N

Cl

CO2H

H 2N OH

HCl

NH2

Cl

OH

N N

58%

NH2

(i) Et 3N, CH2Cl 2 N

Me Me

COCl

NH2

HN NH2

O

Me Me

(ii) EtOH, HCl

N

N H

N

(ClCH2CO)2O

Et

>59%

N

N H

O

65% NH2

N

HN

N

N Et

Cl

Another strategy that has been employed is to utilize a nitroaniline and an aldehyde in the presence of a mild reducing agent.37 OHC EtO2C

NO2 N

H

O

Na2S2O4 DMSO, EtOH

EtO2C

N N

O

>80%

13.9.2

Condensation of an Amidine with a Halocarbonyl Derivative

A good method for preparation of imidazoles is the reaction of an amidine with a carbonyl compound containing a leaving group at the α-position.38 In the second example below, a bromoacetaldehyde equivalent is introduced in the form of the enol ether39 while the third example shows the preparation of an N-substituted imidazole.40 34 35 36 37 38 39 40

Huff, J. R.; King, S. W.; Saari, W. S. The Journal of Organic Chemistry 1982, 47, 582–585. Mertens, A.; Mueller-Beckmann, B.; Kampe, W.; Hoelck, J. P.; Von der Saal, W. Journal of Medicinal Chemistry 1987, 30, 1279–1287. Caron, S.; Do, N. M.; McDermott, R. E.; Bahmanyar, S. Organic Process Research & Development 2006, 10, 257–261. Oda, S.; Shimizu, H.; Aoyama, Y.; Ueki, T.; Shimizu, S.; Osato, H.; Takeuchi, Y. Organic Process Research & Development 2012, 16, 96–101. Tsunoda, T.; Tanaka, A.; Mase, T.; Sakamoto, S. Heterocycles 2004, 63, 1113–1122. Lipinski, C. A.; Blizniak, T. E.; Craig, R. H. The Journal of Organic Chemistry 1984, 49, 566–570. Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Pridgen, L. N. The Journal of Organic Chemistry 1997, 62, 8449–8454.

13.10 1,2,3-Triazoles and Benzotriazole

O

Me

Br

H2N

Me

· HCl

HN

NH

K 2CO3

N Ts

N Ts

toluene >69% NH

Br

H2N

Me O

Me

Me

O NH

NaOAc

OH

OHC HN HN

n-Bu

13.9.3

Me

N

42%

CO2H

N

Br OHC

i-PrO

N

NaOAc

CO2H

N n-Bu

OHC

83%

CO2H

N

+

N

n-Bu

9:1

Condensation of 1,4-Dicarbonyls with an Amine

A 1,4-dicarbonyl compound will react with an amine to first generate an enamine, which then undergoes cyclodehydration. The acyclated α-aminoketone required for this transformation can be accessed using organocatalysis.41 S

I– CHO N

13.9.4

+

N Me +

Ts Ph

NHCHO

OH Ph

Me

THF, Et 3N

NHCHO

Ph

NH4OAc O N

76%

H N N

N

Condensation of 1,2-Dicarbonyls with an Aldehyde and Ammonia

Another method for the preparation of the imidazole ring is the condensation of a 1,2-dicarbonyl with an aldehyde in the presence of an ammonia source.42 In general, ortho-dicarbonyl compounds are not as abundant as the ortho-diamine describe in the first method. O O

Br + OHC

NH4HCO3 AcOH 82%

H N

Br

N

13.10 1,2,3-Triazoles and Benzotriazole The 1,2,3-triazole ring system is a well-studied heterocycle and its preparation is one of the best examples of “click chemistry.”43 In both methods suggested below, an azide reagent is required. It is noteworthy to state that 41 Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer, R. D. Organic Letters 2004, 6, 843–846. 42 Krebs, F. C.; Jorgensen, M. The Journal of Organic Chemistry 2001, 66, 6169–6173. 43 Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137.

633

634

13 Synthesis of Common Aromatic Heterocycles

special precautions should be taken when working with azides as they are highly energetic and often shock-sensitive compounds. In the case of benzotriazoles, the most general synthetic method is the diazotization of an ortho-dianiline. 13.10.1

Dipolar Cycloaddition of Azides with an Alkynes

The most reliable method for the preparation of 1,2,3-triazoles is the cycloaddition of an azide with an alkyne. The two most common reagents to obtain the unsubstituted 1,2,3-triazole are sodium azide44 or trimethylsilyl azide.45 Alkyl azides can also be employed, but the substrates must be selected carefully to avoid mixtures of regioisomers.46

O

N

NaN3 AcOH, DMSO 50 °C

O

O

O

N

N

63%

N

Cl O

O

O

Me

TMSN3 DMAC 110 °C

Me

13.10.2

TMS

O

Me

N

NH N

Me

68%

EtO2C

Ar

Cl

F

NH

Ph N3 toluene 110 °C

Ph EtO2C

91%

N N

N

TMS

Dipolar Cycloaddition of Azides with Enolates

An excellent procedure for the preparation of 4,5-disubstituted-1,2,3-triazoles is the addition of an enolates to an alkylazide, also known as the Dimroth reaction.47 This procedure provides high levels of regiocontrol, which is not always the case for the dipolar cycloaddition of alkynes. Cl

N3 Cl

13.10.3

Me

+ EtO2C O

K 2CO3 DMSO 89%

Cl

N Cl

Me

N

N CO2Et

Diazaotization of o-Dianilines

The preferred method to prepare a benzotriazole is the diazotization of an o-dianiline that is often prepared in situ due to its propensity toward oxidative degradation. Upon treatment with sodium nitrite, the desired benzotriazole is generally obtained in high yields.48 44 Trybulski, E. J.; Benjamin, L.; Vitone, S.; Walser, A.; Fryer, R. I. Journal of Medicinal Chemistry 1983, 26, 367–372. 45 Blass, B. E.; Coburn, K.; Lee, W.; Fairweather, N.; Fluxe, A.; Wu, S.; Janusz, J. M.; Murawsky, M.; Fadayel, G. M.; Fang, B.; Hare, M.; Ridgeway, J.; White, R.; Jackson, C.; Djandjighian, L.; Hedges, R.; Wireko, F. C.; Ritter, A. L. Bioorganic & Medicinal Chemistry Letters 2006, 16, 4629–4632. 46 Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Organic Letters 2005, 7, 1469–1472. 47 Cottrell, I. F.; Hands, D.; Houghton, P. G.; Humphrey, G. R.; Wright, S. H. B. Journal of Heterocyclic Chemistry 1991, 28, 301–304. 48 Maddess, M. L.; Scott, J. P.; Alorati, A.; Baxter, C.; Bremeyer, N.; Brewer, S.; Campos, K.; Cleator, E.; Dieguez-Vazquez, A.; Gibb, A.; Gibson, A.; Howard, M.; Keen, S.; Klapars, A.; Lee, J.; Li, J.; Lynch, J.; Mullens, P.; Wallace, D.; Wilson, R. Organic Process Research & Development 2014, 18, 528–538.

13.12 Tetrazoles

Br

NaNO2 HCl aq

NH2 N H

t-Bu

Br

N

N N t-Bu

>93%

13.11 1,2,4-Triazoles The 1,2,4-triazole unit is far more commonly found in pharmaceutical agents than the 1,2,3-triazole moiety. The ring system is usually obtained through a cyclodehydration approach where the N—N bond originated from a hydrazine. 13.11.1

Cyclodehydration

Most 1,2,4-triazoles and derivatives thereof are prepared by intramolecular cyclodehydration of an amide or an acylhydrazine. The desired substrates can be accessed in a number of ways, either through addition of an acyl hydrazine to an imidate or a nitrile,49 addition of a hydrazine or an alkylhydrazine to an imine,50 or addition to a diazo compound.51 The cyclization itself proceeds under either acidic or basic conditions. OMe

HN Et

O N H

NH2

Et

O N H

87%

MeO

CONH2

OMe

Cl

OMe

EtO ClCH 2CH2Cl reflux

CO2Me

O N H

CO2Me

Cl

DMF·DMA 120 °C

N2

OMe NH2

Et

N

NMe2

NH2NH2·H2O AcOH 90 °C

N

N N MeO

N H

92%

OMe

N N H

71%

O

MeO

94%

OMe

CO2Me

Cl

Cl

NaOAc, MeOH 99%

N

EtOCH 2CH2OH K 2CO3

O

E E N H

N

(i) NaOMe (ii) AcOH 90 °C

N

Cl

Cl E = CO2Me

84%

Cl

N N

N

Cl Cl

13.12 Tetrazoles Tetrazoles represent a carboxylic acid isostere and are by far the most common heterocycle introduced on the side-chain of β-lactam antibiotics. The synthetic strategy for their preparation usually involves the cycloaddition of an azide with a nitrile or an activated amide. 49 Omodei-Sale, A.; Consonni, P.; Galliani, G. Journal of Medicinal Chemistry 1983, 26, 1187–1192. 50 Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse, C. G. Journal of Medicinal Chemistry 2005, 48, 1823–1838. 51 Lin, Y.-I.; Lang, S. A., Jr.; Lovell, M. F.; Perkinson, N. A. The Journal of Organic Chemistry 1979, 44, 4160–4164.

635

636

13 Synthesis of Common Aromatic Heterocycles

13.12.1

Cycloaddition of an Azide and a Nitrile

The most common method to prepare a tetrazole is by cycloaddition of an azide with a nitrile.52 While several of the literature procedures utilize sodium azide in the presence of a proton source at elevated temperature, this method generates hydrazoic acid, which is hazardous under the reaction conditions.53 A safer reaction has been developed at Bristol–Myers Squibb where sodium azide reacts with a nitrile in the presence of benzylamine and benzylamine hydrochloride.54 A method utilizing catalytic quantities of dibutyltin oxide in conjunction with trimethysilyl azide has been developed and is considered less hazardous than the sodium azide method, mainly because of the lower risk in handling TMSN3 .55 CN

N N N N H

NH4Cl NaN3, DMF 120 °C

n-BuO

OH CN

74%

n-BuO

1.2 equiv NaN3 1.2 equiv BnNH3Cl 0.5 equiv BnNH2

OH

THF, H2O 64 °C

Cl

N N N N H

Cl

86%

MeO2C

TMSN3 n-Bu2SnO cat. toluene

CN

MeO2C

110 °C

N N N N H

98%

13.12.2

Activation of an Amide and Addition of an Azide

A less common method for the preparation of a tetrazole is the activation of an amide, mainly to an iminoyl chloride,56 followed by addition of trimethylsilyl azide. This method has also been utilized directly on an amide under Mitsunobu-type conditions.57 CO2Et N

H

(i) PCl5, CH2Cl2 (ii) TMSN3

N

Cl

100%

O N F H

N

Cl O

Cl

(i) PPh3, DIAD (ii) TMSN3 76%

CO2Et N

N N N N

Cl

N F N N N N

Cl Cl

52 Butler, R. N. In Comprehensive Heterocyclic Chemistry II 1996; Vol. 4, p 621–678, 905–1006. 53 Nakamura, T.; Sato, M.; Kakinuma, H.; Miyata, N.; Taniguchi, K.; Bando, K.; Koda, A.; Kameo, K. Journal of Medicinal Chemistry 2003, 46, 5416–5427. 54 Treitler, D. S.; Leung, S.; Lindrud, M. Organic Process Research & Development 2017, 21, 460–467. 55 Wittenberger, S. J.; Donner, B. G. The Journal of Organic Chemistry 1993, 58, 4139–4141. 56 Meanwell, N. A.; Hewawasam, P.; Thomas, J. A.; Wright, J. J. K.; Russell, J. W.; Gamberdella, M.; Goldenberg, H. J.; Seiler, S. M.; Zavoico, G. B. Journal of Medicinal Chemistry 1993, 36, 3251–3264. 57 Nelson, D. W.; Gregg, R. J.; Kort, M. E.; Perez-Medrano, A.; Voight, E. A.; Wang, Y.; Grayson, G.; Namovic, M. T.; Donnelly-Roberts, D. L.; Niforatos, W.; Honore, P.; Jarvis, M. F.; Faltynek, C. R.; Carroll, W. A. Journal of Medicinal Chemistry 2006, 49, 3659–3666.

13.14 Pyridines

13.13 Dihydropyridines The 1,4-dihydropyridine nucleus has been extensively studied because of its pharmacological activity as a calcium channel blocker. Two major synthetic methods have provided access to the basic framework in a single step. It is noteworthy that dihydropyridines can easily be oxidized to the corresponding pyridines and can be used as intermediates in their synthesis. While dihydropyridines are not an aromatic heterocycle, they are discussed here as they are often prepared as a precursor to a pyridine through a facile oxidation. 13.13.1

Reaction of Ketoesters and Aldehydes in the Presence of Ammonia

The Hantzsch dihydropyridine synthesis is by far the most well-known method for the preparation of this class of compounds. The reaction can be low-yielding, but the simplicity of synthesis and low cost of the required starting materials counterbalance this issue. Two equivalents of a β-ketoester react with an aldehyde in the presence of ammonia. It is generally believed that ammonia reacts with one equivalent of the ketoester to generate an aminocrotonate. The second equivalent of the ketoester undergoes Knoevenagel condensation with the aldehyde to provide an enone. The two components undergo condensation followed by ring closure to the dihydropyridine. Using the classical Hantzch dihydropyridine synthesis, only symmetrical products are formed.58 O CO2Me

Me

PhCHO NH4OH, MeOH

Ph MeO2C

70%

13.13.2

Me

CO2Me N H

Me

Reaction of Aminocrotonates with Aldehydes and ß-Ketoesters

The preferred method for the preparation of unsymmetrical dihydropyridines is a stepwise modification of the Hantzsch synthesis. Rather than utilizing two equivalents of the ketoester, only one equivalent is used in the presence of equimolar amounts of a previously prepared aminocrotonate to afford the desired dihydropyridine in high yields.59 NH2 O MeO2C

CHO CO2Me +

Cl Cl

Me

CO2Me

Ar

MeOH

MeO2C

> 60%

Me

CO2Me N H

CO2Me

13.14 Pyridines Pyridines are among the most common heterocycles and numerous methods for their preparation are available and have been reviewed extensively.60 The three most common methods are presented below. 13.14.1

Condensation of a 1,3-Dicarbonyl Derivative with a Cyanoacetamide

Reaction of a β-ketoester with a reagent such as cyanoacetamide, known as the Guareschi–Thorpe pyridine synthesis, is a proven method for the preparation of nicotinamide derivatives. The reaction is usually carried out in an alcoholic solvent in the presence of a mild base such as piperidine. This method leads to a 2,6-dihydroxypyridine (or 6-hydroxypyridone) with substitution possible at the 2-, 3-, 4-, and 6-position.61,62 58 59 60 61 62

Boecker, R. H.; Guengerich, F. P. Journal of Medicinal Chemistry 1986, 29, 1596–1603. Alker, D.; Denton, S. M. Tetrahedron 1990, 46, 3693–3702. Henry, G. D. Tetrahedron 2004, 60, 6043–6061. Holland, G. F.; Pereira, J. N. Journal of Medicinal Chemistry 1967, 10, 149–154. Kutney, J. P.; Selby, R. C. The Journal of Organic Chemistry 1961, 26, 2733–2737.

637

638

13 Synthesis of Common Aromatic Heterocycles

Me Me

CO2Et

NC CONH2 piperidine Me MeOH

O

69%

F3C

CO2Et

HO

NC CONH2 piperidine MeOH 83%

O

13.14.2

Me CN N

OH

CF3 CN HO

N H

O

Condensation of Enolates with Enaminoesters

One of the most common and reliable method for the preparation of 2-hydroxypyridine is the Friedländer condensation, which involves the reaction of an enaminoester with an enolate. While the reaction works well with simple enolates, it is usually more efficient to start with a 1,3-dicarbonyl compound. When an unsubstituted malonate is used, an ester group remains at the 3-position of the pyridine. However, if a substituted ketoester is used, decarboxylation occurs either during the pyridine synthesis or as a subsequent step leading to a 2,3,4-trisubstituted product.63 Me R

NH2 CO2Et

CO2Et Me O

NaOEt, EtOH toluene 69%

Me

OH Me Me

Rʹ N

OH

when R = Me, Rʹ = Me when R = OEt, Rʹ = CO2Et

13.14.3

Condensation of a 1,5-Dicarbonyl Compound with Ammonia

Condensation of a 1,5-dicarbonyl compound with ammonia is a less common method to prepare pyridines, mainly because of the complexity or lack of availability of the starting material. In order to obtain the pyridine, the starting material must contain a functional group poised for elimination, or hydroxylamine can be used in place of ammonia. The reaction has been demonstrated with a hydroxydialdehyde and ammonia.64 It is worthy to note that a 1,5-dicarbonyl is usually the final intermediate prior to condensation with ammonium acetate in the Kröhnke pyridine synthesis that starts from an acylpyridinium salt.65 CF3 OHC

N Ph

+

Br–

CHO NH3/MeOH

HO

CF3

NH4OAc, AcOH CO2H

O

N

+

Br–

O Cl

Me

74%

Ph

N

Me

O

NH4OAc, AcOH H

Br

N Ph

O Ph

70%

MeCN 93%

– +

CO2NH4 Cl

N Br

63 McElroy, W. T.; DeShong, P. Organic Letters 2003, 5, 4779–4782. 64 Jiang, B.; Xiong, W.; Zhang, X.; Zhang, F. Organic Process Research & Development 2001, 5, 531–534. 65 Kroehnke, F. Synthesis 1976, 1–24; Betti, M.; Castagnoli, G.; Panico, A.; Sanna-Coccone, S.; Wiedenau, P. Organic Process Research & Development 2012, 16, 1739–1745.

13.15 Quinolines

Another efficient method for the preparation of pyridines is the reaction of a ketone with an enone and a source of ammonia. Ketone enolates can be converted to bis(methylthio)-enones that undergo pyridine formation upon treatment with ammonium hydroxide.66 An extension of this methodology was discovered at Merck through the use of vinamidinium salts. This method is especially useful for the formation of 2,3-disubstituted pyridines.67,68 (i) t-BuOK SMe N

SMe

N O

SMe

Me O

N N

(ii) NH4OAc, AcOH

N

77% (i) t-BuOK SO2Me

O

Me

Cl

Me2N

+

PF6– NMe2

Cl N

(ii) AcOH, TFA

N

SO2Me

(iii) NH4OH

N

Me

94%

In the example below, conjugate addition on an enamine leads to an enaminoketone, a 1,5-dicarbonyl surrogate, which reacts in high yield and ammonium acetate to provide the desired pyridine.69

SMe Me

SMe

O N

F3C

OEt K 2CO3 toluene

Me

N

MeCN F3C

O

Me

NH4OAc 98%

SMe F3C

N

13.15 Quinolines Quinolines are present in a wide variety of naturally occurring alkaloids as well as in many pharmaceuticals products. Several agents of this class have been utilized as protozoacids for the treatment of malaria. The most common method for the preparation of quinolines is the Friedländer quinoline synthesis. Methods discussed for the preparation of structurally related quinolones and quinolinones are described in Sections 13.17 and 13.16. 13.15.1

Friedländer Quinoline Synthesis

The Friedländer quinoline synthesis involves the reaction of an ortho-aminoacetophenone with an enolizable aldehyde or ketone. One of the major advantages of this method is that highly functionalized quinolines can be readily obtained.70

66 Potts, K. T.; Ralli, P.; Theodoridis, G.; Winslow, P. Organic Syntheses 1986, 64, 189–195. 67 Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele, L.; Dormer, P.; Reider, P. J. The Journal of Organic Chemistry 2000, 65, 8415–8420. 68 Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.; Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. The Journal of Organic Chemistry 2001, 66, 4194–4199. 69 Arndt, K. E.; Bland, D. C.; Irvine, N. M.; Powers, S. L.; Martin, T. P.; McConnell, J. R.; Podhorez, D. E.; Renga, J. M.; Ross, R.; Roth, G. A.; Scherzer, B. D.; Toyzan, T. W. Organic Process Research & Development 2015, 19, 454–462. 70 Mizuno, M.; Inagaki, A.; Yamashita, M.; Soma, N.; Maeda, Y.; Nakatani, H. Tetrahedron 2006, 62, 4065–4070.

639

640

13 Synthesis of Common Aromatic Heterocycles

OMe

OMe OMe

OMe EtO2C

MeO

O

MeO

MeO

EtOH, Et 3N

NH2

13.15.2

Cl O

CO2Et

MeO

88%

N

Cl

Addition to Isatins

The best method to prepare a quinoline containing a carboxylic acid at the 4-position is the Pfitzinger reaction. This synthesis begins with an isatin that is opened to the corresponding isatoic acid. Further reaction with a carbonyl compound generates an imine that undergoes intramolecular condensation to provide the desired quinoline.71 O

Me

N H

13.15.3

CO2H

Me

O

N

O

N

N

KOH, EtOH

Me

67%

Electrophilic Aromatic Substitution

A less popular method for the preparation of quinolines is the electrophilic cyclization of a ketone, known as the Combes reaction. The reaction proceeds under a variety of acidic or dehydrating conditions and is a good route to access polyaromatic systems.72 Me NH

Me O Pr

Pr

83%

N

N OH

OH

13.15.4

N

HCl

Intramolecular Cyclization of an Iminium Ion

The Meth–Cohn quinoline synthesis is a very efficient method for the preparation of a 2-chloroquinoline as it ultimately requires a simple aniline that has been acylated. Reaction of an amide with POCl3 leads to an imidoyl chloride, which further reacts with the Vilsmeier reagent generated in situ from DMF. The iminium intermediate then undergoes an intramolecular electrophilic aromatic substitution to furnish the desired quinoline.73 It is important to understand the regioselectvitiy of the final cyclization when starting from a meta-substituted compound.74 Br

POCl 3 DMF

O N H

Pr

N H

Et N

73% POCl 3 DMF

O MeO

Br

Et

84%

Cl Me

MeO

N

Cl

71 Atwell, G. J.; Baguley, B. C.; Denny, W. A. Journal of Medicinal Chemistry 1989, 32, 396–401. 72 Atkins, R. J.; Breen, G. F.; Crawford, L. P.; Grinter, T. J.; Harris, M. A.; Hayes, J. F.; Moores, C. J.; Saunders, R. N.; Share, A. C.; Walsgrove, T. C.; Wicks, C. Organic Process Research & Development 1997, 1, 185–197. 73 Mabire, D.; Coupa, S.; Adelinet, C.; Poncelet, A.; Simonnet, Y.; Venet, M.; Wouters, R.; Lesage, A. S. J.; Van Beijsterveldt, L.; Bischoff, F. Journal of Medicinal Chemistry 2005, 48, 2134–2153. 74 Chen, X.-W.; Liu, Y.; Jin, X.-Q.; Sun, Y.-Y.; Gu, S.-L.; Fu, L.; Li, J.-Q. Organic Process Research & Development 2016, 20, 1662–1667.

13.16 Quinolinones and 2-Hydroxyquinolines

13.16 Quinolinones and 2-Hydroxyquinolines Quinolinones are very useful synthetic intermediates, especially for further functionalization at the 2-position. There are three main methods for the preparation of quinolinones and their tautomeric 2-hydroxyquinolines. 13.16.1

Electrophilic Cyclization

It is possible to generate the pyridine ring of a quiloninone through electrophilic cyclization although it is not the most general method. The advantage of this method is that simple anilines are used as the starting material. Cyclization of ketoamides, which are easily obtained by condensation of an aniline with diketene,75 and enolethers,76 has been demonstrated. Me O Br

N H

Me

H2SO4 120 °C

O

72%

Br

N H

O

N

OH

OEt Me2N

H2SO4 N H

13.16.2

Me2N

50 °C

O

72%

Intramolecular Aldol Ring Closure

Another method to generate quinolinones is from a dicarbonyl intermediate under basic conditions. A malonamide can be utilized for condensation onto a ketone to provide the desired ring system after dehydration.77 Me

Me

Me

O NH CO2Et

O

Me

EtONa EtOH 93%

CO2Et N H

O

An extension of this procedure is a modified Pfitzinger quinoline synthesis, which utilizes the commonly accessible isatin as the starting material.78 O N H

13.16.3

O

(i) (n-PrCO)2O (ii) NaOH 60%

CO2H Et N H

O

Intramolecular Condensation

Another method to obtain a quinolinone is an intramolecular condensation of an aniline with a carboxylic acid derivative. In the example shown, a mixed anhydride is generated in situ and reacts to provide the desired product. The starting configuration of the acrylate is not important as the starting material isomerizes in the course of the reaction. The inconvenience of this method is that the starting material may not be readily available.79 75 Davis, S. E.; Rauckman, B. S.; Chan, J. H.; Roth, B. Journal of Medicinal Chemistry 1989, 32, 1936–1942. 76 Janiak, C.; Deblon, S.; Uehlin, L. Synthesis 1999, 959–964. 77 Robl, J. A. Synthesis 1991, 56–58. 78 Cappelli, A.; Gallelli, A.; Manini, M.; Anzini, M.; Mennuni, L.; Makovec, F.; Menziani, M. C.; Alcaro, S.; Ortuso, F.; Vomero, S. Journal of Medicinal Chemistry 2005, 48, 3564–3575. 79 Duan, S.; Place, D.; Perfect, H. H.; Ide, N. D.; Maloney, M.; Sutherland, K.; Price Wiglesworth, K. E.; Wang, K.; Olivier, M.; Kong, F.; Leeman, K.; Blunt, J.; Draper, J.; McAuliffe, M.; O’Sullivan, M.; Lynch, D. Organic Process Research & Development 2016, 20, 1191–1202.

641

642

13 Synthesis of Common Aromatic Heterocycles

Me

Me CO2H

N N

Cl

N

Ac2O NMP

NH

Cl

N

N

O

81%

13.16.4

Oxidation of a Quinoline

Oxidation of a quinoline is a very good method for the preparation of quinolinones, especially when the required starting quinoline is readily available. A quinoline can be oxidized to its N-oxide and rearranged to the quinolinone upon treatment with tosyl chloride.80 Alternatively, a quinoline can be quaternized and oxidized with an oxidant such as KMnO4 .81 (i) MeReO3 H2O2

Br

Br N H

(ii) TsCl

N

81%

O

(i) MeI N Me

(ii) KMnO4

N

73%

O

13.17 Isoquinolines Several methods are available for the preparation of isoquinolines. Electrophilic aromatic cyclization of an amide is the most common method to access this heterocycle. If the desired isoquinoline is a synthetic intermediate that will be further elaborated at the 1-position, chlorination of the corresponding quinolinone is often the best choice.82 13.17.1

Intramolecular Cyclization of Imidoyl Chlorides

The method of choice to prepare dihydroisoquinolines is the Bischler–Napieralski reaction, where an amide is treated with a dehydrating agent such as POCl3 to induce cyclization. Electron-rich arenes cyclize readily.83 This ring system can also be obtained through elimination of an ether that is sometimes referred to as the Pictet–Gams reaction.84 O MeO

O

MeO

MeO CF3 HN

Me O

80 81 82 83 84

99%

NHCHO

MeO

MeO

POCl3 CH3CN

POCl3 CH3CN

MeO

81%

MeO

O MeO

O N

MeO

MeO CF3 N Me

CF3

KOH i-PrOH

MeO

85%

MeO

N Me

Payack, J. F.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. The Journal of Organic Chemistry 2005, 70, 175–178. Venkov, A. P.; Statkova-Abeghe, S. M. Tetrahedron 1996, 52, 1451–1460. Tucker, S. C.; Brown, J. M.; Oakes, J.; Thornthwaite, D. Tetrahedron 2001, 57, 2545–2554. Geen, G. R.; Mann, I. S.; Mullane, M. V.; McKillop, A. Tetrahedron 1998, 54, 9875–9894. Poszavacz, L.; Simig, G. Tetrahedron 2001, 57, 8573–8580.

13.18 Isoquinolinones

13.17.2

Intramolecular Cyclization of an Oxonium Ion

Another electrophilic cyclization that leads to an isoquinoline is the formation of a benzylic imine containing an oxonium ion precursor at the β-position. While this sequence is attractive due to the availability of the starting materials, it is unfortunately often low-yielding.85 Cl

OMe

+ MeO

Cl

H2SO4

NH2

49%

Cl

N

Cl

CHO

13.17.3

Condensation of Phenacyl Derivatives with Ammonia

Condensation of ammonia with a putative 1,5-dicarbonyl compound will generate an imine that tautomerizes to an enamine and undergoes intramolecular cyclization to the isoquinoline.86 The disadvantage of this method is that the requisite starting material is not always easily accessible. NH4OH NH4OAc

N

N Bu

>82% O

Bu

13.18 Isoquinolinones There are much fewer attractive methods to prepare isoquinolinones than quinolinones. Two methods are presented below. 13.18.1

Benzamide Imine Condensation

A practical method for the preparation of isoquinolinones is the base-mediated cyclization shown below. The advantage of the method is that the starting material can easily be obtained from an ortho-methyl benzamide derivative. Condensation with DMF⋅DMA, followed by base-mediated cyclization and elimination of dimethylamine provides the target isoquinolinone.87 Me

NMe2

N F

O

13.18.2

t-BuOK NH

THF 94%

F

O

Amide Cyclization

Another method for the preparation of an isoquinolinone is the cyclization of an amide on an aldehyde surrogate. In the example below, the carboxamide is generated in situ from an ester and cyclizes on an enamine obtained from a Heck reaction.88

85 Briet, N.; Brookes, M. H.; Davenport, R. J.; Galvin, F. C. A.; Gilbert, P. J.; Mack, S. R.; Sabin, V. Tetrahedron 2002, 58, 5761–5766. 86 Flippin, L. A.; Muchowski, J. M. The Journal of Organic Chemistry 1993, 58, 2631–2632. 87 Zhao, X.; Xin, M.; Huang, W.; Ren, Y.; Jin, Q.; Tang, F.; Jiang, H.; Wang, Y.; Yang, J.; Mo, S.; Xiang, H. Bioorganic & Medicinal Chemistry 2015, 23, 348–364. 88 Song, Z. J.; Tellers, D. M.; Dormer, P. G.; Zewge, D.; Janey, J. M.; Nolting, A.; Steinhuebel, D.; Oliver, S.; Devine, P. N.; Tschaen, D. M. Organic Process Research & Development 2014, 18, 423–430.

643

644

13 Synthesis of Common Aromatic Heterocycles

O MeO

N

Br

CO2Me

O

Formamide

MeO

NaOMe, MeOH 45 psi, 85 °C

Br

NH O

>89%

13.19 Quinolones (4-Hydroxyquinolines) Quinolones are an important class of compounds because of their antimicrobial activity. Fluoroquinolones have especially been targeted as anti-infectives.89 There are three major reliable methods for the preparation of the 4-quinolone nucleus. 13.19.1

Electrophilic Cyclization

One of the oldest methods for the preparation of quinolones is the Gould–Jacobs reaction. In this reaction, an aniline is condensed with diethyl(ethoxymethylene)malonate and cyclized under Friedel–Crafts conditions or elevated temperatures. When the aniline is meta-substituted, regiomeric mixtures may be obtained. One drawback of this method is that the cyclization usually requires forcing conditions.90 The vinylogous amide intermediate can be obtained by condensation of an aniline with a β-ketoester and cyclization under thermal conditions.91 This reaction is also known as the Conrad–Limpach reaction. CO2Et

EtO

NH2

E

CO2Et toluene

OMe

OMe

O

E

N H

100 °C ~50%

E = CO2Et N NH

O Me

13.19.2

OMe

N NH

CO2Et

CO2Et

CaSO4

NH2

CO2Et

POCl3 PPA

N H

EtOH, AcOH

Me

N H

N NH

O

>200 °C 94%

N H

Me

Nucleophilic Aromatic Substitution

A second and very popular method for preparation of quinolones is through a nucleophilic aromatic substitution. Because a leaving group is activated by the presence of the ketone at the ortho-position, a facile SN Ar usually occurs. This has been the method of choice for the production of fluoroquinolones, since the additional fluorine atoms further activate the system toward cyclization.92

O F F

CO2Et F

O

F

N H

Ar

DBU, LiCl NMP

F

N

35 °C >93%

CO2Et

F

N H2N F

89 Radl, S.; Bouzard, D. Heterocycles 1992, 34, 2143–2177. 90 See Note 72. 91 Moyer, M. P.; Weber, F. H.; Gross, J. L. Journal of Medicinal Chemistry 1992, 35, 4595–4601. 92 Barnes, D. M.; Christesen, A. C.; Engstrom, K. M.; Haight, A. R.; Hsu, M. C.; Lee, E. C.; Peterson, M. J.; Plata, D. J.; Raje, P. S.; Stoner, E. J.; Tedrow, J. S.; Wagaw, S. Organic Process Research & Development 2006, 10, 803–807.

13.20 Pyrimidines and Pyrimidones

13.19.3

Intramolecular Claisen Ring Closure

A third method for the preparation of 4-quinolones is through a condensation of a ketone enolate with an amide followed by dehydration.93 This method is not as popular as it requires the preparation of a more elaborate substrate. O

O NaOH

N Cbz N H O

N Cbz

EtOH

Ar

N H

>75%

Ar

13.20 Pyrimidines and Pyrimidones The pyrimidine ring system is a very prevalent heterocycle. It has been utilized in pharmaceutical agents as antifungals (voriconazole), in neuroscience (buspirone), and in oncology (imatinib). This heterocycle is usually obtained by condensation of an amidine with either a 1,3-dicarbonyl compound or a Michael acceptor. Me N

N N N

N

N N

HO

N

O

N

N

N F

Me

F

F

13.20.1

N

N

HN

O

Voriconazole (Vfend)

N N

O

Me

Buspirone (Buspar)

H N

Buspirone (Buspar)

Condensation of Amidines with 1,3-Dicarbonyl Derivatives

The most common method for preparation of pyrimidines is the reaction of an amidine with a 1,3-dicarbonyl derivative, also known as the Pinner pyrimidine synthesis. The reaction is very general. When a β-ketoester is used, the 2-hydroxypyrimidine (pyrimidone) is obtained,94 while the 2-amino derivative is the product when starting from a β-cyanoester.95 The sodium salt of an aldehyde enolate is also an effective coupling partner.96 In some cases, addition of a Lewis acid has proven to be beneficial.97

·HCl

NH Et F3C

CO2Et O

Ph

NH2

NaOAc, xylenes 135 °C 44% NH

CN CO2Et CO2Et

Me

OH Et F3C

N N

· HCl

NH2

NH2

MeONa, MeOH 48%

Ph

N O CO2Me

N H

Me

93 Willemsens, B.; Vervest, I.; Ormerod, D.; Aelterman, W.; Fannes, C.; Mertens, N.; Marko, I. E.; Lemaire, S. Organic Process Research & Development 2006, 10, 1275–1281. 94 Tice, C. M.; Bryman, L. M. Tetrahedron 2001, 57, 2689–2700. 95 Taylor, E. C.; Gillespie, P. The Journal of Organic Chemistry 1992, 57, 5757–5761. 96 Zhichkin, P.; Fairfax, D. J.; Eisenbeis, S. A. Synthesis 2002, 720–722. 97 Letinois, U.; Schutz, J.; Harter, R.; Stoll, R.; Huffschmidt, F.; Bonrath, W.; Karge, R. Organic Process Research & Development 2013, 17, 427–431.

645

646

13 Synthesis of Common Aromatic Heterocycles

NH

OMe CO2Me

MeO

· HCl

NH2

Me

DMF

ONa

CO2Me

N Me

N

74% NH OHC

CN

N H

CO2Me

N

ZnCl 2 iPrOH, toluene 83%

ONa

13.20.2

· HCl

NH2

Me

Me

N

Condensation of Amidines with Michael Acceptors

Another popular method for the preparation of pyrimidines is the reaction of an amidine with a Michael acceptor. Vinylogous amides can be used as the electrophile for this transformation.98,99 In the last example, the authors describe multiple approaches that have been used for the preparation of the pyrimidine on a large scale.100 NH

O SO2Ph

Me

· AcOH

NH2

Me

THF

NMe2

SO2Ph

N Me

Me

N

80% NH

Me2N

NMe2 N O

·HCl

N R

88% CN NMe2

NH Me

· HCl

N

N R

NH2

NH2

MeONa, MeOH

N

N

EtONa, EtO H

O

NC

NH2 Me Me

CN

N Me

N

90%

13.20.3

Cyclization of Cyano Amides

Another approach for the synthesis of a 4-chloropyrimidine is the intramoleculare cyclization of a nitrile ortho-substituted by an amide through the use of phosphorous pentachloride. While the reaction conditions for this cyclization are somewhat harsh, the ease of preparation of the starting material is appealing for this pyriminine synthesis. The resulting product contains a chloride at the 4-position.101

98 See Note 25. 99 Reiter, L. A. The Journal of Organic Chemistry 1984, 49, 3494–3498. 100 Zhao, L.; Ma, X.-D.; Chen, F.-E. Organic Process Research & Development 2012, 16, 57–60. 101 Storz, T.; Heid, R.; Zeldis, J.; Hoagland, S. M.; Rapisardi, V.; Hollywood, S.; Morton, G. Organic Process Research & Development 2011, 15, 918–924.

13.21 Quinazolines and Quinazolinones

CN N

N

Cl O

N H

PCl 5 (4 equiv)

NO2

CF3

N

Sulfolane 120 °C 90%

N N

N

CF3

NO2

13.21 Quinazolines and Quinazolinones Quinazolines have been prepared in a number of different ways and remain a highly studied heterocycle, especially since they often mimic purines as a pharmacophore. They comprise the main structural component of the “zosin” class of pharmaceutical agents for the treatment of the signs and symptoms of benign prostatic hyperplegia (BPH). 4-Aminoquinazoline derivatives such as erlotinib and gefitinib have also been used extensively as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the treatment of cancer. Most of the methods for the preparation of this ring system begin from an anthranilic acid. O MeO MeO

O

N

N

O

N

O

N N

MeO HN

HN

Cl F

Erlotinib (Tarceva)

13.21.1

Gefitinib (Iressa)

Derivatization of Anthranilic Acids

Several reagents are used for the direct conversion of an anthranilic acid to a quinazolinedione. The use of sodium or potassium cyanate under pH control is an excellent way to obtain the desired heterocycle.102 Another commonly employed reagent is urea, although its use usually requires higher reaction temperatures.103 Cl

NH2 CO2H

NaNCO NaOH pH 6– 7

H N

Cl

NH

94%

O

O NH2 I

CO2H

H2N

H N

NH2

160 °C

O NH

I

96%

13.21.2

O

O

Reaction of Benzonitriles

One of the few methods to access a 2,4-disubstituted quinazoline in a single step is the addition of a Grignard reagent to a 2-aminobenzonitrile. This provides an imine intermediate that can react with an acid chloride to afford the desired quinazoline upon condensation.104 A useful method for the direct preparation of a substituted 4-aminoquinazoline is the addition of an aniline to a benzonitrile.105 102 Goto, S.; Tsuboi, H.; Kanoda, M.; Mukai, K.; Kagara, K. Organic Process Research & Development 2003, 7, 700–706. 103 Lee, A. H. F.; Kool, E. T. The Journal of Organic Chemistry 2005, 70, 132–140. 104 Bergman, J.; Brynolf, A.; Elman, B.; Vuorinen, E. Tetrahedron 1986, 42, 3697–3706. 105 Wissner, A.; Floyd, M. B.; Johnson, B. D.; Fraser, H.; Ingalls, C.; Nittoli, T.; Dushin, R. G.; Discafani, C.; Nilakantan, R.; Marini, J.; Ravi, M.; Cheung, K.; Tan, X.; Musto, S.; Annable, T.; Siegel, M. M.; Loganzo, F. Journal of Medicinal Chemistry 2005, 48, 7560–7581.

647

648

13 Synthesis of Common Aromatic Heterocycles

O

MeO

N

MeO

NH2

(i) PhMgBr (ii) PhCOCl (iii) NH4Cl

N

CN

80%

Ph

NMe2

N

H2N

OMe

MeO

Cl

CN

RO

N N

MeO HN

AcOH 99%

13.21.3

Ph

MeO

OMe Cl

Intramolecular Condensations

A quinazoline can be accessed from a ortho-aminobenzamide derivate by acylation followed by cyclization under basic conditions. In the example below, the condensation proceeds without loss of stereochemical integrity on the acylated sidechain.106 OH

OAc

H N

O CONH2

13.21.4

N

aq KOH

Me

Me NH

80 °C 81%

O

Electrophilic Aromatic Substitution

A method far less utilized for the preparation of a quinazoline is via electrophilic aromatic substitution. However, this method can be advantageous for electron-rich arene substrates, especially in light of the fact that the starting N-acylurea may be obtained by reaction of an isocyanate with an amide.107 H N

MeO

H N O

Me O

OMe

PPA

MeO

H N

O N

93%

OMe Me

13.22 Pyrazines and Quinoxalines Pyrazines and quinoxalines have been used extensively in the pharmaceutical industry. Two important examples of this class of compounds are eszopiclone for the treatment of insomnia and varenicline as an aid for smoking cessation. O

N

N

N

Cl

N O

N

N Me

Eszopicline (Lunesta)

N NH N Varenicline (Chantix)

106 Bergman, J.; Brynolf, A. Tetrahedron 1990, 46, 1295–1310. 107 Bandurco, V. T.; Schwender, C. F.; Bell, S. C.; Combs, D. W.; Kanojia, R. M.; Levine, S. D.; Mulvey, D. M.; Appollina, M. A.; Reed, M. S. et al. Journal of Medicinal Chemistry 1987, 30, 1421–1426.

13.22 Pyrazines and Quinoxalines

13.22.1

Condensation of Dianilines

The most reliable method for the preparation of quinoxaline is the condensation of a dianiline with a 1,2-dicarbonyl compound. When one of the carbonyls is at a higher oxidation state, a quinoxalinone is obtained.108 For the unsubstituted quinoxalines, aqueous glyoxal is generally utilized,109 but other glyoxal equivalents have also been employed.110 For the preparation of pyrazines using 1,2-diaminoethane, an additional oxidation step is necessary after the ring forming reaction.111 NH2 OMe O

NH2

CO2Me

N

MeOH 94%

Br Me NH2 Br

NH2

NH2

N H

NaHCO3 EtOH, H 2O 92% O

OH

O

OH

O

OBn

Me

aq OHC CHO

NH2

N Br

N

N N

EtOH 95%

1) EtOH

N N

N

Br

N

NH2

O

H2N

O

2) Chloranil

N N

N

N

71%

13.22.2

Condensation of Dicarbonyl Derivatives with Ammonia

An excellent method for the preparation of 2-hydroxypyrazine is the condensation of a 1,5-dicarbonyl compound with an ammonia source. The substrate is easily obtained by an amide coupling of an α-ketoacid with an α-aminoketone.112 O

Me Me

O

N H

Ph O

NH4OAc EtOH >67%

O Me Me

H N N

Ph

108 Willardsen, J. A.; Dudley, D. A.; Cody, W. L.; Chi, L.; McClanahan, T. B.; Mertz, T. E.; Potoczak, R. E.; Narasimhan, L. S.; Holland, D. R.; Rapundalo, S. T.; Edmunds, J. J. Journal of Medicinal Chemistry 2004, 47, 4089–4099. 109 Marterer, W.; Prikoszovich, W.; Wiss, J.; Prashad, M. Organic Process Research & Development 2003, 7, 318–323. 110 Venuti, M. C. Synthesis 1982, 61–63. 111 Heirtzler, F. R. Synlett 1999, 1203–1206. 112 Roberts, D. A.; Bradbury, R. H.; Brown, D.; Faull, A.; Griffiths, D.; Major, J. S.; Oldham, A. A.; Pearce, R. J.; Ratcliffe, A. H. et al. Journal of Medicinal Chemistry 1990, 33, 2326–2334.

649

650

13 Synthesis of Common Aromatic Heterocycles

13.23 Pyridazines, Phtalazines, and Cinnolines There are limited synthetic methods for the preparation of pyridazines, phtalazines, and cinnolines. The preferred method for the preparation of pyridazines and phtalazines is the condensation of a hydrazine with a dicarbonyl. For the preparation of cinnolines, the starting material is generally an aniline that is further derivatized. 13.23.1

Addition of Hydrazine to Dicarbonyl Derivatives

The preferred method for the synthesis of pyridazines and phtalazines is the reaction of a hydrazine, with a dicarbonyl compound. The oxidation state of the dicarbonyl dictates if residual substituents are positioned on the product. In the three examples below, the syntheses of a disubstituted,113 monosubstituted,114 and unsubstituted115 heterocycle are demonstrated. O O

S

N

N

Me

N

N2H4 aq

82%

Me OH

O N2H4 aq

t-B u N

CO2t-B u HN CO2t-B u N

CF3

CO2Me

PrO

13.23.2

N O

O

S

H 2O

HO

H N

Cl

N N

AcOH

Cl

>73% F

OHC

N

OHC

N H

F

F N

HBr, AcOH EtOAc 76%

CF3 PrO

N

F N

N CO2Me

N O

Addition to a Diazo Derivative

An elegant method for the preparation of cinnolines is the intramolecular addition of an enolate to a diazo compound prepared in situ from the corresponding aniline.116 This approach also offers the advantage that the starting material is readily prepared. O MeO MeO

Me NH2

NaNO2 HCl H2O 71%

OH MeO MeO

N

N

113 Mennen, S. M.; Mak-Jurkauskas, M. L.; Bio, M. M.; Hollis, L. S.; Nadeau, K. A.; Clausen, A. M.; Hansen, K. B. Organic Process Research & Development 2015, 19, 884–891. 114 Thiel, O. R.; Achmatowicz, M.; Bernard, C.; Wheeler, P.; Savarin, C.; Correll, T. L.; Kasparian, A.; Allgeier, A.; Bartberger, M. D.; Tan, H.; Larsen, R. D. Organic Process Research & Development 2009, 13, 230–241. 115 Bowman, R. K.; Brown, A. D.; Cobb, J. H.; Eaddy, J. F.; Hatcher, M. A.; Leivers, M. R.; Miller, J. F.; Mitchell, M. B.; Patterson, D. E.; Toczko, M. A.; Xie, S. The Journal of Organic Chemistry 2013, 78, 11680–11690. 116 Hu, E.; Ma, J.; Biorn, C.; Lester-Zeiner, D.; Cho, R.; Rumfelt, S.; Kunz, R. K.; Nixey, T.; Michelsen, K.; Miller, S.; Shi, J.; Wong, J.; Hill Della Puppa, G.; Able, J.; Talreja, S.; Hwang, D.-R.; Hitchcock, S. A.; Porter, A.; Immke, D.; Allen, J. R.; Treanor, J.; Chen, H. Journal of Medicinal Chemistry 2012, 55, 4776–4787.

13.24 1,2,4-Triazines

13.23.3

Electrophilic Aromatic Substitution

Cinnolines have also been prepared through an intramolecular electrophilic aromatic substitution. An acylated hydrazone reacts in the presence of a Lewis acid at elevated temperature to generate the desired heterocycle.117 NH2

N

Br

CONH2 N H

N

CONH2

AlCl3 PhCl 115 °C 77%

N

N

Br

13.24 1,2,4-Triazines 1,2,4-Triazines have had a limited use until recently as they have been identified aspotential kinase inhibitors. While 1,3,5-triazines generally arise from derivatization of a barbituric acid compound, a few methods have proven effective for the preparation of 1,2,4-triazines through formation of the ring containing the nitrogen atoms. 13.24.1

Reaction of Amidrazones with Glyoxal Derivatives

An efficient method to access 1,2,4-triazines is the condensation of an amidrazone with a ketoaldehyde.118 O

NH N H Cl

13.24.2

NH2

Ph

Ph

N CHO

EtOH, reflux 64%

N

N

Cl

Reaction of Nitroanilines with Cyanamide

The most common method for the preparation of a benzotriazine is the reaction between cyanamide and an ortho-nitroaniline.119 As mentioned in the experimental section, precaution is necessary in this reaction due to a very exothermic reaction. Me

NO2

(i) NH2CN conc. HCl

Me

NH2

(ii) NaOH aq

Me

O– + N N

Me

N

97%

13.24.3

NH2

Reaction of Aminopyrroles

For the preparation of pyrrolotriazine, the preferred synthetic method is the use of an aminopyrrole with an electrophile containing a nitrogen atom to generate the second ring through condensation with an ester.120,121

117 Smith, C. R.; Dougan, D. R.; Komandla, M.; Kanouni, T.; Knight, B.; Lawson, J. D.; Sabat, M.; Taylor, E. R.; Vu, P.; Wyrick, C. Journal of Medicinal Chemistry 2015, 58, 5437–5444. 118 O’Rourke, M.; Lang, S. A., Jr.; Cohen, E. Journal of Medicinal Chemistry 1977, 20, 723–726. 119 Pchalek, K.; Hay, M. P. The Journal of Organic Chemistry 2006, 71, 6530–6535. 120 Shi, Z.; Kiau, S.; Lobben, P.; Hynes, J.; Wu, H.; Parlanti, L.; Discordia, R.; Doubleday, W. W.; Leftheris, K.; Dyckman, A. J.; Wrobleski, S. T.; Dambalas, K.; Tummala, S.; Leung, S.; Lo, E. Organic Process Research & Development 2012, 16, 1618–1625. 121 Zheng, B.; Conlon, D. A.; Corbett, R. M.; Chau, M.; Hsieh, D.-M.; Yeboah, A.; Hsieh, D.; Müslehiddino˘glu, J.; Gallagher, W. P.; Simon, J. N.; Burt, J. Organic Process Research & Development 2012, 16, 1846–1853.

651

652

13 Synthesis of Common Aromatic Heterocycles

EtO2C

Me

HCONH2 H3PO4 120 °C

CO2Et N NH2

N

EtO2C

N

N

79%

CO2Et

OH

Me

NH2 •AcOH

HN

CO2Et N NH2

OH

Me

N

EtO2C

Et 3N, i-PrOH

N

N

92%

13.25 Furans and Benzofurans Furans and benzofurans have been used extensively as synthetic intermediates and also as pharmaceutical targets in antibiotics such as ceftiofur. Most of the syntheses of furans start from either a 1,3- or 1,4-dicarbonyl compound. In the case of benzofurans, metal-mediated approaches have gained widespread use in recent years. H2N S

N N MeO

H N

H

O

S

O

N

O

S CO2H

O

Ceftiofur (Excenel)

13.25.1

Condensation of 1,3-Dicarbonyls with an 𝛂-Halocarbonyl

A well-precedented method for the synthesis of furans is the condensation of a 1,3-dicarbonyl compound with a α-halocarbonyl compound, known as the Feist–Bénary reaction. The resulting 1,3-dicarbonyl intermediate possesses a leaving group that undergoes cyclization to provide the furan. The advantage of this method is the wide availability of the two key starting materials. This method always affords a 3-acyl furan analog.122 A variation of this method uses an α-hydroxyaldehyde, such as glyceraldehyde, in place of the haloaldehyde.123 O

O Cl O

CHO

NaOH, KI H2O 58%

HO

O

O

CHO

MeO2C

OH

Me CO2Me

DMF, 90 °C

OH O

>84%

122 Zambias, R. A.; Caldwell, C. G.; Kopka, I. E.; Hammond, M. L. The Journal of Organic Chemistry 1988, 53, 4135–4137. 123 Toro, A.; Deslongchamps, P. Synthetic Communications 1999, 29, 2317–2321.

13.26 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone

13.25.2

Cyclodehydration of a 1,4-Dicarbonyl Compound

Another proven method is the Paal–Knorr furan synthesis that is analogous to the better-known Paal–Knorr pyrrole synthesis. In this case, a 1,4-dicarbonyl is treated under acidic conditions to induce cyclodehydration. One of the disadvantages of this method is that the starting material is not as easily accessible as for the previous method, but it allows for the preparation of furans that do not contain a 3-acyl group.124 MeOH HCl

O

MeO2C

13.25.3

HO

70%

O

HO

MeO2C O

Dehydration

A hydroxydihydrofuran can easily be dehydrated to the furan. This has been accomplished from an aldol adduct with sulfuric acid125 or from the product of an organometallic reagent addition to a ketone with p-TsOH.126 O Br

O O

O

MeO

13.25.4

O

CO2Et

OH CO2H

K 2CO3, i-PrO H

CO2H

H2SO4, H2O O

52%

O OH

CH2CHCH2MgBr CeCl 3, THF

O

O

p-TsOH MeO

O

72%

O

MeO

Metal-Mediated Cyclization

Another method for the preparation of benzofurans is the cyclization of a phenol onto an alkyne. One attractive feature of this process is that a readily available ortho-halophenol can be utilized in a tandem Sonogashira coupling and furan formation under the same reaction conditions.127 HO NC

PdCl 2(PPh 3)2, CuI I OH

NC

HO

i-Pr 2NH, i-PrOAc 85%

O

13.26 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone The benzopyran-4-one heterocycle is abundant in natural products and has been studied for medicinal properties. It is most often prepared by intramolecular cyclization of a phenol.

124 Effland, R. C. Journal of Medicinal Chemistry 1977, 20, 1703–1705. 125 Ragan, J. A.; Murry, J. A.; Castaldi, M. J.; Conrad, A. K.; Jones, B. P.; Li, B.; Makowski, T. W.; McDermott, R.; Sitter, B. J.; White, T. D.; Young, G. R. Organic Process Research & Development 2001, 5, 498–507. 126 Ohno, M.; Miyamoto, M.; Hoshi, K.; Takeda, T.; Yamada, N.; Ohtake, A. Journal of Medicinal Chemistry 2005, 48, 5279–5294. 127 Pu, Y.-M.; Grieme, T.; Gupta, A.; Plata, D.; Bhatia, A. V.; Cowart, M.; Ku, Y.-Y. Organic Process Research & Development 2005, 9, 45–50.

653

654

13 Synthesis of Common Aromatic Heterocycles

13.26.1

Condensation of ortho-Phenoxy-1,3-dicarbonyl Derivatives

The most reliable method for the synthesis of a benzopyran-4-one is the cyclization of a phenol onto a 1,3-dicarbonyl substituent at the ortho-position, usually under acidic conditions.128 An extension of this methodology is the cyclization onto a vinylogous amide under acidic conditions.129 OH

O Me Me

O

MeOH, HCl THF

N N N N H

13.26.2

N N N N H

>94% O

O

O

Me Me aq H2SO4

NMe2 Me Me

O

OH

88%

O

Me Me

Condensation of ortho-Acylcarbonyl Derivatives

A common method for the preparation of chromen-4-ones is the Kostanecki–Robinson reaction.130 Depending on the substrate, this reaction will sometimes provide mixtures of the chromen-4-one and the coumarin. HO

(i) BF3·Et2O DMAC, 50 °C (ii) MsCl DMAC, 75 °C

OH

O

13.26.3

OH

HO

O

77%

O

Me

OH

Electrophilic Cyclization

The preferred method for the synthesis of xanthones is the electrophilic cyclization of an ortho-aryloxy carboxylic acid in the presence of Eaton’s reagent (phosphorous pentoxide in MsOH). The reaction usually proceeds at room temperature but requires a careful work-up to quench the residual P2 O5 .131 OMe OMe O CO2H

13.26.4

OMe

P2 O5 MsOH 92%

O

OMe

O

OMe OMe

Nucleophilic Aromatic Substitution

If one of the aromatic rings in the xanthone contains an appropriately substituted electron-withdrawing group, a nucleophilic aromatic substitution is an appropriate synthetic strategy for the preparation of these compounds from a diarylketone. The example below is operationally simple and was conducted on 140 g scale.132 128 Geen, G. R.; Giles, R. G.; Grinter, T. J.; Hayler, J. D.; Howie, S. L. B.; Johnson, G.; Mann, I. S.; Novack, V. J.; Oxley, P. W.; Quick, J. K.; Smith, N. Synthetic Communications 1997, 27, 1065–1073. 129 Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Abe, S.; Hida, T.; Higashi, S.; Hishinuma, I.; Yamanaka, T. Journal of Medicinal Chemistry 1995, 38, 3163–3173. 130 Al-Maharik, N. I.; Kaltia, S. A. A.; Mutikainen, I.; Waehaelae, K. The Journal of Organic Chemistry 2000, 65, 2305–2308. 131 Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J., III. The Journal of Organic Chemistry 1998, 63, 6338–6343. 132 Greco, M. N.; Rasmussen, C. R. The Journal of Organic Chemistry 1992, 57, 5532–5535.

13.27 Coumarins

CO2H

OH O

85%

Cl

CO2H Cl

O

aq K2CO3

Cl

O

13.27 Coumarins Coumarins are a very well-known class of natural products and pharmaceutical agents. This class of compounds (e.g. warfarin) are commonly used anticoagulants and have been on the market in the US since 1954. The best method for their preparation is an intramolecular condensation. O

O Me

OH

Ph

O

Warfarin (Coumadin)

13.27.1

Condensation of ortho-Acylcarbonyl Derivatives

The best method for preparation of coumarins is the Perkin reaction or its modifications. The reaction proceeds by acylation of a phenol to provide an enolizable ester, which condenses with an ortho-carbonyl substituent. The acylation can be accomplished using standard conditions with an acid chloride133 or an anhydride.134 This reaction can also lead to the chromen-4-one, especially for unactivated esters with a higher pK a . PhCH 2COCl K 2CO3 acetone

O H

OMe

O HO2C

OH

HO

13.27.2

O

90%

OH

Me +

Ph

Ac 2O, Et 3N 148 °C

OMe

Me

77%

OMe

O

HO

O

O

OMe

Arylation of Bromobenzoic Acid Derivatives

Another method to access a coumarin is through a copper-catalyzed arylation of a bromobenzoic acid known as the Hurtley reaction. The product of the cross-coupling is a phenoxyacid that cyclizes to provide the coumarin.135 HO

OH HO

CO2H

O

O

Br NHAc

CuI, Na2CO3 H2O

NHAc

77%

133 Rao, P. P.; Srimannarayana, G. Synthesis 1981, 887–888. 134 Li, X.; Jain, N.; Russell, R. K.; Ma, R.; Branum, S.; Xu, J.; Sui, Z. Organic Process Research & Development 2006, 10, 354–360. 135 Kudo, K.; Yamamoto, N. Organic Process Research & Development 2015, 19, 309–314.

655

656

13 Synthesis of Common Aromatic Heterocycles

13.28 Thiophenes and Benzothiophenes Thiophenes and benzothiophenes have been studied extensively as pharmaceutical agents and have proven to be an important pharmacophore in several therapeutic areas. Examples of this class of compounds are clopidogrel (anticoagulant), duloxetine (antidepressive), olanzapine (antipsychotic), raloxifene (treatment and prevention of osteoporosis), and tiotropium (management of chronic obstructive pulmonary disease or COPD). All reliable methods usually involve a cyclodehydration. O

N N Cl

MeHN N

S

Clopidogrel (Plavix)

O

N HO

S

CO2H

13.28.1

N

O

Me

N H

Duloxetine (Cymbalta)

S

S

Me

Olanzapine (Zyprexa)

OH Raloxifene (Evista)

Aldol Condensation

The preferred method to prepare a benzothiophene is from an α-halobenzaldehyde and a thioglycollic acid derivative under basic conditions.136,137 While the product of the reaction contains a carboxylic acid, it can readily be decarboxylated to yield the benzothiophene. Boc N

HS

N CHO

DMF 105 °C

Boc N N

78%

Cl Cl CHO Cl

CO2H NaOH

HS

CO2H NaOH

DME, H2O reflux

S

CO2H

Cl

S

CO2H

78%

13.28.2

Knoevenagel Condensation

Thiophenes and benzothiophenes can be obtained by Knoevenagel condensation of an enolate with a carbonyl compound under acidic138 or basic139 conditions. The starting material can be easily obtained and the reaction usually proceeds in high yield. In some cases, the desired substrate can be generated in situ.140 A limitation on the scope of this approach is its specificity to the formation of 2-acylthiophenes. 136 Wu, C.; Chen, W.; Jiang, D.; Jiang, X.; Shen, J. Organic Process Research & Development 2015, 19, 555–558. 137 Miyake, M.; Shimizu, M.; Tsuji, K.; Ikeda, K. Organic Process Research & Development 2016, 20, 86–89. 138 LaLonde, R. T.; Florence, R. A.; Horenstein, B. A.; Fritz, R. C.; Silveira, L.; Clardy, J.; Krishnan, B. S. The Journal of Organic Chemistry 1985, 50, 85–91. 139 Hsiao, C. N.; Bhagavatula, L.; Pariza, R. J. Synthetic Communications 1990, 20, 1687–1695. 140 Huang, Q.; Richardson, P. F.; Sach, N. W.; Zhu, J.; Liu, K. K. C.; Smith, G. L.; Bowles, D. M. Organic Process Research & Development 2011, 15, 556–564.

13.29 Isoxazoles and Benzisoxazoles

Ph

S CHO

Me

AcOH 120 °C

Ph Me

Ph

99%

O

Ph S

O

SO3·pyr DMSO

OH S

HS

CN

MeS

CO2Et

NC

Et 3N EtOH

SMe

13.28.3

S

79%

O

NC

Me

Et 3N, CH2Cl 2

Me

MeS

67%

O

NH2 CO2Et

S

Cyclodehydration of 1,4-Dicarbonyl Derivatives

Thiophenes and benzothiophenes can be obtained by cyclodehydration of 1,4-dicarbonyl compounds in the presence of a sulfur source.141 N NH O

O O

13.28.4

SMe

N

P2 S5 pyridine

N O

79%

S

N

N SMe

Nucleophilic Addition to Sulfur Followed by Cyclocondensation

A very efficient method for the preparation of 2-aminothiophene is the Gewald reaction in which an anion is generated and trapped with elemental sulfur. The resulting thiolate provides the desired aminothiophene upon condensation on the nitrile.142 O2 N

NaHCO3 S8 THF, H2O

CN

CN

80%

CN

Me

O2N

S

NH2

13.29 Isoxazoles and Benzisoxazoles Isoxazoles and benzisoxazoles are a common class of compounds in the pharmaceutical industry. They have been used extensively as sidechains for a number ofβ-lactams (oxacillin), and in agents for the treatment of schizophrenia (risperidone) and inflamation (leflunomide). Several methods exist for their preparation, but the most common is the condensation of hydroxylamine with a 1,3-dicarbonyl or Michael acceptor. O Me

N

Ph H N O O

H

S

N

F3C Me Me

CO2H

Oxacillin (Bactocill)

O N H

Me Leflunomide (Arava)

N O

141 Ibrahim, Y. A.; Al-Saleh, B.; Mahmoud, A. A. A. Tetrahedron 2003, 59, 8489–8498. 142 Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.; Tedrow, J. S.; Dalla Riva Toma, J. Tetrahedron 2006, 62, 11311–11319.

657

658

13 Synthesis of Common Aromatic Heterocycles

13.29.1

Hydroxylamine Addition to 1,3-Dicarbonyl Derivatives/Enaminoketones

Condensation of hydroxylamine to a 1,3-dicarbonyl compound or a Michael acceptor containing a β-leaving group is a common way to prepare isoxazoles. This method is especially useful for symmetrical 1,3-diketones143 substrates with a clear regiochemical preference for the amine addition.144 Unsymmetrical 1,3-diketones typically yield a mixture of regioisomers unless one of the carbonyls is converted to an enaminoketone to induce regioselectivity.145 O

Cl

O

O

Cl

88%

Me

N O Ph

93% NH2OH·HCl

NH2 O

Cl

Me

N O

DMF

MeO2C

OC5H11

96%

OC5H11

13.29.2

N O Cl

NH2OH·HCl THF

O

Ph

NH2OH·H2SO4 AcOH

MeO2C

Alkylation of Dihalides

Alkylation of a dihalide, which arose from halogenation of an alkene, with hydroxyurea provides an oxazole under mild basic conditions.146 HO Br CO2Me

MeO2C

NH2

O t-BuOK MeOH

Br

13.29.3

H N

O N MeO2C

OH

66%

Dipolar Cycloaddition

The reaction of a nitrone147 or hydroximoyl halide148 with an acetylene is a method for the rapid and highly convergent preparation of highly substituted isoxazoles. However, the yield and regioselectivity can vary greatly depending on the substrate, and this method requires starting materials that may not be readily available. Me

Me

+ O– N Me

Me CO2H THF, reflux 2 days 100%

Me

Me

N O

Me

Me

CO2H

143 Mashraqui, S. H.; Keehn, P. M. The Journal of Organic Chemistry 1983, 48, 1341–1344. 144 Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Organic Process Research & Development 2004, 8, 28–32. 145 Ohigashi, A.; Kanda, A.; Tsuboi, H.; Hashimoto, N. Organic Process Research & Development 2005, 9, 179–184. 146 Zhang, W.-Y.; Hogan, P. C.; Chen, C.-L.; Niu, J.; Wang, Z.; Lafrance, D.; Gilicky, O.; Dunwoody, N.; Ronn, M. Organic Process Research & Development 2015, 19, 1784–1795. 147 Lee, C. K. Y.; Herlt, A. J.; Simpson, G. W.; Willis, A. C.; Easton, C. J. The Journal of Organic Chemistry 2006, 71, 3221–3231. 148 Yao, C.-F.; Kao, K.-H.; Liu, J.-T.; Chu, C.-M.; Wang, Y.; Chen, W.-C.; Lin, Y.-M.; Lin, W.-W.; Yan, M.-C.; Liu, J.-Y.; Chuang, M.-C.; Shiue, J.-L. Tetrahedron 1998, 54, 791–822.

13.30 Oxazoles and Benzoxazoles

S

N

Me

Ph

Ph

Cl

Et 3N, CH2Cl2

OH

Me

13.29.4

N

S

92%

Me

O

Me

Nucleophilic Aromatic Substitution

Benzisoxazoles have been prepared by intramolecular nucleophilic aromatic substitution. A carbonyl compound is treated with hydroxylamine to provide an oxime that undergoes cyclization.149 For this reaction to be productive when the substrate is not symmetrical, the Z-isomer of the oxime must be able to isomerize to the E-isomer, which undergoes cyclization.150 O

F

N H

KOH

OH

F

OH

H2O

F

O

70%

N

N HN N F

THF

OH

N

HN

t-BuOK

O

69%

N

13.30 Oxazoles and Benzoxazoles Oxazoles and benzoxazoles are a common class of compounds in the pharmaceutical industry. Oxaprozin is a nonsteroidal anti-inflammatory from this structural class. Two excellent methods are utilized for their syntheses depending on the desired substitution pattern in the product. Ph Ph

O

CO2H

N

Oxaprizin (Daypro)

13.30.1

Cyclization on an Activated Carbonyl Derivative

The cyclodehydration of an acylated α-aminoketone is the most common method for the preparation of oxazoles. One of the advantages of the method is the ease of preparation of the required starting material. The most common reagent for this preparation is POCl3 , although many other dehydrating agents have been utilized.151 For the preparation of benzothiazole, the starting material of choice is an ortho aminophenol that reacts with a carbonyl derivative.152 O

O N H

Me CO2Bn

Me POCl3 DMF 86%

O

CO2Bn N

149 Widlicka, D. W.; Murray, J. C.; Coffman, K. J.; Xiao, C.; Brodney, M. A.; Rainville, J. P.; Samas, B. Organic Process Research & Development 2016, 20, 233–241. 150 Fink, D. M.; Kurys, B. E. Tetrahedron Letters 1996, 37, 995–998. 151 Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. The Journal of Organic Chemistry 2003, 68, 2623–2632. 152 Baxter, C. A.; Cleator, E.; Brands, K. M. J.; Edwards, J. S.; Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D. J. Organic Process Research & Development 2011, 15, 367–375.

659

660

13 Synthesis of Common Aromatic Heterocycles

Cl

13.30.2

NH2

CSCl2

OH

MeOH, H2O 0 °C 90%

Cl

N

SH

O

Dipolar Cycloaddition

The dipolar cycloaddition of an isonitrile, most commonly tosylmethyl isocyanide (TosMIC), with an aldehyde is a popular method for the preparation of 5-substituted oxazoles. The reaction proceeds in high yield on simple substrates153 as well as on materials that might be sensitive to dehydrating conditions.154

O2 N

CHO

TosMIC K 2CO3

OMe

MeOH

N O O 2N

96%

OMe N

CHO NPr 2

O

TosMIC NaOMe

NPr 2

MeOH 91%

HN

HN

Me TosMIC:

S O O

NC

13.31 Isothiazoles and Benzisothiazoles Isothiazoles and benzisothiazoles are usually prepared through an intramolecular cyclization using a number of different methods. The choice of method usually depends on the ease of preparation of the requisite starting material. An example of this class of compound is ziprasidone, an atypical antipsychotic. Cl

H N

O

N N S N Ziprasidone (Geodon)

13.31.1

Intramolecular Cyclization

An efficient method to generate the isothiazole ring is through an intramolecular cyclization to generate the N—S bond. This method has proven successful under oxidative conditions starting from thioamides in the preparation of 5-aminoisothiazoles.155 This strategy also works in the preparation of benzothiazoles from benzophenone derivatives,156 and isothiazoles from oximes.157 153 Herr, R. J.; Fairfax, D. J.; Meckler, H.; Wilson, J. D. Organic Process Research & Development 2002, 6, 677–681. 154 Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. The Journal of Organic Chemistry 1997, 62, 8634–8639. 155 Etzbach, K. H.; Eilingsfeld, H. Synthesis 1988, 449–452. 156 Dehmlow, H.; Aebi, J. D.; Jolidon, S.; Ji, Y.-H.; Von Mark, E. M.; Himber, J.; Morand, O. H. Journal of Medicinal Chemistry 2003, 46, 3354–3370. 157 Dieter, R. K.; Chang, H. J. The Journal of Organic Chemistry 1989, 54, 1088–1092.

13.32 Thiazoles and Benzothiazoles

O

NH2

HN

S

O

S

NH2

(i) SO2Cl2, CH2Cl2 (ii) NH3, EtOH

MeO HO

N

MeO

SOCl 2, pyr CH2Cl 2

SMe

Et

S N

>73%

Br

SMe

N

80%

Me

13.31.2

N

HN

91%

O H N 2 SBn O

O

H2O2 AcOH

S

Br

SMe Me

Et

Addition to ortho-Thiobenzonitriles

One of the best synthetic methods for the preparation of a 3-aminobenzisothiazole is by addition of an amine to an ortho-thiobenzonitrile. The disulfide is generally used as the thiophenol derivative since it is easily prepared and has a good leaving group embedded in it.158 This strategy is not as efficient for the preparation of carbon derivatives at the 3-position.159 NH

HN CN S

DMSO, i-PrOH 120 °C

S

N

72%

CN

N

H N

CN

MeLi THF

SH

30%

S

N

Me N

S

N

13.32 Thiazoles and Benzothiazoles Thiazoles and benzothiazoles have been studied extensively as pharmaceutical and agrochemical agents. A few methods have proven to be reliable for their preparation, most notably alkylation of thioamide derivatives followed by cyclodehydration. 13.32.1

Condensation of Thioamides with Haloketones

A practical method for the preparation of a thiazole is the condensation of a thioacetamide with a haloketone, which generally proceeds in high yield.160 This reaction also works on more complicated substrates such as thioureas to generate 2,4-diaminothiazoles.161

158 159 160 161

Walinsky, S. W.; Fox, D. E.; Lambert, J. F.; Sinay, T. G. Organic Process Research & Development 1999, 3, 126–130. Chimichi, S.; Giomi, D.; Tedeschi, P. Synthetic Communications 1993, 23, 73–78. Rooney, C. S.; Cochran, D. W.; Ziegler, C.; Cragoe, E. J., Jr.; Williams, H. W. R. The Journal of Organic Chemistry 1984, 49, 2212–2217. Masquelin, T.; Obrecht, D. Tetrahedron 2001, 57, 153–156.

661

662

13 Synthesis of Common Aromatic Heterocycles

O

S Br

H2N

EtOH

Cl

PhHN

F

N H

S

NH2

O Ar S

F

DBU, DMF

N NHPh

99%

13.32.2

SO2NH2

Cl

NH

S Br

S Cl

71%

Cl O

N

SO2NH2

Condensation of Carboxylic Acid Derivatives with 2-Aminothiols

The most common method for preparation of benzothiazoles is the reaction of 2-aminothiols with carboxylic acid derivatives. Reaction with an acid chloride is usually straightforward, and toluene has been demonstrated to be the preferred solvent for the transformation.162 NH2 SH

13.32.3

t-BuCOCl

N

Toluene

S

t-Bu

93%

Nucleophilic Aromatic Substitution

A less commonly used method for preparation of benzothiazoles is an intramolecular nucleophilic aromatic substitution. This method is especially attractive for electron-deficient substrates.163 S

F

NH2

EtO

F

DMF, 95 °C 91%

H N

SK F

S

S

13.33 1,2,4-Oxadiazoles 1,2,4-Oxadiazoles have been common in the pharmaceutical industry. In just about all practical cases, they originate from condensation of a hydroxyurea with a carboxylic acid or derivatives. 13.33.1

Condensation of Hydroxyurea with Carboxylic Acids

When possible, the advantage of using a carboxylic acid directly in the condensation is that it avoids the additional step of derivatization of the acid. In the two examples below, dicyclohexylcarbodiimide (DCC)164 or N,N′ -carbonyldiimidazole (CDI)165 are used to promote the reaction. CDI would be preferable as it is a greener reagent.

162 163 164 165

Rudrawar, S.; Kondaskar, A.; Chakraborti, A. K. Synthesis 2005, 2521–2526. Zhu, L.; Zhang, M. The Journal of Organic Chemistry 2004, 69, 7371–7374. Schmidt, G.; Reber, S.; Bolli, M. H.; Abele, S. Organic Process Research & Development 2012, 16, 595–604. Lukin, K.; Kishore, V.; Gordon, T. Organic Process Research & Development 2013, 17, 666–671.

13.34 1,3,4-Oxadiazoles

Et 2N N Me

·HCl ·H2O

Cl

+

HO

N

Me Me

+

N

N

O N R

N

i-PrO

N R=

13.33.2

Me

Cl

92%

OH

Me

MeCN R

Me

N

N

CDI DBU

NH2 Cl HO

O N

Et 2N

THF 73%

OH

CO2H

i-PrO

DCC Et 3N HOBt

NH2

CO2H

CO2t-Bu

O

Condensation of Hydroxyurea with Carboxylic Acid Derivatives

In many cases, an activated carboxylic acid is utilized as the coupling partner. One possible advantage of this method is when the carboxylic acid has poor solubility. In the first two examples below, an ester166 and an acid chloride167 are used. In the third example, the hydroxyurea is generated from a nitrile, and the 1,2,4-oxadiazole is formed with an anhydride.168 BocHN

CO2Me

+

BocHN

COCl HO N +

N OMe

K2CO3

NH2 HO

Me

N

NH2

OEt

Et R

(ii) Toluene

O

BocHN Et R

N N

Me

MeO

80%

R= O

(i) NH2OH·HCl NaOAc, AcOH (ii) Ac2O, AcOH

Me

N

O N

(i) Et3N CH2Cl2

Me

N

Toluene 93%

O N

BocHN

O

Me Me O

O N Me

N

CO2Et

95%

13.34 1,3,4-Oxadiazoles 1,3,4-Oxadiazoles are not as common as the 1,2,4-oxadiazole counterpart. The preferred synthetic method to their preparation is the dehydration of hydrazide derivative. 13.34.1

Cyclodehydration of Hydrazide

Acylhydrazines will react with a carboxylic acid derivative to generate the hydrazides. Upon activation to an imidoyl chloride, cyclization occurs to provide the desired heterocycle.169,170 166 Copp, R. R.; Abraham, B. D.; Farnham, J. G.; Twose, T. M. Organic Process Research & Development 2011, 15, 1344–1347. 167 Schmidt, G.; Bolli, M. H.; Lescop, C.; Abele, S. Organic Process Research & Development 2016, 20, 1637–1646. 168 Ruck, R. T.; Huffman, M. A.; Stewart, G. W.; Cleator, E.; Kandur, W. A.; Kim, M. M.; Zhao, D. Organic Process Research & Development 2012, 16, 1329–1337. 169 Karlsson, S.; Bergman, R.; Loefberg, C.; Moore, P. R.; Ponten, F.; Tholander, J.; Soerensen, H. Organic Process Research & Development 2015, 19, 2067–2074. 170 Golden, M.; Legg, D.; Milne, D.; Bharadwaj, M, A.; Deepthi, K.; Gopal, M.; Dokka, N.; Nambiar, S.; Ramachandra, P.; Santhosh, U.; Sharma, P.; Sridharan, R.; Sulur, M.; Linderberg, M.; Nilsson, A.; Sohlberg, R.; Kremers, J.; Oliver, S.; Patra, D. Organic Process Research & Development 2016, 20, 675–682.

663

664

13 Synthesis of Common Aromatic Heterocycles

(i) Et3N, anisole O Cl EtO O

O H2N

N H OMe

13.34.2

(ii) SOCl2, anisole

O EtO2C

N

N

O

OMe

67%

Nitrogen Extrusion

A unique method for the preparation of the 1,3,4-oxadizaole is to take advantage of an acylated tetrazole as a starting material. Upon extrusion of nitrogen gas, the oxygen of the acyl group cyclizes to generate the five-membered ring.171 H

Me

N N N N

O

ClCOCO 2Et Et 3N, 0 °C Toluene

Me

N N N N

CO2Et

(i) 70 °C, –N2 (ii) KOH, EtOH Me

N N O

CO2K

91%

171 Humphrey, G. R.; Pye, P. J.; Zhong, Y.-L.; Angelaud, R.; Askin, D.; Belyk, K. M.; Maligres, P. E.; Mancheno, D. E.; Miller, R. A.; Reamer, R. A.; Weissman, S. A. Organic Process Research & Development 2011, 15, 73–83.

665

14 Access to Chirality Angela L. A. Puchlopek-Dermenci and Robert W. Dugger (Retired) Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 665 Using the Chiral Pool, 665 Classical Resolutions, 668 Dynamic Kinetic Resolutions, 673 Desymmetrization of Meso Compounds, 675 Chiral Chromatography, 676

14.1 Introduction Synthesis of optically active compounds, whether natural products or synthetic molecules, is a significant challenge to the synthetic organic chemist.1 Throughout this book are many examples of using chiral reagents, catalysts, and auxiliaries to influence the creation of new chiral centers (hydroboration, hydrogenation, aldol reactions, etc.). In this chapter, we will focus on other methods of obtaining molecules in enantiomerically pure form. It is important to note that often times multiple methods may be applied in combination with one another to achieve the stereochemical purity required in the synthesis of the desired compound. The discussion which follows in this chapter is intended to provide an overview of examples of methods for accessing chirality which either have and/or should be considered when scaling up a process.

14.2 Using the Chiral Pool An obvious starting point for the synthesis of chiral molecules is to use a natural product that is readily available as a single enantiomer. Many sugars, terpenes, amino acids, etc. have been used as the starting materials for the synthesis of a wide variety of chiral molecules. Obviously, this method works best when there is a large degree of structural similarity between the chiral pool starting material and the final product. The greater the structural differences, the more complex the synthesis will become. Additionally, in most instances, nature has not always seen fit to provide us with both enantiomers of a chiral molecule, thereby further limiting the availability of starting materials. As a result, this type of strategy can suffer from economic viability concerns wherein the cost of purchasing the desired stereogenic centers becomes prohibitive to long-term industrial manufacture. Thus, it is most common to employ chiral starting materials that exist abundantly in nature or can be easily isolated via fermentation process and subsequently extracted and isolated as a pure enantiomer leading to a cheaper starting raw material. For example, darunavir is a preferred protease inhibitor for treatment of HIV-AIDS as it displays lower toxicity and better resistance than comparators but currently suffers from high cost and has therefore seen limited use outside the 1 Corey, E. J.; Kurti, L. Enantioselective Chemical Synthesis; Direct Book Publishing, LLC, 2010. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

666

14 Access to Chirality

developed world.2 Recently, researchers at the Clinton Health Initiative have published a route employing isocitric acid, a chiral pool starting material isolated from the fermentation of sunflower oil. In a forward sense, potassium isocitrate can be elaborated to a key chiral furofuranol intermediate in the manufacturing route of darunavir. HO

OH KO2C

O Ph O S OH iPr N

H

CO2H O

OH Potassium isocitrate

H

O

O O

Ph

Furofuranol intermediate

H O O H

Darunavir

Both naturally occurring sugars and amino acids3 are common ways to access chirality in synthesis, and several examples can be found in the literature. Beneath are a few examples that have been demonstrated on multikilogram scale in the synthesis of active pharmaceutical ingredients (APIs). In the synthesis of ertugliflozin, Pfizer’s SGLT2 inhibitor for the treatment of Type 2 diabetes, d-glucose is employed as a chiral pool starting material.4 The high degree of structural similarity between commercially available 2,3,4,6-tetra-O-benzyl-d-glucose and the sugar moiety contained in ertugliflozin lends itself to chiral pool-based strategy. The natural abundance of glucose, and in this case its protected derivative, renders this a cost effective starting material for the synthesis. O

BnO

OEt

OH

O

HO

BnO

OBn

HO

OBn

Cl OH

OH

O HN

HO2C

Ertugliflozin L-PGA

The example below employs a combined strategy with a chiral pool starting material (amino acid) and chiral salt resolution in the preparation of a core scaffold used in pharmaceutical targets.5 The initial manufacturing route involved the synthesis of a bicyclic piperazine fragment containing a pendant alcohol and required a chiral salt resolution, followed by epimerization to install the required stereochemistry of the bicyclic piperazine. Further optimization of the synthetic route focused on the use of l-aspartic acid as a chiral pool starting material to install the required stereochemistry of piperazine ring. The bicyclic ring structure can then be forged in subsequent steps to furnish the key bicyclic t-Bu ester as a 20 : 1 ratio of diastereomers. Following resolution with d-tartaric acid, the key bicyclic piperazine fragment is obtained as a single diastereomer. The process improvements allowed synthesis and isolation of the bicyclic ring structure as a single diastereomer avoiding the need for classical salt resolution and represent a significant improvement over the initial manufacturing route. tBuO

O

tBuO

NH2 HO2C L-aspartic

CO2H aci d

D-Tartaric

N Bz

HO2C

acid

MeOH, MTBE N

O

N

HO N

OH CO2H

Bz

In the synthesis of an LFA-1 inhibitor demonstrated on metric ton scale, two amino acids are used to establish the chiral stereogenic centers in the drug candidate.6 The synthesis commences with Boc-d-alanine, and following three 2 Moore, G. L.; Stringham, R. W.; Teager, D. S.; Yue, T.-Y. Organic Process Research & Development 2017, 21, 98–106. 3 Rommelmann, P.; Betke, T.; Gröger, H. Organic Process Research & Development 2017, 21, 1521–1527. 4 Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E. C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.; Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C. L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Organic Process Research & Development 2014, 18, 66–81. 5 Sieser, J. E.; Singer, R. A.; McKinley, J. D.; Bourassa, D. E.; Teixeira, J. J.; Long, J. Organic Process Research & Development 2011, 15, 1328–1335. 6 Wang, X.-J.; Frutos, R. P.; Zhang, L.; Sun, X.; Xu, Y.; Wirth, T.; Nicola, T.; Nummy, L. J.; Krishnamurthy, D.; Busacca, C. A.; Yee, N.; Senanayake, C. H. Organic Process Research & Development 2011, 15, 1185–1191.

14.2 Using the Chiral Pool

steps the imidazolidinone can be prepared as a mixture of cis- and trans-isomers. Crystallization-driven resolution in a heptane solution of interconverting isomers facilitates isolation of the trans-isomer. Following protection of the imidazolidinone, the chiral quaternary center was installed via a highly diastereoselective alkylation. In the final step of the synthesis, l-alaninamide is coupled to incorporate the stereochemistry of the sulfonamide portion of the molecule. CF3

CF3 Me Me BocHN

O OH

HN

Me • HCl

O Cl

N

H2NOC

O

Me O O N N S R N

iPr Cl

R = Cl or OH

NH2

NaOH THF/DMF/H2O

Cl

O Me Me O O N N S N H2NOC H N

Cl

Cl

Cl

In an interesting example, Takeda process chemists were challenged with identifying a more efficient route to a TORC 1/2 inhibitor containing a chiral morpholine fragment with a quaternary center so as to avoid late stage supercritical fluid chromatography (SFC) separation.7 Initial efforts focused on derivatization of α-methylserine and cyclization to the desired morpholinone were unfruitful presumably due to steric reasons, as similar chemistry on serine was precedented. Instead, the morpholine derivative was prepared via a five-step route from serine. Interestingly, α-methylation of the Boc-protected morpholine at low temperature using NaHMDS and MeI furnishes the quaternary center, and following analysis of the product, it was determined that during the reaction some “memory of chirality” was observed yielding the desired α-methylated morpholine intermediate in 97% ee, with >99% conversion. On the contrary, the corresponding Bn-protected intermediate shows no memory of chirality and led to complete erosion of enantioselectivity. It is proposed that the Boc-protecting group favors an equatorial position resulting in the ability of the morpholine ring to adopt a chiral ring orientation. This hypothesis was investigated further through the use of different counterions (e.g. lithium hexamethyldisilazide [LiHMDS] and potassium hexamethyldisilazide [KHMDS]), less polar solvents (e.g. toluene), and warmer temperatures and the resulting ees of the product were found to be lower. In these cases, chelation of the counterion to the carbonyl of the Boc group is proposed to disrupt the chiral ring conformation. The enantiopurity of the morpholine intermediate could be further upgraded following removal of the Boc group and crystallization as the (+)-CSA salt to achieve a stable solid in >99% ee. OH H HO2C

NHBn

O H MeO2C

N Boc 99% ee

NaHMDS MeI THF, −78 °C

O Me MeO2C

N Boc 97% ee

Often times, asymmetric methods for setting stereogenic centers are employed in combination with resolution strategies for further chiral purity upgrades. For example, in the synthesis of letermovir, an antiviral developed by Merck, an asymmetric cinchonidine-based phase transfer catalyzed aza-Michael reaction was employed to establish the piperidine intermediate in 76% ee.8 Subsequent crystallization as the di-p-toluoyl-(S,S)-tartaric acid salt was found to upgrade the chiral purity of the intermediate to >99% ee.

7 Hicks, F.; Hou, Y.; Langston, M.; McCarron, A.; O’Brien, E.; Ito, T.; Ma, C.; Matthews, C.; O’Bryan, C.; Provencal, D.; Zhao, Y.; Huang, J.; Yang, Q.; Heyang, L.; Johnson, M.; Sitang, Y.; Yuqiang, L. Organic Process Research & Development 2013, 17, 829–837. 8 Humphrey, G. R.; Dalby, S. M.; Andreani, T.; Xiang, B.; Luzung, M. R.; Song, Z. J.; Shevlin, M.; Christensen, M.; Belyk, K. M.; Tschaen, D. M. Organic Process Research & Development 2016, 20, 1097–1103.

667

668

14 Access to Chirality

O (i) K3PO4, PhMe/H2O (ii) Cinchonidine PTC MeO (5 mol%) K3PO4 (1.5 equiv)

MeO CO2Me HN N

CF3 N

PhMe/H2O, 0 °C 98%

N F

Me O

O MeO

N

CF3

N

PhMe/EtOAc

N F

OMe

(S,S)-DTTA

Me O

N

N F

OMe

76% ee

CF3

•(S,S)-DTTA •EtOAc

N

97% ee

OMe

14.3 Classical Resolutions Despite advances in enantioselective synthesis, classical resolution is still one of the most widely utilized methods for the production of enantiopure substances. The most common variation is the formation of diastereomeric salts via combination of a racemate with a single enantiomer, producing a 1 : 1 mixture of diastereomeric salts. These salts can then be separated by physical means, usually by crystallization from an appropriate solvent or combination of solvents. Since the goal is to try to selectively crystallize one diastereomeric salt while leaving the other in solution, solvents of intermediate polarity, like the lower alcohols, often work the best. Organic salts are highly soluble in polar organic solvents such as N,N-dimethylformamide (DMF), thus, such solvents are rarely used since both salts will likely dissolve. Likewise, very nonpolar solvents (heptane, toluene, etc.) will not dissolve most salts and thereby will not be useful for selective crystallization of one salt. A survey of diastereomeric salt resolutions9 shows that over 50% of published resolutions are carried out in the lower alcohols (MeOH, EtOH, and i-PrOH), sometimes with a small amount of water added. Other common solvents are EtOAc and acetone. Fortunately, a variety of chiral acids and bases are available from the chiral pool or are inexpensive commodity chemicals. Acids such as tartaric, dibenzoyltartaric, ditoluoyltartaric, mandelic, and camphorsulfonic are often used to resolve basic molecules (75% of the cases in reference 1) and bases such as sec-phenethylamine, brucine, ephedrine, quinine, cinchonine, and cinchonidine are typically used to resolve acids (70% of the cases in reference 1). For example, treatment of racemic phenethylamine with (+)-tartaric acid in methanol results in the precipitation of the (−)-phenethylamine-(+)-tartaric acid salt.10 Conversion of the salt to the free amine using NaOH followed by distillation produces (S)-phenethylamine in 29% yield (58% of theory) and 98% ee. OH NH2 Me

HO2C

CO2H OH MeOH

NH2 Me

OH • HO2C

CO2H OH

aq NaOH 29%

NH2 Me 98% ee

Although chromatography can be scaled, often times a resolution strategy is preferred to avoid throughput issues that can arise upon scaling chromatographic steps. In the development of a FLAP inhibitor, process chemists at Boehringer Ingelheim (BI) were challenged with identifying a process more amenable to scale for the isolation of a key fragment containing a chiral quaternary center.11 While discovery chemists were utilizing SFC to isolate the desired enantiomer, the process team was able to develop a process wherein resolution of the dicyclohexylamine (DCA) salt of a carboxylic

9 Kozma, D. CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation; CRC Press, 2001. 10 Ault, A. Organic Syntheses 1969, 49, 93–98. 11 Mulder, J. A.; Gao, J.; Fandrick, K. R.; Zeng, X.; Desrosiers, J.-N.; Patel, N. D.; Li, Z.; Rodriguez, S.; Lorenz, J. C.; Wang, J.; Ma, S.; Fandrick, D. R.; Grinberg, N.; Lee, H.; Bosanac, T.; Takahashi, H.; Chen, Z.; Bartolozzi, A.; Nemoto, P.; Busacca, C. A.; Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C. H. Organic Process Research & Development 2017, 21, 1427–1434.

14.3 Classical Resolutions

acid intermediate as the (1R,2R)-1,3-dihyroxy-1-(4-nitrophenyl)-propan-2-amine (DNP) salt was demonstrated on multi-kilogram scale. More than 46 kg of the resolved salt were isolated in >99% ee following two recrystallization enrichments. Resolution of the corresponding racemic carboxylic acid to avoid the use of the DCA salt yielded lower overall recovery of the desired product DNP salt with product being lost to the mother liquors. OH −

O Me CO2− +

H2N(c-hex)2

Br

OH +

N O

Me

NH2

OH

CO2−

(0.8 equiv)

i-PrOH (75 to 20 °C) 28–32%, >99% ee

Br

OH

−

O

+

NH3

N

+

O

Process optimization studies determined that the route to alvimopan could be streamlined via reordering of steps to move the resolution of the piperidinone to the beginning of the synthesis rather than at an advanced intermediate to allow for more efficient recycling of the undesired enantiomer.12 Following two cycles of racemization of the undesired enantiomer under basic conditions and resolution, the (S)-piperidone could be isolated in 75–80% yield with 90–93% ee. Moreover, the process was optimized further to recover the (−)-di-p-toluoyl-d-tartaric acid resolving agent via extraction and pH adjustment process. When recycled resolving agent was used in the resolution of the piperidone, it was found to behave similarly. O Me N

+ (−)-DPTTA

O

MeOH 25–35 °C

Me Alvimopan N

Me

Me

Although asymmetric routes are often preferred, there are cases where a classical resolution strategy is chosen for reasons which include avoiding the use of proprietary technologies, reducing complexity in the process, and delivering material with higher enantiomeric purity than the reported asymmetric routes. One such example is in the synthesis of (R)-3,5-bis(trifluoromethyl)-𝛼-methyl-N-methylbenzylamine, a key building block in several NK-1 receptor antagonists, where a team of researchers at Glaxo Smith Kline (GSK) optimized a Pasteurian classical resolution via crystallization with l-(−)-malic acid.13 While multiple asymmetric synthetic methods were evaluated, those routes either allowed no freedom to operate (i.e. use of proprietary ligands) or furnished desired product that lacked the desired enantiopurity thus requiring additional purification. Instead, guidance from ternary phase diagrams developed from solubility experiments facilitated optimization of the resolution conditions. On 25 kg scale, a solution of the racemic amine could be heated and treated with l-(−)-malic acid, cooled, and seeded to afford the desired diastereomer in >99% chiral purity with an average yield of 34%. An additional recrystallization was required to further upgrade the chiral purity of the compound to deliver the desired diastereomer with 99% ee).14 12 Reddy, B. R.; Reddy, K. S.; Dubey, M. K.; Kumari, Y. B.; Bandichhor, R. Organic Process Research & Development 2014, 18, 163–167. 13 Brandel, C. M.; Cooke, J. W. B.; Horan, R. A. J.; Mallet, F. P.; Stevens, D. R. Organic Process Research & Development 2015, 19, 1954–1965. 14 Kiss, V.; Egri, G.; Bálint, J.; Fogassy, E. Chirality 2006, 18, 116–120.

669

670

14 Access to Chirality

HO2C OH

O

Me CH2Cl2, TEA O

O

(i) Cinchonidine O (ii) Na 2CO3; aq HCl Me (iii) aq NaOH

OH Me

41% yield

O

(R)

An empirical screening method that can be used to select a resolving agent and solvent to first attempt when scaling up has been published. It relies on slurrying the racemic compound with the resolving agent in various solvents and assessing the effectiveness of the resolution by high performance liquid chromatography (HPLC) analysis of the mother liquor.15 Another method using differential scanning calorimetry (DSC) to determine whether or not resolving agents will form diastereomeric salts has also been published.16 14.3.1

The Family Approach (the Dutch Resolution)

In an attempt to accelerate the process of finding the best resolving agent, researchers at Syncom treated a racemic compound with a mixture of resolving agents in the hopes that the least soluble diastereomeric salt would precipitate, thereby self-selecting the best resolving agent from the mixture.17 To their surprise, the salts that crystallized contained mixtures of the resolving agents and the ratio did not change appreciably upon recrystallization of the salt. Additionally, the optical purity of the resolved material was often higher than that obtained by forming salts with the individual resolving agents. For example, treatment of p-methyl phenethylamine with a 1 : 1 mixture of (S)-mandelic acid and (S)-p-methyl mandelic acid produced crystals that contained amine of 87% ee and contained a 1 : 4 ratio of the two acids. Treating p-methyl phenethylamine with only (S)-p-methyl mandelic acid produced crystals in which the amine was only 57% ee. 14.3.2

Separation of Covalent Diastereomers

Another resolution strategy is to covalently derivatize a racemate with a single enantiomer of a chiral molecule, producing a mixture of diastereomers that can be separated by crystallization or chromatography. A particularly successful example of this process is the reaction of racemic timolol with dibenzoyltartaric acid anhydride in acetone.18 A single diastereomer precipitates from the reaction mixture in 42% yield (50% maximum) and in high optical purity. Hydrolysis to the optically pure timolol is straightforward. BzO

O N N

OH O

S N Timolol

14.3.3

NHt-Bu

O

OBz O

O

Acetone 42% (84% of theory)

BzO O N N

S N

O

CO2H

O

OBz O

O

NHt-Bu

aq H2SO4 100%

N N

OH O

NHt-Bu

S N

98% de

Kinetic Resolutions

A kinetic resolution occurs when a racemate undergoes reaction with a chiral agent (reagent, catalyst, etc.) and the enantiomers react at different rates. If the difference in reaction rates is high enough, one enantiomer of product and/or starting material can often be isolated in high yield. As with classical salt forming resolutions, the maximum yield is 50%. If the reaction follows first-order kinetics, equations can be derived to calculate the enantioselectivity (s) of a reaction based on the percent conversion (C) and ee of the product (Eq. (14.1)). Likewise, the enantioselectivity can be calculated from the ee of the unreacted starting material (ee′ , Eq. (14.2)). 15 Borghese, A.; Libert, V.; Zhang, T.; Alt, C. A. Organic Process Research & Development 2004, 8, 532–534. 16 Dyer, U. C.; Henderson, D. A.; Mitchell, M. B. Organic Process Research & Development 1999, 3, 161–165. 17 Vries, T.; Wynberg, H.; Van Echten, E.; Koek, J.; Ten Hoeve, W.; Kellogg, R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; Van der Sluis, S.; Hulshof, L.; Kooistra, J. Angewandte Chemie, International Edition in English 1998, 37, 2349–2354. 18 Varkonyi-Schlovicsko, E.; Takacs, K.; Hermecz, I. Journal of Heterocyclic Chemistry 1997, 34, 1065–1066.

14.3 Classical Resolutions

ln[(1 − C)(1 − ee)] ln[(1 − C)(1 + ee)] ln[(1 − C)(1 + ee′ )] s= ln[(1 − C)(1 − ee′ )]

(14.1)

s=

(14.2)

In order to obtain a high yield and high optical purity, the enantioselectivity of the reaction needs to be greater than 100. If the enantioselectivity is lower, it is still possible to obtain high ee material if one is willing to sacrifice yield. For example, if the unreacted starting material is the desired product and enantioselectivity is 10, running the reaction to 70% conversion should produce unreacted starting material in >99% ee. Although there are many examples of non-enzymatic kinetic resolution processes, this is an area in which enzymatic reactions are used extensively. 14.3.3.1

Resolution of Alcohols

A classic example of kinetic resolution can be found in the Sharpless epoxidation of chiral, racemic allylic alcohols. For example, epoxidation of 1-nonen-3-ol using (+)-diisopropyl tartrate, Ti(O-i-Pr)4 and t-butylhydroperoxide (TBHP) to 52% conversion produced the epoxide in 49% yield and >96% ee (erythro/threo ratio was 99 : 1).19 The unreacted alcohol was the (R)-enantiomer. L-(+)-DIP T

Ti(O-i-Pr)4 0.6 equiv TBHP

OH Me

OH Me

CH2Cl2

O

Processed to 52% conversion

49% yield >96% ee

OH Me

+ >96% ee

Enzymatically, alcohols can be resolved either by acylation of the alcohol or by hydrolysis of an ester of the alcohol. It is important to note that these are complementary processes (see Section 15.2.2.2 in Biocatalysis chapter for additional examples). OH RL

RS

OAc RL

RS

(S)-selective enzyme R3OAc

OAc

(S)-selective enzyme H2O

RS

RL

OH RL

RS

+

+

OH RL

RS

OAc RL

RS

If an enzyme has a preference for reacting with the (S)-enantiomer, then an acylation process will produce the ester of the (S)-enantiomer and the unreacted alcohol will be the (R)-enantiomer. If the same enzyme is used in a hydrolytic process, then the enzymatic reaction will produce the (S)-alcohol and the remaining ester will be the (R)-enantiomer. Typically, vinyl esters, isopropenyl esters, or acid anhydrides are used as the acylating agent because they react irreversibly. Although used extensively to prepare small quantities of optically pure alcohols, the major problem with this approach is the separation of the alcohol and ester. Often, the physical properties are similar and the only method for separation is chromatography. One approach to solving this problem is the use of cyclic anhydrides as the acylating agent. The product and unreacted starting material can then easily be separated by extraction. In the example below, the racemic hydroxynitrile was acylated with succinic anhydride catalyzed by the lipase candida antarctica lipase B (CALB) in an immobilized form (Novozym 435).20 The hemisuccinate was extracted into a mildly basic aqueous phase and the unreacted hydroxynitrile remained in the methyl t-butyl ether (MTBE) layer. Addition of NaOH to the aqueous layer hydrolyzed the hemisuccinate and the desired product was extracted into MTBE.

19 Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. Journal of the American Chemical Society 1981, 103, 6237–6240. 20 Vaidyanathan, R.; Hesmondhalgh, L.; Hu, S. Organic Process Research & Development 2007, 11, 903–906.

671

672

14 Access to Chirality

OH

(i) MTBE, 40–50 °C Novozym 435

CN

(ii) O

Racemic

O

COO−

O

O CN In aqueous solution

O

(i) NaOH

OH

(ii) MTBE/dil. HCl extractions

CN ~90% ee solution in MTBE

(iii) MTBE/aq K2HPO4 extractions

Another interesting solution for the separation issue is to make the acylating agent highly lipophilic so that the acylated product is very soluble in nonpolar organic solvents such as heptane.21 The unreacted alcohol can be washed out of the heptane layer using water or methanol. O

O

OH O

Novozym 435, heptane

Me

14.3.3.2

(CH2)10CH3

O

OH

(CH2)10CH3

KOH, MeOH 26% overall

Me

Me 96% ee

Resolution of Amines

Like alcohols, some amines can be resolved by enzymatic acylation. (See Section 15.2.2.2 in Biocatalysis chapter for additional examples) A number of lipases are known to catalyze the acylation of amines by esters. In this case, the products are usually easy to separate by extraction since the product is neutral and the remaining unreacted amine is basic. One example is the acylation of sec-phenethylamine with ethyl methoxyacetate, catalyzed by a lipase from Burkholderia plantarii.22 Running the reaction to 52% conversion affords the (S)-enantiomer of phenethylamine in 46% yield and the methoxyamide in 48% yield and 93% ee. NH2 Me

O

NH2

10 wt% B. plantarii lipase 1 eq MeOCH2COOEt MTBE

Me

46% 99% ee

14.3.3.3

OMe

HN

+

Me

48% 93% ee

Resolution of Epoxides

Epoxides are a very useful functional group due to the ease with which they can be transformed into other functionality. Numerous strategies have been employed to produce optically enriched epoxides (see Section 3.10.4). An alternative strategy would be a kinetic resolution approach. Jacobsen has discovered that (salen)Co complexes can effectively hydrolyze many terminal epoxides with very high enantioselectivity.23 H

H N

t-Bu

O Me

O

Co

N O

t-Bu t-Bu 0.2 mol% 0.55 eq H2O, THF

rac

t-Bu H

O

Me 45% 99% ee

OH

+ Me

OH 50% 98% ee

21 ter Halle, R.; Bernet, Y.; Billard, S.; Bufferne, C.; Carlier, P.; Delaitre, C.; Flouzat, C.; Humblot, G.; Laigle, J. C.; Lombard, F.; Wilmouth, S. Organic Process Research & Development 2004, 8, 283–286. 22 Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W. Journal für Praktische Chemie/Chemiker-Zeitung 1997, 339, 381–384. 23 Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. Journal of the American Chemical Society 2002, 124, 1307–1315.

14.4 Dynamic Kinetic Resolutions

14.4 Dynamic Kinetic Resolutions Unlike classical resolutions that can produce a maximum 50% yield of the desired enantiomer, dynamic resolutions allow for the production of a 100% yield of a single enantiomer from a racemate. This can be accomplished by incorporating a racemization reaction into the resolution process. 14.4.1

Dynamic Kinetic Resolutions via Chemical Reactions

One of the classic examples of dynamic kinetic resolution was published by Noyori in 1989.24 He demonstrated that it was possible to reduce α-substituted β-keto esters with a chiral catalyst to produce a single diastereomer in high ee. The β-ketoesters rapidly racemize via tautomerization to the enol form and one enantiomer of the keto form is selectively reduced by the chiral catalyst. One key example is the reduction of an α-amidomethyl substrate to the corresponding β-hydroxyester in 98% ee. The product can be converted into the acetoxy azetidinone, a key starting point for many β-lactam antibiotics. O

O

Me

H2 (R)-BINAP-Ru

OMe

TBSO

OH O Me

NHCOPh

H

Me

OMe NHCOPh

OAc NH

O

98% ee

A number of optically enriched amino acids can be produced from their corresponding racemates via an enzymatically catalyzed hydrolysis of the readily enolized azalactone derivatives.25 This is a particularly useful way to make non-natural amino acids. Me Me

Me CO2H NH2

(i) PhCOCl (ii) Ac 2O

Me Me

Me

O N

O Ph

Lipozyme, 1-BuOH, TEA Toluene 94%

Me Me

Me CO2Bu NHCOPh 99.5% ee

An interesting method for performing a dynamic kinetic resolution of secondary alcohols has evolved over the past decade. Several metals are known to racemize secondary alcohols via a reversible oxidation/reduction process. With readily oxidized alcohols, the redox process is rapid enough that it can be coupled with an enzymatic acylation to produce high yields of the resolved alcohol ester. For example, Bäckvall and coworkers have published a procedure for resolving phenethyl alcohol on mole scale using only 0.05 mol% of the ruthenium catalyst shown below and the enzyme CALB.26 OH Me

Isopropenyl acetate, CALB, Na2CO3, toluene 70 °C, 20 h Ph

0.05 mol% Ph

OAc Me

Ph

Ph Ph OC Ru Cl CO

97% yield >99.8% ee

A similar process has been demonstrated with amines using a catalyst that induces the epimerization at lower temperatures.27 (Also see Section 15.2.1 in Biocatalysis chapter)

24 Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T. Journal of the American Chemical Society 1989, 111, 9134–9135. 25 Turner, N. J.; Winterman, J. R.; McCague, R.; Parratt, J. S.; Taylor, S. J. C. Tetrahedron Letters 1995, 36, 1113–1116. 26 Bogár, K.; Martín-Matute, B.; Bäckvall, J.-E. Beilstein Journal of Organic Chemistry 2007, 3, 50. 27 Blacker, A. J.; Stirling, M. J.; Page, M. I. Organic Process Research & Development 2007, 11, 642–648.

673

674

14 Access to Chirality

Candida rugosa, toluene 40 °C MeO

O

MeO

OEt O

NH

MeO

Cp* 0.2 mol%

Me

I

Ir

I I

MeO Ir

I

MeO

N Me

Cp*

OEt O

86% yield 96% ee

14.4.2

Dynamic Kinetic Resolutions via Crystallization

The dynamic kinetic resolution can also be driven by a physical process, such as crystallization, rather than by a chemical transformation. For example, a group at Glaxo intensively studied the resolution of phenylglycinate esters with l-tartaric acid.28 A key finding of their work, which has been adopted by many others, was the observation that addition of a variety of carbonyl compounds accelerated the rate of the racemization process. NH2 CO2Me

L-tartaric

NH2

acid

CO2Me • L-tartaric acid

85%

99% ee

Presumably, the carbonyl additive reacts with the amine to form an imine that enhances the acidity of the α-proton, thereby increasing the rate of enolization and epimerization. Another interesting example was reported by a Hoechst group.29 d-p-hydroxyphenylglycine is used in the side chain of a number of semisynthetic β-lactams. They found that heating racemic p-hydroxyphenylglycine with (+)-3-bromocamphor-8-sulfonic acid (BCSA) to 70 ∘ C in acetic acid with salicylaldehyde as the epimerization catalyst produced a 99% yield of the salt of the D-isomer in 98–99% de. NH2 CO2H HO

NH2

(+)-BCSA HOAc salicylaldehyde

CO2H • (+)-BCSA HO

99%

98% de

This process can also be applied to other amino acids with less acidic α-protons. For example, (R)-proline can be obtained from the natural occurring (S)-proline or racemic proline by treatment with d-tartaric acid in butanoic acid at 80 ∘ C with 10 mol% butanal.30 The (R)-proline d-tartaric acid salt is obtained in 97% yield and 93–95% de. D-tartaric

N H

CO2H

acid

Butanoic acid, butanal 97%

N H

CO2H •

D-tartaric

acid

93–95% de

More complex molecules are also readily amenable to dynamic kinetic resolution. For example, the fluorophenyloxazine precursor to the antiemetic drug aprepitant undergoes a dynamic kinetic resolution with (−)-3-bromocamphor-8-sulfonic acid (BCSA) in 90% yield and 99% de.31

28 Clark, J. C.; Phillipps, G. H.; Steer, M. R. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 1976, 475–481. 29 Bhattacharya, A.; Araullo-Mcadams, C.; Meier, M. B. Synthetic Communications 1994, 24, 2449–2459. 30 Shiraiwa, T.; Shinjo, K.; Kurokawa, H. Bulletin of the Chemical Society of Japan 1991, 64, 3251–3255. 31 Kolla, N.; Elati, C. R.; Arunagiri, M.; Gangula, S.; Vankawala, P. J.; Anjaneyulu, Y.; Bhattacharya, A.; Venkatraman, S.; Mathad, V. T. Organic Process Research & Development 2007, 11, 455–457.

14.5 Desymmetrization of Meso Compounds

O

O (−)-BCSA

N Bn

i-PrOAc, 89 °C F 90%

O

O • (−)-BCSA

N Bn

F 99% de

For the preparation of a dibenzoazepinone intermediate, initial efforts involved classical crystallization of the desired enantiomer with numerous acids and Boc-d-phenyl alanine was found to be superior leading to solids in multiple solvents including dicholoroethane, toluene, ethyl acetate, and acetonitrile in 43% yield and 99.5% ee.32 With this knowledge in hand, several aromatic aldehydes were evaluated as catalytic racemization catalysts. Key to the racemization was the addition of a catalytic amount of water. Following optimization, a one-pot crystallization-driven dynamic resolution was achieved using catalytic 3,5-dichlorosalicylaldehyde, water, and Boc-d-phenyl alanine in toluene at reflux. The salt could be free-based through use of aqueous sodium hydroxide to provide the desired enantiomer of the dibenzoazepinone intermediate in 80% yield and 99% ee. H N

O NH2

H N

Boc-D-Phe-OH 3,5-dichlorosalicyldehyde (2 mol%)

O NH2

H2O (1.5–2.0 mol%), heating toluene

aq NaOH 99%

H N

O NH2

Boc-D-Phe-OH

82%, 99.4% ee

In all of the cases above, the racemization occurs under acidic conditions. Merck chemists have reported a case where the epimerization occurs faster under basic conditions. Treatment of the 3-aminobenzodiazapinone with a full equivalent of (+)-10-camphorsulfonic acid (CSA) led to very slow racemization. If slightly less than one equivalent was used, racemization was substantially faster, providing a 91% yield of the salt (99% based on CSA) after 12 hours at 25 ∘ C.33 Me N

O N

NH2

0.92 equiv (+)-CSA Acetonitrile 3 mol% 3,5-dichlorosalicylaldehyde 91%

Me N

O N

NH2

• (+)-CSA

>99.5% de

The vast majority of examples in the literature involve enolization at a chiral center alpha to a carbonyl, but there are also examples of atropisomer interconversion, Michael/retro-Michael reactions, and reversible additions to a carbonyl.34,35

14.5 Desymmetrization of Meso Compounds One intriguing method for producing a chiral compound involves the desymmetrization of a meso compound. A particularly useful aspect of this transformation is the potential to convert all of the meso compound into a single enantiomer product. It is also possible to produce several chiral centers at once using this method. Typically, the desymmetrization is accomplished by selectively derivatizing one of two prochiral functional groups present in the molecule. Diols, diesters, and cyclic anhydrides are the typical substrates. For example, 3-methyl glutaric anhydride was reacted with (S)-1-(1′ -naphthyl)ethanol, followed by esterification with diazomethane to give a high yield of the diester.36 Subsequent conversion to 3-methylvalerolactone and comparison to literature data showed that the (R)-enantiomer had been produced in approximately 86% ee.

32 33 34 35 36

Karmakar, S.; Byri, V.; Gavai, A. V.; Rampulla, R.; Mathur, A.; Gupta, A. Organic Process Research & Development 2016, 20, 1717–1720. Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. The Journal of Organic Chemistry 1987, 52, 955–957. Pellissier, H. Tetrahedron 2003, 59, 8291–8327. Pellissier, H. Tetrahedron 2008, 64, 1563–1601. Theisen, P. D.; Heathcock, C. H. The Journal of Organic Chemistry 1993, 58, 142–146.

675

676

14 Access to Chirality

Me

Me OH

+ O

O

O

Me

(i) CH2Cl2, DMAP (ii) CH2N2

Me Np

97% yield

O

O

Me CO2Me

O

O

86% ee

Numerous other examples with various nucleophiles exist.37 The major drawback of such an approach is the use of a stoichiometric amount of a chiral agent that will usually have to be removed later. Catalytic methods are preferable, and enzymatic methods have been particularly valuable.38 For example, the monoacid below can be obtained by resolution of the racemate with cinchonidine, but of course the maximum yield is 50%. Chemists at Bristol–Myers Squibb developed an enzymatic hydrolysis of the meso diester that provided the desired mono acid in >99% ee and 98% yield.39 CO2Me

(i) pH 10 buffer Novozym 435

CO2H

CO2Me

(ii) HCl, MTBE

CO2Me >99% ee 98% yield

In another example, a key building block for the synthesis of vitamin D analogs can be obtained in excellent ee by acylation of the meso diol.40 OH

TBSO

OAc

Lipase QL, vinyl acetate 22 °C, 46 hr OH

>99% ee, 100% yield

TBSO

OH

14.6 Chiral Chromatography Preparative chiral column chromatography is a valuable method for the resolution of enantiomers. For small amounts of material, it is often easier and faster to use a racemic synthesis followed by chiral column chromatography than to develop an asymmetric synthesis. This is particularly true in medicinal chemistry, where the individual enantiomers need to be assayed but the asymmetric synthesis of numerous analogs would be prohibitively time consuming.41 Even on multi-kilogram scale, chiral column chromatography can be practical if the molecule to be resolved is relatively inexpensive, and the chromatography is efficient in terms of having a good resolution (𝛼 value) and a high loading. Because of the potential high cost of the chiral stationary phase for large scale applications, it is often necessary to reuse the chiral stationary phase to lower the economic impact. One interesting example of the large scale application of chiral chromatography is in the resolution of the tetralone used in the manufacture of sertraline.42 The desired 4-(S)-tetralone is obtained in >94% yield and 99.7% ee. In this particular case, the undesired enantiomer can be racemized by treatment with base, providing more racemic feed.

37 38 39 40 41 42

Atodiresei, I.; Schiffers, I.; Bolm, C. Chemical Reviews 2007, 107, 5683–5712. Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chemical Reviews 2005, 105, 313–354. Goswami, A.; Kissick, T. P. Organic Process Research & Development 2009, 13, 483–488. Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681–694. Leonard, W. R.; Henderson, D. W.; Miller, R. A.; Spencer, G. A.; Sudah, O. S.; Biba, M.; Welch, C. J. Chirality 2007, 19, 693–700. Quallich, G. J. Chirality 2005, 17, S120–S126.

14.6 Chiral Chromatography

O

O

NHMe

O

Chromatography

+

Cl

Cl

Cl

Base

Cl

Cl

Cl Cl Sertraline

Cl

Another interesting example is the chromatographic resolution of cetirizine.43 In this case, derivatives of the desired acid were found to be much more soluble in the mobile phase thereby increasing the potential loading and efficiency relative to chromatography of the acid. The efficiency was further increased by screening different derivatives to find the one with the highest resolution (𝛼 value) which led to the selection of the primary amide. Chromatography produced the desired enantiomer in 99.8% ee and 98% recovery. NH2

O N

N

O Chromatography

N

NH2

O

Cl

O

N

Cl

OH

O N

O

N

• 2HCl

Cl Cetirizine

A complementary approach to liquid chromatography that runs in batch mode with minimal system hold up and can be easily scaled from analytical scale to preparative scale is SFC. SFC employs the use of carbon dioxide as a cosolvent in separation. Moreover, it generally results in faster separations, is more cost effective, and is considered to be a green technology due to the ability to recycle the carbon dioxide used. In an example from Bristol Myers Squibb (BMS), where a classical resolution alone or a classical resolution coupled with a secondary resolution was not enough to meet the chiral purity specification, the enriched mixture from the classical resolution was subjected to SFC to achieve the desired enantiomer.44 The use of an enriched solution resulted in increased throughput where process rates of up to 80 mL/h of an 85 : 15 mixture of diastereomers were achieved. In total, 1 kg of the desired enantiomer in >99.5% ee was obtained following processing for 23 days. Me Me

O

(i) Classical resolution with cinchonidine

OH

Me Me

O OH

(ii) SFC O

N

Cl

O

N

Cl

Another example employing SFC includes the resolution of commercially available racemic tert-butyl-3hydroxyazepane-1-carboxylate.45 The (S)-enantiomer was desired as a key intermediate. Although researchers considered adapting the existing route into an asymmetric one, the technology did not exist to do so and would likely require a longer synthetic sequence. Instead, a chiral SFC method was optimized to facilitate isolation of 10 g of the desired enantiomer in >98% ee. Simulated moving bed (SMB) chromatography is a continuous chromatographic process that is advantageous to normal preparative chromatography in that less solvent and adsorbent are typically required. In an example of a

43 Pflum, D. A.; Wilkinson, H. S.; Tanoury, G. J.; Kessler, D. W.; Kraus, H. B.; Senanayake, C. H.; Wald, S. A. Organic Process Research & Development 2001, 5, 110–115. 44 de Mas, N.; Natalie, K. J.; Quiroz, F.; Rosso, V. W.; Chen, D. C.; Conlon, D. A. Organic Process Research & Development 2016, 20, 934–939. 45 Carry, J.-C.; Brohan, E.; Perron, S.; Bardouillet, P.-E. Organic Process Research & Development 2013, 17, 1568–1571.

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14 Access to Chirality

di-substituted piperidine where all four diastereomers were desired, a combination of normal phase chromatography to separate the cis-isomers from the trans-isomers was implemented, followed by the use of SMB to separate the racemates.46 Each pure enantiomer was isolated in >99% ee via this protocol. A modification of the SMB chromatographic technique is found in the Varicol process. Both Varicol and SMB chromatography have become key chromatographic methods for chiral resolution in industrial scale process applications and represent chromatographic processes which are viable for long term implementation due to their continuous nature. In fact, the Varicol process in combination with enantioselective crystallization has been employed on metric ton scale for the preparation of difluoromethylornithine.47 Both coupled batch and more recently coupled continuous preferential crystallization have shown potential advantages to chiral chromatography as they avoid the use of expensive chiral stationary phases, have potential to be scaled up, and typically realize reduced solvent usage. Currently, this technology is limited to conglomerate forming systems and has been demonstrated experimentally on systems such as dl-asparagine monohydrate.48 While lacking broad applicability, this concept is likely to become more widely studied with the emergence of continuous processing.

46 Hartwieg, J. C. D.; Priess, J. W.; Schütz, H.; Rufle, D.; Valente, C.; Bury, C.; La Vecchia, L.; Francotte, E. Organic Process Research & Development 2014, 18, 1120–1127. 47 Perrin, S. R.; Hauck, W.; Ndzie, E.; Blehaut, J.; Ludemann-Hombouger, O.; Nicoud, R.-M.; Pirkle, W. H. Organic Process Research & Development 2007, 11, 817–824. 48 Chaaban, J. H.; Dam-Johansen, K.; Skovby, T.; Kiil, S. Organic Process Research & Development 2013, 17, 1010–1020.

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15 Biocatalysis Carlos A. Martinez, Rajesh Kumar, and John Wong Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 679 Group Transfer Reactions, 682 Reductions, 688 Oxidations, 693 C—C Bond Forming Reactions, 699 Future Developments, 703

15.1 Introduction Biocatalysis in its simplest definition is the use of enzymes to perform synthetic organic reactions.1,2,3,4 The objective of this chapter is to offer readers a resource to prioritize options while employing enzymes for preparative scale applications. A typical workflow for applying biocatalysis includes three basic stages: (i) biocatalytic retrosynthesis;5,6 (ii) screening a panel of enzymes,7 and (iii) reaction optimization.8 The integration of biocatalysis in the retrosynthesis discussions is a critical first step to identify high-value routes that incorporate biocatalysis. Evaluating the feasibility for biocatalytic transformations then depends on the availability of enzyme collections for various transformations. Recent advances in biotechnology have made numerous genome sequences available, dramatically increasing the number of enzymes identified for biocatalysis, many of which are commercially available. The screening of enzymes can be done in 96 well plates, at volumes ranging from 0.1–0.5 ml and requiring 0.1–0.5 mg of substrate per enzyme screened. Therefore, 10–50 mg of substrate is sufficient for screening hundreds of enzymes. In some cases, it is advantageous to screen at high substrate concentrations, which would require 10–100 times more substrate. Screening in 384 well format could not only reduce substrate requirements but also require specialized equipment and expertise.9 Enzymatic process optimization is geared toward increasing substrate concentration to greater than 200–500 mM, and the use of the lowest amount of enzyme possible, to operate a process in less than 24 hours. The substrate to enzyme ratio is perhaps the most important metric determining the practicality of an enzymatic transformation and attaining substrate to enzyme

1 Faber, K. In Biotransformations in Organic Chemistry: A Textbook; Springer-Verlag: Berlin, Heidelberg, 2011, p 31–313. 2 Turner, N. J.; Humphreys, L. Biocatalysis in Organic Synthesis: The Retrosynthesis Approach; Royal Society of Chemistry, 2018. 3 Turner, N. J.; Kumar, R. Current Opinion in Chemical Biology 2018, 43, A1–A3. 4 Goswami, A.; Stewart, J. D. In Organic Synthesis Using Biocatalysis; Goswami, A., Stewart, J. D., Eds.; Academic Press: 2016, p iii. 5 Turner, N. J.; O’Reilly, E. Nature Chemical Biology 2013, 9, 285. 6 de Souza, R. O. M. A.; Miranda, L. S. M.; Bornscheuer, U. T. Chemistry – A European Journal 2017, 23, 12040–12063. 7 Yazbeck, D. R.; Tao, J.; Martinez, C. A.; Kline, B. J.; Hu, S. Advanced Synthesis & Catalysis 2003, 345, 524–532. 8 Sheldon, R. A.; Pereira, P. C. Chemical Society Reviews 2017, 46, 2678–2691. 9 Dörr, M.; Fibinger, M. P.; Last, D.; Schmidt, S.; Santos-Aberturas, J.; Böttcher, D.; Hummel, A.; Vickers, C.; Voss, M.; Bornscheuer, U. T. Biotechnology and Bioengineering 2016, 113, 1421–1432. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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ratios exceeding 10–100 : 1 is desirable. Optimization involves the systematic alteration or engineering of reaction components such as the substrate, enzyme, reaction medium, enzyme formulation, and reactor configuration.10 The evaluation of reaction parameters such as temperature, pH, enzyme formulation, organic cosolvents, and substrate load can be evaluated rapidly, typically in a matter of days. These studies can be performed in a one-factor-at-a-time (OFAT) format, or using design of experiment (DOE) approaches.11 The engineering of the enzyme is often required for applications at multikilo scale, and this part of the workflow may take two to three months or more time, depending on the level of activity improvement or stabilization that is required and available resources. This ability to engineer an enzyme, mutating individual amino acids in a protein backbone, then recombining beneficial mutations, enables the generation of improved variants in a process that mimics the natural evolution of biocatalysts, but at a significantly reduced timescale. At present, the use of so-called evolved biocatalysts is common practice in industrial applications.12,13,14 The five success factors that influence enzyme scalability in organic chemistry are 1. Synthetic utility of the transformation. 2. Enzyme availability from commercial sources, or easily expressed in a standard microbial host such as Escherichia coli (this requires either internal expertise or a vendor offering this service). 3. Broad substrate scope or specificity. 4. Scalability to multigram applications often defined by a reasonable enzyme activity and operational stability. 5. Technical complexity, in terms of specialized equipment, cofactor recycling requirements, or additional enzymes needed for activity. The examples that follow are grouped based on reaction type. The large majority of transformations discussed are demonstrated at multigram scale, at relatively high substrate loading (>50 g/l), and using crude enzyme preparations that can either be obtained from commercial sources or prepared rapidly from gene sequences available in the literature or in gene banks and easily expressed in a standard microbial host such as E. coli.

Substrate

Product

Synthetic utility

Enzyme availability

Broad Substrate scope

Scalability

Low complexity

Ketone Reductase (KRED) Lipase, Protease, Esterase

+++

+++

+++

+++

+++

++

+++

+++

+++

+++

Oxygenase

+++

++

++

+

+

Oxynitrilase

+++

++

++

+++

+++

Aldolase

+++

++

++

+++

+++

Biocatalyst

Synthesis of alcohols OH

O R1

R1

R2

OH

O R3

O R1

R2

R1

R + 2 R3-CO 2H

OH

H R1

R2

R1

O R1

R2

R2

O R1

+

10 11 12 13 14

R2 OH * CN R2

OH H

R1

R3 O

R2

O R2

R2

R3

See Note 8. Weissman, S. A.; Anderson, N. G. Organic Process Research & Development 2015, 19, 1605–1633. Lalonde, J. Current Opinion in Biotechnology 2016, 42, 152–158. Turner, N. J. Nature Chemical Biology 2009, 5, 567. Wang, J.-B.; Li, G.; Reetz, M. T. Chemical Communications 2017, 53, 3916–3928.

15.1 Introduction

Substrate

Product

O

O

R1 + H O R2

Synthetic utility

Enzyme availability

Broad Substrate scope

Scalability

Low complexity

Lyase, Decarboxylase

+++

++

++

+++

+

Hydratase

+++

+

+

+

+++

Transaminase

+++

+++

+++

+++

+++

Amine Dehydrogenase

+++

+

+

+++

+++

Amine Oxidase

++

+

+

++

+++

Reductive Aminase (RedAm)

+++

++

+

++

+++

Imine Reductase (IRED)

+++

++

++

++

+++

Ammonia Lyase

+++

+

+

++

+++

Hydrolase

+++

+++

+++

+++

+++

Lipase

+++

+++

+++

+++

+++

Nitrilase

++

+++

+++

+++

+++

Nitrile Hydratase

++

+

+

+++

+++

Enoate Reductase (ERED)

+++

+++

+++

+++

+++

Biocatalyst

R2

R1

OH

H OH

R

R

Synthesis of amines O R1

NH 2

R2

R1

O R1

NH 2

R2

R1

NH 2 R1

R2

R2 NH

R2

R1

R2

+

NH 2 R2

R1

NR 3R4

NH2 R3

+ O

R1 R3

R1

R4

R2

R2 N

R1

NR 3R4

R4

R1

R2 R2

R1

R2 NH 2

R2

R1

Miscellaneous Reactions O

O R1

OR 2

R1

OH O

OH R1

R2

R1 N R

R2 O

R

N R

R3

O

OH O

R

NH 2

R3

R4

R3

R4

R1

R2

R1

R2

681

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15 Biocatalysis

Substrate

Product

OH

OH

X

R

R Nu

OH

O R

OH

R

Synthetic utility

Enzyme availability

Broad Substrate scope

Scalability

Low complexity

Halohydrin Dehalogenase (HHD)

++

+++

+++

+++

+++

Epoxide Hydrolase, HHD

++

++

++

+++

+++

Biocatalyst

R NO2

R NH2

Nitro Reductase

+++

+

+

+

+++

R CN

R

Nitrile Reductase

+++

+

+

+

+++

Carboxylic Acid Reductase (CAR)

+++

+

+

+

+

Fluorinase

+++

+

+

+

+

O

O R

NH 2

OH

R F

LG R1

R2

R1

R2

The symbol +++ meaning success criteria fulfilled in most cases, ++ partially fulfilled, and + when criteria has not been fulfilled.

15.2 Group Transfer Reactions Group transfer reactions are quite common in biocatalysis and can be observed with transferases and hydrolases. Although a wide variety of substrates such as ketones, alcohols, amines, amides, carboxylic acids, esters, alkyl halides, amino acids, ketoacids, epoxides, nucleotides, and carbohydrates exhibit this type of reaction, the majority of practical applications in organic synthesis involves the use of transaminases to catalyze the transfer of amino groups between a primary amine donor and a carbonyl acceptor, and the hydrolysis and synthesis of esters and amides catalyzed by lipases, esterases, and proteases. Transaminases became established as a method of choice for the synthesis of primary amines in the past decade, and practical examples will be discussed in Section 15.2.1. The group of hydrolytic enzymes catalyzing acyl transfer reactions has historical significance in establishing biocatalysis as a technology during the last three decades of the twentieth century, and they will be discussed in Section 15.2.2. There are miscellaneous hydrolases that may suffer from limited substrate scope, availability and scalability, or simply lower synthetic utility, and will be briefly discussed at the end of Section 15.2.2. 15.2.1

Amine Synthesis Catalyzed by Transaminases

The synthesis of amines using transaminases (TAs) involves the transfer of the amine group from a primary amine to a ketone or aldehyde to produce a new primary amine and the corresponding carbonyl coproduct. The reaction can be performed in resolution and synthesis mode. Resolution involves the selective transfer of an amine group from one of the enantiomers of a racemic mixture to a carbonyl acceptor, leaving behind the desired chiral amine. In practice, the synthesis mode is the preferred path because the overall yield has a theoretical maximum of 100%. Thermodynamic equilibrium is one of the technical challenges faced while scaling up a transaminase reaction, and depending on the amine donor used, several coproduct removal strategies have been reported, and reviewed elsewhere.15,16,17 The most successful TA reactions reported so far have been performed in aqueous media, often requiring organic cosolvents, like dimethyl sulfoxide (DMSO), and using stirred tank reactors. A small number of substrates have been reported using organic solvents saturated with water, and employing immobilized enzymes in flow configurations using continuous reactors.18,19 15 16 17 18 19

Satyawali, Y.; Ehimen, E.; Cauwenberghs, L.; Maesen, M.; Vandezande, P.; Dejonghe, W. Biochemical Engineering Journal 2017, 117, 97–104. Slabu, I.; Galman, J. L.; Lloyd, R. C.; Turner, N. J. ACS Catalysis 2017, Ahead of Print. Tufvesson, P.; Lima-Ramos, J.; Jensen, J. S.; Al-Haque, N.; Neto, W.; Woodley, J. M. Biotechnology and Bioengineering 2011, 108, 1479–1493. Andrade, L. H.; Kroutil, W.; Jamison, T. F. Organic Letters 2014, 16, 6092–6095. Truppo, M. D.; Strotman, H.; Hughes, G. ChemCatChem 2012, 4, 1071–1074.

15.2 Group Transfer Reactions

Three notable enzymes identified in the early 2000s have facilitated the development of practical applications in this field. Discovery of the S-selective TAs from the bacterium Vibrio fluvialis JS17 and Arthrobacter citreus and the R-selective TA from Arthrobacter sp. KNK168 have led to valuable structural information enabling the discovery of thousands of homologous sequences and enzyme mutants20,21,22,23 The application of TAs in organic synthesis has been extensively reviewed in the last decade, and the focus of this discussion is to use selected examples to illustrate basic principles of conducting 𝜔-TAs at scale.24,25,26,27,28,29,30,31,32 F F

F O

O N

N F

N

N

CF3

TA CDX-017 (5.8 g/l), PLP (0.1 g/l)

F

N

Me

N Sitagliptin

N

CF3

87–90%, >99.9% ee

O

Me

NH2 O N

DMSO (48%), pH 8.5 triethanolamine buffer (50 mM), 300 Torr, 45 °C, 15 h NH2

Me

F

Me

Through collaboration between Codexis and Merck, protein engineering on the 𝜔-TA from Arthrobacter sp. KNK168, generated an enzyme that performed at 200 g/l substrate load in the presence of 50% DMSO, with excellent activity and enantioselectivity.33 The final catalyst contains 27 amino acid substitutions, with only seven active site residues being mutated. The process is performed at multi-kilogram scale, at 45 ∘ C using a fed batch addition of substrate and isopropylamine, and reduced pressure to shift the equilibrium by removing the coproduct acetone, thus driving the reaction to completion. F

F

ATA-47 (0.15 g/l), PLP (1.2 g/l)

O

NH3+•HPO 4−

30 °C, 15 h-pH 7.3

F

NH3+•HPO 4− Me

Me

F >94%, >99% ee

O Me

Me

Another strategy to shift the equilibrium of TA reactions toward complete conversion involves the removal of product or coproduct via precipitation or chemical reaction.34,35,36 The transamination of a highly insoluble difluorotetralone to produce enantiopure aminotetralin with >99% ee was conducted in the presence of aqueous isopropylamine phosphate 20 Martin, A. R.; DiSanto, R.; Plotnikov, I.; Kamat, S.; Shonnard, D.; Pannuri, S. Biochemical Engineering Journal 2007, 37, 246–255. 21 Shin, J.-S.; Kim, B.-G.; Liese, A.; Wandrey, C. Biotechnology and Bioengineering 2001, 73, 179–187. 22 See Note 16. 23 Yamada, Y. K., (JP); Iwasaki, A. (Akasahi, JP); Kizaki, N. (Takasago, JP); Ikenaka, Y. (Akashi, JP); Ogura, M. (Ono, JP); Hasegawa, J. (Akashi, JP). (R)-transaminase from arthrobacter. United States6344351 2002. 24 See Note 17. 25 Hoehne, M.; Bornscheuer, U. T. Application of transaminases. in: K. Drauz, H. Gröger, O. May (Eds.), Enzyme Catalysis in Organic Synthesis (3rd Ed.), Vol. 2, Wiley-VCH: Weinheim, 2011, pp. 779-820. 26 Mathew, S.; Yun, H. ACS Catalysis 2012, 2, 993–1001. 27 Mutti, F. G.; Kroutil, W. Asymmetric bio-amination of ketones in organic solvents. Advanced Synthesis and Catalysis, 2012, 354, 3409–3413. doi:10.1002/adsc.201200900. 28 Berglund, P.; Humble, M. S.; Branneby, C. In Comprehensive Chirality; Elsevier: Amsterdam, 2012, p. 390–401. 29 Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.; Emerson, K. M. Organic Process Research & Development 2014, 18, 215–227. 30 Kelly, S. A.; Pohle, S.; Wharry, S.; Mix, S.; Allen, C. C. R.; Moody, T. S.; Gilmore, B. F. Chemical Reviews 2017, 1, 349–367. 31 Guo, F.; Berglund, P. Green Chemistry 2017, 19, 333–360. 32 Calvelage, S.; Dörr, M.; Höhne, M.; Bornscheuer, U. T. Advanced Synthesis & Catalysis 2017, 359, 4235–4243. 33 Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science 2010, 329, 305–309. 34 Heintz, S.; Boerner, T.; Ringborg, R. H.; Rehn, G.; Grey, C.; Nordblad, M.; Kruehne, U.; Gernaey, K. V.; Adlercreutz, P.; Woodley, J. M. Biotechnology and Bioengineering 2017, 114, 600–609. 35 Burns, M.; Martinez, C. A.; Vanderplas, B.; Wisdom, R.; Yu, S.; Singer, R. A. Organic Process Research & Development 2017, 21(6), 871–877. 36 Truppo, M. D.; Rozzell, J. D.; Turner, N. J. Organic Process Research & Development 2010, 14, 234–237.

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15 Biocatalysis

as an amine donor and buffer. The transformation was performed as a slurry reaction in 100% aqueous media, due to the limited solvent stability of the enzyme. The aminotetralin product was precipitated as the phosphate salt in situ, and quantitatively recovered from the reaction. The process was scaled up to >50 kg quantities for the S enantiomer using c-LEcta’s ATA-47, with ketone to enzyme ratio >200 : 1 (w/w).37 Synthesis of (R)-aminotetralin was also carried out at multigram scale with an Aspergillus 𝜔-TA. The equilibrium of a TA reaction can also be shifted toward complete conversion by coupling the amine generation to a second chemical reaction. This method has been successfully applied to the transamination of ethyl 4-acetylbutyrate at 50 g/l yielding 6-methyl-2-piperidone in >90% isolated yield and >99% ee.38 The same principle has been explored in multiple transaminase cascade reactions aimed at coupling several reactions in one vessel.39 O

ATA-113 (5 g/l), PLP (0.5 g/l)

O

Me

OEt

Potassium phosphate buffer (100 mM), 20 °C, 15 h-pH 9.5 NH2

Me

NH2 Me

O

O

Me

Me

OEt >90%, >99% ee

O

Me

H N

Me

TAs have also been reported in dynamic kinetic resolution (DKR) processes involving racemic aldehydes to produce the corresponding amines.40 An aqueous solution of a bisulfate adduct of the aldehyde (∼100 g/l substrate load) was used in the transamination reaction, yielding a cyclized product in 84% isolated yield. The transamination occurs only with the (S)-enantiomer of the aldehyde, and the unreacted R-aldehyde isomer is racemized under the alkaline reaction conditions in sodium borate buffer. O-iPr

O

Sodium borate buffer (200 mM), 45 °C, 44 h-pH 10.5

O

Br

H N

ATA-302 (37 g/l), PLP (1.0 g/l)

CHO

NH2 Me

>84%, >99% ee

O

Me

Me

Me

In another unique example, ATA-036 catalyzes the highly efficient transamination with DKR on a 2-substituted-Nmethylpiperidin-4-one in high conversion and excellent selectivity.41 The racemization of the unreacted enantiomer occurred at 40 ∘ C in the presence of 25% DMSO and aqueous buffer at pH 10, via a proposed retro-aza-Michael reaction mechanism. O

O H N

N Me

N

H N

NH Me

NH2

ATA-036 (10 g/l), PLP (0.5 g/l)

N

NH2 Me

Me

H N

N

Water, 25% DMSO 50 °C, 50 h, pH 10.0

Me

N

O Me

Me

>85%, >99% ee 10 : 1 anti/syn

In general, wild type TAs display a rather narrow substrate scope, and there is often a need to employ enzyme engineering to produce enzymes for industrially relevant process applications. In addition, enzyme stability is another major challenge to industrial application of TAs, especially when cosolvents and extreme conditions in terms of pH

37 38 39 40 41

See Note 35. See Note 36. Simon, R. C.; Richter, N.; Busto, E.; Kroutil, W. ACS Catalysis 2014, 4, 129–143. See Note 29. Peng, Z.; Wong, J. W.; Hansen, E. C.; Puchlopek-Dermenci, A. L. A.; Clarke, H. J. Organic Letters 2014, 16, 860–863.

15.2 Group Transfer Reactions

and temperature are required. The amination of sterically hindered ketones is also challenging, and promising results have been reported for novel R and S selective enzymes.42,43 15.2.2

Reactions Catalyzed by Hydrolases

Hydrolases catalyze the hydrolytic cleavage of covalent bonds, and in some cases, the formation of the same linkages. Depending on the enzyme class, substrates can range from esters and lactones, amides, hydantoins, nitriles, epoxides, glycosides, and complex sugars. One attractive characteristic of hydrolases and a key advantage for their use in biocatalysis is that they are cofactor independent and therefore reactions are simple to set up. Early synthetic applications were facilitated by the availability of industrial enzymes from applications outside of chemical synthesis such as the detergent, paper, leather, and food industries, which provided enzymes widely available at low cost. Commercial lipases from Candida antarctica (CAL-B), Thermomyces lanuginosus (TLL), Rhizomucor miehei (RML), Pseudomonas cepacia (PCL), Candida rugosa (CRL) and proteases from Bacillus lentus (savinase), and Bacillus licheniformis (alcalase) and esterases from pig liver (PLE) are frequently reported for use in chemical synthesis.44 Hydrolases have been applied to the preparation of complex chiral carboxylic acid, often involving regio- and stereoselectivity, and in desymmetrization reactions on meso substrates bearing ester, amine, and alcohol functional groups. 15.2.2.1

Chiral Carboxylic Acids and Amides from Esters

The enzymatic hydrolysis of esters generates a carboxylic acid that ionizes in aqueous buffer and typically requires addition of a base to maintain favorable pH for the enzymatic reaction. While kinetic resolution of racemic esters is inherently inefficient due to the theoretical yield of 50%, the reaction can be useful for inexpensive esters and particularly when the undesired isomer can be recycled. The synthesis of a precursor for pregabalin, the active component of the drug Lyrica, represents an example where the hydrolytic kinetic resolution of an ester is done at very high concentration (750 g ester/l) in water using lipolase, the commercial lipase from T. lanuginosus. Efficient recycling of the undesired R-enantiomer using sodium ethoxide in ethanol was also demonstrated in this example.45 T. lanuginosus Lipase

CO2Et Me

CO2Et Me

CN

H2O, pH 7.0 30°C, 24h

CO2Et Me

CO2Et

Me CO2Et + Me

CO2H Me

CN

CN

>45%, >99% ee Sodium ethoxide/ ethanol

Recently, a protease-catalyzed kinetic resolution of a 2-propylsuccinate diester was conducted at greater than 10 kg scale and at 100 g/l substrate loading, with 42% yield and 97% ee to enable the synthesis of the antiepileptic drug Brivaracetam. The racemization of undesired S-enantiomer was also demonstrated and provided greater than 50% yield.46 O MeO

Me

B. subtilis Protease C

H2O, pH 8.5 CO2t-Bu 30°C, 18h

O MeO

O Me CO2t-Bu

+ HO

Me CO2t-Bu

>42%, >97% ee TBD/toluene at 80 °C, 2 h

Hydrolases are also commonly used in the desymmetrization of diesters. The synthesis of a 3-hydroxy-glutaric acid monoester precursor of rosuvastatin, the active component of the drug Crestor, started with a hydrolytic desymmetrization of a meso diethyl glutarate at 492 g/l, with quantitative conversion and 97% ee for the R isomer.47 The multi 42 Pavlidis, I. V.; Weiß, M. S.; Genz, M.; Spurr, P.; Hanlon, S. P.; Wirz, B.; Iding, H.; Bornscheuer, U. T. Nature Chemistry 2016, 8, 1076. 43 Weiß, M. S.; Pavlidis, I. V.; Spurr, P.; Hanlon, S. P.; Wirz, B.; Iding, H.; Bornscheuer, U. T. ChemBioChem 2017, 18, 1022–1026. 44 Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio-and Stereoselective Biotransformations; John Wiley & Sons, 2006. 45 Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Organic Process Research & Development 2008, 12, 392–398. 46 Schülé, A.; Merschaert, A.; Szczepaniak, C.; Maréchal, C.; Carly, N.; O’Rourke, J.; Ates, C. Organic Process Research & Development 2016, 20, 1566–1575. 47 Metzner, R.; Hummel, W.; Wetterich, F.; König, B.; Gröger, H. Organic Process Research & Development 2015, 19, 635–638.

685

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15 Biocatalysis

kilogram scale hydrolysis of a similar prochiral glutarate 3-aryldiester to yield the (S)-configuration has also been reported with lipase B from C. antarctica as the catalyst.48 O

OAc O

EtO

O

α-Chymotrypsin 50 mM KPB, pH 8.0 25 °C, 24 h

OEt

OAc O

HO

OEt >95%, 97% ee

The enzyme catalyzed intramolecular aminolysis of a meso fluoroester resulted in an enantiopure (S)-fluorolactam in >99% ee.49 The reaction is catalyzed by immobilized CAL-B and carried out in aqueous buffer with no observed hydrolysis. The enzyme is recovered quantitatively and recycled three times with no loss of activity. O MeO

O

F

O

CAL-B OMe NH3+Cl−

60 mM KPB, pH 7.3 20 °C, 8 h

F

MeO

O NH

43%, 99% ee

PLE is one of the most versatile biocatalysts having been reported for kinetic resolutions and desymmetrizations of prochiral substrates and nucleoside derivatives.50 The enzyme is also available at a relatively low cost and displays high operational stability and very broad substrate specificity. During the past decade, recombinant versions of PLE have been reported in scale up applications and offer great promise for the use of this versatile esterase. A notable example is the desymmetrization of dimethyl cyclohex-4-ene-cis-1,2-dicarboxylate by a recombinant isoform of PLE, yielding >82% conversion to the (1S,2R)-monoester in >99% ee and at 350 g scale.51 CO2Me CO2Me

ECS-PLE6 Aqueous NaHCO3 40 °C, 4 h, pH8

CO2H CO2Me >82% , >99% ee

The hydrolysis of highly water insoluble esters is still problematic, and the use of cosolvents is quite common and necessary in such situations. An alternative approach involves the use of water saturated organic solvents as a potential option for hydrolysis, but at present this methodology is not practical due to low reaction rates. 15.2.2.2

Acylation of Racemic and Prochiral Alcohols and Amines in Organic Solvents

The enzyme mediated direct esterification of carboxylic acids in the presence of alcohols, is a much less common transformation in organic chemistry as it lacks generality, and requires the removal of water from the reaction.52 In most synthetic applications, the use of an enol ester acyl donor is preferred. These reactions can be carried out in a broad range of organic solvents, and the work up typically consists of a simple filtration to remove the enzyme, followed by concentration of the filtrate containing the product. The lipases used in most applications are commercially available and typically immobilized in acrylate polymers.53 The regioselective acylation of a primary alcohol intermediate to reboxetine in the presence of a secondary alcohol was carried out at 30 ∘ C in toluene using isopropenyl acetate. The acylation was conducted at 200 g/l, under mild conditions and approximately 50 : 1 diol:enzyme (wt:wt). The enzyme was removed by filtration and the filtrate progressed to the next step.

48 Homann, M. J.; Vail, R.; Morgan, B.; Sabesan, V.; Levy, C.; Dodds, D. R.; Zaks, A. Advanced Synthesis & Catalysis 2001, 343, 744–749. 49 Willis, N. J.; Fisher, C. A.; Alder, C. M.; Harsanyi, A.; Shukla, L.; Adams, J. P.; Sandford, G. Green Chemistry 2016, 18, 1313–1318. 50 Domínguez de María, P.; García-Burgos, C. A.; Bargeman, G.; van Gemert, R. W. Synthesis 2007, 2007, 1439–1452. 51 Süss, P.; Illner, S.; von Langermann, J.; Borchert, S.; Bornscheuer, U. T.; Wardenga, R.; Kragl, U. Organic Process Research & Development 2014, 18, 897–903. 52 Stergiou, P.-Y.; Foukis, A.; Filippou, M.; Koukouritaki, M.; Parapouli, M.; Theodorou, L. G.; Hatziloukas, E.; Afendra, A.; Pandey, A.; Papamichael, E. M. Biotechnology Advances 2013, 31, 1846–1859. 53 Adlercreutz, P. Chemical Society Reviews 2013, 42, 6406–6436.

15.2 Group Transfer Reactions

OEt

OEt CAL-B

O

O

Toluene, 30 °C, 17 h i-PropenylOAc (2 equiv)

OH OH

OAc OH >82%, >99% ee

The desymmetrization of a substituted cyclopenten-1,3-diol to a monoacetate with isopropenyl acetate as the acylating agent, took place in 80% yield and 98% ee.54 The reaction was catalyzed by lipase PS-30 (100 wt% with respect to diol) from P. cepacia in heptane/MTBE (methyl-t-butyl ether) (10 : 1) and 2 equiv of isopropenyl acetate. Excellent reviews have been published on enzymatic desymmetrization.55 OBn HO

OH

Lipase PS, 33 °C, 72 h Heptane/MTBE 10 : 1 i-PropenylOAc (2 equiv)

OBn AcO

OH

>82%, >99% ee

The enzymatic resolution and desymmetrization of amines utilizes acyl donors such as ethyl acetate, isopropyl acetate, diethyl malonate, and carbonates. The versatility of CAL-B has been demonstrated in the resolution of a cyclohexylamine, with 20 : 1 amine to enzyme ratio and 100 g/l substrate load.56 H2N

CO2i-Pr

CAL-B

AcHN

CO2i-Pr

iPrOAc, 20 °C, 12 h >40%, >99% ee, (recrystallyzed from 86% ee)

A DKR of racemic aminoindane using CAL-B and a Pd nanocatalysts at high substrate loads also has the potential to have broad applicability.57 The solvent-free amidation of racemic methyl benzylamine with diethyl malonate also has great potential for large-scale applications.58 In terms of the applicability of enzymes for amide bond formation beyond acetylation, enzymes do not offer a general methodology, as reviewed recently.59 The desymmetrization of 2-(2-methylbenzyl)propane-1,3-diamine has been demonstrated at multi-kilogram scale.60 The reaction takes place in 2-methyl THF (tetrahydrofuran) in the presence of three equivalents of diallyl carbonate. Me H2N H2N

Amano PS lipase Diallyl carbonate 30 °C, 12 h

Me

O O

N H NH2

>40%, >99% ee (recrystallyzed from 86% ee)

15.2.2.3

Miscellaneous Hydrolases

Epoxide hydrolases (EPHx), nitrilases, and nitrile hydratases are also used in organic synthesis but, in general, have lower commercial availability compared to hydrolases described in Sections 15.2.2.1 and 15.2.2.1.2. Epoxide hydrolases catalyze the selective hydrolysis of epoxides and are often used in biphasic reaction media to minimize background hydrolysis. The resolution of 2-butyl-2-ethyloxyrane has been scaled up at 300 g/l substrate concentration using an 54 Patel, R. N.; Banerjee, A.; Pendri, Y. R.; Liang, J.; Chen, C.-P.; Mueller, R. Tetrahedron: Asymmetry 2006, 17, 175–178. 55 García-Urdiales, E.; Alfonso, I.; Gotor, V. Chemical Reviews 2011, 111, PR110–PR180. 56 Karlsson, S. Organic Process Research & Development 2016, 20, 1336–1340. 57 Ma, G.; Xu, Z.; Zhang, P.; Liu, J.; Hao, X.; Ouyang, J.; Liang, P.; You, S.; Jia, X. Organic Process Research & Development 2014, 18, 1169–1174. 58 Uthoff, F.; Reimer, A.; Liese, A.; Gröger, H. Sustainable Chemistry and Pharmacy 2017, 5, 42–45. 59 Dorr, B. M.; Fuerst, D. E. Current Opinion in Chemical Biology 2018, 43, 127–133. 60 Lindhagen, M.; Klingstedt, T.; Andersen, S. M.; Mulholland, K. R.; Tinkler, L.; McPheators, G.; Chubb, R. Organic Process Research & Development 2016, 20, 65–69.

687

688

15 Biocatalysis

enzyme from Agromyces mediolanus in phosphate buffer. The desired R epoxide was obtained in 20% isolated yield after a distillation to separate the enantiopure epoxide from the diol.61 EPHx from A. mediolanus

Bu

O

Et

Potassium phosphate buffer, 30 °C, 12 h

O

HO

Bu

+

Et

OH

20%, >99% ee

Bu Et

Nitrilases catalyze the hydrolysis of nitriles to produce carboxylic acids. A recent report by Wang et al. highlights a cost-effective and highly efficient enantioselective nitrilase from Burkholderia cenocepacia J2315 which was used for the biotransformation of mandelonitrile to (R)-mandelic acid. The whole cells containing the nitrilase were used in a multi-kilogram fed-batch reaction to reach product concentrations approaching 350 g/l with 97.4% ee.62 OH CN

OH

Nitrilase in E. coli cells 10 g/l

CN

Sodium phosphate buffer pH 8.0, 30 °C, 25 h

OH +

COOH >80%, 97.4% ee

Spontaneous racemization

Nitrile hydratases catalyze the selective hydrolysis of nitriles to produce the corresponding carboxamide. The reaction is illustrated by the selective hydrolysis of 3-cyano pyridine to nicotinamide as reported by Li et al. at >200 g/l substrate concentration using a commercial hydratase at 100 : 1 substrate to enzyme ratio, in under five hours.63 O CN N

NHT-120 Potassium phosphate buffer pH 7.5, 30 °C, 20 h

NH2 N >98% yield

15.3 Reductions Enzymatic reactions are available for several functional group reductions. The enzyme-catalyzed reduction of carbonyl compounds is well established for the preparation of stereochemically defined alcohols. Another useful enzymatic transformation provides access to chiral alkanes through the asymmetric reduction of activated alkenes. Recently, the enzymatic reduction of imines has been investigated for the synthesis of primary and secondary amines. These biocatalytic functional group reductions all require nicotinamide cofactors that are impractical to use as stoichiometric reagents due to their cost. However, several efficient methods are available for recycling these cofactors in situ enabling their use in catalytic quantities. Efficient recycling of cofactors is required for the practical application of enzymatic reductions and a variety of methods have been developed.64 Two strategies are commonly used for recycling nicotinamide cofactors. One of these strategies uses glucose dehydrogenase (GDH) to oxidize glucose to gluconic acid. The oxidation of glucose is irreversible and therefore helps drive the reduction. GDH uses NAD+ or NADP+ and is highly active and therefore low loadings of this enzyme are typically used. Addition of a base is often required to control pH due to the production of gluconic acid. The second commonly used cofactor recycling strategy involves the enzyme catalyzed oxidation of isopropanol to acetone. A second enzyme may be required for oxidation of isopropanol, but frequently this reaction can also be catalyzed by the ketoreductase (KRED) used for reduction of the target substrate. Removal of acetone and an excess of isopropanol are typically used to drive this equilibrium reaction. Another practical method for recycling of NAD+ utilizes the oxidation of formate catalyzed by formate dehydrogenase. Oxidation of formate is irreversible which helps to drive the reduction, and pH control is not required with this method. This 61 Roiban, G.-D.; Sutton, P. W.; Splain, R.; Morgan, C.; Fosberry, A.; Honicker, K.; Homes, P.; Boudet, C.; Dann, A.; Guo, J.; Brown, K. K.; Ihnken, L. A. F.; Fuerst, D. Organic Process Research & Development 2017, 21, 1302–1310. 62 Wang, H.; Fan, H.; Sun, H.; Zhao, L.; Wei, D. Organic Process Research & Development 2015, 19, 2012–2016. 63 Li, B.; Su, J.; Tao, J. Organic Process Research & Development 2011, 15, 291–293. 64 Huisman, G. W.; Liang, J.; Krebber, A. Current Opinion in Chemical Biology 2010, 14, 122–129.

15.3 Reductions

section presents examples of various enzyme-catalyzed functional group reductions along with typical procedures for recycling nicotinamide cofactors. Reduction of C=C Bonds

15.3.1

The practical application of biocatalytic C—C bond reduction has focused on alkene substrates conjugated to electron-withdrawing groups (e.g. carbonyl, carboxylic acid and derivatives, nitrile, nitro). Enzymes that catalyze conjugate alkene reductions are generally referred to as ene-reductases (EREDs) that belong primarily to the “old yellow enzyme” family of nicotinamide-dependent flavoenzymes.65,66 ERED-catalyzed reductions result in the addition of hydrogen across the double bond in a trans-specific fashion. Currently, the commercial availability of EREDs is limited, and many applications utilize these enzymes as whole cell biocatalysts expressed in E. coli. Alkenes activated with two ester moieties successfully undergo reduction with EREDs, while alkenes conjugated to a single ester moiety are generally poor substrates. Reduction of dimethyl 2-methylmaleate to dimethyl (R)-2-methylsuccinate was carried out with an ERED identified by screening of a commercial enzyme kit.67 O

O

Me

OMe OMe

ERED ER-104

Me

OMe OMe

CRED, NAD+, i-PrOH

O

O 91%, 99.8% ee

NAD+ was recycled by a carbonyl reductase (CRED) that catalyzed the oxidation of the isopropanol cosubstrate. The reaction was carried out on a 70 g scale with air sparging to remove the acetone coproduct. Recently, Wang and others reported using EREDs to prepare enantioenriched 2-aryl substituted succinate derivatives from 2-aryl 1,4-dicarbonyl compounds.68 O Ar

O R1

R2

ERED Glucose dehydrogenase glucose, NADP+ phosphate buffer

O

Ar

Ar = Ph, 4-FPh, 4-Cl-Ph, 3-CF3Ph R1 = OMe, Ot-Bu, Me R2 = OEt, Ot-Bu, OBn, 4-FPh

R1

R2 O 69–85%, 85–99% ee

Alkenes conjugated to nitrile groups are also substrates for EREDs. Reduction of (Z)-2-phenylbut-2-enenitrile with ERED 112 afforded (R)-2-phenylbutanenitrile in 98% ee.69 NADP+ was recycled using phosphite dehydrogenase to reduce sodium phosphite. Ph

CN

ERED 112

Me

Phosphite dehydrogenase sodium phosphite, NADP+

Ph

CN Me

70%, 98% ee

Reduction of a β-cyanoacrylate ester enabled a novel asymmetric route to pregabalin.70 Ethyl (E)-3-cyano-5methylhex-2-enoate was reduced with ERED OPR1 to give ethyl (S)-3-cyano-5-methylhexanoate, an advanced intermediate to pregabalin. OPR1 was one of several EREDs identified in a screen for reduction of (E)-alkene to the 65 Williams, R. E.; Bruce, N. C. Microbiology 2002, 148, 1607–1614. 66 Scholtissek, A.; Tischler, D.; Westphal, A. H.; van Berkel, W. J.; Paul, C. E. Catalysts 2017, 7, 130. 67 Mangan, D.; Miskelly, I.; Moody, T. S. Advanced Synthesis & Catalysis 2012, 354, 2185–2190. 68 See Note 14. 69 Kosjek, B.; Fleitz, F. J.; Dormer, P. G.; Kuethe, J. T.; Devine, P. N. Tetrahedron: Asymmetry 2008, 19, 1403–1406. 70 Debarge, S. B.; McDaid, P.; O’Neill, P.; Frahill, J.; Wong, J. W.; Carr, D.; Burrell, A.; Davies, S.; Karmilowicz, M.; Steflik, J. Organic Process Research & Development 2014, 18, 109–121.

689

690

15 Biocatalysis

pregabalin precursor.71 The reaction was carried out with OPR1 expressed in E. coli cells and Lactobacillus brevis alcohol dehydrogenase (ADH) to oxidize isopropanol for NADP+ recycling. The double-bond geometry was an important consideration in this work as ethyl (Z)-3-cyano-5-methylhex-2-enoate was not a substrate for the EREDs tested. However, the ester moiety also appeared to play a role in substrate recognition as the methyl ester of the (Z)-alkene was a substrate for OPR1 and other EREDs. Me

CN

Me

ERED OPR1

Me

Me

LbADH, IPA, NADP+

CO2Et

CN CO2Et

69%, 99% ee

Development of a process for the synthesis of ethyl (S)-2-ethoxy-3-(p-methoxyphenyl)propanoate (EEHP), an intermediate for the synthesis of PPAR-α/γ agonists such as Tesaglitzar, illustrates the application of EREDs for the reduction of enals.72 The enal reduction was carried out with Old Yellow Enzyme 3 (OYE3) and GDH separately expressed in E. coli. XAD 1180 resin was used to maintain enal and product concentrations at levels that avoided inhibitory effects on OYE3. Oxidation of the reduction product gave EEHP in 94% yield and 98% ee over two steps. O H OEt

MeO

O

OYE3

H

GDH, glucose, NADP+ phosphate buffer MeO XAD 1180

OEt

O

NaClO2 t-BuOH H2O

OH OEt

MeO

94%, 98% ee

Brenna et al. reported the application of EREDs and ADHs to prepare the four stereoisomers of the insect pheromone, 4-methylheptan-3-ol, from the corresponding enone.73 Reduction of enone with OYE2.6 gave (R)-ketone while reduction with OYE1-W116V afforded the (S)-ketone. Four separate reactions with sequential addition of ERED and ADH gave each of the four stereoisomers of 4-methylheptan-3-ol in high enantiomeric and diastereomeric excess with absolute configuration determined by the choice of enzymes. NADP+ was recycled in both reactions using GDH and glucose. O Me

Me Me

ERED OYE2.6 or OYE1-W116V GDH, glucose, NADP+ phosphate buffer

O Me

* Me

Me

OH

ADH 270 or 440 GDH, glucose, NADP+ phosphate buffer

Me

* Me

Me *

(3R,4R): 83%, 99% ee, 99% de (3S,4R): 76%, 99% ee, 99% de (3R,4S): 81%, 99% ee, 92% de (3S,4S): 72%, 99% ee, 94% de

15.3.2

Reductive Amination of 𝛂-Ketoacids to 𝛂-Amino Acids

Amino acid dehydrogenases (AADHs) catalyze the interconversion of 2-ketoacids and α-amino acids and have been exploited for the synthesis of proteinogenic and nonproteinogenic amino acids.74,75 The mechanism for amination involves enzyme catalyzed coupling of a 2-ketoacid with ammonia to form an imino acid intermediate which is then reduced by the nicotinamide cofactor to give the amino acid product. Stereoselectivity is typically very high and enzymes such as leucine dehydrogenase (LeuDH) and phenylalanine dehydrogenase (PheDH) catalyze the formation of l-amino acids. Parker and coworkers at BMS reported using LeuDH to prepare a key intermediate for a corticotropin 71 Winkler, C. K.; Clay, D.; Davies, S.; O’Neill, P.; McDaid, P.; Debarge, S.; Steflik, J.; Karmilowicz, M.; Wong, J. W.; Faber, K. The Journal of Organic Chemistry 2013, 78, 1525. 72 Bechtold, M.; Brenna, E.; Femmer, C.; Gatti, F. G.; Panke, S.; Parmeggiani, F.; Sacchetti, A. Organic Process Research & Development 2011, 16, 269–276. 73 Brenna, E.; Crotti, M.; Gatti, F. G.; Monti, D.; Parmeggiani, F.; Pugliese, A. Molecules 2017, 22, 1591. 74 Hummel, W. Trends in Biotechnology 1999, 17, 487–492. 75 Mangas-Sanchez, J.; France, S. P.; Montgomery, S. L.; Aleku, G. A.; Man, H.; Sharma, M.; Ramsden, J. I.; Grogan, G.; Turner, N. J. Current Opinion in Chemical Biology 2017, 37, 19–25.

15.3 Reductions

releasing factor-1 receptor antagonist.76 A reaction on 50 g of ketoacid was performed in water (8.2 vol) with 2 equiv of ammonium formate for recycling NAD+ (0.15 mol%). LeuDH and FDH were prepared by fermentation of recombinant E. coli and prepared as clarified lysates which could be stored at –20 ∘ C for four months without loss of activity. CO2−K+

LeuDH

CO2H

FDH, NAD+ NH2 ammonium formate (2 equiv) 99%, 99% ee pH 8, 40 °C, 17 h

O

BMS workers also reported the synthesis of (R)-2-amino-5,5,5-trifluoropentanoic acid from the corresponding ketoacid using a d-AADH with glucose-GDH for NADP+ recycling.77 A reaction on 60 g of ketoacid gave 84% yield and 100% ee using commercial AADH and GDH. Park et al. reported the preparation of an (S)-amino acid using commercial AADH and GDH.78 The enzymatic reaction was the second step in a one-pot three-step process and afforded an assay yield of 88% and 99.8% ee. O

NH2

CDX-012 CO2−Na+

GDH, glucose, NH4Cl NAD+, 30 °C, overnight

CO2− Na+ 88%, 99.8% ee

15.3.3 15.3.3.1

Reduction of C=O Bonds Reduction of Ketones and Aldehydes

Reductions of ketones and aldehydes using enzymatic methods are well established for the practical preparation of chiral alcohols.79 Enzymes that catalyze these transformations include ADHs and KREDs, which are also referred to as CREDs. Many KRED enzymes are commercially available or can be prepared by fermentation of recombinant microorganisms. The mechanism of carbonyl reduction with KREDs involves hydride transfer from nicotinamide cofactors. The examples presented illustrate the selectivity and substrate scope of enzyme-catalyzed carbonyl reductions. Enzymatic reductions carried out with microorganisms such as Baker’s yeast were often reported under dilute conditions due to several drawbacks including low levels of enzymes and/or low activity of the enzymes under process conditions. The availability of isolated enzymes produced by recombinant microorganisms and enzymes improved by genetic engineering has enabled contemporary enzymatic processes that operate under a wide range of conditions at concentrations rivaling those of chemical processes. An intermediate for a γ-secretase inhibitor, tert-butyl (R)-2-hydroxypentanoate was prepared by enzymatic reduction of a ketoester.80 A reaction was carried out on 35 kg of ketoester in approximately 13 volumes of phosphate buffer and glycerol and utilized low enzyme loadings of ADH-108L (0.16 wt%) and GDH (0.19 wt%). NAD+ (0.09 mol%) was efficiently recycled using GDH and glucose. O Me

OH

ADH-108L CO2t-Bu

GDH, glucose, NAD+ phosphate buffer, 25 °C

Me

CO2t-Bu

88%, 96.7% ee

An engineered KRED was used in a process for an intermediate to montelukast, the active pharmaceutical ingredient in Singulair.81 A reaction carried out on 230 kg of ketone as a slurry in a mixture of isopropanol, toluene, and triethanolamine buffer, afforded 97% yield. During the reaction, crystallization of the monohydrate of the alcohol product helped to drive the reaction to very high conversion without the need to remove acetone. CDX-026 also served to recycle NADP+ by oxidizing isopropanol to acetone. The process mass intensity (PMI) of the enzymatic reaction (PMI ∼34) compared favorably to a process using diisopinocampheylchloroborane (DIP-Cl) (PMI ∼52).

76 77 78 79 80 81

Parker, W. L.; Hanson, R. L.; Goldberg, S. L.; Tully, T. P.; Goswami, A. Organic Process Research & Development 2012, 16, 464–469. Hanson, R. L.; Johnston, R. M.; Goldberg, S. L.; Parker, W. L.; Goswami, A. Organic Process Research & Development 2013, 17, 693–700. Park, J.; Moore, J. C.; Xu, F. Organic Process Research & Development 2015, 20, 76–80. Wildeman, S. M. A. D.; Sonke, T.; Schoemaker, H. E.; May, O. Accounts of Chemical Research 2007, 40, 1260–1266. See Note 35. See Note 64.

691

692

15 Biocatalysis

O

N

Cl

CO2Me

KRED CDX-026

N

Cl

OH

CO2Me

i-PrOH, toluene, triethanolamine buffer, NADP+, 40–45 °C, 45 h 97.2%, >99.9% ee

Codexis workers reported development of a scalable process for (S)-licarbazepine using another engineered KRED.82 The process was carried out on 50 g of ketone and afforded 96% yield of crude (S)-licarbazepine after distillation to remove isopropanol and filtration to recover the solid product. KRED CDX-021 was also used to recycle NADP+ by oxidation of isopropanol and a nitrogen sweep was utilized to remove acetone to drive the reaction. O

HO KRED CDX-021 IPA, NADP+, 55 °C, 24 h triethanolamine buffer NADP+ , 55 °C, 24 h

NH2

O

O

NH2

96%, >99.9% ee

Guo et al. reported using a wild-type KRED from Leifsonia sp. S749 to prepare (S)-2-chloro-1-(3,4-difluorophenyl) ethanol, an intermediate for Ticagrelor.83 The enzyme (KR-01) was overexpressed in a recombinant E. coli strain and used in the form of a wet cell paste. The process was carried out under very concentrated conditions in isopropanol and phosphate buffer. KR-01 was also used to recycle NAD+ by oxidation of isopropanol. The authors also reported the use of KR-01 to prepare (R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethanol from the corresponding acetophenone in 95% yield and >99.9% ee. O F

Cl

F

OH

KRED KR-01 (10 wt% wet cells)

F

i-PrOH (1.4 vol) phosphate buffer (0.6 vol), NAD+, 35 °C, 18 h

F

Cl

96%, >99.9% ee

Fryszkowska et al. discovered a wild-type KRED from Sphingomonas wittichii for the reduction of 5-androstene-3,17dione (5-AD) to dehydroepiandrosterone (DHEA).84 The KRED was cloned and overexpressed in a recombinant E. coli strain. The highly stereo- and regioselective reaction gave DHEA with 0.5% diol but no detectable 3α-epimer. Me O Me O

Me O

S. wittichii KRED (0.25 wt%) GDH CDX-901 (0.1 wt%), glucose (1.2 equiv) EtOAc(10 vol), phosphate buffer (5 vol, pH 6.3) NADP+, 33 °C, 21 h

Me HO 90%, >99 de

KREDs have been used to perform highly diastereoselective carbonyl reductions.85 Hanson et al. at BMS reported the preparation of two 𝛼-substituted chiral alcohols using enzymatic reduction.86 In both cases, a single diastereomer was obtained exclusively as a result of stereoselective reduction of 𝛼-substituted ketones involving DKR. Reduction of the Cbz-protected aminoketone on a 1 g scale with KRED-245 afforded only the 1S,2R-diastereomer in high yield. However, the dilute conditions and high enzyme loading (40 wt%) of this reaction are not practical for preparation of large quantities of material. Conditions for reduction of piperidinone were practical for scale up and used to prepare 6.2 kg of (3R,4R)-alcohol in high enantiomeric and diastereomeric excess. Interestingly, GDH, which was initially used 82 Modukuru, N. K.; Sukumaran, J.; Collier, S. J.; Chan, A. S.; Gohel, A.; Huisman, G. W.; Keledjian, R.; Narayanaswamy, K.; Novick, S. J.; Palanivel, S. Organic Process Research & Development 2014, 18, 810–815. 83 Guo, X.; Tang, J.-W.; Yang, J.-T.; Ni, G.-W.; Zhang, F.-L.; Chen, S.-X. Organic Process Research & Development 2017, 21, 1595–1601. 84 Fryszkowska, A.; Peterson, J.; Davies, N. L.; Dewar, C.; Evans, G.; Bycroft, M.; Triggs, N.; Fleming, T.; Gorantla, S. S. C.; Hoge, G. Organic Process Research & Development 2016, 20, 1520–1528. 85 Applegate, G. A.; Berkowitz, D. B. Advanced Synthesis & Catalysis 2015, 357, 1619–1632. 86 Hanson, R. L.; Guo, Z.; González-Bobes, F.; Fenster, M. D.; Goswami, A. Journal of Molecular Catalysis B: Enzymatic 2016, 133, 20–26.

15.4 Oxidations

for cofactor recycling, was found to reduce the piperidinone with much higher selectivity than a panel of 24 commercially available KREDs. F

F Cbz

N

H

KRED-245 (40 wt%)

Br N

O

Cbz Br

GDH, glucose phosphate buffer, DMSO NAD+, 30 °C, 41 h

F

N

H

OH

N

F

96%, 99.7% ee, 99.9% de O

OH GDH-105 (2 wt%)

Me N Ph

Glucose Tris/phosphate buffer NAD+, 30 °C, 24 h

Me N Ph 71–73% 99.9% ee, 99.9% de

Another example of enzymatic carbonyl reduction with DKR was reported by Hyde et al. for the preparation of an intermediate for a GPR40 partial agonist.87 A screen of KREDs identified enzymes with high selectivity for the undesired diastereomers, but only a moderately selective enzyme (KRED-208, 2.4 : 1 dr) for the desired diastereomer. To access the desired (S,S)-alcohol, enzyme engineering was undertaken resulting in KRED-264. Reduction of ketoester with KRED-264 gave the desired diastereomer in high yield and dr. Cl

Cl

KRED-264 (2 wt%)

N O

CO2tBu

i-PrOH (10 vol), phosphate buffer (10 vol, pH 9) NADP+(0.09 mol%), 50 °C, 22 h

N OH

CO2tBu

97%, >30 : 1 dr

15.4 Oxidations Biocatalytic oxidations are very attractive as they offer potential advantages of stereo and regio-selectivity compared to chemical oxidations. In addition, enzymatic oxidations are often highly atom economical and environmentally benign since they avoid the use of harsh oxidizing agents including metals such as chromium, manganese, and iron.88 However, enzymatic oxidations are less established and fewer examples at preparative scale have been reported compared to other enzymatic transformations such as those catalyzed by hydrolases, KREDs, and transaminases. 15.4.1

Baeyer–Villiger Monoxygenase (BVMO) Oxidations

Baeyer–Villiger Monoxygenase(BVMOs) catalyze oxidative insertion across C—C bonds in cyclic and acyclic ketones to give corresponding esters or lactones.89 O2 BVMO

O R1

H2O R1

R2 NADPH + H+

NADP+

O

O O

O2

H2O BVMO

O

R2 NADPH + H+

O

NADP+

87 Hyde, A. M.; Liu, Z.; Kosjek, B.; Tan, L.; Klapars, A.; Ashley, E. R.; Zhong, Y.-L.; Alvizo, O.; Agard, N. J.; Liu, G. Organic Letters 2016, 18, 5888–5891. 88 Mallat, T.; Baiker, A. Chemical Reviews 2004, 104, 3037–3058. 89 Mihovilovic, M. D. Current Organic Chemistry 2006, 10, 1265–1287.

693

694

15 Biocatalysis

BVMOs are often employed to catalyze kinetic resolution and desymmetrization of substituted ketones as described in a recent article.90 Among various types of BVMOs, Type 1 with noncovalently bound FAD and NADPH dependence are the most studied and reported for preparative scale reactions. Developments in molecular biology tools have enabled cloning and expression of new, more thermally stable BVMOs resulting in expansion of the pool of BVMO enzymes.91 In a recent article, biocatalytic oxidations of alkyl levulinates to 3-hydroxypropionates and 3-acetoxypropionates were reported on gram scale using an engineered cyclopentanone monooxygenase (CPMO).92 O

Me

BVMO in E. coli

Me

CO2R

O2, NADPH

O

CO2R

O R = Et (~62% conversion)

R = Me, Et, n-Bu, n-Oct, Bn

Advances in enzyme engineering technology have enabled engineering of BVMOs to expand their substrate scope and to make them suitable for large-scale applications.93 Baldwin et al. described in great detail, a successful scale up of BVMOs for oxidative resolution of racemic bicyclo[3.2.0]hept-2-en-6-one.94 This process was successfully conducted in a pilot plant on a 200 l scale. O

O

H 2O

O2

O

CHMO +

E. coli 37 °C, pH 7 NADPH

O

+ O

NADP+

O

BVMOs have also been engineered to expand their substrate scope to include sulfide oxidations.95 A recent report described the successful use of an evolved BVMO enzyme for the synthesis of a pharmaceutical compound on kilogram scale.96 In this process, complete conversion of substrate (100 g/l) was carried out with 5–10 wt% of evolved enzyme in six hours. O

O

N

BVMO/O2

Me

N O

N Me

S

N

Cl

NADPH

Acetone

NADP+

Me

S

Me N

N

Cl

i-PrOH

One of the technical challenges in scaling up BVMO catalyzed reactions is supplying oxygen to the reaction, which is limited by oxygen solubility in aqueous media. This limitation could be alleviated by air sparging to keep the reaction mixture saturated with oxygen. 15.4.2

C—H Oxidations

Enzymatic oxidation of nonactivated C—H bonds is a highly desirable transformation as it can result in high selectivity and often leads to functionalization that would require multiple synthetic steps via chemical methods. Though many 90 Hollmann, F.; Arends, I.W.; Buehler, K.; Schallmey, A.; Buhler, B. Green Chemistry 2011, 13, 226–265. 91 Ceccoli, R. D.; Bianchi, D. A.; Fink, M. J.; Mihovilovic, M. D.; Rial, D. V. AMB Express 2017, 7, 87. 92 Fink, M. J.; Mihovilovic, M. D. Chemical Communications 2015, 51, 2874–2877. 93 Reetz, M. T.; Wu, S. Journal of the American Chemical Society 2009, 131, 15424–15432. 94 Baldwin, C. V.; Wohlgemuth, R.; Woodley, J. M. Organic Process Research & Development 2008, 12, 660–665. 95 Riebel, A.; Dudek, H.; De Gonzalo, G.; Stepniak, P.; Rychlewski, L.; Fraaije, M. Applied Microbiology and Biotechnology 2012, 95, 1479–1489. 96 Goundry, W. R.; Adams, B.; Benson, H.; Demeritt, J.; McKown, S.; Mulholland, K.; Robertson, A.; Siedlecki, P.; Tomlin, P.; Vare, K. Organic Process Research & Development 2017, 21, 107–113.

15.4 Oxidations

examples of enzymatic C—H activation have been reported, practical, scalable examples are uncommon. The activation of molecular oxygen needs to take place before the enzyme is able to catalyze the oxygenation reaction. Depending on the enzyme, this activation can be done using a cofactor such as flavin or pterin (flavin and pterin-dependent aromatic monooxygenases), by a metal such as copper or iron (copper, heme, and nonheme-dependent monooxygenases), and in some cases by the substrate.97,98 The use of hydrogen peroxide as a more reactive oxygen source has also been considered as a viable alternative in the form of cofactor independent peroxygenases.99 The heme-containing cytochrome P450 monooxygenases represent the most thoroughly investigated enzyme class for sp3 and sp2 hybridized carbon atoms and have been extensively reviewed.100,101 However, application of P450s is rather limited for preparative organic synthesis, due to a combination of limited substrate scope, low activity and poor stability.102 One of the notable examples of P450 biocatalytic applications was recently reported by Kaluzna et al.103 using a permeabilized whole cell formulation of a dual expression system consisting of wild-type BM3 and NAD(P)H-dependent GDH in E. coli for the production of 4-hydroxy-α-isophorone on kilogram scale at 10 g/l product concentration with a space time yield of 1.5 g/l/h. OH

Me

Me

Me

Me

Cytochrome P450

+ O2

Me

O

GDH

Glucose

+ H2O

O

NADP+

NADPH + H+

Me

Gluconic acid

Nonheme iron dependent monooxygenases, though limited in substrate scope, seem to have more potential in terms of enzyme activity and stability. Notable biocatalysts in this family are the 2-oxoglutarate (2OG)-dependent oxygenases that utilize 2OG as a reductant that participates in the activation of oxygen in the iron center, and is converted stoichiometrically to succinate. Hara et al. reported the hydroxylation of lysine to form (2S,3S)-3-hydroxylysine at an impressive substrate load of 86.1 g/l in 52 hours. OH H2N

COOH L-lysine

K3H-1, O2

NH2

Fe2+ 2-Oxoglutarate

H2N

COOH NH2

+ CO 2

(2S,3S)-3-hydroxylysine Succinate

Proline hydroxylases (PHs) also belong to the family of 2OG-dependent oxygenases and are potentially useful for the synthesis of proline and pipecolic acid derivatives.104,105 Recently, engineered variants of proline hydroxylase have been reported in the patent literature, to perform reactions under similar conditions as described for lysine, using proline and pipecolic acid.106 15.4.3

C=C Oxidations

Enzymes also catalyze the regio- and enantiospecific hydroxylation of aromatic compounds, which is not always possible via chemical methods. Most of these enzymes are found in arene degradation pathways and are classified based 97 Torres Pazmiño, D. E.; Winkler, M.; Glieder, A.; Fraaije, M. W. Journal of Biotechnology 2010, 146, 9–24. 98 Fetzner, S.; Steiner, R. A. Applied Microbiology and Biotechnology 2010, 86, 791–804. 99 See Note 14. 100 See Note 79. 101 Fasan, R. ACS Catalysis 2012, 2, 647–666. 102 Martinez, C. A.; Rupashinghe, S. G. Current Topics in Medicinal Chemistry 2013, 13, 1470–1490. 103 Kaluzna, I.; Schmitges, T.; Straatman, H.; van Tegelen, D.; Müller, M.; Schürmann, M.; Mink, D. Organic Process Research & Development 2016, 20, 814–819. 104 Koketsu, K.; Shomura, Y.; Moriwaki, K.; Hayashi, M.; Mitsuhashi, S.; Hara, R.; Kino, K.; Higuchi, Y. ACS Synthetic Biology 2015, 4, 383–392. 105 Johanna, M.; Wolfgang, H. ChemBioChem 2017, 18, 1523–1528. 106 Nazor, J.; Osborne, R.; Liang, J.; Vroom, J.; Zhang, X.; Entwistle, D.; Voladri, R.; Garcia, R. D.; Moore, J. C.; Grosser, S.; Kosjek, B.; Truppo, M. Biocatalysts and methods for hydroxylation of chemical compounds, US 10,184,117 B2.

695

696

15 Biocatalysis

on the aromatic hydrocarbon used in bioremediation studies. Toluene dioxygenases (TDOs) are the most developed and have been used for the preparative scale dihydroxylation of toluene to give the corresponding diol.107 However, the activity of TDOs is sensitive to substrate concentration and therefore substrate feeding or two phase reaction systems have been used to maintain substrate concentrations at useful levels. Despite these challenges, up to 35 g/l substrate concentrations have been achieved using whole-cell fermentation with recombinant TDO expressed in E. coli for the synthesis of cis-3-bromo-1,2-dihydrocatechol.108 One notable application of dioxygenases is the use of TDO for the synthesis of the antiviral drug Tamiflu. The synthesis involves whole cell fermentation of ethyl benzoate with E. coli JM109 (pDTG601) containing overexpressed TDO to give cis-hydroxylated diol, a key intermediate for the synthesis of oseltamivir.109 In this fermentation process, 1 g/l of diol was obtained, which was converted to oseltamivir through a series of chemical transformations and gave an azide-free efficient synthesis of oseltamivir. CO2Et OH

CO2Et E. coli JM 109 ~1 g/l

CO2Et

OH

H2N

O NHAc

Me Me

Oseltamivir

15.4.4

Alcohol Oxidations

A variety of different enzyme classes are reported to catalyze oxidation of alcohols, including cofactor-dependent and cofactor-independent enzymes.110 Enzymatic oxidation of alcohols could be carried out regio- and stereo-selectively under mild reaction conditions and thus yield products not readily obtained via chemical methods.

15.4.4.1

Cofactor-Dependent Alcohol Oxidations

ADHs are nicotinamide cofactor-dependent enzymes that catalyze the reversible oxidation of alcohols to carbonyl compounds. Despite their natural role to oxidize alcohols to ketones/aldehydes, they have been exploited for the reverse reaction as described in Section 15.3.3.1.111 As highlighted by Kroutil et al. the application of ADHs for the oxidation of alcohols to ketones has not been well developed, mainly due to the lack of methods for efficient recycling of reduced NAD(P)H back to the oxidized form NAD(P)+ .112 Kinetic resolution OH R1

R2

OH

+ R1

ADH-1

R2 NADP+

NADPH

OH R1

R2

+

R1

OH

ADH-2

O R2

NADPH

NADP+

R1

R2

Deracemization

ADH-mediated oxidation of alcohols (mainly sec alcohols) could be used for deracemization or kinetic resolution of racemic alcohols, a highly desirable transformation. Multiple approaches to recycle nicotinamide cofactor, such as substrate-coupled or enzyme-coupled approaches using a second ADH, have been reported. However, these are often

107 Buitelaar, R.; Bucke, C.; Tramper, J.; Wijffels, R. Immobilized Cells: Basics and Applications; Elsevier, 1996; Vol. 11. 108 Vila, M. A.; Brovetto, M.; Gamenara, D.; Bracco, P.; Zinola, G.; Seoane, G.; Rodriguez, S.; Carrera, I. Journal of Molecular Catalysis B: Enzymatic 2013, 96, 14–20. 109 Bradford, S.; Ignacio, C.; Melissa, D.; Tomas, H. Angewandte Chemie International Edition 2009, 48, 4229–4231. 110 See Note 79. 111 Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Accounts of Chemical Research 2007, 40, 1412–1419. 112 Kroutil, W.; Mang, H.; Edegger, K.; Faber, K. Current Opinion in Chemical Biology 2004, 8, 120–126.

15.4 Oxidations

very challenging due to low rates of reaction. Recent discovery and application of efficient cofactor recycling systems such as NAD(P)H oxidases or ADH’s capable of taking a sacrificial ketone (e.g. acetone) as the hydride acceptor have opened up the potential for preparative scale application of ADHs for alcohol oxidation.113 OH

OH Me

+

Me

OH

O

LbADH

Me NAD+

O2

+

Me

NADH H2O or H2O2

NADH Oxidase

Enzyme coupled cofactor recycling was successfully used for the oxidative kinetic resolution of racemic 1-phenyl-ethanol using NADH oxidases from Lactobacillus brevis and Lactobacillus sanfranciscensis. However, NADH and NADPH oxidases often have low activity and may require enzyme engineering to make them suitable for large-scale applications. OH

OH RasADH O

NADPH

OH

RasADH

NADP+

OH

NADP+

O

NADPH

P450BM3F87A

OH

O

O2

H2O/H2O2

Recently, P450 BM3 monooxygenase was reported to be an efficient enzyme for NAD(P)H oxidation in ADH catalyzed desymmetrization of cis-4-cyclopenten-1,3-diol.114 In this transformation, an ADH from Ralstonia sp. (RasADH) was used for oxidative desymmetrization, while cofactor recycling was performed using the F87A mutant of P450 BM3. Multiple substrate coupled approaches have been effectively used for efficient cofactor recycling. Kumar et al. used 2-oxoglutaric acid as a cosubstrate during the oxidation of sodium gluconate using gluconate-5-dehydrogenase to give 5-keto-gluconic acid at 50 g scale.115 OH OH O HO

O

GNO OH

OH

OH OH Gluconic acid

OH O

HO OH OH NADPH

NADP+

5-KGA

Enzyme GluDH O OH

HO O

O

NH2 HO

OH O

O

113 Geueke, B.; Riebel, B.; Hummel, W. Enzyme and Microbial Technology 2003, 32, 205–211. 114 Holec, C.; Neufeld, K.; Pietruszka, J. Advanced Synthesis & Catalysis 2016, 358, 1810–1819. 115 Kumar, R.; Cawley, J.; Karmilowicz, M.; Martinez, C. A.; Wymer, N.; Yuan, B.; Escalettes, F.; Turner, N. J.; Sattler, J. H.; Tauber, K. Practical Methods for Biocatalysis and Biotransformations 2012, 2, 163–179.

697

698

15 Biocatalysis

In another report,116 the oxidation of cholic acid to give 12-ketochenodeoxy cholic acid was carried out with acetone as the sacrificial substrate and a second ADH to regenerate NADP+ . HO

Me Me

O

CO2H

12α-HSDH

Me HO

H

CO2H

Me OH

NADPH

NADP+

i-PrOH

15.4.4.2

Me Me

HO

H

OH

Acetone

ADH

Cofactor-Independent Alcohol Oxidations

Oxidases such as galactose oxidase and glucose oxidase oxidize alcohols with dioxygen giving the corresponding ketones and hydrogen peroxide or water. In practice, this reaction requires the addition of catalase to convert hydrogen peroxide to water and oxygen, thus preventing enzyme deactivation. These enzymes do not require any cofactors such as nicotinamide and hence are very attractive for preparative applications. However, naturally occurring oxidases are highly specific for their natural substrates, limiting their wider applications. For example, naturally occurring galactose oxidase is very efficient in catalyzing the oxidation of the C6 hydroxyl group of d-galactose to the corresponding aldehyde but displays narrow substrate specificity toward closely related galactose derivatives.117 HO HO

OH Galactose oxidase

O OH

OH O2

HO CHO O HO OH

H2O2

OH

Several literature reports have described the generation of variants of galactose oxidase via enzyme engineering with activity on a wide range of primary and secondary alcohols.118,119 In particular, a variant M3-5 of galactose oxidase has been reported by the Turner group with activity for the oxidation of benzylic alcohols and was used as a model system by Woodley and colleagues to study process requirements for scaling up such reactions.120 Among various parameters studied, oxygen solubility in aqueous media was found to be very important with an observed 30% increase in galactose oxidase activity by aerating the enzyme solution. H OH

Galactose oxidase O2

O

H2O2

Glucose oxidase is a flavoenzyme and catalyzes the oxidation of β-d-glucose to d-glucono-𝛿-lactone, which spontaneously hydrolyzes to gluconic acid. Due to its very high substrate specificity, this enzyme has been mainly used for diagnostic application121 and has limited application for preparative scale. 15.4.5

C—N Oxidations

Compared to the corresponding chemical oxidations, enzymatic C—N oxidations are highly selective and do not form multiple oxidation products. Monoamine oxidases (MAOs) are flavin-dependent enzymes that catalyze the C—N oxidation of amines to imines, with generation of hydrogen peroxide as coproduct.122 The Turner group has reported 116 Fossati, E.; Polentini, F.; Carrea, G.; Riva, S. Biotechnology and Bioengineering 2006, 93, 1216–1220. 117 Siebum, A.; van Wijk, A.; Schoevaart, R.; Kieboom, T. Journal of Molecular Catalysis B: Enzymatic 2006, 41, 141–145. 118 Sun, L.; Bulter, T.; Alcalde, M.; Petrounia, I. P.; Arnold, F. H. ChemBioChem 2002, 3, 781–783. 119 Escalettes, F.; Turner, N. J. ChemBioChem 2008, 9, 857–860. 120 Toftgaard Pedersen, A.; Birmingham, W. R.; Rehn, G.; Charnock, S. J.; Turner, N. J.; Woodley, J. M. Organic Process Research & Development 2015, 19, 1580–1589. 121 Bankar, S. B.; Bule, M. V.; Singhal, R. S.; Ananthanarayan, L. Biotechnology Advances 2009, 27, 489–501. 122 Turner, N. J. Chemical Reviews 2011, 111, 4073–4087.

15.5 C—C Bond Forming Reactions

the characterization of a MAO from Aspergillus niger and subsequent enzyme engineering to generate mutants with complementary substrate specificities.123 R

R

R

MAO-N

R

R

Nu addition FAD

N H meso cis

FADH2

N

Nu

N H

O2

H 2 O2

R

Engineered MAOs have also been used to oxidize meso-pyrrolidines, and applied in the synthesis of a key intermediate in the synthesis of Telaprevir.124

MAO-N N H

FAD

O N

FADH2

N O2 77%, 94% ee

H2O2

N

H N

N H

O

O

OAc

H N

O Me

t-Bu

O

N

H N

Telaprevir

A similar approach was also used for the asymmetric oxidation of 6,6-dimethyl-3-azabicyco[3.1.0] using an evolved MAO and the imine product subsequently converted to a bisulfite adduct (63 g/l concentration), which was used in the synthesis of Boceprevir for commercial manufacturing.125 One critical factor for the scale up of the MAO-mediated oxidation is oxygen availability, and higher activities were observed by operating the processes in a closed reactor under pressure. Me Me

FAD N H meso cis

Me Me

MAO-N

H2O2

Me Me NaCN

NaHSO3

FADH2 O2

Me Me

N

SO3Na

N H

CN N H 90%, >99% ee

Me Me H N

N t-Bu

H N

H N O

O CONH2

O O

t-Bu Boceprevir

Flavin-dependent amino acid oxidases also catalyze the oxidation of C—N bonds; however, they are highly specific to amino acids. Several reports describe the use of l or d amino acid oxidases for kinetic resolution126 or deracemization127 of amino acids.

15.5 C—C Bond Forming Reactions Carbon–Carbon bond formation reactions such as Heck, Negishi, Suzuki coupling or aldol condensation are well established via chemical methods and have been regularly used for industrial applications.128 In contrast, enzyme catalyzed 123 Köhler, V.; Bailey, K. R.; Znabet, A.; Raftery, J.; Helliwell, M.; Turner, N. J. Angewandte Chemie 2010, 122, 2228–2230. 124 Znabet, A.; Polak, M. M.; Janssen, E.; de Kanter, F. J.; Turner, N. J.; Orru, R. V.; Ruijter, E. Chemical Communications 2010, 46, 7918–7920. 125 Li, T.; Liang, J.; Ambrogelly, A.; Brennan, T.; Gloor, G.; Huisman, G.; Lalonde, J.; Lekhal, A.; Mijts, B.; Muley, S. Journal of the American Chemical Society 2012, 134, 6467–6472. 126 Dobrovinskaya, N. A.; Archer, I.; Hulme, A. N. Synlett 2008, 2008, 513–516. 127 Beard, T. M.; Turner, N. J. Chemical Communications 2002, 246–247. 128 Blaser, H.-U. Chemical Communications 2003, 293–296.

699

700

15 Biocatalysis

C—C bond-forming reactions are not used as frequently for preparative scale applications.129,130 This is mainly due to inherent challenges including very high substrate specificity of certain enzymes for their natural substrates, unfavorable equilibrium, and the lack of commercially available enzymes. Despite these challenges, enzymatic C—C bond formation remains very attractive due to the potential for a highly stereo-controlled reaction without cross reactivity.131 Various types of enzymatic C—C bond formation have been reviewed extensively.132,133 15.5.1

Aldol Reaction

Biocatalytic aldol reactions are catalyzed by aldolases and involve a reversible reaction between a nucleophilic donor (aldehyde or ketone) and an electrophilic acceptor (aldehyde or ketone) in a stereospecific manner. Aldolase-mediated C—C bond formation is very attractive due to high catalytic efficiency and stereoselectivity.134 15.5.1.1

Acetaldehyde Aldolases

2-deoxy-d-ribose 5-phosphate aldolase (DERA) catalyzes the formation of 2-deoxy-d-ribose 5-phosphate by the reversible addition of acetaldehyde to d-glyceraldehyde-3-phosphate.135 They are also capable of catalyzing the aldol addition of acetaldehyde to a variety of aldehydes and can accept more than one acetaldehyde in a sequential manner. They have attracted a lot of attention due to their potential for the synthesis of key chiral side chains in various statin-based drug molecules.136,137 F

F

F

OH OH O N

Ph Ph

OH OH O OH

Me N H

O Me

O O N S N Me N

OH

OH

Me

N

Me

Me

Atorvastatin (Lipitor)

OH OH O Me Me

Rosuvastatin (Crestor)

Pitavastatin (Livalo)

A DERA-catalyzed one pot tandem aldol reaction involves sequential addition of two molecules of acetaldehyde to acceptor aldehyde derivative. The addition of second molecule of acetaldehyde to the mono-acetaldehyde adduct results in a bis-addition product that spontaneously cyclized to give a lactol, driving the reaction in the forward direction. This is a highly selective and very productive method to introduce two stereogenic centers in a single step. O O R

H3C H

O H

DERA

H3C

R

H

H

DERA

OH OH R

O H

Monoadduct

R = H, Cl, OMe, N3 R

OH O

O

OH

NaOCl, AcOH

R

O

O

H2O, rt OH Lactol

OH R = Cl, >99.9 % ee, >99.8% de Lactone

129 Clapés, P.; Fessner, W.-D.; Sprenger, G. A.; Samland, A. K. Current Opinion in Chemical Biology 2010, 14, 154–167. 130 Breuer, M.; Hauer, B. Current Opinion in Biotechnology 2003, 14, 570–576. 131 Sukumaran, J.; Hanefeld, U. Chemical Society Reviews 2005, 34, 530–542. 132 Brovetto, M.; Gamenara, D.; Saenz Mendez, P.; Seoane, G. A. Chemical Reviews 2011, 111, 4346–4403. 133 Fesko, K.; Gruber-Khadjawi, M. ChemCatChem 2013, 5, 1248–1272. 134 Machajewski, T. D.; Wong, C. H. Angewandte Chemie International Edition 2000, 39, 1352–1375. 135 Wong, C.-H.; Garcia-Junceda, E.; Chen, L.; Blanco, O.; Gijsen, H. J.; Steensma, D. H. Journal of the American Chemical Society 1995, 117, 3333–3339. 136 DeSantis, G.; Liu, J.; Clark, D. P.; Heine, A.; Wilson, I. A.; Wong, C.-H. Bioorganic & Medicinal Chemistry 2003, 11, 43–52. 137 Müller, M. Angewandte Chemie International Edition 2005, 44, 362–365.

15.5 C—C Bond Forming Reactions

Multiple efforts have been successfully applied to improve the stability and substrate scope for DERA enzymes by enzyme engineering.138,139 For a chloroacetaldehyde acceptor, an E. coli DERA enzyme was successfully evolved for increased stability against higher acetaldehyde concentrations to make it suitable for large-scale application.140 Enzyme engineering was also applied to broaden the substrate scope to include cyanoacetaldehyde and 3-azidopropanal as acceptor substrates, which were successfully used to synthesize the side chain of atorvastatin.141 15.5.1.2

Pyruvate-Dependent Aldolases

N-Acetylneuraminic acid aldolase (NeuA), 3-deoxy-D-mannooctulosonate aldolase (KDO), 2-keto-3-deoxy-6-phosphogluconate aldolase (KDPG), and 2-keto-3-deoxy-6-phosphogalactonate (KDPGal) are widely studied pyruvatedependent aldolases. These enzymes are highly specific for pyruvate being a donor, and usually suffer from unfavorable equilibrium with the retro-aldol reaction being favored.142 These enzymes also exhibit more flexibility for acceptor molecules and have been engineered successfully to broaden the acceptor substrate scope. In general, these enzymes can provide efficient syntheses of various polyols, for example N-acetyl-D-neuraminic acid can be prepared using Neu5Ac aldolase as a whole cell biocatalyst in high purity and yields.143 In this process, pyruvate was generated in situ from lactate using a lactate oxidase enzyme which then underwent aldol reaction with N-acetyl-D-mannosamine to give the desired product. Despite the highly successful synthesis of specific polyols using pyruvate aldolase, the donor specificity for pyruvate remains a challenge, limiting their use for preparative scale applications. OH Me

CO2H Lactate Oxidase (LOX) O

OH HO HO AcHN

O OH

15.5.1.3

HO

pH 10.5 Epimerization

HO HO

NHAc O

Me OH

OH OH

HO

CO2H

HO AcHN

Neu5Ac aldolase Whole cell

O

COOH

HO

DHAP Aldolases

Multiple DHAP (dihydroxyacetone phosphate)-dependent aldolases are commercially available and are highly selective for the formation of products with a specific configuration (see figure below). These are very useful biocatalysts for synthetic chemistry as they can install two stereocenters in a controlled manner and show broad substrate scope for aldehyde acceptors, including aliphatic, aromatic, and heteroatom substituted compounds. DHAP aldolases have been used for the synthesis of iminocyclitol, pipecolic acids, homoiminocyclitols, and aminocyclitol functionalities. Industrial application of DHAP includes the synthesis of a key C-3-C-9 fragment using 4-benzyloxybutyraldehyde, for the synthesis of the macrolactone (+)-aspicillin.144 OH

O OBn

H + HO

O

FruA OPO32− Acid Phosphatase 42%

OH OH

BnO HO

O

Steps

OH O Me

OH O

(+)-aspicillin

However, DHAP dependent aldolases are limited to DHAP as a donor, which is expensive and unstable, thus limiting preparative scale applications of these enzymes. Significant efforts145 have been directed at identifying less expensive syntheses of DHAP, or evolving DHAP-dependent enzymes to accept a less expensive and more widely available 138 Greenberg, W. A.; Varvak, A.; Hanson, S. R.; Wong, K.; Huang, H.; Chen, P.; Burk, M. J. Proceedings of the National Academy of Sciences of the United States of America 2004, 101, 5788–5793. ˇ 139 Ošlaj, M.; Cluzeau, J.; Orki´c, D.; Kopitar, G.; Mrak, P.; Casar, Z. PLoS One 2013, 8, e62250. 140 Jennewein, S.; Schürmann, M.; Wolberg, M.; Hilker, I.; Luiten, R.; Wubbolts, M.; Mink, D. Biotechnology Journal 2006, 1, 537–548. 141 Wolberg, M.; Dassen, B. H.; Schürmann, M.; Jennewein, S.; Wubbolts, M. G.; Schoemaker, H. E.; Mink, D. Advanced Synthesis & Catalysis 2008, 350, 1751–1759. 142 Clapes, P.; Garrabou, X. Advanced Synthesis & Catalysis 2011, 353, 2263–2283. 143 Xu, P.; Qiu, J. H.; Zhang, Y. N.; Chen, J.; Wang, P. G.; Yan, B.; Song, J.; Xi, R. M.; Deng, Z. X.; Ma, C. Q. Advanced Synthesis & Catalysis 2007, 349, 1614–1618. 144 Chênevert, R.; Lavoie, M.; Dasser, M. Canadian Journal of Chemistry 1997, 75, 68–73. 145 Schümperli, M.; Pellaux, R.; Panke, S. Applied Microbiology and Biotechnology 2007, 75, 33.

701

702

15 Biocatalysis

dihydroxyacetone (DHA) as a donor molecule, to increase the utility of DHAP aldolases. D-Fructose-6-phosphate Aldolase (FSA) is a promising catalyst which accepts nonphosphorylated DHA donors such as DHA, hydroxyacetone, and 1-hydroxybutanone, and also shows wide scope for acceptor molecules. This opens up possibilities for preparative scale application of this class of enzymes. 15.5.1.4

Threonine Aldolase

Threonine aldolases are the only class of aldolase family that requires pyridoxal phosphate (PLP) as a cofactor and results in the formation of β-hydroxy-α-amino acids by addition of glycine to acetaldehyde. Goldberg et al.146 successfully used a recombinant D-ThrA for the synthesis of (2R,3S)-2-amino-3-hydroxy-3(pyrid-aminoin-4-yl)-propanoic acid via the aldol condensation of 4-pyridinecarboxaldehyde with glycine on a kilogram scale. In this reaction high diastereoselectivity was achieved by performing the reaction at 25 ∘ C and stabilizing the enzyme with a divalent cation, followed by in situ crystallization of the desired product from the reaction mixture. O

OH H +

N

H2N

CO2H

OH O CO2H

D-ThrA pH 8.0, 25 °C PLP

N

N N

NH2

NH2

100% ee, 97.5% de

15.5.2

Cyanohydrin Formation

Hydroxynitrile lyases (HNL, also known as oxynitrilase) catalyze the reversible addition of HCN to prochiral aldehydes or ketones to give cyanohydrins. This is a valuable reaction due to the generation of a new stereo-center with an additional carbon. O R

R′

+

HCN

HnL

HO CN R

Aqueous/Organic

R′

or

HO CN R

R′

In general, HNL-catalyzed cyanohydrin formation is highly stereoselective, however, the pH of the reaction needs to be carefully adjusted (typically between 3.5 and 5.5) to prevent the spontaneous addition of HCN to the carbonyl substrate. Addition of water immiscible solvents, such as ethyl acetate, diisopropyl, or tert-butyl methyl ether usually suppress the background chemical reaction to a significant extent, providing access to highly selective R or S cyanohydrins. The major challenge for the large-scale use of HnLs is the use of toxic HCN, which, in practice, needs to be generated in situ. Both R and S-selective HNLs are known in the literature and accept aldehyde as well as ketones as substrates. Generally, aldehydes have shown higher reactivity, whereas for ketones, very low activities are observed. Several hydroxynitrile lyases are known in the literature, all from plant origin, including the R selective Prunus amygdalus (PaHNL from almonds), Linum usitatissimum (LuHNL from flax), and Arabidopsis thaliana (AtHNL from thale cress); as well as the S selective enzymes from Manihot esculenta (MeHNL from tomato), Sorghum bicolor (SbHNL from millet), and Hevea brasiliensis (HbHNL from rubber tree). HbHNL was used by DSM on kilogram scale to make the (R)-cyanohydrin of furan-2-carbaldehyde with 99.5% ee, which was then chemically reduced to give (R)-2-amino-1-(2-furyl)ethanol.147 O H O

15.5.3

OH

HbHnL HCN/TBME/Buffer pH 4.9, 0 oC

CN O

NaBH4 CF3CO2H THF

OH NH2 O

84–95%, 99.5% ee

Acyloin Condensation

The enzymatic version of the acyloin condensation requires thiamine pyrophosphate (TPP) as a cofactor. In this reaction, TPP reacts with a donor aldehyde molecule to enable the polarity inversion via a thiazolium ring within the 146 Goldberg, S. L.; Goswami, A.; Guo, Z.; Chan, Y.; Lo, E. T.; Lee, A.; Truc, V. C.; Natalie, K. J.; Hang, C.; Rossano, L. T. Organic Process Research & Development 2015, 19, 1308–1316. 147 Purkarthofer, T.; Pabst, T.; van den Broek, C.; Griengl, H.; Maurer, O.; Skranc, W. Organic Process Research & Development 2006, 10, 618–621.

15.6 Future Developments

hydrophobic core of the enzyme. This umpolung active species reacts with the electrophilic acceptor aldehyde to give the α-hydroxyketone product. Enzymes catalyzing this reaction include benzaldehyde lyase (BAL), pyruvate decarboxylase (PDC), phenylpyruvate decarboxylase (PPD), and benzoylformate decarboxylase (BFD). Liese and coworkers have reported preparative scale examples of this reaction using the BAL from Pseudomonas fluorescens. This enzyme catalyzes the self-condensation of aromatic aldehydes to produce (R)-benzoins. In addition, the enzyme also catalyzes the crossed acyloin condensations between aromatic aldehydes and acetaldehyde.148 O Ar

H

+

O R

BAL H

pH 9.5

R = phenyl, CH3

O Ar

R OH

>90% yield, 99% ee

In the self-condensation of benzaldehyde, 240 g/l per day of (R)-benzoin were produced. For the synthesis of (R)-2-hydroxy-1-phenyl-propanone by coupling benzaldehyde and acetaldehyde, 36 g/l per day were obtained with a maximum product concentration of 15–20 g/l (97% ee) in 10–15 hours. The synthesis of (R)-2-hydroxy-1-phenyl-propanone in a continuous process in combination with membrane technology enabled the synthesis of 1120 g/l per day in >99% ee.149 More recently, the P. fluorescens BAL and the engineered Pseudomonas putida BFD were used to prepare (R)- or (S)-configured 2-hydroxy-1-phenylpropanones at preparative scale.150

15.6 Future Developments Practical application of biocatalysis has expanded rapidly over the last decade fueled by increased availability of enzymes for various synthetic transformations. Further increase in the use of biocatalysis is likely with the discovery and particularly engineering of enzymes suitable for industrial processes. Enzyme stability is a very important attribute for scalability and various technologies, in addition to enzyme engineering, show promise for improving enzyme stability. The potential that unnatural amino acids could have in stabilizing enzymes is intriguing, and recent reports look promising.151 The stabilization of enzymes via immobilization has also been demonstrated and the smooth integration of enzyme engineering and enzyme immobilization will be key in developing superior processes.152 The use of biocatalysts in continuous systems is also an attractive option, which is often facilitated by employing immobilization or membrane reactors, offering a reduced footprint, modularity, and flexibility of applications.153 In a recent report, the performance of batch vs. continuous processes was evaluated based on relevant process metrics while establishing the best solution to a problem. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.154 Many areas of biocatalysis are still under development with respect to practical applications. Reductive amination of ketones to amines (AmDH and RedAm) is a very useful transformation that is currently under rigorous investigation by a number of groups. The development of scalable application of these enzymes will likely require the use of enzyme engineering as discussed in recent reviews.155,156 Enzyme cascades are another topic that is prevalent in the current biocatalysis literature. Various challenges to the development of practical enzyme cascades include the matching of optimal conditions for each enzyme and differences in rates which impacts substrate loads, and substrate specificity.157 In addition, many enzymatic transformations are either underutilized or need more development for practical use. For example, addition and elimination of water and other nucleophiles to olefins, decarboxylations, fluorination, C—H 148 de María, P. D.; Stillger, T.; Pohl, M.; Wallert, S.; Drauz, K.; Gröger, H.; Trauthwein, H.; Liese, A. Journal of Molecular Catalysis B: Enzymatic 2006, 38, 43–47. 149 Stillger, T.; Pohl, M.; Wandrey, C.; Liese, A. Organic Process Research & Development 2006, 10, 1172–1177. 150 Wachtmeister, J.; Jakoblinnert, A.; Rother, D. Organic Process Research & Development 2016, 20, 1744–1753. 151 Deepankumar, K.; Shon, M.; Nadarajan, S. P.; Shin, G.; Mathew, S.; Ayyadurai, N.; Kim, B.-G.; Choi, S.-H.; Lee, S.-H.; Yun, H. Advanced Synthesis & Catalysis 2014, 356, 993–998. 152 Bernal, C.; Rodríguez, K.; Martínez, R. Biotechnology Advances 2018, 36, 1470–1480. 153 Britton, J.; Majumdar, S.; Weiss Gregory, A. Chemical Society Reviews 2018, 47, 5891–5918. 154 Hugentobler, K. G.; Rasparini, M.; Thompson, L. A.; Jolley, K. E.; Blacker, A. J.; Turner, N. J. Organic Process Research & Development 2017, 21, 195–199. 155 Hughes, D. L. Organic Process Research & Development 2018, 22, 1063–1080. 156 Velikogne, S.; Resch, V.; Dertnig, C.; Schrittwieser, J. H.; Kroutil, W. ChemCatChem 2018, 10, 3236–3246. 157 Schrittwieser, J. H.; Velikogne, S.; Hall, M.; Kroutil, W. Chemical Reviews 2018, 118, 270–348.

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oxygenation, epoxidation, cyclopropanation, isomerizations, rearrangements, methyl transfer, and nitrile reduction are among the transformations in need of further development. Often, underutilization may be associated with lack of commercial availability; at present, this obstacle is easily remedied by available vendors that offer gene synthesis and crude protein expression at low cost. The effectiveness of enzyme engineering in improving substrate scope, selectivity, and stability has been demonstrated in the past decades and is expected to continue as a driver to enable scalable solutions. Integration of biocatalysis into process chemistry with collaboration between synthetic chemists and biocatalysis experts should continue to increase acceptance of this technology as a mainstream technology for organic synthesis.

705

16 Green Chemistry Juan Colberg, Jared L. Piper, and John W. Wong Pfizer Chemical R&D, Worldwide Research & Development, Groton, CT, USA

CHAPTER MENU Introduction, 705 Green Chemistry Metrics, 706 Solvent and Reagent Selection, 710 Green Reactions/Reagents, 716 Examples of Green Methods and Reagents for Common Reaction Types, 716 Predictive Tools to Design for Green Chemistry, 724 Green Chemistry Improvements in Process Development, 725

16.1 Introduction The green chemistry movement gained support as a major discipline in the early 1990s.1,2,3 Since then, there have been major contributions globally, with more than 50 000 publications in this area. The evaluation of the environmental impact of a pharmaceutical process requires the consideration of many factors. Robustness and cost-effectiveness continue to be primary considerations for development chemists as a new drug candidate progresses toward commercialization. In addition, the safety of a process carried out on an industrial scale must consider not only worker exposure but also the patient ultimately receiving the final product. High-quality standards exist throughout the design of a process and remain highly regulated throughout a product lifecycle. Within these limitations, green chemistry emerges as a practical approach to satisfy all of these design requirements, and further illustrates how it can achieve project goals associated with environmental impact, process safety, and energy consumption.4,5,6 Each of these components must be evaluated across several synthetic steps, which may include a wide range of functional group transformations, and hundreds of options for reagents and solvents. As the industry moves toward accelerated development paradigms for innovative, life-saving therapies, development chemists are tasked with implementing greener processes more rapidly.7 To achieve an efficient, environmentally benign synthesis, a chemist needs to have the necessary tools to guide reagent and solvent selection, as well as metrics to assess the changes being made. Many tools have been developed over the years to assist chemists and engineers to meet this challenge. From solvent and reagent selection tools to easy-to-use green metrics, the Pharma industry has invested in developing guides for their scientists during the entire chemical development cycle, from discovery to commercial manufacturing. Working together under the consortia approach, the pharmaceutical industry has found effective means to collaborate under precompetitive space with organizations

1 Anastas, P.; Warner, J. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, UK, 1998. 2 Anastas, P. T.; Williamson, T. C. ACS Symposium Series 1996, 626, 1–17. 3 Anastas, P. T.; Williamson, T. C.; Oxford University Press: 1998, p. 1–26. 4 Zhang, T. Y. Chemical Reviews (Washington, DC, U. S.) 2006, 106, 2583–2595. 5 Cue, B. W.; Zhang, J. Green Chemistry Letters and Reviews 2009, 2, 193–211. 6 DeVierno Kreuder, A.; House-Knight, T.; Whitford, J.; Ponnusamy, E.; Miller, P.; Jesse, N.; Rodenborn, R.; Sayag, S.; Gebel, M.; Aped, I.; Sharfstein, I.; Manaster, E.; Ergaz, I.; Harris, A.; Nelowet Grice, L. ACS Sustainable Chemistry & Engineering 2017, 5, 2927–2935. 7 Rubin, E. H.; Gilliland, D. G. Nature Reviews Clinical Oncology 2012, 9, 215–222. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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like the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PRT),8 innovative medicines initiative (IMI)-Chem21,9 government cofunded programs, and others.10 These collaborations have resulted in accelerated adoption and implementation of these critical tools across the chemical industry, as well as academic groups.11 The 12 green chemistry principles 1. Prevent waste rather than treat

7. Use renewable raw materials

2. Maximize incorporation of all materials (atom economy)

8. Minimize unnecessary derivatization

3. Design synthesis to use or generate least hazardous chemical substances

9. Use catalytic vs. stoichiometric reagents

4. Design safer chemicals to do the desired function

10. Process related products should be designed to be biodegradable

5. Minimize or use innocuous auxiliary agents (solvents, etc.)

11. Use online analytical process monitoring to minimize formation of hazardous byproducts

6. Minimize energy requirements

12. Choose safer reagents that minimize the potential for accidents The 12 green principles of process engineering

1. Designers need to strive to ensure that all material and energy inputs and outputs are as inherently nonhazardous as possible

7. Targeted durability, not immortality, should be a design goal

2. It is better to prevent waste than to treat or clean up waste after it is formed

8. Design for unnecessary capacity or capability (e.g. “one size fits all”) solutions should be considered a design flaw

3. Separation and purification operations should be designed to minimize energy consumption and materials use

9. Material diversity in multicomponent products should be minimized to promote disassembly and value retention

4. Products, processes, and systems should be designed to maximize mass, energy, space, and time efficiency

10. Design of products, processes, and systems must include integration and interconnectivity with available

5. Products, processes, and systems should be “output pulled” rather than “input pushed” through the use of energy and materials

11. Products, processes, and systems should be designed for performance in a commercial “afterlife”

6. Embedded entropy and complexity must be viewed as an investment when making design choices on recycle, reuse, or beneficial disposition

12. Material and energy inputs should be renewable rather than depleting

16.2 Green Chemistry Metrics In addition to the green chemistry and engineering principles that allow chemists to perform a qualitative assessment, quantitative metrics are needed for process comparison on both laboratory and larger scale. In general, this type of metric should provide a simple, measurable, and objective guidance that ultimately enables the development of the most efficient, environmentally benign process. Perhaps the simplest of all process chemistry metrics is overall yield. Yield is one measure of a step’s or a process’ efficiency but does not consider by-product formation or waste generation, which can carry significant cost and environmental impact. As a result, several other metrics have been proposed to more fully gauge the overall “greenness” of a process, the most common of which will be presented in the following sections. 8 Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chemistry 2007, 9, 411–420. 9 Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. Green Chemistry 2016, 18, 288–296. 10 Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chemistry 2008, 10, 31–36. 11 Koenig, S. G.; Leahy, D. K.; Wells, A. S. Organic Process Research & Development 2018, 22, 1344–1359.

16.2 Green Chemistry Metrics

16.2.1

Atom Economy (AE)

Atom economy (AE), first introduced by Barry Trost,12 is a metric designed to encourage greater efficiency and lessen environmental impact when planning the synthesis of complex organic molecules. The classic definition of atom economy is the percentage of the molecular weight of the starting materials present in the molecular weight of the desired product after multiple chemical transformations. AE can also be thought of as a comparison of the molecular weight of the product to the sum of the molecular weights all of the products (salts, activating groups, removed protecting groups, etc.). Catalysts, solvents, and stoichiometric excesses are typically not included in the analysis. The concept can also be used to calculate the efficiency of a single reaction. AE is expressed as follows for a single step: A

+

B

−−−−→[ P

] m.w. of P × 100 Atom Economy = m.w. of A + m.w. of B For a multistep process, a more complex calculation is needed, including all new reagents (A, B, D, and F), but not the intermediate products (C and E), to avoid double counting weights. A

+

B

−−−−→

C

C

+

D

−−−−→

E

E

+

F

−−−−→[

P

] m.w. of P × 100 Atom Economy = m.w. of A + m.w. of B + m.w. of D + m.w. of F For convergent syntheses, the calculations are similar, and examples are available in the literature.13 Trost has also published AE analyses for a variety of reactions.14 The atom economy metric, which is solely based on the molecular weights of the reaction components, is limited by not taking into account yield, stoichiometric excess, catalyst or solvent usage, or work-up materials. 16.2.2

Reaction Mass Efficiency (RME)

Reaction mass efficiency (RME)15,16,17,18 is the percentage of the reactant mass going into a reaction that remains in the final product. This metric takes atom economy into account but also the stoichiometry of reagents and yield contributions from reaction steps. For the reaction: A

+

B [

−−−−→

P

] total mass of P × 100 RME = total mass of A + total mass of B This calculation can be used to quantitate process improvements over time as conditions change. An increasing RME will result from increasing yield or smaller stoichiometric excess of reagents, as well as improvements in the AE associated with the reagent choice. 16.2.3

E Factor

As neither atom economy nor RME account for chemical usage beyond reagents, Roger Sheldon developed the E factor metric.19,20,21,22,23,24 The E factor is calculated as the ratio of total weight of waste generated to the total weight 12 13 14 15 16 17 18 19 20 21 22 23 24

Trost, B. M. Science 1991, 254, 1471–1477. Auge, J. Green Chemistry 2008, 10, 225–231. Trost, B. M. Accounts of Chemical Research 2002, 35, 695–705. Andraos, J. Organic Process Research & Development 2005, 9, 404–431. Andraos, J. Organic Process Research & Development 2005, 9, 149–163. Andraos, J. Organic Process Research & Development 2006, 10, 212–240. Andraos, J.; Sayed, M. Journal of Chemical Education 2007, 84, 1004–1010. Sheldon, R. A. Chemistry and Industry 1998, 75, 273–288. See Note 13. See Note 16. See Note 15. See Note 18. Eissen, M.; Metzger, J. O. Chemistry - A European Journal 2002, 8, 3580–3585.

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of product isolated. E factor =

total waste (kg) kg of product

This metric allows for rapid comparison of many different routes to the same product or across multiple products. It can also serve as a metric across different organizations in a similar field. Because the E factor looks across the whole multistep process, RME or AE may be more useful for process development for a single step. 16.2.4

Process Mass Intensity (PMI)

Process mass intensity (PMI)25,26,27,28 is a variation of the E factor that calculates the ratio of the total mass used in a process relative to the mass of the product PMI =

total mass used in a process or process steps mass of final product

For this metric, “total mass used” includes reactants, reagents, solvents, catalysts, acids, bases, salts, and work-up solvents (for washes, extractions, crystallizations, solvent displacements, etc.). To use PMI to compare a set of processes,29 consistency is needed in terms of what makes up the total mass used in the process. This makes it very difficult to compare PMI values from different laboratories or across companies. 16.2.5

Life Cycle Assessment (LCA)

The Life cycle assessment (LCA)30,31,32,33 metrics take into consideration the safety, energy, and environmental aspect of the life of a product, from cradle to grave. LCA is used not only to assess the processes and materials but also the impact generated by the waste streams. This type of analysis is typically done by chemical engineers and other environmental health and safety (EHS) specialists due to the extensive number of considerations that need to be taken into account. There are currently some LCA tools available for the research chemist and can be used during PMI determination, although these analyses are typically reserved for late-stage and commercial processes. 16.2.6

Innovation Green Aspiration Level (iGAL) Methodology

A common issue for some of the previously discussed metrics is a lack of harmonization criteria, and allowing the user to define the factors contained in the calculations. This includes the use of inconsistent and nonstandardized parameters across projects, something that could mislead a scientist on the “green” status of their synthesis. The innovation green aspiration level (iGAL) allows for a green, goal-driven synthesis approach that can also serve as an important comparison tool across development stages within a company and the industry.34,35,36,37 The iGAL takes into consideration molecular complexity, development stage of the active pharmaceutical ingredient (API), and a defined starting point of the synthesis, which allows a more robust comparison across the molecules evaluated. iGAL = iGAL (per transformation) × Complexity, 25 See Note 13. 26 See Note 16. 27 See Note 18. 28 See Note 15. 29 Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Green Chemistry 2002, 4, 521–527. 30 Sheldon, R. A. ACS Sustainable Chemistry & Engineering 2018, 6, 32–48. 31 Artz, J.; Mueller, T. E.; Thenert, K.; Kleinekorte, J.; Meys, R.; Sternberg, A.; Bardow, A.; Leitner, W. Chemical Reviews (Washington, DC, U. S.) 2018, 118, 434–504. 32 Veleva, V. R.; Cue, B. W.; Todorova, S. ACS Sustainable Chemistry & Engineering 2018, 6, 2–14. 33 Sheldon, R. A. Green Chemistry 2017, 19, 18–43. 34 Roschangar, F.; Sheldon, R. A.; Senanayake, C. H. Green Chemistry 2015, 17, 752–768. 35 Roschangar, F.; Colberg, J.; Dunn, P. J.; Gallou, F.; Hayler, J. D.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Mergelsberg, I.; Tucker, J. L.; Sheldon, R. A.; Senanayake, C. H. Green Chemistry 2017, 19, 281–285. 36 Roschangar, F.; Zhou, Y.; Constable, D. J. C.; Colberg, J.; Dickson, D. P.; Dunn, P. J.; Eastgate, M. D.; Gallou, F.; Hayler, J. D.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Mergelsberg, I.; Scholz, U.; Smith, A. G.; Henry, M.; Mulder, J.; Brandenburg, J.; Dehli, J. R.; Fandrick, D. R.; Fandrick, K. R.; Gnad-Badouin, F.; Zerban, G.; Groll, K.; Anastas, P. T.; Sheldon, R. A.; Senanayake, C. H. Green Chemistry 2018, 20, 2206–2211. 37 Roschangar, F.; Colberg, J.; John Wiley & Sons Ltd.: 2018, p. 1–19.

16.2 Green Chemistry Metrics

where iGAL (per transformation) is iGAL (per transformation) =

xEF , (Average complexity)

with xEF = sEF or cEF

In the above two equations, the authors based the iGAL calculations on modified E factors, simple E factor (sEF), and complete E factor (cEF), as well as process complexity factors associated to the stage of development. The iGAL also defines the starting point of chemical synthesis from materials costing US$100/mol, which helps harmonize the analysis. Roschangar (Boehringer Ingelheim) exemplified the new methodology using the sildenafil citrate process of Pfizer.38 Starting from the original publication disclosing green metrics analyses,39,40 the original E factor, RME, AE, and chemical yield (CY) for all stages of development and the commercial synthesis were compared to iGAL calculations. To start the analysis, the authors determined the sEF and cEF metrics in combination with their starting point concept of US$100/mol cost. The overall commercial process scheme for Pfizer’s sildenafil citrate is shown below. O Step 2

O

Me N N

HO

SOCl2 cat. DMF

O2 N Me

Toluene, D; aq NH3 92%

Step 1a OEt CO2H

O H2N

Step 3a Me N N

Me

CO2H

ClSO3H SOCl2 25 °C 91%

Pd/C EtOAc 100%

N

O2S

O OEt HN

N CO2H

Me N N

N

Me tBuOH,D 92% O2S

N

OEt

Me N N Me Sildenafil

Me

Citric acid Step 5 2-butanone 99%

Me O2S

Step 4 KOtBu

O

EtOAc 90% Me

Water, 25 °C; neutralization 86%

SO2Cl

OEt HN

CDI

H2N

Step 1b

HN

Me N N

H2N

H2

O2N

OEt

O

Me N N

H2N

Step 3b

Sildenafil citrate

N N

Me

Using this methodology, the authors explored 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid and 2-ethoxybenzoic acid as the starting point of the synthesis. Based on the cost restrictions defined by their calculation, additional steps to prepare the pyrazole were necessary for inclusion in calculating the E factor. O EtO

Step S1 OEt

O + O Me

Step S3 Me2SO4

NaOEt

O

Step S2

O

NH2NH2

EtO2C

92%

Me

EtO2C

H N

N

AcOH 76% Me

Me

EtO2C

Me N N

Step S4 aq NaOH

90 °C 79%

71% Me

HO2C

Me N N

Step S5 HNO3 H2SO4 55 °C Me 96%

HO2C

Me N N

O2 N Me

The authors concluded that an additional 40% E factor increase was needed to account for the predicted waste generated during the production of the pyrazole. They also concluded that even with the additional steps added to the

38 See Note 34. 39 Dunn, P. J.; Galvin, S.; Hettenbach, K. Green Chemistry 2004, 6, 43–48. 40 Dunn, P. J. The Chemical Development of The Commercial Route to Sildenafil Citrate; CRC Press LLC: 2008, p. 267–277.

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16 Green Chemistry

analysis, the Viagra process was at the top percentage of the iGAL calculation, indicating a green process that is nearly ideal based on its level of complexity.

16.3 Solvent and Reagent Selection Selecting a particular solvent or reagent in chemical synthesis remains paramount in obtaining successful reaction outcomes. In many cases, the chemist will choose a solvent that has been demonstrated in a given literature preparation, or will default to convenience or availability.41,42,43,44 Many reactions described in the chemical literature contain transformations carried out using solvents and reagents selected to maximize yield or selectivity, but authors rarely discuss if the selections pose an environmental concern, or are strictly controlled by legislative or regulatory agencies.45,46,47,48 For industrial chemists, there is a greater focus on the choice of solvents and reagents, since products are prepared on a much larger scale and have the capability of generating significant amounts of waste.49 In addition, many pharmaceutical, fine chemical, and chemical manufacturing industries are committing to substantial green chemistry initiatives aligned with societal expectations.50,51 The practicing chemist of today has at their disposal many tools for implementing green chemistry from the outset52,53,54,55 including a growing database of scientific publications and successful examples on the topic to aid in the design of more environmentally responsible processes.56,57,58 16.3.1

Organic Solvent Selection

Solvent selection is crucial to the outcome of many chemical reactions and impacts the overall efficiency and sustainability of a process. Although solvent usage on laboratory scale is of minimal impact, the perpetuation of a poor solvent choice can lead to magnified impact further in development. Solvents, including water for processing and aqueous work-ups, are usually the biggest contributors to the waste generated in chemical reactions, representing as much as 85% of the total weight.59,60,61 Solvents are generally required during a reaction to enable heat and mass transfer, and during postreaction processing and isolation of products. Although it could be argued that the absence of solvent would be the most beneficial choice, solvents can also increase the given safety of chemical reactions. A number of these common solvents have been questioned in recent years due to their hazardous characteristics. As environmental, safety and health issues from common solvents such as dichloromethane, toluene, and dimethylsulfoxide emerged, pharmaceutical and fine chemical manufacturers pursued suitable alternatives.62 This need was further increased by strict regulation of “undesired” solvents by regulatory agencies. 41 Lawrenson, S.; North, M.; Peigneguy, F.; Routledge, A. Green Chemistry 2017, 19, 952–962. 42 Lipshutz, B. H.; Gallou, F.; Handa, S. ACS Sustainable Chemistry & Engineering, 2016, 4, 5838–5849. 43 Dunn, P. J. Chemical Society Reviews 2012, 41, 1452–1461. 44 Ashcroft, C. P.; Dunn, P. J.; Hayler, J. D.; Wells, A. S. Organic Process Research & Development 2015, 19, 740–747. 45 Henderson, R. K.; Jimenez-Gonzalez, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Green Chemistry 2011, 13, 854–862. 46 Sheldon, R. A. Green Chemistry 2005, 7, 267–278. 47 Bryan, M. C.; Dunn, P. J.; Entwistle, D.; Gallou, F.; Koenig, S. G.; Hayler, J. D.; Hickey, M. R.; Hughes, S.; Kopach, M. E.; Moine, G.; Richardson, P.; Roschangar, F.; Steven, A.; Weiberth, F. J. Green Chemistry 2018, 20, 5082–5103. 48 Pollet, P.; Davey, E. A.; Urena-Benavides, E. E.; Eckert, C. A.; Liotta, C. L. Green Chemistry 2014, 16, 1034–1055. 49 Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H. M.; Clark, J. H.; Farmer, T. J.; Hunt, A. J.; McElroy, C. R.; Sherwood, J. Sustainable Chemical Processes 2016, 4, 7/1–7/24. 50 See Note 11. 51 Erythropel, H. C.; Zimmerman, J. B.; de Winter, T. M.; Petitjean, L.; Melnikov, F.; Lam, C. H.; Lounsbury, A. W.; Mellor, K. E.; Jankovic, N. Z.; Tu, Q.; Pincus, L. N.; Falinski, M. M.; Shi, W.; Coish, P.; Plata, D. L.; Anastas, P. T. Green Chemistry 2018, 20, 1929–1961. 52 See Note 10. 53 See Note 9. 54 Buckley, H. L.; Beck, A. R.; Mulvihill, M. J.; Douskey, M. C. Journal of Chemical Education 2013, 90, 771–774. 55 Ekins, S.; Clark, A. M.; Williams, A. J. ACS Sustainable Chemistry & Engineering 2013, 1, 8–13. 56 Nosko, S. LaborPraxis 1991, 15, 723–724, 726, 728–730, 732, 734. 57 Taygerly, J. P.; Miller, L. M.; Yee, A.; Peterson, E. A. Green Chemistry 2012, 14, 3020–3025. 58 Orha, L.; Akien, G. R.; Horvath, I. T. Synthesis in Green Solvents; Wiley-VCH Verlag GmbH & Co. KGaA: 2012; Vol. 7, p. 93–120. 59 Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Organic Process Research & Development 2011, 15, 912–917. 60 See Note 44. 61 Haeckl, K.; Kunz, W. Comptes Rendus Chimie 2018, 21, 572–580. 62 Lopez, J.; Pletscher, S.; Aemissegger, A.; Bucher, C.; Gallou, F. Organic Process Research & Development 2018, 22, 494–503.

16.3 Solvent and Reagent Selection

This raised the challenge of identifying substitutes with the appropriate physical characteristics (boiling point, vapor pressure, etc.) and molecular properties (dipolar moment, polarizability, etc.) without negatively impacting reactivity and ease of processing. As a result, several companies have developed solvent selection guides that suggest potential alternatives for commonly used nongreen solvents.63,64,65,66,67,68,69 One example is the guide developed by Pfizer70 that presents a simple solvent selection tool for evaluating each solvent on three key areas: (i) Worker safety, including carcinogenicity, mutagenicity, reproductive toxicity, skin absorption/sensitization, and toxicity. (ii) Process safety, including flammability, potential for high emissions through high vapor pressure, static charge, and potential for peroxide formation and odor issues. (iii) Environmental and regulatory considerations, including ecotoxicity and ground water contamination, potential EHS regulatory restrictions, ozone depletion potential, and photoreactive potential. For most of the solvents in the “undesired” category, there exists viable replacements, although polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc), and N-methyl pyrrolidinone (NMP) remain challenging.71 Ideally, running a reaction in the absence of solvent presents the most environmentally friendly scenario,72,73 but as most reactions require some solvent, water or an aqueous mixture is the second best alternative. 16.3.2

Aqueous Systems

The use of water as a solvent for organic reactions continues to remain a focus for many research applications. This has been driven by both an increase in sustainability and greenness and by advantages in reactivity/selectivity for some classic reactions.74,75,76 In some cases, rates and selectivity are increased due to hydrophobic effects when reactions are conducted in water.77,78,79,80,81,82,83 Enzymatic reactions will be discussed in greater detail later in Section 16.7 of this chapter, and biotechnology groups have been investigating organic reactions in aqueous environments routinely.84,85,86 One critical important aspect to be considered when using water/aqueous media as solvent, is the need for water waste recycling and treatment, something that enables reusing of this precious natural resource. This is needed to avoid environmental issues like pharmaceuticals in the environment (PIE) and potential antibiotic resistance impact. 16.3.3

Classic Reactions in Aqueous Systems

Organic synthesis has traditionally relied upon organic solvents to carry out transformations, due to the low solubility of most molecules in water.87 Since nature has always carried out exceedingly difficult transformations with exquisite 63 Diorazio, L. J.; Hose, D. R. J.; Adlington, N. K. Organic Process Research & Development 2016, 20, 760–773. 64 Prat, D.; Hayler, J.; Wells, A. Green Chemistry 2014, 16, 4546–4551. 65 See Note 45. 66 Prat, D.; Pardigon, O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Organic Process Research & Development 2013, 17, 1517–1525. 67 See Note 41. 68 See Note 9. 69 See Note 64. 70 See Note 10. 71 Duereh, A.; Sato, Y.; Smith, R. L.; Inomata, H. Organic Process Research & Development 2017, 21, 114–124. 72 Cook, T. L.; Walker, J. A.; Mack, J. Green Chemistry 2013, 15, 617–619. 73 Rong, L.; Han, H.; Jiang, H.; Tu, S. Journal of Heterocyclic Chemistry 2009, 46, 465–468. 74 Lindstroem, U. M. Chemical Reviews 2002, 102, 2751–2771. 75 Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chemistry 2006, 8, 960–964. 76 Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2007, 2683–2686. 77 Hayashi, Y.; Urushima, T.; Aratake, S.; Okano, T.; Obi, K. Organic Letters 2008, 10, 21–24. 78 Hamada, T.; Manabe, K.; Kobayashi, S. Journal of the American Chemical Society 2004, 126, 7768–7769. 79 Bhattacharya, S.; Srivastava, A.; Sengupta, S. Tetrahedron Letters 2005, 46, 3557–3560. 80 Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chemical Communications 2006, 2801–2803. 81 Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angewandte Chemie, International Edition 2007, 46, 3798–3800. 82 Fringuelli, F.; Piermatti, O. Pericyclic Rearrangements: Sigmatropic, Electrocyclic, and Ene Reactions; Georg Thieme Verlag: 2012, p. 481–510. 83 Kitanosono, T.; Masuda, K.; Xu, P.; Kobayashi, S. Chemical Reviews (Washington, DC, U. S.) 2018, 118, 679–746. 84 Raj, M.; Singh, V. K. Chemical Communications (Cambridge, U. K.) 2009, 6687–6703. 85 Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh, T.-P. Organic Letters 2010, 12, 1220–1223. 86 Hailes, H. C. Organic Process Research & Development 2007, 11, 114–120. 87 Serrano-Luginbuhl, S.; Ruiz-Mirazo, K.; Ostaszewski, R.; Gallou, F.; Walde, P. Nature Reviews Chemistry 2018, 2, 306–327.

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16 Green Chemistry

selectivity in aqueous systems, it raises the question of why?88 The following examples serve as a reminder that many transformations carried out in organic solvents can be run in water under the right set of conditions. Following the initial report of the MacMillan group (Cal Tech) on organocatalyzed Diels–Alder reactions in water,89 Chen and coworkers (Sichuan University) reported on the organocatalyzed inverse-demand aza–Diels–Alder reaction of electron-deficient ketimines and enals in aqueous acetonitrile to prepare heterocycles.90

N H N

R3

Ts

BzOH

+

R2

OTMS

(10 mol%)

CHO

Ts

Ph Ph

R4

R5

CH3CN/H2O, rt

HO

H

R4

N

R2

R3

R5

Up to 96% yield Up to E/Z 8.9 : 1 Up to >99% ee

R2 = Ph, CO2Et, 4-BrC6H4, 4-MeC6H4, 2-thienyl R3 = Me, Ph, CO2Et, 4-BrC6H4, 4-MeC6 H4 R4 = Me, Et, n-Pr R5 = H, Me

The reactions were found to proceed in high yields with excellent selectivity in the presence of water. When water was omitted from the reaction, the researchers noted that no products were observed, indicating the importance of water in these systems. Mannich-type reactions have also been run successfully in water.91 Lu and coworkers (NU Singapore) reported aqueous conditions for three component Mannich reactions with p-anisidine and aliphatic or aromatic aldehydes in high yield and enantioselectivity.92

Me O +

Me OBn (3 equiv)

NH2 (1.1 equiv)

+ H

R (1 equiv)

OMe

NH2 (10 mol%)

O

MeO

OTBS CO2H

H2O (10 equiv), rt 98% 97% ee

O

HN

Me OBn

N

13 : 1 anti:syn Many other examples

The combination of the benzyl protecting group, the utilization of a threonine-derived organocatalyst, and an aqueous environment provided the best diastereoselectivity and enantioselectivity for this class of substrates. Hayashi et al. (Tokyo University) also reported a proline-derived catalyst for the asymmetric Mannich reactions involving aldehydes and α-imino glyoxylates with protected siloxyproline organocatalysts.93 The reactions proceed in high enantioselectivity and good yield in the presence of water.

88 See Note 11. 89 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. Journal of the American Chemical Society 2000, 122, 4243–4244. 90 Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Angewandte Chemie International Edition 2009, 48, 5474–5477, S5474/5471–S5474/5461. 91 Mase, N.; Barbas, C. F., III Organic & Biomolecular Chemistry 2010, 8, 4043–4050. 92 Cheng, L.; Wu, X.; Lu, Y. Organic & Biomolecular Chemistry 2007, 5, 1018–1020. 93 See Note 77.

16.3 Solvent and Reagent Selection

TBDPSO CO2H N H (10 mol%)

MeO

O +

H

N

Et

H

OMe

H2O, NaHCO3 (9 equiv), rt CO2Et

O

HN

H

CO2Et Et

78% yield, 90% de, 98% ee

Several other successful Mannich and Mannich-type reactions in water have been reported.94,95,96,97,98,99,100,101,102,103,104,105 Palladium coupling reactions, such as the Suzuki–Miyaura variant, have also been extensively explored with water as the solvent.106,107,108,109,110,111,112,113 In cases where homogeneous catalysts are needed, the typical approach involves modification of the ligands with groups that result in sufficient aqueous solubility. Plenio and coworkers (Eduard-Zintl-Institut) reported the synthesis of disulfonated N-heterocyclic imidazolium and imidazolinium salt ligands and their use in aqueous Suzuki–Miyaura coupling reactions. These conditions provided high yields when tested with aryl chlorides and aryl boronic acids, even at 0.1% catalyst loading.114 iPr −

N

O3S iPr

Cl R1

+

iPr

(HO)2B R2

+

H

−

N

SO3

iPr

Na2PdCl4 KOH (3 equiv) H2O, 100 °C

R1

R2

56–99% conversion

It should also be noted that the reaction was tolerant of nitrogen-containing heterocycles, including difficult to couple substrates, such as 4-amino-2-chloropyridine. Building on this concept, Kühn and coworkers (Technische Universität München) published on sulfonated, water-soluble pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-Pd-N-heterocyclic

94 See Note 78. 95 Kobayashi, S. Pure and Applied Chemistry 2007, 79, 235–245. 96 Ogawa, C.; Kobayashi, S. Toward Truly Efficient Organic Reactions in Water; CRC Press LLC: 2008, p. 249–265. 97 Azizi, N.; Torkiyan, L.; Saidi, M. R. Organic Letters 2006, 8, 2079–2082. 98 Hamada, T.; Manabe, K.; Kobayashi, S. Chemistry - A European Journal 2006, 12, 1205–1215. 99 Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2006, 4075–4080. 100 Ollevier, T.; Nadeau, E.; Guay-Begin, A.-A. Tetrahedron Letters 2006, 47, 8351–8354. 101 Shimizu, S.; Shimada, N.; Sasaki, Y. Green Chemistry 2006, 8, 608–614. 102 Xiao, J.; Loh, T.-P. Synlett 2007, 815–817. 103 Pan, C.; Wang, Z. Coordination Chemistry Reviews 2008, 252, 736–750. 104 See Note 92. 105 Li, P.; Wang, L. Tetrahedron 2007, 63, 5455–5459. 106 Anderson, K. W.; Buchwald, S. L. Angewandte Chemie, International Edition 2005, 44, 6173–6177. 107 Paul, S.; Islam, M. M.; Islam, S. M. RSC Advances 2015, 5, 42193–42221. 108 See Note 79. 109 Seifried, M.; Knoll, C.; Giester, G.; Welch, J. M.; Mueller, D.; Weinberger, P. European Journal of Organic Chemistry 2017, 2017, 2416–2424. 110 Lysen, M.; Koehler, K. Synthesis 2006, 692–698. 111 Biffis, A.; Centomo, P.; Del Zotto, A.; Zecca, M. Chemical Reviews (Washington, DC, U. S.) 2018, 118, 2249–2295. 112 Crabtree, R. H. Chemical Reviews (Washington, DC, U. S.) 2012, 112, 1536–1554. 113 Liu, C.; Zhang, Y.; Liu, N.; Qiu, J. Green Chemistry 2012, 14, 2999–3003. 114 Fleckenstein, C.; Roy, S.; Leuthaeusser, S.; Plenio, H. Chemical Communications 2007, 2870–2872.

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16 Green Chemistry

carbene (NHC) catalysts to carry out Suzuki–Miyaura cross-couplings under aqueous and aerobic conditions.115 Et N

N

SO3Na

Et Pd Br Br N

X R1 (X = Br, Cl)

+

(HO)2B

(0.1 mol%) R2

KOH (2 equiv) H2O rt, under air

R2

R1

42–94% yields

The most promising catalyst identified from this work furnished good-to-excellent yields for a variety of aryl bromides at room temperature using a catalyst loading of 0.1 mol%, and recycling was found to tolerate four consecutive runs without significant loss in activity. The catalyst is prepared in two steps from readily available materials and was also effective for aryl chloride cross-coupling partners but required increased catalyst loading (1.0 mol%) and elevated temperatures (100 ∘ C) to reach completion. The researchers also demonstrated that hindered aryl chlorides and bromides with ortho-substituted arylboronic acids was challenging, providing only trace amounts of product at room temperature. Other types of metal-catalyzed reactions have been studied in aqueous systems as well, including Sonogashira,116,117,118 Heck,119,120,121,122 and Ullmann couplings.123,124,125,126 An increasing important field in organic synthesis in water is micellar catalysis, which involves the use of surfactants that self-aggregate in water to form micelles.127 The heterogeneous systems that are formed, sometimes referred to as nanoreactors, provide an interface where catalytic reactions can occur in the presence of water.128 Nearly all of biological reactions occur at gas–liquid interfaces, or by an enzyme that is bound to a membrane. The chemical industry carries out many processes that occur on the surfaces of solid catalysts as well, and the addition of agents that take no part in the chemical reaction itself can have profound effects by determining the properties of the catalytic surface.129 Lipshutz and coworkers (UC Santa Barbara) reported on the monophospine ligand HandaPhos and the surfactant Nok130 to carry out Suzuki–Miyaura cross-couplings for a number of highly functionalized substrates in water at room temperature.131

115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131

Zhong, R.; Poethig, A.; Feng, Y.; Riener, K.; Herrmann, W. A.; Kuehn, F. E. Green Chemistry 2014, 16, 4955–4962. Liu, S.; Xiao, J. Journal of Molecular Catalysis A: Chemical 2007, 270, 1–43. Lamblin, M.; Nassar-Hardy, L.; Hierso, J.-C.; Fouquet, E.; Felpin, F.-X. Advanced Synthesis and Catalysis 2010, 352, 33–79. Bakherad, M. Applied Organometallic Chemistry 2013, 27, 125–140. See Note 79. Christoffel, F.; Ward, T. R. Catalysis Letters 2018, 148, 489–511. Shi, X.; Han, X.; Ma, W.; Fan, J.; Wei, J. Applied Organometallic Chemistry 2012, 26, 16–20. Khalafi-Nezhad, A.; Panahi, F. ACS Sustainable Chemistry & Engineering 2014, 2, 1177–1186. Li, H.; Chai, W.; Zhang, F.; Chen, J. Green Chemistry 2007, 9, 1223–1228. Huang, J.; Yin, J.; Chai, W.; Liang, C.; Shen, J.; Zhang, F. New Journal of Chemistry 2012, 36, 1378–1384. Marinelli, F. Current Organic Synthesis 2012, 9, 2–16. Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Chemical Society Reviews 2014, 43, 3525–3550. Khan, M. N.; Editor Micellar Catalysis; CRC Press, 2006. Butler, R. N.; Coyne, A. G. Organic & Biomolecular Chemistry 2016, 14, 9945–9960. Lipshutz, B. H.; Ghorai, S.; Cortes-Clerget, M. Chemistry - A European Journal 2018, 24, 6672–6695. Klumphu, P.; Lipshutz, B. H. The Journal of Organic Chemistry 2014, 79, 888–900. Handa, S.; Andersson, M. P.; Gallou, F.; Reilly, J.; Lipshutz, B. H. Angewandte Chemie International Edition 2016, 55, 4914–4918.

16.3 Solvent and Reagent Selection

Br

OHC

O P(OEt)2 OMe

+

OHC O P(OEt)2 OMe O F 82% F

F As above

F

+

S

OMe

(HO)2B

O Br

(Boc)2N

1000 ppm (L)Pd(OAc)2 2 wt% Nok (0.5 M) Et3N (2.0 equiv), rt

OMe

(HO)2B

N

S

(Boc)2N

N

Br +

BF3K

N Boc

N

As above

92%

N

O

O

BocN

87% Many other examples Ligand

O

Surfactant O

iPr

O H

P

n

O

n = c. 13

H

HandaPhos

OMe

O

H

iPr

OMe iPr

MeO

H

Nok (SPGS-550-M)

The methodology accepted a range of boron sources, including boronic acids, Bpin, B(MIDA), and BF3 K salts, and yields for the reaction were good to excellent with catalyst loadings as low as 1000 ppm. Aryl bromides, chlorides, and iodides worked in the chemistry, but most aryl chloride substrates required heating to 45 ∘ C to reach completion. Gallou (Novartis) published on micellar catalysis to carry out safer nitro group reductions with Fe/ppm Pd nanoparticles in water at room temperature for scale-up.132,133 O

NH2

NO2 R

BocHN

Cl

Fe/ppm Pd NPs KBH4

94%

2 wt% TPGS-750-M∗ H2O, rt

MeO

TPGS-750-M O O n O

Br 91% NH2

NH2 EtO

O

O

O

95% (contained 15% reduced alkane)

88% ∗ Surfactant

N H 93%

Br Br Me Me

NH2

NH2

Me O O

Me Me

O

Me

Me

Me Me

Me

132 Gabriel, C. M.; Parmentier, M.; Riegert, C.; Lanz, M.; Handa, S.; Lipshutz, B. H.; Gallou, F. Organic Process Research & Development 2017, 21, 247–252. 133 Feng, J.; Handa, S.; Gallou, F.; Lipshutz, B. H. Angewandte Chemie International Edition 2016, 55, 8979–8983.

715

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16 Green Chemistry

Using an aqueous solution of the surfactant TPGS-750-M and KBH4 as reductant, the researchers noted that the procedure uses low metal loadings of Pd (80–200 ppm), avoids the high-pressure equipment needed for these types of reductions, and had high functional group tolerance. Calorimetry was performed and confirmed there were no significant safety concerns, and since the reactions were run in water, the work-up and purification was operationally simple to carry out, with isolated products containing very low levels of residual metal.

16.4 Green Reactions/Reagents Once a synthetic strategy has been chosen, the selection of reaction conditions and reagents to provide an economical, environmental, and safe process becomes increasingly important. In 2005, Dugger et al. published a review of reactions performed in a good manufacturing practice (GMP) facility at Pfizer, and found that carbon–carbon and carbon–nitrogen bond formation were two of the most common reactions in API synthesis.134 The methodology used for carbon–carbon bond formation varied from the use of organolithium reagents to metal-catalyzed coupling reactions. For carbon–nitrogen bond formation, reductive amination and metal-catalyzed coupling were the most common. A cross-site analysis among Pfizer, GlaxoSmithKline, and AstraZeneca also found that carbon–carbon and carbon–heteroatom bond formation were the most common.135 With the variety of reagents/conditions available to perform these transformations, it can be challenging for a chemist to decide which one to use. Metrics, such as those introduced in Section 16.2, can assist in comparisons between methods, but do not provide guidance for reagent selection. Many companies have developed tools, similar to the solvent selection tool, to help their scientists choose green reagents during their route selection process. As an example, Pfizer published a reagent guide as part of an extensive publication to target both greener solvent and reagent selections by providing alternative chemical methods for several reaction types.136 These methods were chosen because of established performance, scalability, and greenness. The guide is intended to help introduce green reagents earlier in the discovery/development process. Although green alternatives have been identified for several transformations, gaps exist where there is no useful green substitute. The ACS GCI PRT in 2007 identified the following gaps: reduction of amides, bromination, sulfonation, atom economical amide formations, nitrations, demethylations, Friedel–Crafts reactions, ester hydrolysis, alcohol substitution for displacement, epoxidation, and carbonyl olefinations.137 In 2018, the GCI PRT reported on considerable progress toward achieving these synthetic short comings, and greener alternatives have appeared in the literature over the last decade.138

16.5 Examples of Green Methods and Reagents for Common Reaction Types 16.5.1

Formation of Aryl Amines and Aryl Amides

Aryl amines and aryl amides can be formed from a coupling of an amine or amide with an aryl halide, with or without metal catalysis (see Chapter 6).139,140,141 Direct displacement of an aryl halide with an amine is very atom efficient and leads to virtually no side products of concern but typically requires harsh conditions. As a result, the substitution is more commonly conducted in the presence of small amounts of a heavy metal catalyst under milder conditions. This method is effective for coupling to aryl bromides, iodides, and triflates. Several reviews have been published in the aryl amination area, including some that address large-scale reactions for both ligand preparation and their use in multi-kilo scale aryl aminations.142 134 135 136 137 138 139 140 141 142

Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Organic Process Research & Development 2005, 9, 253–258. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Organic & Biomolecular Chemistry 2006, 4, 2337–2347. See Note 10. See Note 8. See Note 47. Senra, J. D.; Aguiar, L. C. S.; Simas, A. B. C. Current Organic Synthesis 2011, 8, 53–78. Ruiz-Castillo, P.; Buchwald, S. L. Chemical Reviews 2016, 116, 12564–12649. Guram, A. S. Organic Process Research & Development 2016, 20, 1754–1764. Magano, J.; Dunetz, J. R. Chemical Reviews (Washington, DC, U. S.) 2011, 111, 2177–2250.

16.5 Examples of Green Methods and Reagents for Common Reaction Types

Bourbeau et al. (Amgen) disclosed a Pd-catalyzed Buchwald–Hartwig coupling as a key bond forming step toward a GK-GKRP disruptor candidate for diabetes.143

F3C HO

CF3

H N

+

NH2

L Cl (4 mol%)

F3C HO

i-PrO

PCy Oi-Pr

Me

CF3

Me

CF3

N N

NaOt-Bu, 80 °C dioxane

N Bn

Br

Pd

Me

F3C HO

N NBn

GK-GKRP disruptor

100% yield

SO2 N NH2

L = RuPhos ligand

Utilizing the effective catalytic system discovered by the Buchwald (MIT) group,144 the chemistry was performed on >60 g scale in high yield, improve the safety of the process, and significantly increase the overall efficiency of the synthetic route. Chung et al. (Pfizer) published on Pd-catalyzed aminocarbonylation to prepare carboxamides from aryl tosylates.145 O

O F3C

N

OTs R

Cy2P +

R2

H N

R3

Pd(OAc)2 (6 mol%) PCy2 •2HBF 4

MeO2C

OMe

O

80%

60%

O

(6 mol%)

DMF, K2CO3 (1 equiv) CO, 80 °C

N

NBoc

N H OMe

MeO2C

OH

O Me

N

88%

85% O

Me

O NC

H N

N H 76% (99% ee)

Me

N

N O

S 58%

The method was able to tolerate a variety of amines, including less basic amines such as anilines and morpholine. Aryl tosylates containing electron-withdrawing substituents performed extremely well, while substrates lacking electron-withdrawing groups or containing ortho-directing alkoxy groups did not reach full conversion. This was attributed to the rate of oxidative addition of Pd(0), which if not rapid can permit alternative, unproductive pathways leading to catalyst deactivation by the amine. Shekhar and colleagues (Abbvie) developed a Cu-catalyzed synthesis of amides directly from alcohols and secondary amines, using the O2 in air to serve as the terminal oxidant.146

143 Bourbeau, M. P.; Ashton, K. S.; Yan, J.; St. Jean, D. J. The Journal of Organic Chemistry 2014, 79, 3684–3687. 144 Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. Journal of the American Chemical Society 2008, 130, 6686–6687. 145 Chung, S.; Sach, N.; Choi, C.; Yang, X.; Drozda, S. E.; Singer, R. A.; Wright, S. W. Organic Letters 2015, 17, 2848–2851. 146 Krabbe, S. W.; Chan, V. S.; Franczyk, T. S.; Shekhar, S.; Napolitano, J. G.; Presto, C. A.; Simanis, J. A. The Journal of Organic Chemistry 2016, 81, 10688–10697.

717

718

16 Green Chemistry

(Het)Ar

OH

Amine:

+

R1

H N

Cu(Phen)Cl2 (10 mol%) DBADH2 (10 mol%) R2

K2CO3 or K3PO4 (3 equiv) toluene, 75 °C oxygen in air

H N

O (Het)Ar

N R1

R2

H N O

Entry 1 2 3 4 5 6

Ar Yield (%) Ph 83 2-Cl-C6H4 76 81 3-Me-C6H4 76 4-F-C6H4 66 3-NMe2-C6H4 83 2-Naphthyl

Entry 7 8 9 10 11 12

Ar Yield (%) 3-CF3-C6H4 84 3-NMe2-C6H 88 4-Cl-C6H4 92 4-OMe-C6H4 84 4-OMe-C6H4 91 3-Pyridinyl 82

The process was noted as operationally simple and features the nonprecious metal catalyst Cu(phen)Cl2 , di-tert-butyl hydrazine dicarboxylate (DBADH2 ), and inorganic base. To further increase reactivity for a number of benzamides, the researchers noted that the electronics of the alcohol, as well as the pK a of the amine conjugate acid, were needed to choose the optimal base. 16.5.2

Carbon–Carbon Bond Formation

When forming carbon–carbon bonds, palladium-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, etc.) can serve as a green alternative to more traditional methods. For instance, the Heck reaction can be used to produce Wittig-type products without the phosphorus oxide waste. For the Heck, as with other palladium-catalyzed coupling reactions, bulky phosphorus ligands tend to work the best.147,148,149 Ligands such as the type developed by Buchwald and Hartwig and coworkers have shown remarkable results for this type of reaction under mild conditions.150,151,152 Several other ligands, also used for aryl amination reactions, have been found to be efficient for a variety of Heck reactions including the Nolan imidazolinium type and modified ureas.153,154,155 As the availability of boronic acid and ester derivatives increases at commercial scale, the Suzuki reaction has become a feasible alternative to organometallic chemistry such as organomagnesium or organolithium reactions. These developments make the use of economical substrates such as aryl chlorides become more practical.156,157,158 Reaction methodology to couple hindered substrates or those with asymmetric centers with retention of configuration have also been developed.159,160,161 Other traditional bond formations found in water include Claisen rearrangements,162,163 asymmetric aldol,164,165 and catalytic hydrogenation.166,167 147 Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Advanced Synthesis & Catalysis 2006, 348, 23–39. 148 Altman, R. A.; Buchwald, S. L. Nature Protocols 2007, 2, 3115–3121. 149 Yeung, C. S.; Dong, V. M. Chemical Reviews (Washington, DC, U. S.) 2011, 111, 1215–1292. 150 Surry, D. S.; Buchwald, S. L. Chemical Science 2011, 2, 27–50. 151 Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. Journal of the American Chemical Society 2006, 128, 3584–3591. 152 Hie, L.; Chang, J. J.; Garg, N. K. Journal of Chemical Education 2015, 92, 571–574. 153 Valente, C.; Calimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angewandte Chemie International Edition 2012, 51, 3314–3332. 154 See Note 79. 155 See Note 120. 156 See Note 111. 157 See Note 83. 158 Yuan, B.; Pan, Y.; Li, Y.; Yin, B.; Jiang, H. Angewandte Chemie International Edition 2010, 49, 4054–4058, S4054/4051-S4054/4020. 159 Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chemical Reviews (Washington, DC, U. S.) 2015, 115, 9587–9652. 160 Swift, E. C.; Jarvo, E. R. Tetrahedron 2013, 69, 5799–5817. 161 Zhang, D.; Wang, Q. Coordination Chemistry Reviews 2015, 286, 1–16. 162 Majumdar, K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2007, 64, 597–643. 163 Clark, J. H.; Tavener, S. J. Organic Process Research & Development 2007, 11, 149–155. 164 Mlynarski, J.; Paradowska, J. Chemical Society Reviews 2008, 37, 1502–1511. 165 Jimeno, C. Organic & Biomolecular Chemistry 2016, 14, 6147–6164. 166 Foubelo, F.; Najera, C.; Yus, M. Tetrahedron: Asymmetry 2015, 26, 769–790. 167 Schaper, L.-A.; Hock, S. J.; Herrmann, W. A.; Kuehn, F. E. Angewandte Chemie International Edition 2013, 52, 270–289.

16.5 Examples of Green Methods and Reagents for Common Reaction Types

16.5.3

Oxidation

The oxidation of alcohols is a common transformation for both industrial and laboratory scale synthesis, but traditional methods present efficiency and safety limitations (see Chapter 10).168,169,170 Alcohol oxidation has frequently been performed with stoichiometric inorganic oxidants, such as chromium(VI) reagents,171,172 which have a number of safety concerns, or by Swern-type oxidations.173,174 The Swern oxidation is challenging on large scale due to, in most cases, the need for cryogenic temperatures and the extremely reactive reagent oxalyl chloride, which can present handling and safety issues. In addition, large amounts of gas by-products (CO2 and CO) are produced, presenting a potential safety and environmental issue. In addition, halogenated solvents, poor atom economy, and difficult-to-handle by-products often prompt industrial chemists to start at the required (or higher) oxidation state in order to avoid these limitations.175 The use of 1-oxy-2,2,6,6-tetramethylpiperidinyl (TEMPO) for oxidation has been employed by various groups as a green alternative,176,177,178,179,180,181 including its use in continuous flow reactors.182 Hardouin et al. (Oril Industrie) published on a large-scale TEMPO oxidation as part of an efficient synthetic route to an acetylcholine nicotinic receptor agonist.183

O HO

N Me

TEMPO (1 mol%) OtBu

KBr (10 mol%), NaOCl EtOAc, H2O, rt 95%

O O

N H

Me

Steps

N

OtBu

H N

N H

Me

OH OH HO2C

CO2H OH OH

Acetylcholine nicotinic receptor agonist

The initial conditions that relied on the solvent dichloromethane were replaced with ethyl acetate, and the crude product was not isolated but taken to the subsequent step without purification. Additional process improvements resulted in the removal of NaHCO3 as base, and a significant reduction of the KBr and volumes of water used. Stahl and coworkers (U. Wisconsin) have reported on a greener oxidation of alcohols to aldehydes using a CuI/TEMPO catalyst system that includes N-methylimidazole (NMI) and 2,2′ -bipyridine (bpy) to carryout aerobic oxidations.184,185,186

168 Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chemical Reviews 2006, 106, 2943–2989. 169 Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chemical Reviews (Washington, DC, U. S.) 2013, 113, 6234–6458. 170 Cao, Q.; Dornan, L. M.; Rogan, L.; Hughes, N. L.; Muldoon, M. J. Chemical Communications (Cambridge, U. K.) 2014, 50, 4524–4543. 171 Luzzio, F. A.; Guziec, F. S., Jr. Organic Preparations and Procedures International 1988, 20, 533–584. 172 Hayashi, M.; Kawabata, H. Advances in Chemistry Research 2006, 1, 45–62. 173 Tidwell, T. T. Organic Reactions (New York) 1990, 39, 297–572. 174 Ahmad, N. M. In Name Reactions for Functional Group Transformations; John Wiley & Sons, Inc.: Hoboken, N. J., 2007, 291–308. 175 See Note 168. 176 Vogler, T.; Studer, A. Synthesis 2008, 1979–1993. 177 Ashcroft, C. P.; Dessi, Y.; Entwistle, D. A.; Hesmondhalgh, L. C.; Longstaff, A.; Smith, J. D. Organic Process Research & Development 2012, 16, 470–483. 178 Rossi, F.; Corcella, F.; Caldarelli, F. S.; Heidempergher, F.; Marchionni, C.; Auguadro, M.; Cattaneo, M.; Ceriani, L.; Visentin, G.; Ventrella, G.; Pinciroli, V.; Ramella, G.; Candiani, I.; Bedeschi, A.; Tomasi, A.; Kline, B. J.; Martinez, C. A.; Yazbeck, D.; Kucera, D. J. Organic Process Research & Development 2008, 12, 322–338. 179 Beejapur, H. A.; Campisciano, V.; Giacalone, F.; Gruttadauria, M. Advanced Synthesis and Catalysis 2015, 357, 51–58. 180 Zheng, Z.; Wang, J.; Zhang, M.; Xu, L.; Ji, J. ChemCatChem 2013, 5, 307–312. 181 Ciriminna, R.; Pagliaro, M. Organic Process Research & Development 2010, 14, 245–251. 182 Leduc, A. B.; Jamison, T. F. Organic Process Research & Development 2012, 16, 1082–1089. 183 Hardouin, C.; Poixblanc, A.; Bariere, F.; Tamion, R.; Dubuffet, T.; Hervouet, Y.; Mouchet, P. Organic Process Research & Development 2018, 22, 1419–1425. 184 Hoover, J. M.; Stahl, S. S. Organic Syntheses 2013, 90, 240–250. 185 Hoover, J. M.; Ryland, B. L.; Stahl, S. S. Journal of the American Chemical Society 2013, 135, 2357–2367. 186 Hoover, J. M.; Stahl, S. S. Journal of the American Chemical Society 2011, 133, 16901–16910.

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16 Green Chemistry

R

OH

5% (bpy)CuI(OTf) 5% TEMPO 10% NMI air or O2 ACN, rt

Mechanism R

O N

O

N TEMPO

92% O

O

96% Cl

HO

O Cl

98%

1/2 [LnCu]2(O2) TEMPO - H

R

LnCuII

OH

TEMPO

Cl 98%

O 94%

1/2 O2

O

O

NO2 98%

R

O

H2O

F

H2N

LnCuI

H H

92%

NH2 95%

LnCuII O

98%

O + TEMPO - H TEMPO

NMI

O

O

O

R

N

95%

Highlights of this chemistry include faster catalytic rates than previous Pd-catalyzed systems, selectivity for the conversion of primary alcohols to aldehydes, and significant substrate scope, such as pyridines, thioethers, and halogenated arenes. The group was also able to carry out the reaction in a plug flow reactor, and demonstrate the stability of this homogeneous catalyst for implementation on larger scale.187 This can be challenging in a manufacturing setting due to the flammable/explosive atmospheres created by mixtures of organic solvent and air/O2 gas, and the methodology benefits from built in safety features, such as a special plug flow reactor and fixing the O2 gas at low concentrations in N2 . Several companies recently disclosed the minimum partial pressure of oxygen that supports a combustible mixture. This limiting oxygen concentration (LOC) values were calculated for nine common organic solvents at elevated temperatures and pressures, and can be used as a guide to operating safer oxidations with O2 .188 Ortiz et al. (Bristol–Myers Squibb) reported an air oxidation of alcohols in the second-generation synthesis of the HIV maturation inhibitor, Bristol-Myers Squibb (BMS)-955176. The synthesis was conducted on a larger scale and consisted of an 9-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO)/Cu(I)-mediated aerobic oxidation of the readily available and inexpensive natural product Betulin.189

187 Greene, J. F.; Hoover, J. M.; Mannel, D. S.; Root, T. W.; Stahl, S. S. Organic Process Research & Development 2013, 17, 1247–1251. 188 Osterberg, P. M.; Niemeier, J. K.; Welch, C. J.; Hawkins, J. M.; Martinelli, J. R.; Johnson, T. E.; Root, T. W.; Stahl, S. S. Organic Process Research & Development 2015, 19, 1537–1543. 189 Ortiz, A.; Soumeillant, M.; Savage, S. A.; Strotman, N. A.; Haley, M.; Benkovics, T.; Nye, J.; Xu, Z.; Tan, Y.; Ayers, S.; Gao, Q.; Kiau, S. The Journal of Organic Chemistry 2017, 82, 4958–4963.

16.5 Examples of Green Methods and Reagents for Common Reaction Types

Me H Me HO

Me 2 mol% ABNO 10 mol% TEMPO 10 mol% Cu(MeCN)4OTf

H

H

OH

20 mol% NMI ACN/CH2Cl2 O2/N2 (220 psi, 1 : 9)

Me Me Me Me H

Me HO

84%

Betulin

H O

H Me Me

H

Me MeH

Me H Me

6 steps

H

H Me Me

HO2C

H

HN

N SO2

Me MeH BMS-955176

The synthetic route clearly demonstrates the advantages of an oxidation that can be executed on a larger scale, providing the API in seven steps and 47% overall yield from betulin in a convergent and efficient synthesis. For the oxidation, the ABNO is the active catalyst, and TEMPO is added to inhibit what is thought to be radically induced over oxidation of the aldehyde and alkene moieties. 16.5.4

Nonprecious Metals Catalysis

Despite the prevalence of palladium catalysis for transition-metal-catalyzed processes, new methods have emerged that employ more abundant, cheaper, and in some cases less toxic metals to assist in the preparation of small molecules.190,191,192,193,194,195,196 Potential benefits of substituting rare, transition metals with nonprecious metals in synthetic chemistry is summarized below.

Metal

Cost (US$ oz t)197

Annual production-2016 (tons)198

Permitted daily exposure (PDE) (oral) (𝛍g/d)199

Natural abundance (ppm)200

Carbon footprint (kg/CO2 e)201

Pd

1 378

215.6

100

0.015

3 880

Ni

0.40

1.35 × 106

200

90

6.5

7

Cu

0.19

1.5 × 10

3 000

68

2.8

Fe

0.02

1.2 × 109

Other element

56 300

1.5

190 Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chemical Reviews (Washington, DC, U. S.) 2004, 104, 6217–6254. 191 Dander, J. E.; Garg, N. K. ACS Catalysis 2017, 7, 1413–1423. 192 Standley, E. A.; Tasker, S. Z.; Jensen, K. L.; Jamison, T. F. Accounts of Chemical Research 2015, 48, 1503–1514. 193 Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chemical Reviews 2011, 111, 1346–1416. 194 Bauer, E. B. Current Organic Chemistry 2008, 12, 1341–1369. 195 Pototschnig, G.; Maulide, N.; Schnuerch, M. Chemistry - A European Journal 2017, 23, 9206–9232. 196 Chirik, P.; Morris, R. Accounts of Chemical Research 2015, 48, 2495. 197 http://www.infomine.com/investment/metal-prices/ (accessed February 2019). 198 See Note 47. 199 ICH Q3D step 4: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf other element = elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in the guideline. The EMEA Oral pde is 13 000 μg/d: https://www.ema.europa.eu/documents/scientific-guideline/ guideline-specification-limits-residues-metal-catalysts-metal-reagents_en.pdf (accessed February 2019, procedure is under revision). 200 https://education.jlab.org/itselemental/index.html (accessed February 2019). 201 Nuss, P.; Eckelman, M. J. PLoS One 2014, 9, e101298/101291–e101298/101212, 101212 pp.

721

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16 Green Chemistry

Magano and Monfette (Pfizer) published on the synthesis of the precatalyst NiCl(o-tolyl)TMEDA (TMEDA, tetramethylethylenediamine) and its applications to a wide array of coupling reactions, including Suzuki, Kumada, Heck, Negishi, amination, borylation, and reductive couplings.202,203 Cl Me

Ni(cod)2 +

+

Me2N

NMe2

Me

Neat 22 °C, 66 h 91%

Me

N N

Me Ni

Cl

Me

Multi-gram scale Cl

B(OH)2 +

Ph

[Ni] (5 mol%) PCy3 (12 mol%)

87% yield

K3PO4 • H2O (3 equiv) THF, 68 °C, 18 h

OMe

OMe

(1.2 equiv) Cl + CF3

H N

[Ni] (5 mol%) SiPr·HCl (12 mol%)

O

NaOt-Bu (2 equiv) CPME, 100 °C, 4 h

O N

91% yield

F 3C

(1.2 equiv)

ZnBr

Cl +

N Boc

Ph

[Ni] (2 mol%) PPh3 (5 mol%) THF, 20 °C, 18 h

(1.2 equiv)

62% yield N Boc

In all of the reactions explored, NiCl(o-tolyl)(TMEDA) performed as well or better than Ni(cod)2 and NiCl2 (dme). The precatalyst was stabile in air for months without loss of reactivity, had good solubility in a number of common organic solvents, and was amenable to high throughput experimentation (HTE). Buono et al. (Boehringer Ingelheim) reported on Fe-catalyzed Kumada cross-couplings of 2-chloropyrazine with a number of aryl Grignard reagents in a continuous plug flow reactor.204 FT-IR flow cell

N N Cl Fe(acac)3 (0.5 mol%) In THF

X

MgBr In THF

N

Tube-in-tube reactor Jacketed static-mixer 4 min residence time Temp. probe

N X

4 g scale

X Yield (%) Entry F 63 1 70 2 H 81 3 Me 63 4 Cl 75 5 OMe

Kumada biaryl cross-coupling reactions to form C(sp2 )—C(sp2 ) bonds are difficult due to limited substrate scope and functional group tolerance, as well as formation of homo-coupling adducts and decomposition of catalyst. The 202 Magano, J.; Monfette, S. ACS Catalysis 2015, 5, 3120–3123. 203 Shields, J. D.; Gray, E. E.; Doyle, A. G. Organic Letters 2015, 17, 2166–2169. 204 Buono, F. G.; Zhang, Y.; Tan, Z.; Brusoe, A.; Yang, B.-S.; Lorenz, J. C.; Giovannini, R.; Song, J. J.; Yee, N. K.; Senanayake, C. H. European Journal of Organic Chemistry 2016, 2016, 2599–2602.

16.5 Examples of Green Methods and Reagents for Common Reaction Types

improved continuous process provided higher yields, higher reproducibility, and was more amenable to scale since catalyst loadings were low (0.5 mol%) when compared against the standard batch conditions. Hansen (Pfizer) and Weix (U. Wisconsin) reported a breakthrough in nonprecious metal catalysis in 2016, where they identified amidine ligands for Ni-catalyzed reactions by mining an internal Pfizer compound library.205 Unlike Pd-catalyzed reactions, which can benefit from a number of diverse and widely available phosphine ligands, the options for nitrogen-, oxygen- and sulfur-based ligands for other metals in catalysis is limited. Investigation of these newly identified ligands provided cross-electrophile couplings for several 2-bromoarenes and 3-bromopyridine derivatives with alkyl halides. *Ligand Br

DG

NiCl2(dme) (5 mol%) Ligand* (5 mol%)

Br or R′

NaI (0.25 equiv) Zn (2.0 equiv) TFA (0.1 equiv) DMA

Br N

R

N

alkyl

O

NH

OEt

NH2

MeO

Ph 79%

NH H2N

O

NH N

Ph

EtO

NH2

N 78% 15 additional examples (39–85% yield)

Later, the same researchers reported the application of these ligands for the Ni-catalyzed sp2 -sp3 cross-coupling using electrochemistry, which provided a tunable parameter for reliable Ni catalyst activation and turnover and reaction optimization.206 In 2016, Desrosiers et al. (Boehringer Ingelheim) reported on a Ni-catalyzed intramolecular Heck reaction to prepare quaternary stereocenters of 3,3-disubstituted oxindoles in moderate-to-good yields.207 Nickel-catalyzed Heck cyclization X

Ni0

O R

R

R1

X = Cl, Br, I

R1 [NiCl2(PnBu3)2] Mn Na2CO3 DMF, 60 °C

Me

Me

O

N

F

O

F

O

O

N

NC

Me 66%

R2

NiH(X)

72%

O

N R

NC

O Me

Me

O

N

Me

53%

Me

MeO N 60%

Me

O F

N Me 67%

O 62%

N Me

O

205 Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.; Weix, D. J. Nature Chemistry 2016, 8, 1126–1130. 206 Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Organic Letters 2017, 19, 3755–3758. 207 Desrosiers, J.-N.; Hie, L.; Biswas, S.; Zatolochnaya, O. V.; Rodriguez, S.; Lee, H.; Grinberg, N.; Haddad, N.; Yee, N. K.; Garg, N. K.; Senanayake, C. H. Angewandte Chemie International Edition 2016, 55, 11921–11924.

723

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16 Green Chemistry

The reaction possessed high functional group tolerance and benefitted from the use of an air stable catalyst that simplified the process and minimized cost. The researchers noted that regeneration of active catalyst from NiII back to Ni0 is more demanding than similar Pd systems, and that the NiII species (resting state) can lead to isomerization and over-reduction side products.208 Furthermore, density functional theory (DFT) calculations reported in the literature suggest an 8.7 kcal/mol higher energy barrier for β-hydride elimination in Ni systems compared to Pd, suggesting protonolysis or dimerization pathways could occur before desired product formation. The researchers were able to overcome these challenges with the discovery of electron-rich, nonhindered monophosphine ligands, such as PnBu3 , as well as Mn to serve as the optimal reductant. The researchers later disclosed an asymmetric version of the transformation,209 providing substrates in 55–96% ee using P-chiral bisphosphine QuinoxP* as ligand.210 The use of nonprecious metals to catalyze bond formation is an active area of research within both academia and industry. As researchers look to expand the available methods used for the preparation of organic molecules within the scientific community, more abundant earth metals could have applications that provide an improvement in sustainability, safety, and protect the environment. Although there are still challenges associated with replacing all precious metal catalyzed processes with a corresponding nonprecious alternative, significant progress has been made with regards to Ni-, Cu-, and Fe-mediated reactions.

16.6 Predictive Tools to Design for Green Chemistry In 2017, Eastgate and coworkers (Bristol–Myers Squibb) published on a predictive analytics framework coupled to Monte Carlo simulation as a means for assessing the green chemistry potential for a series of synthetic transformations.211,212 Select ranges for Step PMI and Step Yield based on experience or database

Sample both Step PMI and Step Yield from a given step based on a correlated normal distribution assumption

Calculate Cumulative PMI for target using predefined blocks of linear and/or convergent synthesis modules back propagated to raw materials

Y/N

10 000 + iterations

Target compound Raw material

Collect average Cumulative PMI and confidence intervals

This data-driven strategy allows scientists the ability to compare different synthetic routes before the start of laboratory investigation by predicting probable PMI outcomes, and can aid decision-making during the critical phases of the route discovery process. The approach can also be used as a benchmarking tool, allowing the user to make direct comparisons 208 Lin, B.-L.; Liu, L.; Fu, Y.; Luo, S.-W.; Chen, Q.; Guo, Q.-X. Organometallics 2004, 23, 2114–2123. 209 Desrosiers, J.-N.; Wen, J.; Tcyrulnikov, S.; Biswas, S.; Qu, B.; Hie, L.; Kurouski, D.; Wu, L.; Grinberg, N.; Haddad, N.; Busacca, C. A.; Yee, N. K.; Song, J. J.; Garg, N. K.; Zhang, X.; Kozlowski, M. C.; Senanayake, C. H. Organic Letters 2017, 19, 3338–3341. 210 Nagata, K.; Matsukawa, S.; Imamoto, T. The Journal of Organic Chemistry 2000, 65, 4185–4188. 211 Li, J.; Simmons, E. M.; Eastgate, M. D. Green Chemistry 2017, 19, 127–139. 212 Li, J.; Albrecht, J.; Borovika, A.; Eastgate, M. D. ACS Sustainable Chemistry & Engineering 2018, 6, 1121–1132.

16.7 Green Chemistry Improvements in Process Development

with similar chemistry and across molecules and is now a publicly open web application.213 While PMI cannot distinguish the impact of the individual reagents and consumables, it provides a simple and well established approach to assessing the efficiency of a set of potential processes and has been shown to correlate directly to production costs. Later, in collaboration with the ACS GCI PRT, the initial data base of BMS was expanded upon by 12 additional pharmaceutical companies from internal data bases and the literature.214 The tool now has over 1800 examples for a number of different synthetic transformations, representing reactions that were optimized and scaled up in pilot plants and provides increased confidence in the tool’s predictive power.

16.7 Green Chemistry Improvements in Process Development Throughout the development of a commercial route for an API, process chemists face numerous challenges, including the need to select the best route, starting materials, synthetic methods, and technologies that provide the desired target under a timeline dictated by project needs and loss of exclusivity due to patent lifetimes. The overall goal of a process chemist is to develop the most cost-effective process for large-scale synthesis of an API. A cost-effective process typically has high overall yield, little waste (cost for disposal and cost of material use), and good reagent/reactant utilization factors, among others. As development progresses and these factors improve, the process becomes greener. In terms of metrics, the RME increases as the yield increases and the reagents are used more sparingly. The E factor will also decrease over time as the waste is decreased with more efficient workups, telescoping, and reduced use of solvent. The process can then be further improved when “greener” methods/reagents are introduced. Biocatalysis is one of these “greener” methods that has become a valuable technology for sustainable manufacturing in fine chemical, pharmaceutical, and other industries.215,216 Second-generation processes for pregabalin, the API in Lyrica , and sitagliptin, the API in Januvia , both utilize biocatalysis and will be presented as case studies to illustrate the value of biocatalysis for green chemistry and process development.

®

16.7.1

®

Pregabalin

Pregabalin is the API in Lyrica, marketed by Pfizer for treatment of fibromyalgia, postherpetic neuralgia, neuropathic pain associated with diabetic peripheral neuropathy and spinal cord injury, and as an adjunctive therapy for partial onset seizures. Lyrica was launched in the United States in 2005 and rapidly reached blockbuster status with global sales of US$1.16 billion in 2006 and US$2.57 billion by 2008.217 The initial manufacturing route to pregabalin started with cyanodiester, which was prepared by condensation of isovaleraldehyde and diethylmalonate followed by cyanation.218 Hydrolysis and decarboxylation of cyanodiester afforded cyanoacid, which was reduced with Raney nickel to give pregabalin as a racemic mixture. A classical resolution with (S)-mandelic acid followed by recrystallization gave pregabalin in the desired (S)-configuration with high enantiomeric purity and 18–21% overall yield from cyanodiester. Me

CO2Et Me CN

CO2Et

KOH, MeOH H2O, reflux

Raney Ni

Me Me CN

Cyanodiester (S)-mandelic acid iPrOH, H2O

CO2H

Cyanoacid Me Me

CO2H NH2 HO2C

OH Ph

Me

EtOH H2O

iPrOH H2O

Me

Me Me

CO2H NH2

CO2H NH2

Pregabalin

213 Borovika, A.; Li, J.; Albrecht, J.; Eastgate, M. D.; American Chemical Society: 2018, p. GC+E-242. 214 Borovika, A.; Albrecht, J.; Li, J.; Wells, A. S.; Briddell, C.; Dillon, B. R.; Diorazio, L. J.; Gage, J. R.; Gallou, F.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Martinez, I.; Olbrich, M.; Piper, J. L.; Roschangar, F.; Sherer, E. S.; Eastgate, M. D. ChemRxiv 2019, 1–19. 215 Sheldon, R. A.; Woodley, J. M. Role of biocatalysis in sustainable chemistry. Chemical Reviews 2017, 118(2), 801–838. 216 Wohlgemuth, R. Current Opinion in Biotechnology 2010, 21, 713–724. 217 Dunn, P.J.; Hettenbach, K.; Martinez, C. A. The development of a green, energy efficient, chemoenzymatic manufacturing process for pregabalin. In: Dunn, P. J.; Wells, A. S.; Williams, M. T. (eds) Green Chemistry in the Pharmaceutical Industry; Wiley-VCH Verlag GmbH & Co, KGaA: Weinheim, 2010. 218 Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Organic Process Research & Development 1997, 1, 26–38.

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16 Green Chemistry

This classical resolution process was suitable for API manufacture but suffered from low efficiency mainly due to the penultimate resolution step in which the undesired isomer is discarded. The efficiency of the classical resolution process was quantified by an E factor analysis showing that 86 kg of waste was produced for each kilogram of pregabalin API. Various approaches including asymmetric hydrogenation219 were investigated to improve process efficiency and ultimately a biocatalytic approach was implemented as a second-generation manufacturing process.220

Me Base CO2Et

Me

Me CN

Lipolase

CO2Et

H2O

Cyanodiester

KOH, H2O

CO2Et CO2Et Me CN (R)-cyanodiester + CO2Et

Me

Me CN

CO2H

Decarboxylation

Me Me CN

H2O

CO2Et

(S)-cyanoester

(S)-cyanomonoester Me Me CN

CO2H

(S)-cyanoacid

Raney Ni H2O

Me Me

CO2H NH2

Pregabalin

The biocatalytic process still required resolution of cyanodiester, however, several key features of the new route contributed to significant improvements in process efficiency over the classical resolution process: 1. Early resolution of cyanodiester reduced waste and increased throughput by eliminating need to carry undesired isomer through several steps. 2. Enzymatic resolution of cyanodiester completely eliminated use of (S)-mandelic acid as stoichiometric resolving agent. 3. Reactions were all carried out in water greatly reducing use of organic solvents. 4. Reactions were telescoped eliminating isolations. 5. Base catalyzed epimerization of (R)-cyanodiester enabled recycle of undesired isomer. These improvements resulted in an overall yield of 40–45% from cyanodiester, with the incorporation of a single recycle of (R)-cyanodiester. The E factor of the biocatalytic route was 17, a fivefold improvement over the classical resolution route, and further improved to 8 with recycle of (R)-cyanodiester.

16.7.2

Sitagliptin

Januvia is a DPP-4 inhibitor marketed by Merck for the treatment of Type II diabetes. The drug was launched in the first quarter of 2011 and reached global sales of US$3.91 billion in 2016. The first generation route to sitagliptin phosphate employed asymmetric hydrogenation to introduce chirality and Mitsunobu chemistry to install the chiral amine.221 This route gave an overall yield of 52% over eight steps starting from a β-ketoester and was used to manufacture clinical supplies.

219 Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A. The Journal of Organic Chemistry 2003, 68, 5731–5734. 220 Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Organic Process Research & Development 2008, 12, 392–398. 221 Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera, N.; Steinhuebel, D.; Armstrong, J. D.; Askin, D. Organic Process Research & Development 2005, 9, 634–639.

16.7 Green Chemistry Improvements in Process Development

F F

O

F

(i) [(S)-binapRuCl2] HBr, H2

O OMe

F

OH O OH

(ii) NaOH

F

Base

F

N

HN BnO

N NH

O

N

F F

BnO

CF3

N

N

EDC

OH

H2PO4−

F

O

F

N

F

NH3+ O

(i) H2, Pd/C

N

O

F F

NH

BnO N

F

(ii) DIAD, PPh3

F F

F

(i) BnONH2 •HCl EDC, LiOH

N

N

(ii) H3PO4

F

N

CF3 Sitagliptin phosphate

N

CF3

Further process development resulted in a second-generation manufacturing process that used a three-step, one-pot process to produce dehydrositagliptin in 82% yield from a trifluorophenyl acetic acid.222 Chirality was introduced by rhodium catalyzed asymmetric hydrogenation of the enamine to give sitagliptin in 98% yield and 95% ee. Salt formation and recrystallization afforded the API in 65% overall yield. F

F F

F

Meldrum's acid

O

− Cl+ H

N

OH O

iPr2NEt, DMAP OH CH3CN

F Trifluorophenyl acetic acid

O

F NH4OAc

F

O F

β-ketoamide

[Rh(COD)Cl]2

NH2 O

MeOH

N

N F

N Dehydrositagliptin

N

t-Bu Josiphos H2, MeOH

CF3

98% yield 95% ee

F

(i) Heptane iPrOH

NH2 O N

N F

N N

F

F

O N

TFA

Me Me

O

F

N

CF3

O F

N

2N

N Sitagliptin

N

CF3

(ii) H3PO4 81% 99.9% ee

N

CF3

Sitagliptin phosphate

Compared to the first-generation process (E factor = 250), the second-generation route (E factor = 50) represented a large improvement in efficiency and received a Presidential Green Chemistry Challenge Award in 2006 in the Greener Reaction Pathways category. However, several drawbacks relating to the asymmetric hydrogenation step (need for high pressure hydrogenation, moderate stereochemical control, and removal of metal impurities) inspired development of the third-generation manufacturing process.223 Merck and Codexis collaborated to engineer a transaminase for reductive amination of β-ketoamide, starting with an enzyme that showed no activity for β-ketoamide and introducing 27 mutations over 11 rounds of engineering. The evolved enzyme operated on β-ketoamide in 50% dimethyl sulfoxide (DMSO) and gave complete stereochemical control. The third-generation process gave a 13% improvement in overall yield and a 19% reduction in waste compared to the second-generation process and was awarded a 2010 Presidential Green Chemistry Challenge Award for Green Reaction Conditions. F F

O

O

Transaminase N

N F

N β-ketoamide

N

CF3

PLP, isopropylamine

Sitagliptin

H3PO4

Sitagliptin phosphate

92% >99.9% ee

222 Desai, A. A. Angewandte Chemie International Edition 2011, 50, 1974–1976. 223 Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Science 2010, 329, 305–309.

727

729

17 Continuous Chemistry David D. Ford 1 , Robert J. Maguire 2 , J. Christopher McWilliams 3 , Bryan Li 3 , and Jared L. Piper 3 1

Snapdragon Chemistry Inc., Waltham, MA, USA

2 Cybrexa Therapeutics, New Haven, CT, USA 3

Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 729 Aliphatic Nucleophilic Substitutions, 731 Additions to C—Het Multiple Bonds, 735 Addition to C—C Multiple Bonds, 735 Nucleophilic Aromatic Substitutions, 739 Electrophilic Aromatic Substitution, 739 Catalysis, 741 Rearrangements, 743 Eliminations, 746 Reductions, 748 Oxidations, 751 Free Radical Reactions, 757 Syntheses of Organometallic Reagents, 760 Synthesis of Aromatic Heterocycles, 766 Access to Chirality, 770 Biotransformations, 771

17.1 Introduction Since the earliest examples of organic synthesis, the vast majority of reactions have been carried out in batch reactors. This standard laboratory or manufacturing tool, which includes round bottom flasks and large reactors, allows fixed quantities of reactants, solvents, and reagents to be added sequentially, and mixed by various means to perform chemical reactions. Continuous processing, or flow chemistry is an alternative approach to achieving chemical synthesis by bringing reactive components together in a continuous reactor while simultaneously avoiding a high concentration of reagents in the presence of the product formed.1,2,3,4,5,6 The most common types of continuous reactors are tubes (plug flow reactors – PFRs), tanks (continuous stirred tank reactors – CSTRs), and beds packed with solid-supported reagents or catalysts (packed bed reactors – PBRs). In general, compared to batch processes at equivalent throughput, continuous processes use smaller reactors, offer access to faster heating and cooling rates, and can be designed to both reduce unit operations and labor costs due to elimination of both content transfers from one reactor to another and 1 Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos, A. Accounts of Chemical Research 2015, 48, 349–362. 2 Knochel, P.; Molander, G. A. E. Comprehensive Organic Synthesis; 2nd ed.; 2014; Vol. 9. 3 Darvas, F.; Dorman, G.; Hessel, V.; Editors Flow Chemistry, Volume 2: Applications; Walter de Gruyter GmbH, 2014. 4 Wiles, C.; Watts, P.; Editors Micro Reaction Technology in Organic Synthesis; CRC Press, 2011. 5 Luis, S. V.; Garcia-Verdugo, E.; Editors Chemical Reactions and Processes Under Flow Conditions; Royal Society of Chemistry, 2010. 6 Hessel, V.; Renken, A.; Schouten, J. C.; Yoshida, J.-I.; Editors Micro Process Engineering: A Comprehensive Handbook, Volume 1: Fundamentals, Operations and Catalysts; Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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17 Continuous Chemistry

time-consuming reaction cleaning between batches. In general, continuous processing simplifies the number of unit of operations for a given process. The advantages of flow chemistry can be diminished by added complexity in terms of additional equipment that is required and a greater amount of design effort, as pumps and reactors are typically selected for each specific process. For this reason, using continuous reactors was long seen as a solution only fit for commodity chemical manufacturing and extremely hazardous processes, applications where the increased engineering cost associated with designing and implementing a continuous process can be justified. In commodity chemical manufacturing, the efficiency gains in continuous processing can make the difference between profit and loss, and for that reason, continuous processes are preferred.7,8 Hazardous chemistry has long been an area where continuous processing has been applied at smaller scales. For example, nitroglycerin manufacturing in continuous flow dates back to at least the 1940s.9,10 Over time, attitudes toward continuous processes have changed, and many organic chemists and engineers now recognize that significant benefits over batch processes can be realized with simple reactor systems. In recent years, flow chemistry has seen a rapid uptake in the pharmaceutical and fine chemical industries.11 The exploration of the benefits of using continuous reactor platforms compared to traditional batch methods for practicing organic chemists continues to be an active area of research, and continuous flow chemistry has the potential to significantly intensify production while minimizing cost for the preparation of complex molecules on larger scale.12,13,14,15 In addition, many syntheses of complex targets can involve the use of expensive precious metals, or complex ligands under high pressure to achieve reactivity and selectivity.16 Continuous processes have the potential to enable alternatives, or enable safe access to extreme reaction conditions not amenable to typical batch processes, with small, flexible reactor systems.17,18,19,20 Flow chemistry can also enhance the quality of the intended process by performing several unit operations simultaneously, such as work-ups and extractions in one reactor set-up with better control of reaction parameters. This can remove lengthy and expensive unit operations, including vessel readiness, extractions, and associated clean-up tasks that are common in traditional batch chemistry for regulated industries. Continuous chemistry can also benefit larger-scale reactions, since they can improve mass and heat transfer, and have relatively small equipment footprints relative to batch reactors, which result in lower capital and operating costs. In some cases, it is important to design a process through the lens of continuous processing. This could influence decision-making in terms of process design such as solvent choices (i.e. the benefit of working with solutions), definition of the necessity for product isolation vs. flowing into the next unit of operations, catalyst selection which may be unique to continuous processing, to name a few examples. Flow technology can often be controlled with automation coupled to online process analytical tools (PATs), which allows faster optimization in the lab and improved performance on scale for these integrated systems.21,22 Although the literature is replete with new applications of flow chemistry, there are still many reaction types that have yet to be examined, and this area will continue to expand to achieve selectivity, reactivity, and industrial process intensity goals. The batch process procedures for the reactions covered herein have been reviewed comprehensively in other chapters. The reaction categories in this chapter are organized following the same order of the book chapters and using the same subject titles to maintain consistency and to make it easier to locate comparable processes. 7 Hofmann, H. Chemie Ingenieur Technik 1991, 63, 103. 8 Fogler, H. S. Elements of Chemical Reaction Engineering; 4th ed.; Pearson Education: Upper Saddle River, NJ., 2006. 9 Carlisle, R. P. Powder and Propellants: Energetic Materials at Indian Head, Maryland, 1890–2001; 2nd ed.; University of North Texas Press, 2002. 10 Ruth, J. A. Nitration of glycerol Copyright (C) 2018 American Chemical Society (ACS). All Rights Reserved. 1955 11 Cole, K. P.; Johnson, M. D. Expert Review of Clinical Pharmacology 2018, 11, 5–13. 12 Lummiss, J. A. M.; Morse, P. D.; Beingessner, R. L.; Jamison, T. F. Chemical Record 2017, 17, 667–680. 13 Baumann, M.; Baxendale, I. R. Beilstein Journal of Organic Chemistry 2015, 11, 1194–1219. 14 Baxendale, I. R.; Braatz, R. D.; Jensen, K. F.; Hodnett, B. K.; Johnson, M. D.; Sharratt, P.; Sherlock, J.-P.; Florence, A. J. Journal of Pharmaceutical Sciences 2015, 104, 781–791. 15 Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein Journal of Organic Chemistry 2017, 13, 520–542. 16 Johnson, M. D.; May, S. A.; Haeberle, B.; Lambertus, G. R.; Pulley, S. R.; Stout, J. R. Organic Process Research & Development 2016, 20, 1305–1320. 17 Gutmann, B.; Cantillo, D.; Kappe, C. O. Angewandte Chemie International Edition 2015, 54, 6688–6728. 18 Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chemistry - A European Journal 2015, 21, 2298–2308. 19 Cossar, P. J.; Hizartzidis, L.; Simone, M. I.; McCluskey, A.; Gordon, C. P. Organic & Biomolecular Chemistry 2015, 13, 7119–7130. 20 Kulkarni, A. A. Beilstein Journal of Organic Chemistry 2014, 10, 405–424, 420 pp. 21 Challener, C. A. Pharmaceutical Technology 2017, 4, 6. 22 Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P. Science 2016, 352, 61–67.

17.2 Aliphatic Nucleophilic Substitutions

Throughout this chapter, drawings are used to illustrate representative continuous processes. To facilitate the reader’s understanding, abbreviations, commonly used symbols and pictorial elements are summarized in the following table.

Symbols

Meaning

Symbols

Meaning

Pump

Pressure controller

Mixing T

Back pressure regulator

Plug flow reactor (PFR)

Packed bed reactor

Static mixer

𝜏

Nominal residence time, defined as reactor volume/flow rate

Heat exchanger

𝜏 eff

Effective residence time after factoring solvent expansion

17.2 Aliphatic Nucleophilic Substitutions 17.2.1

Aliphatic Nucleophilic Substitutions at sp3 Carbons

Alkylation of phenols, alcohols, and amines are some of the most common aliphatic nucleophilic substitutions, and typically employ active electrophiles. High temperature and pressure-enabled flow platforms allow for the alkylation of nucleophiles with less reactive reagents. For example, Tilstam developed a flow process for the methylation of phenols and naphthols using dimethylcarbonate (DMC) at 220 ∘ C in a PFR with a nominal residence time of 10 minutes.23 Dimethyl carbonate is preferred to methyl iodide and dimethyl sulfate from a safety, environmental impact and cost-perspective. Where the reaction mixture is homogeneous, the reaction can be performed without added solvent. It is interesting that the author selected DMF as a solvent given its known instability at higher temperatures. The author did note an impurity formed that was unrelated to the phenol/naphthol substrates, presumably arising from some reaction and/or decomposition of the reagents and/or solvent. O OH R

or

X

OH

R = 2-NO2, 4-Cl-2-Me, 3-Br X = C, N

MeO

OMe

OMe

220 C, τ 10 min R

Neat or w/DMF

or

X

OMe

R = 2-NO2, 4-Cl-2-Me, 3-Br X = C, N

The Jamison and Jensen groups show that thermal aminolysis of epoxides in PFR reactors under pressure has distinct advantages to lower temperature, batch processes.24,25 Volatile amines can be used at temperatures far above their boiling points without the concerns of lower yields due to the headspace partitioning one observes in batch processing. A small amount of ethanol was used to accelerate the aminolysis reaction. In the largest scale example, styrene epoxide was opened with 3 equiv of the aminoindane at 220 ∘ C to give a 78% yield of the amino-alcohol.

23 Tilstam, U. Organic Process Research & Development 2012, 16, 1150–1153. 24 Zaborenko, N.; Bedore, M. W.; Jamison, T. F.; Jensen, K. F. Organic Process Research & Development 2011, 15, 131–139. 25 Bedore, M. W.; Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Organic Process Research & Development 2010, 14, 432–440.

731

732

17 Continuous Chemistry

O OH

0.8 M in MeCN/EtOH

τ 15 min

78% yield (9 g scale)

220 °C 500 psi bpr

H2N

H N

2.4 M in MeCN/EtOH

17.2.2

Amidations

The Shotten–Baumann reaction is a popular method for amide formations as it often provides fast reaction kinetics and clean reaction profiles. Classic Schotten–Baumann reaction conditions take advantages of the much faster reaction kinetics of the amidation than the rate of acid chloride hydrolysis by water. Both PFRs and CSTRs can be used effectively for Schotten–Baumann reactions. The main driver in the reactor selection should be based on reaction kinetics, optimum reagent stoichiometry, impurity profiles, and isolated yields. Eli Lilly developed a continuous process for the pilot scale production of LY2886721 using a PFR design.26 The acid chloride, prepared in situ by reacting 6-fluoronicotinic acid with the Vilsmeier reagent generated from DMF and oxalyl chloride, was used as a feed solution in acetonitrile, and the diamine was solubilized in aqueous EtOH solvent systems containing THF and AcOH. No exogenous base was used in the reaction as the product formed the hydrochloride salt. The reaction system afforded a monophasic reaction matrix with good solubility for both reactants and HCl salt of the product. A fully automated, telescoped continuous process was developed for the workup and isolation, and demonstrated for a production rate of 3 kg/d through 72 hours continuous. O Cl N

Solution in CH3CN

H

F

N

H S

O

Static Mixer

F

N

NH2 O NH

S

O

Online HPLC

F

NH2

τ 30 sec Ambient

N

F

LY2886721 94%

NH2 Solution in H2O/EtOH/THF with AcOH (0.5 equiv)

For the scale-up of tasisulam sodium, a highly potent drug candidate for cancer treatment, continuous manufacturing brings additional benefits as it significantly reduces potential worker exposure by cutting down unit operations and allows commercial-scale active pharmaceutical ingredients (APIs) production in laboratory fume hoods. Under Shotten–Baumann reaction conditions, the sulfonamide was reacted with the acid chloride, and the reaction mixture was telescoped into continuous counter-current extraction, solvent-exchange, and crystallization.27 A fully automatic, 5 kg/d commercial scale production in 120 hours was successfully demonstrated using a three-stage CSTR (target volume of 3.3 l). Several factors were considered for the selection of CSTR as the reactor. Sodium carbonate was found to be the base of choice from the reaction screening, and the generation of carbon dioxide in the liquid–liquid biphasic reaction would favor the use of CSTR as it allowed the gas to be partitioned into the reactor headspace. Additionally, 26 Polster, C. S.; Cole, K. P.; Burcham, C. L.; Campbell, B. M.; Frederick, A. L.; Hansen, M. M.; Harding, M.; Heller, M. R.; Miller, M. T.; Phillips, J. L.; Pollock, P. M.; Zaborenko, N. Organic Process Research & Development 2014, 18, 1295–1309. 27 White, T. D.; Berglund, K. D.; Groh, J. M.; Johnson, M. D.; Miller, R. D.; Yates, M. H. Organic Process Research & Development 2012, 16, 939–957.

17.2 Aliphatic Nucleophilic Substitutions

extended residence time was needed to decompose 2,4-dichlorobenzoic acid anhydride, a process impurity formed in the reaction, and the required reactor size was more straightforward to achieve in a stirred tank compared to tubing. Finally, in a production setting, under circumstances where pumps must be temporarily stopped, a CSTR system with mechanical mixing would outperform a PFR system, as the latter is highly dependent on flow rates. Attention should be given to the choices of pump heads, reactors, and fittings material of construction since metallic components in contact with the acid chloride solution can be corroded. O

Cl

Cl To continuous extraction and isolation

Cl Solution in toluene

Na Br

S O

S

NH2 O

S

Br

Solution in 2-MeTHF/iPrOAc

Cl

N S O O

Cl

Tasisulam sodium

Total volume of 3.3 l, τ 60 ± 5 min, 65 °C

Na2CO3 in water

O

Hydroxamic acids can be readily prepared from their corresponding methyl or ethyl carboxylic esters in good yields. Using a Vapourtec flow reactor, a laboratory PFR,28 a carboxylic ester was combined with aqueous hydroxylamine and sodium methoxide in methanol and heated at 70 ∘ C to give the product in high yield. The reaction is compatible with functionalities including N-Boc and sulfonamide groups and the chiral integrity of 𝛼-amino acid ester starting material is not affected.

®

RCOORʹ + H 2NOH

Static mixer

Rʹ = Me or Et

O R

NaOMe

τ 30 min

NHOH

82–100%

70 °C

An example using continuous processing to control the scale-up of a lactone opening with an amine was presented by the Jensen lab.29 In their preparation of aliskiren fumarate, the final steps required the 2-ethylhexanoic acid-mediated opening of a lactone with an amine to form the protected amide, followed by acidic N-Boc deprotection and fumarate salt formation of the final drug substance. O

O O

O OMe

MeO

Me

NHBoc Me

Me Me

H2N

Me Me

2-Ethylhexanoic acid Neat

Me HO

NH2 O OMe

MeO

Me

NH-R Me

Me H Me Me N NH2 O

O

R = Boc aq HCl Fumaric acid

R=H R = H • 1/2 fumaric acid

To achieve efficient lactone opening, the group created a melt of the lactone and amine, and combined the molten streams of neat reactants with the 2-ethylhexanoic acid in ratio of 1 : 10 : 1 in an inline helical static mixer, and passed 28 Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Martinelli, M. The Journal of Organic Chemistry 2009, 74, 3540–3543. 29 Heider, P. L.; Born, S. C.; Basak, S.; Benyahia, B.; Lakerveld, R.; Zhang, H.; Hogan, R.; Buchbinder, L.; Wolfe, A.; Mascia, S.; Evans, J. M. B.; Jamison, T. F.; Jensen, K. F. Organic Process Research & Development 2014, 18, 402–409.

733

734

17 Continuous Chemistry

through a heated coil to achieve a residence time of four hours and 90% conversion. The reaction effluent was then diluted with ethyl acetate and water and the phases separated by an inline liquid–liquid membrane separator in a processing time of 96% yield at a production rate of 16–28 g/h, the individual flow systems were combined to make the methyl ester of 3-nitrobenzoic acid in quantitative yield. This was achieved at a combined reaction time of 5.5 minutes at a production rate of 95 mmol/h.

17.3 Additions to C—Het Multiple Bonds 17.3.1

Reductive Aminations

Reductive amination is versatile reaction for monoalkylations of amines. Frederick et al. used a pipes-in-series continuous reactor to create a piperizinylmethyl pyridine required for the synthesis of anti-cancer API abemaciclib with a Leukart–Wallach reductive amination.33 The original reductive amination using the more common conditions of sodium triacetoxyborohydride afforded an alcohol impurity that could not be easily purged. After managing the deleterious impact of water produced from the amination with trimethyl orthoformate, scaling up the Leukart–Wallach reaction in batch proved challenging due to side reactions between formic acid and ethyl piperazine over the course of a prolonged reaction at elevated temperature. Converting the process to a continuous mode using a pipes-in-series reactor afforded rapid conversion to the desired bromopyridine at 140 ∘ C. It is noteworthy that this process has the potential for a competing SN Ar reaction of the piperazine with the 2-bromopyridinyl ring. However, the addition of 2 equiv of trimethyl orthoformate suppressed this competing reaction. F F Br

N

+ CHO

N

Et

HN

Leukart– Wallach amination

N Br

N

HCO2H

N N

Et

N HN

N

Me N

Me Me N

Et

N Abemaciclib

17.4 Addition to C—C Multiple Bonds 17.4.1

Cyclopropanation

Synthetic methods for the preparation of cyclopropanes have gained considerable interest due to an increase in the number of molecules emerging from pharmaceutical and agricultural industries, as well as limited methods available for their construction. A number of these transformations involve functionalization of an alkene using intramolecular cyclizations, metal catalyzed addition of diazo esters, the Simmons–Smith reaction, and sulfur ylides (see Section 3.15.4 and Chapter 6). Delhaye et al. developed a scalable route for the cyclopropanation of trans-ethyl crotonate with dimethylsulfoxonium methylide.34 This transformation can be low yielding and difficult to handle on large scale due to decomposition of the highly reactive ylide and significant adiabatic temperature rise. Following extensive design of experiment (DoE) 31 Rossi, E.; Woehl, P.; Maggini, M. Organic Process Research & Development 2012, 16, 1146–1149. 32 Lehmann, H. Green Chemistry 2017, 19, 1449–1453. 33 Frederick, M. O.; Pietz, M. A.; Kjell, D. P.; Richey, R. N.; Tharp, G. A.; Touge, T.; Yokoyama, N.; Kida, M.; Matsuo, T. Organic Process Research & Development 2017, 21, 1447–1451. 34 Delhaye, L.; Stevens, C.; Merschaert, A.; Delbeke, P.; Brione, W.; Tilstam, U.; Borghese, A.; Geldhof, G.; Diker, K.; Dubois, A. Organic Process Research & Development 2007, 11, 1104–1111.

735

736

17 Continuous Chemistry

work to optimize the reaction, a PFR set-up containing a micromixer, two HPLC pumps, and stainless steel HPLC tubing performed comparably to the batch process. The ylide was preformed prior to use, kept at room temperature to avoid decomposition, and mixed with a preheated solution of the crotonate. With a flow rate of 1–10 mL/min, and a residence time of one minute, the trans-cyclopropane was formed in 48% yield. O Me

OEt

Heat exchanger

1 equiv in DMSO

O

Me3SOI

Me

BPR

O KOH Me S DMSO Me 1.1 equiv in DMSO

80 °C

OEt 48% yield >98% trans

τ 1 min

Boehringer–Ingelheim utilized a modular tubular flow reactor for a cyclopropanation in 92% yield.35 The authors produced 3.3 kg of the desired product and stated the process decreased cost due to the increase of yield and robustness over existing batch conditions. The formed products were then heated to 140 ∘ C in p-xylene using catalytic DBU as base and recrystallized in ethanol to give the trans-isomer in high purity. Li and Guinness36 described a CSTR flow process for the preparation of diethyl cyclopropane-cis-1,2-dicarboxylate. The slurry reaction involving the handling of lithium hydride with generation of highly flammable hydrogen gas was successfully handled at multi-hundred-gram scale. The laboratory CSTR systems allowed them to obtain diethyl cyclopropane-1,2-dicarboxylate in ∼9 : 1 cis to trans isomeric ratio. It is noteworthy that the reaction was determined best to be carried out at 100 ∘ C to avoid any delayed reaction onset, yet the cis/trans ratio remained optimal at this temperature. Catalytic amount of ethanol was introduced to remove the lithium oxide coating present on the surface of LiH granules and the LiH suspension in toluene was readily managed by feeding with a peristaltic pump. OEt

Cl O

O +

LiH OEt Toluene, EtOH

EtO

OEt O

O

+

EtO

OEt O

O

cis/trans ratio: 89/11

Cooled knockout pot 0 °C

N2

LiH suspension in toluene Ethyl acrylate ethyl chloroacetate ethanol (cat.)

0.1 l 105 °C 0.8 l 105 °C

0.1 l 35 °C

Receiver vessel

0.8 l 105 °C

Charette and coworkers described the preparation of difluorocyclopropanes and difluorocyclopropenes, which are found in a number of pharmaceutical agents and can be further manipulated to provide access to useful fluorinated building blocks, from a variety of alkenes and alkynes using a TMSCF3 -mediated protocol.37 Using a PFR, TMSCF3 in the presence catalytic NaI generated the reactive carbene in situ. Using a 10-minute residence time, they arrived at a process with a 1 mmol/min production rate and optimized carbene generation pressure as well as reduced the amount of solvent and carbene precursor needed. Methacrylate, highly substituted alkenes, and even cyclic alkenes reacted smoothly to provide good to modest yield of the corresponding difluorocyclopropanes. 35 Buono, F. G.; Eriksson, M. C.; Yang, B.-S.; Kapadia, S. R.; Lee, H.; Brazzillo, J.; Lorenz, J. C.; Nummy, L.; Busacca, C. A.; Yee, N.; Senanayake, C. Organic Process Research & Development 2014, 18, 1527–1534. 36 Li, B.; Guinness, S. ACS Symposium Series 2014, 1181, 383–402. 37 Rulliere, P.; Cyr, P.; Charette, A. B. Organic Letters 2016, 18, 1988–1991.

17.4 Addition to C—C Multiple Bonds

R2

R1 R4

NaI (0.1 equiv)

R2

R1

R3 + TMSCF3 (2.0 equiv) THF

R4

BPR

F

R3 F

120 °C

τ 10 min

F

Me

F

Me

F

F

F F

O Oi-Bu Me

Me 88%

F F

63%

Me

F 3C 70%

94%

In the case of difluorocyclopropenes, it was discovered that phenylacetylene derivatives, as well as aliphatic alkynes, react under the same conditions to furnish the desired products. The reaction was tolerant of esters and unprotected alcohols, although the latter substrates were isolated as the trimethylsilyl (TMS) protected ether. NaI (0.01 equiv) R2 + TMSCF3 (2.0 equiv)

R1

F F BPR

THF

R1

R2

120 °C

τ 10 min

F

CO2Me

F

F 57%

17.4.2

OTMS

F 40%

F F Ph 81%

F F Pr

Ph 93%

Hydroformylation

Hydroformylation, defined as the addition of a formyl group (CHO) and a hydrogen atom to a carbon–carbon double bond, is a powerful transformation in organic synthesis. Although the chemistry provides access to useful building blocks that can be further manipulated, the process requires handling hydrogen gas, an explosion hazard, as well as carbon monoxide, a toxic gas. Because both gases have low solubility in organic solvents at atmospheric pressure, high reactor pressures are typically needed to carry out productive reactions. This leads to an increased risk of gas release. To address these safety concerns, proper engineering controls were in place for larger-scale hydroformylation, scientists at Eli Lilly designed and built a 360 l vertical bubble-flow, pipes-in-series reactor.38 The numerous advantages to this design included adjustable hydraulic residence time, high vapor–liquid mass transfer rates, high heat transfer rates, and intermediate sample points along the length of the PFR, which could be linked to online HPLC and NMR analytical capabilities. In addition, since the pipes-in-series reactor operates at 98% liquid fill, the amount of hazardous reagent gas is minimized in the case of a leak or rupture. 360 l vertical bubble-flow, pipes-in-series reactor

F Gas Mass flow meter

BPR N2 Gas vent

Reactant feed(s)

Product solution

38 Johnson, M. D.; May, S. A.; Calvin, J. R.; Lambertus, G. R.; Kokitkar, P. B.; Landis, C. R.; Jones, B. R.; Abrams, M. L.; Stout, J. R. Organic Process Research & Development 2016, 20, 888–900.

737

738

17 Continuous Chemistry

Using this reactor design, an enantioselective hydroformylation of 2-vinyl-6-methoxynaphthalene was accomplished using a rhodium-bisdiazaphos as catalyst in toluene at 70 ∘ C and 400 psi.39 pipes-in-series reactor Me

0.074% Rh(acac)(BDP) 400 PSI, CO:H2 (1 : 1) 70 °C, τ 8.3 h

MeO

O

H +

H

MeO

O MeO

Branched Ph

Ph

NH

HN

OO N P N OO

OO P N N OO

NH

HN

Linear 98% conversion branched:linear (27 : 1) 92% ee

Ph

Ph

BDP = (R, R, R)-BisDiazaPhos-SPE

Cole–Hamilton and coworkers achieved the hydroformylation of 1-octene using supercritical carbon dioxide in flow across a supported ionic liquid phase (SILP) catalyst consisting of [PrMIM][ (3-SO3 C6 H4 )Ph2 P], [Rh(acac)(CO)2 ], and [OctMIM][Tf2 N] supported on silica gel.40 The researchers found that the reaction proceeded in high conversion, with a typical linear/branch ratio of 3 : 1. Optimization of the reaction system led to significant efficiency gains, including an 800 mol substrate per mol catalyst per hour rate. Advantages for the flow reactor include the supercritical fluid ability to extract trace aldol condensation by-products that could poison the catalyst system. Furthermore, the reactor possessed excellent diffusion of the substrate and gases to the catalyst surface, and excellent solubility of the substrates and gases within the supported ionic liquid. Me

SILP packed bed

ssCO2

Me

CHO Linear +

100 °C τ2h

preheating coil

Me

Me Branched

LP CO2

17.4.3

Syngas (CO/H2)

CHO

>95% conversion linear/branched (3:1)

Compressor

Hydroboration/Oxidation of Olefins

Souto et al.41 described a method for the continuous preparation of alcohols by hydroboration/oxidation of olefins. Using a simple laboratory set up, up to 120 mmol per hour of the desired alcohol can be generated.

39 Abrams, M. L.; Buser, J. Y.; Calvin, J. R.; Johnson, M. D.; Jones, B. R.; Lambertus, G.; Landis, C. R.; Martinelli, J. R.; May, S. A.; McFarland, A. D.; Stout, J. R. Organic Process Research & Development 2016, 20, 901–910. 40 Hintermair, U.; Zhao, G.; Santini, C. C.; Muldoon, M. J.; Cole-Hamilton, D. J. Chemical Communications (Cambridge, U. K.) 2007, 1462–1464. 41 Souto, J. A.; Stockman, R. A.; Ley, S. V. Organic & Biomolecular Chemistry 2015, 13, 3871–3877.

17.6 Electrophilic Aromatic Substitution

1 mL/min

Olefin in THF (1 M)

Alcohol product

BH3·THF in THF (1 M)

4.2 mL, 25 °C τ 25 s

2 mL, 25 °C τ 1 min

1 mL/min

12 examples 28 – 99% yields

8 mL/min NaOH,H2O2 EtOH, Water

17.5 Nucleophilic Aromatic Substitutions Pellegatti et al. developed a continuous SN Ar process in which a 2-aminopyridine derivative was lithiated in the presence of a 2-chloropyrimidine heterocycle using a PFR containing a static mixer at 60 ∘ C.42 The reaction was complete within a 3.2 minute residence time, after which the mixture was mixed with hydrochloric acid in a second PFR at 60 ∘ C, effecting the removal of the N-Boc protecting group. The process was demonstrated on 76 g scale, providing the product in high yield. 3N HCl(aq)

BocN N

N

0.070 M in THF N N

Cl

N

N 5.6 mL/min

NH2

HN

N

N

CONMe 2

N

3.1 mL/min 60 °C τ 13.1 min

CONMe 2

N

•HCl

N H 76 g (92.5% Yield)

0.068 M in THF LiHMDS 1.5 M in THF

3.1 mL/min

60 °C

τ 3.2 min

17.6 Electrophilic Aromatic Substitution 17.6.1

Nitration

While nitration reactions are a useful method to create C—N bonds, they present a number of challenges on scale-up. Nitration reactions can be strongly exothermic, and the reaction mixture is often thermally unstable. These reactions also present the possibility of forming products that are explosive or thermally unstable. In particular, any residual alcohols or amines can be converted to dangerous nitrate esters and nitramines. Additionally, the relatively low boiling point of nitric acid means that its vapors are also a concern, particularly because respirator cartridges typically do not provide adequate protection from nitric acid vapors. Given the safety concerns associated with these reactions, continuous processing is a natural fit. Mixtures of nitric acid and sulfuric acid form a potent nitration reagent, as sulfuric acid serves to dehydrate nitric acid, forming the highly reactive nitronium ion (NO2 + ). Researchers at AstraZeneca published an article summarizing 42 Pellegatti, L.; Hafner, A.; Sedelmeier, J. Journal of Flow Chemistry 2016, 6, 198–201.

739

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17 Continuous Chemistry

their experience developing a series of different nitration processes using a range of different flow reactors.43 The authors found that the flow reactors allowed them to maintain the target temperatures more accurately compared to batch reactors, and thereby suppress formation of undesired byproducts. In 2012, Gage et al. described the work scaling up an aromatic nitration reaction to prepare a nitroaromatic intermediate that was required as a starting material for a drug candidate.44 Process safety concerns drove the transition to a continuous process at the kilogram scale. The reactor was a stainless steel tubing coil with a jacket controlled at 50−55 ∘ C, and the product was collected in a quench vessel charged with water. One noteworthy feature of this example is that the authors switched from using HPLC pumps for their proof-of-concept apparatus to using pressurized feed tanks and flow meters to control flow for their scale-up. They were able to use this apparatus to isolate 36.5 kg of product over several days of operation.

Pressure controllers

P

P N2

200-l feed vessels

F

F

Me Br

NO2 N

Me

HNO3 in H2SO4

Br

τ~20 min

NH2

After quench

50 °C

N

NHAc

Solution in H2SO4

Another example of continuous mixed acid nitration was reported in 2016 by Su and coworkers.45 They prepared a nitroaromatic precursor of the herbicide Mesotrione to demonstrate the utility of continuous processing for nitration reactions. Using a stainless steel tube reactor, the reaction was performed without temperature control: instead, the authors insulated the reactor and used the heat of reaction to allow the reaction mixture temperature to rise to approximately 100 ∘ C. After five second residence time in the reactor, the reaction mixture was quenched by dilution. In spite of the lack of an elaborate temperature control strategy, they were able to suppress formation of the undesired dinitration product. The authors reported preparing over 400 g of product in only a few minutes of operation with this apparatus. H3CO2S

Me

Solution in H2SO4 HNO3

H3CO2S

τ5 s

Me NO2

rt to c. 100 °C (Pseudo-adiabatic)

Another potent nitrating mixture can be formed with mixtures of nitric acid and acetic acid, or acetic anhydride. These mixtures often present different reactivity patterns and are complementary to the mixed acid conditions described above. Novartis reported three examples of this type of nitration using a simple tube PFR.46 In the first example, the 43 44 45 46

Pelleter, J.; Renaud, F. Organic Process Research & Development 2009, 13, 698–705. Gage, J. R.; Guo, X.; Tao, J.; Zheng, C. Organic Process Research & Development 2012, 16, 930–933. Yu, Z.; Zhou, P.; Liu, J.; Wang, W.; Yu, C.; Su, W. Organic Process Research & Development 2016, 20, 199–203. Brocklehurst, C. E.; Lehmann, H.; La Vecchia, L. Organic Process Research & Development 2011, 15, 1447–1453.

17.7 Catalysis

transition to a continuous process was driven by process safety concerns. The researchers in this report developed the process first using batch techniques, followed by a gradual scale-up using a commercially available flow reactor platform. They demonstrated a continuous process with a residence time of three minutes at 90 ∘ C that could achieve an 86% yield to produce just over 200 g of product in two hours of operation.

O

N H

Br Solution in acetic acid

NO2 O

HNO3

90 °C τ 3 min

N H

25 °C τ 0.75 min

Br

For their second example, the Novartis team evaluated a reaction to prepare a nitramine from the corresponding aniline derivative. While acetic anhydride was necessary to achieve the desired reactivity, its presence led to the formation of an acylated byproduct. Quenching the reaction mixture into ice water led to the formation of a crystalline solid with no detectable acylated byproduct. The authors reported a 84% isolated yield preparing 1.2 g/min of product using this configuration. H2N MeO2C

Br

Solution in acetic acid O2N NH HNO3

MeO2C

30 °C

Br

τ 1.3 min Ac2O

30 °C

τ 1 min

17.7 Catalysis Cross-coupling reactions are generally carried out under transition metal catalysis and are among the most common transformations in organic chemistry, therefore, a popular topic of review articles.47,48,49 The following examples highlight recent scale-up applications, and other examples can be found in Chapter 6 of this book. A continuous processing approach to cross-coupling can be particularly beneficial when one of the coupling partners is unstable under batch processing reaction conditions.50 The high thermal transfer rates and precision residence time control of PFR reactors compared to batch reactors minimizes the time spent under conditions of instability. Linghu et al. a sequential continuous Grignard exchange followed by a palladium catalyzed Kumada–Corriu coupling after observing a decrease in batch process yields from 80% to 40% when the reaction was scaled from 2 to 40 kg.51 The intermediate pyridinyl Grignard was found to be unstable below the coupling reaction temperature, especially in the presence of the palladium catalyst. The continuous PFR process allowed consistent control of residence time for the formation of the organomagnesium reagent and minimized the time required to heat the reaction solution to the temperature where cross-coupling becomes competitive with decomposition. Similar observations have been observed in other cross-coupling reactions.52 47 Reynolds, W. R.; Frost, C. G. In Palladium-Catalyzed Coupling Reactions; 1st ed.; Molnár, Á., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: 2013, p 409–443. 48 Noel, T.; Buchwald, S. L. Chemical Society Reviews 2011, 40, 5010–5029. 49 Frost, C. G.; Mutton, L. Green Chemistry 2010, 12, 1687. 50 Roesner, S.; Buchwald, S. L. Angewandte Chemie International Edition 2016, 55, 10463–10467. 51 Linghu, X.; Wong, N.; Jost, V.; Fantasia, S.; Sowell, C. G.; Gosselin, F. Organic Process Research & Development 2017, 21, 1320–1325. 52 Von dem Bussche-Huennefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719–5730.

741

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17 Continuous Chemistry

F

Br

N

N F

35 kg in THF (1.2 equiv)

N Cl SMe 20 kg (1.0 equiv)

MgX N

i-PrMgCl•LiCl in THF 1.2 equiv

–5 to –10 °C τ 8 min

i-Pr 60 – 65 °C τ 16 min

i-Pr N

i-Pr Cl

i-Pr Pd

Cl

N

F N

N

N

N

Cl PEPPSI-iPr 1.2 mol% in THF

SMe 23 kg (82%) Citric acid quench tank

A general continuous processing approach to Buchwald–Hartwig palladium-catalyzed C—N coupling has been developed and was used to prepare an Astra–Zeneca drug candidate intermediate.53 The reaction was demonstrated at a reaction flow rate of 1 l/h over three hours, achieving high in situ assay yield. The process used a custom-built reactor that resembled a series of vertical CSTRs and had the advantage of no unmixed connections between the agitated segments, although it is likely a standard CSTR configuration would suffice. The authors optimized the process with small-scale PFR technology, using a sonicator to prevent solid plugging. The product was readily separated from the organic solution containing catalyst and starting material via an acidic quench and continuous separation of the product-containing, acidic aqueous solution. Consequently, the palladium content in the product was 99%). One should be cautioned that the reaction time is not the overall cycle time in the process. The fast reaction kinetics was the result of the much greater mixing and the capability of heat removal with the use of micromixers. The micromixer enabled the oxidation of sulfides to be completed in a much shorter reaction time. As the stoichiometry of sodium hypochlorite can be better regulated under flow conditions by adjusting the feed rates of each pump, the over-oxidation impurity can be minimized to give higher throughput of benzimidazole drugs. R2

R3 Cl + HS N

R1

N

NaOH

N H

R2

R4 H2O

S N

R1

R4

N

R3

N H

NaOH CH3CN

R1

R2

R3

R4

Lansoprazole

H

F3CCH2O

Me

H

Pantaprazole

H

MeO

MeO

F2CHO

Rabeprazole

Me

MeO(CH2)3O

Me

H

Water in Water out

R2 R1

R4

N

R3

NaOCl aq

N

S O

N H

Thermocouple

P1 Thioether solution

Micromixer 1

P2 NaOCl solution

P3

Micromixer 2

Product

Water

88 Reddy, G. S.; Reddy, N. S.; Manudhane, K.; Rama Krishna, M. V.; Ramachandra, K. J. S.; Gangula, S. Organic Process Research & Development 2013, 17, 1272–1276.

17.11 Oxidations

The Moffatt–Swern oxidation was successfully adapted to continuous reaction conditions.89 The flow process offers significant advantages over the batch process. The small reactor volume minimizes the accumulation of the labile trifluoroacetoxydimethylsulfonium and alkoxydimethylsulfonium salts.90,91 Impurities from Pummerer rearrangement of the unstable intermediate are suppressed because of much shorter residence times.92 In the three-stage reaction, the mixing of dimethyl sulfoxide (DMSO) with TFAA used a microreactor of 2 μl volume, the mixing with the alcohol in the second stage used a microreactor of 5.1 μl volume and the reaction with base in the final stage used a microreactor of 253 μl. With the rapid mixing and heat transfer under short residence time, the process can be operated at 0–20 ∘ C in comparison with –70 ∘ C under batch reactions. The microreactor reactor system was operated for several hours and shown to be scalable without fouling. Cooling in

Cooling out

Pt-100 Thermocouple

Microreactor 1 2 μl, τ 12 ms

4.0 M DMSO

Microreactor 2 5.1 μl, τ 20 ms 2.0 M TFAA

Microreactor 3 253 μl, τ 760 ms

2.0 M alcohol Product 5.8 M bas e

Oxidation reaction under phase-transfer catalysis (PTC) is a well-established methodology using environmentally benign reagents and solvents.93 The mild reaction conditions, operational simplicity and high selectivity make it attractive for industrial scaleup. However, because of the biphasic nature of the reaction, scaling up in batch reactors can be very challenging as mixing is critical to the reaction kinetics and impurity profiles. The oxidation is exothermic, and thermal degradation of the oxidizing agent can occur. The possibility of poor mixing and local exotherms also raise concerns of safety risks with scale-up in batch reactors, while the excellent heat and mass transfer of continuous flow approaches are effective in addressing these issues.94 PTC hypochlorite oxidation reactions were carried out using either microfluidic or mesoscale systems with a productivity from miligrams to grams per minutes.95 The oxidation of benzaldehyde to methyl benzoate under continuous conditions gave 99% yield with a one minute residence time, significantly outperforming the batch conditions. OH R2

O

Bleach (14.6% chlorine) n-Bu4NBr (7.5%)

R2

EtOAc, rt R1 = H, R2 = Me, t 1 min

R1

R1 = NO2, R2 = H, t 1 min

O H

89 90 91 92 93 94 95

Bleach (14.6% chlorine) n-Bu4NBr (10%) MeOH, rt τ 1 min, 99% yield

R1

O OMe

van der Linden, J. J. M.; Hilberink, P. W.; Kronenburg, C. M. P.; Kemperman, G. J. Organic Process Research & Development 2008, 12, 911–920. Omura, K.; Sharma, A. K.; Swern, D. The Journal of Organic Chemistry 1976, 41, 957–962. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660. Rudolf, P. Berichte der deutschen chemischen Gesellschaft 1910, 43, 1401–1412. Albanese, D. C. M.; Foschi, F.; Penso, M. Organic Process Research & Development 2016, 20, 129–139. Leduc, A. B.; Jamison, T. F. Organic Process Research & Development 2012, 16, 1082–1089. Zhang, Y.; Born, S. C.; Jensen, K. F. Organic Process Research & Development 2014, 18, 1476–1481.

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A benzylic hydroperoxide rearrangement was the key step in the synthesis of brivanib alaninate. To mitigate the risk of the potential thermal runaway reaction, a safe and scalable continuous flow process was developed. In the PFR reactor design, a two-stage heat exchange (–5 ∘ C and 12–15 ∘ C, respectively) with a total residence time of 14 minutes was used to ensure safety, efficiency, and high-product quality and yield. The process was conducted for up to 33 days continuously with no safety or quality related incidents, and more than 2 metric tons of the product has been manufactured at commercial scale using this technology.96 O

Me Me

HO

NH N

Me

N

50 wt% H2O2

HO

CH3SO3H (cat.)

O

O

Me Me

NH N

Me

O

Me

NH

HO

N

N

N

Anhydrous tert-butyl hydroperoxide (TBHP) is a powerful oxidizing agent in many chemical transformations.97,98 Despite the versatility in organic reactions; the use of anhydrous TBHP has been greatly limited due to the safety concerns of its shipping, handling and storage, particularly on the production scale. A continuous production of anhydrous TBHP solution in nonane using a membrane pervaporation system has been exemplified. Commercially available 70% aqueous TBHP is continuously extracted with nonane using a Karr column in a counter-current fashion. The resulting ∼1% water wet TBHP solution is continuously dried using a membrane pervaporation system to reach a water content of 90% yield. The publication provides some practical guidance on their experiences with the equipment and some of the issues they encountered. Me2SO4

F Li

F

HexLi

Me

F

F

F

F

–45 to –60 °C

A continuous directed ortho-metalation-borylation process of an aryl fluoride substrate has also been disclosed.118 The authors were able to observe the aryllithium intermediate as well as its decomposition by in situ IR spectroscopy. They were also to establish that while the borylation step is purely dose-controlled at −65 ∘ C, the lithiation step is somewhat slower, particularly at high conversion. Using these insights with careful monitoring of the reaction temperature allowed the development of a tube-based PFR system that produced about 100 g of product over a seven hours. An unusual feature of this study was the formation of a gel that would lead to the pressure rising steadily before the higher pressure forced the gel from the reactor. They used 100-mL syringe pumps to ensure a very even flow rate even while the pressure was fluctuating. While this type of nonideal behavior is often observed in the development lab, it must be avoided in a manufacturing setting which is often straightforward, as the larger tubing sizes used at production scale are less prone to clogging. OMe Cl

F

B(OMe)3 OMe Cl

F B(OH) 2

n-BuLi

–40 °C, τ 7.4 min

–40 °C, τ 4.8 min

Another mechanism that can be harnessed to prepare highly functionalized organolithium intermediates is lithium–halogen exchange of an organic halide. These reactions are typically very fast, making them often mixing-sensitive. A continuous process to prepare potassium bromomethyltrifluoroborate has been reported.119 In the process, the dibromomethane and triisopropyl borate were premixed in one stream, while the butyllithium was introduced in a second stream. The two were mixed together in a plate reactor to prepare the boron “ate” species. The researchers found that the KHF2 used to convert the ate intermediate to the trifluoroborate had low solubility in water that was impacting the downstream workup operations. They instead selected HF, which is available in concentrations of up to 40% w/w in water. While this reagent is notoriously dangerous to handle in the lab, at production scale, it was possible to perform an automated dose of HF and design the process to minimize operator interaction. In spite of the advantages of reducing reaction mixture volume using these conditions, they found that small amounts of LiF were precipitating and clogging the reactor. This led them to perform the fluorination stage of the reaction in a 30-l CSTR.

118 Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Turner, R. M.; Heider, P. L.; Harji, B. H.; Browne, D. L.; Ley, S. V. Organic Process Research & Development 2014, 18, 1221–1228. 119 Broom, T.; Hughes, M.; Szczepankiewicz, B. G.; Ace, K.; Hagger, B.; Lacking, G.; Chima, R.; Marchbank, G.; Alford, G.; Evans, P.; Cunningham, C.; Roberts, J. C.; Perni, R. B.; Berry, M.; Rutter, A.; Watson, S. A. Organic Process Research & Development 2014, 18, 1354–1359.

17.13 Syntheses of Organometallic Reagents

30% HF CH2Br2 + B(O-i-Pr)3 Br n-BuLi

BF3Li

–60 °C τ 2 min

In transitioning the process to a kilo lab, several challenges were observed. The exotherm in the lithium–halogen exchange stage was not well-managed in a larger shell-and-tube heat exchanger in place of the plate-style reactor used in the lab. To address this issue, they reduced the concentration to allow the heat to be dissipated to a larger reaction mass and found that a higher flow rate led to improved results. They also performed the n-butyllithium dose in two stages. The process was conducted for 10 days continuously, producing a total of 100 kg with average assay yield of 66% of the lithium salt. The lithium salt was converted to the potassium salt in a subsequent step that afforded the potassium trifluoroborate in 91% yield. Conversion of an aryl bromide to the corresponding formyl compound via lithium–halogen exchanged followed by a treatment with dimethylformamide, preparing 707 g of product in one hour has been reported.120 The very short residence times were still adequate to achieve complete conversion, and observed higher yield (85% vs. 76%) and diminished levels of debrominated starting material (4% vs. ∼8%) compared to the batch process. Li N

Boc –78 °C τ2s

Cl N Br Solution in THF

–78 °C τ 2.5 s

n-BuLi

NHBoc Cl

DMF in THF

N

CHO

After aqueous quench

An example of arene borylation via lithium–halogen exchange followed by treatment with triisopropyl borate has been published.121 The flow process enabled the authors to prepare 1.2 kg of product over a 10.2 hour in 70% yield. Br

N

NHBoc O Solution in THF

0 °C

τ 0.25 s 0 °C

τ>1s

n-BuLi

HO

OH B

N O

B(O-i-Pr)3

17.13.2

NH2

After deprotection and isolation

Organomagnesium

Organomagnesium reagents have a rich history in organic synthesis, and they have been an area of focus in the flow chemistry literature as well. We divide this section broadly into two categories: reactions in which a Grignard reagent solution is used as a feedstock, and reactions in which a Grignard reagent is formed through use of magnesium metal. 120 Grongsaard, P.; Bulger, P. G.; Wallace, D. J.; Tan, L.; Chen, Q.; Dolman, S. J.; Nyrop, J.; Hoerrner, R. S.; Weisel, M.; Arredondo, J.; Itoh, T.; Xie, C.; Wen, X.; Zhao, D.; Muzzio, D. J.; Bassan, E. M.; Shultz, C. S. Organic Process Research & Development 2012, 16, 1069–1081. 121 Usutani, H.; Nihei, T.; Papageorgiou, C. D.; Cork, D. G. Organic Process Research & Development 2017, 21, 669–673.

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17 Continuous Chemistry

A production-scale process for the addition of a Grignard reagent to a ketone has been reported.122 One significant challenge in designing the continuous process is that the ketone starting material has limited solubility in the reaction solvent. This was addressed by using a CSTR under heterogeneous conditions, with the ketone reacting as it dissolved. The solution phase, containing some unreacted ketone, was continuously drawn off from the heterogeneous mixture through a submerged filter. The effluent was fed into a series of jacketed PFR reactors fitted with multiple dosing locations for additional Grignard reagent to effect additional conversion of the unreacted ketone. A static mixer was used at each dosing location to suppress formation of an impurity that is formed in the presence of excess Grignard reagent. The PFR effluent was monitored using near-IR spectroscopy with a chemometric model, allowing scientists to adjust the feed rate to the PFR. The process was used to prepare multi-kilogram quantities of the product in >95% yield and >96% purity. O Cl S Solids

OMgCl

MgCl

Cl

S

MgCl

AstraZeneca reported a continuous process for the use of methylmagnesium chloride to convert an ethyl ester to the corresponding methyl ketone.123 A double-addition product was observed at high loadings of methylmagnesium bromide, and during the quench of the magnesiated intermediate with acetic acid, the ketone could be converted to the cross-aldol product. Both impurities could be suppressed in continuous reactors with good mixing. When processing 500 g of ester starting material, the authors found that the reactor clogged repeatedly. To address the issue, they automated a cleaning cycle in which the acetic acid quench solution was back-flushed through the reactor every 45 minutes. This led to a lower yield, but it allowed the process to be conducted for extended periods of time. HOAc quench Cl

N N N N

OEt O

τ 5.2 s

τ 2.8 s

+4 °C

Cl

N N N N

Me O

MeMgBr

Functionalized Grignard reagent can also be prepared with a continuous process through the use of a CSTR.124 A chemical engineering analysis of the reactor and tube used to withdraw the newly formed Grignard reagent allowed the authors to prevent the magnesium turnings from being drawn out of the reactor. The two centerpieces of the strategy were a custom-designed dip tube (settling tube) and a subsequent unstirred vessel for the magnesium turnings to settle (Mg trap). The authors built a kinetic model for the process using in situ mid-IR spectroscopy and offline HPLC analysis. The kinetic model allowed for portionwise addition of magnesium turnings to keep the process operating

122 Pedersen, M. J.; Holm, T. L.; Rahbek, J. P.; Skovby, T.; Mealy, M. J.; Dam-Johansen, K.; Kiil, S. Organic Process Research & Development 2013, 17, 1142–1148. 123 Odille, F. G. J.; Stenemyr, A.; Pontén, F. Organic Process Research & Development 2014, 18, 1545–1549. 124 Wong, S.-W.; Changi, S. M.; Shields, R.; Bell, W.; McGarvey, B.; Johnson, M. D.; Sun, W.-M.; Braden, T. M.; Kopach, M. E.; Spencer, R. D.; Flanagan, G.; Murray, M. Organic Process Research & Development 2016, 20, 540–550.

17.13 Syntheses of Organometallic Reagents

smoothly. The article provides an excellent example of how chemical engineering principles can be used to handle the challenging case of working with a solid metal reagent. Mg OMe (Solids)

F

F

Br Toluene solution

OMe MgBr

2-MeTHF

Mg trap Settling pipe

An example of a related transformation performed under Barbier conditions, in which the Grignard reagent is formed in the presence of its coupling partner has also been published.125 As in the example above, the authors opted to perform portionwise addition of the magnesium instead of using a continuous solids feeder. They also took advantage of the experience using the settling pipe and magnesium trap in their previous work, although these were scaled down for this process. The authors used this process to prepare 5.7 kg of the product over a 78-hours campaign with HPLC online monitoring to obtain 87% yield after isolation as the methanesulfonic acid salt. Mg (Solids) Cl

O

H

O

O

N Bn

17.13.3

AcOH/H2O

O

N O

N Bn

H

O O

Organozinc

Loh et al. developed a continuous Reformatsky process using a CSTR to form the key organozinc species and a static mixer for the subsequent reaction with the aldehyde coupling partner.126 The authors performed a process safety assessment of the reaction using reaction calorimetry, determining that the reaction thermal profiles posed potential thermal hazard risks for both stages of the reaction. The formation of the organozinc intermediate was associated with a temperature rise from ambient temperature to 170 ∘ C under adiabatic conditions, while the coupling step was associated with a slightly milder exotherm, leading to a maximum temperature of about 110 ∘ C under adiabatic conditions.

125 Braden, T. M.; Johnson, M. D.; Kopach, M. E.; McClary Groh, J.; Spencer, R. D.; Lewis, J.; Heller, M. R.; Schafer, J. P.; Adler, J. J. Organic Process Research & Development 2017, 21, 317–326. 126 Loh, G.; Tanigawara, R.; Shaik, S. M.; Sa-ei, K.; Wong, L.; Sharratt, P. N. Organic Process Research & Development 2012, 16, 958–966.

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17 Continuous Chemistry

Zn (solids) DIBAL (3 mol %) O Br

OEt OH O Ph PhCHO

OEt Product (overflow)

Acid waste

Citric acid quench

Performing the first stage of the reaction in a CSTR allows for conditions mimicking the semibatch conditions typically employed for this type of reaction. Because the reactor is held at a steady-state where the conversion is high (i.e. low accumulation), the heat of reaction can be absorbed by the reaction mixture that has already been converted fully to product. The zinc granules were metered into the reactor using a screw feeder at a rate of 1.1 g/min and the reaction mixture was withdrawn from the CSTR using a tube designed to prevent drawing the zinc granules out. The linear velocity was designed to be less than the settling velocity of a particle thus preventing these large particles from clogging the tubing and mixers downstream. To control the temperature, the benzaldehyde dose was divided between two positions, each with a static mixer to rapidly blend the two streams together and the mixture was quenched with aqueous citric acid solution. The apparatus was operated at steady-state for about four hours, processing 200 g of benzaldehyde over that period of time.

17.14 Synthesis of Aromatic Heterocycles 17.14.1

Synthesis of Aromatic Hyterocycles under Superheated Conditions

One attractive feature of continuous processes is the ability to superheat solvents under pressure to access more extreme conditions and afford the uninterrupted delivery of product. On the lab scale, these conditions can be readily created by microwave irradiation of small batches in a sealed vessel, but this approach is currently scale-limited. Estel has recently reviewed progress on process-scale microwave reactor development and also published on the design and implementation of a continuous microwave reactor capable of processing the acid-catalyzed dehydration hexylene glycol to a mixture of 1,3-hexadienes a rate of 1.5 kg/h.127,128 This approach offers the advantage of heating the reaction from the “inside-out” and not relying on conductance of heat from the vessel walls into the solvent; however, the penetration depth of microwave irradiation is limited depending on frequency and solvent. Kappe has demonstrated that lab-scale batch microwave conditions can be converted into continuous PFR microreactor processes and evaluated the two approaches in condensations to create a benzimidazole and a pyrazole.129 NH2

+

MeCO2H

NH2

Neat (1–5 M)

N

Microwave or flow

N H

Me

Me H2N

N H

Ph

O

+ Me

EtOH (3 M), HCl

O Me

Microwave or flow

Me

N N Ph

127 Polaert, I.; Estel, L.; Delmotte, M.; Luart, D.; Len, C. AIChE Journal 2017, 63, 192–199. 128 Estel, L.; Poux, M.; Benamara, N.; Polaert, I. Chemical Engineering and Processing: Process Intensification 2017, 113, 56–64. 129 Damm, M.; Glasnov, T. N.; Kappe, C. O. Organic Process Research & Development 2010, 14, 215–224.

17.14 Synthesis of Aromatic Heterocycles

After calculating the reaction to be completed in three minutes at 200 ∘ C (pressure limited reaction temperature), using a range of commercial microwave reactors, it was shown that up to 466 and 468 g of the benzimidazole and pyrazole, respectively, could be generated with these reactors using a rotary sealed vessel system in about 40–50 minutes of processing time. The team adapted a Thales X-cube to perform the reaction at 270 ∘ C due to the higher pressure limits available in continuous processing. The reaction was performed in a 4 mL reaction coil pumping at 8 mL/min and generated the benzimidazole and pyrazole at a rate of 50 and 225 g/h, respectively, depending on the initial concentration of the reactants. In terms of process intensification, the flow production rate shows an increase in space–time yield of 0.16–3.52 kg/(m3 s) for the benzimidazole and 0.19–15.7 kg/(m3 s) for pyrazole. White et al. described an excellent example wherein continuous synthesis enabled the efficient scale up of a process that would be highly challenging to scale in batch. The group described the use of a fill-react-empty continuous process to achieve the scale-up of a high temperature quinoline formation via a Gould–Jacobs reaction.130 The batch process was challenged by impurity formation, the need for undesirable solvents, and specialized reactors to achieve the necessary reaction temperature on process scale. Br EtOH

CO2Et

N H

O

Br

Heat

CO2Et

C

OH

CO2Et

Br

CO2Et

Heat

N

N

To effect the transformation, the team developed a preheated 25 mL autoclave that could be filled with a solution of starting substrate, rapidly heated to the desired reaction temperature, stirred for a defined period of time, rapidly cooled, and rinsed in automated cycles. The small reactor volume allowed 15 mL of the substrate solution in toluene to be heated to 265 ∘ C in three minutes, held at temperature for five minutes, and cooled to 40 ∘ C in one minute on reactor exit. The product quinoline was poorly soluble, requiring solvent volume optimization such that the product slurry could be cleared out of the reactor and filtered. Although the product yield was 40%, the remaining substrate in the mother liquor was pure enough to be isolated and recycled. Using this approach, the group completed 700 cycles, with recycles, in the reactor to process 300 g over a four-day period without fouling the reactor. The power of microfluidic devices to control heat transfer, control exothermic processes and afford high productivity from relatively small devices was demonstrated for a pyrrole synthesis.131 The condensation of 2,5-hexanedione with either ethylamine or ethanolamine, to form pyrroles was studied using a DoE approach. The authors studied the impact of stoichiometry, time, and temperature initially on a 7.02 μl glass chip, and then scaled the optimal conditions to a 2.4 mL chip. This work identified conditions of 5 : 1 amine:diketone stoichiometry at 20 ∘ C for 100 seconds that afforded a 100% conversion for ethanolamine and 93% for ethanolamine. The team then scaled the reaction by “numbering up,” placing four such reactors in parallel for a total reactor volume of 9.6 mL, generating 55.6 g of the N-hydroxyethylpyrrole in 60 minutes. O

Me +

Me O

Me

R

H2N

Me

N

R

R = H, OH

The synthesis of imidazoles by condensation of ammonia with a ketoamide to afford an imidazole has been achieved in continuous flow after finding the batch process slowed markedly on scale-up due to loss of ammonia to the headspace.132 The authors substituted the des-fluoro analog of the substrate for their process development studies. O

NBoc

H N O

R CF3 R=F R=H

N

AcONH4 MeOH PFR

N H R

NBoc

N

HCl(g) n-BuOH

N H

NH

R CF3

CF3

R=F

130 White, T. D.; Alt, C. A.; Cole, K. P.; Groh, J. M.; Johnson, M. D.; Miller, R. D. Organic Process Research & Development 2014, 18, 1482–1491. 131 Nieuwland, P. J.; Segers, R.; Koch, K.; van Hest, J. C. M.; Rutjes, F. P. J. T. Organic Process Research & Development 2011, 15, 783–787. 132 See Note 68.

767

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The team used a range of stainless steel coils, precisely heated by a gas chromatography oven, to optimize the process and demonstrated that using a 541 mL reactor at 170 ∘ C at 12 mL/min (V reactor /Qfeed = 45 minutes) could process 775 g in four hours, consistent with a delivery of 4.6 kg/d. Ketoamide in MeOH

500 psig

NH4OAc/TEA in MeOH

Product collection vessel

GC oven

Having demonstrated that a continuous process was the superior method for achieving imidazole formation, the desired substrate fluoro-ketoamide was explored. The subtle differences in physical properties did necessitate a change in conditions to a V reactor /Qfeed = 90 minutes at 140–150 ∘ C to find a balance between conversion and product deprotection. With the new conditions, 55 kg of ketoamide was processed in 141 hours in a 7.1 l plug-flow reactor. It is worth noting that the long-term stability of the premixed substrate and ammonium acetate reaction, not detected by NMR or HPLC, did provide a challenge to the six-day continuous process, and it was recommended to deliver the substrates as separate feeds for the multiday processing. Cole et al. also published a seminal paper on the kilogram-scale cGMP synthesis of prexasertib monolactate via eight continuous unit operations to meet the needs of small volume continuous (SVC) manufacturing of this potent anti-cancer compound.133 This approach generated 24 kg of API at a rate of 3 kg/d. The continuous synthesis started with the condensation of hydrazine with an 𝛼-cyanoketone to afford the aminopyrazole. The continuous flow process was found to be superior to batch conditions by accelerating the reaction and minimizing the amount of hydrazine required for good conversion. Using a 3.2 mL stainless steel reactor, the reaction was optimized to operate at 130 ∘ C at 500 psi for 60 minutes with only a slight excess of hydrazine. This process was scaled using a 1.4 l coil reactor constructed of 91 m of 4.57 mm-ID tubing contained within a modified GC oven which contained only 20 g of hydrazine at any one time, minimizing exposure to this hazardous reagent. Indeed, in terms of risk mitigation, only 0.49% of the total reaction volume was within the reactor vessel at any one time. It is also worth noting that the N-Boc amine-protecting group survived the reaction conditions. OMe O

CN

O NH2NH2 AcOH

NHBoc MeOH/THF 130 °C N

NH2 OMe N H O

N

NHBoc

Cl

CN

N N

N

(Z30) n-Etmorpholine

HN OMe

DMSO 85 °C

N H O

CN N

HN OMe N H

N

N

CN N

NH3+.L-Lactate

O NHBoc

Prexasertib

The reaction effluent was processed by the addition of toluene and sodium bicarbonate, followed by continuous counter-current extraction with water, removing the excess hydrazine and minor deprotection product. The effluent was concentrated in a pseudo-continuous fashion by collection in a surge tank and evaporation on a 20 l rotary evaporator at a maximum processing temperature of 110 ∘ C. Addition of DMSO to the residue allowed the aminopyrazole to be collected and introduction into the subsequent SN Ar reaction with chloropyrazine to afford the 133 Cole, K. P.; Groh, J. M.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M.; May, S. A.; Miller, R. D.; Mitchell, D.; Myers, D. P.; Myers, S. S.; Phillips, J. L.; Polster, C. S.; White, T. D.; Cashman, J.; Hurley, D.; Moylan, R.; Sheehan, P.; Spencer, R. D.; Desmond, K.; Desmond, P.; Gowran, O. Science 2017, 356, 1144–1150.

17.14 Synthesis of Aromatic Heterocycles

advanced pyrazolylaminopyrazine intermediate. This work continues to describe the subsequent isolation of pyrazole by continuous crystallization, followed by formic acid-mediated N-Boc deprotection and salt swap to afford the prexasertib monolactate by traditional batch crystallization. The combination of eight unit operations in a continuous sequence on kilo scale is a remarkable achievement. OMe

OMe O MeO

Me

OMe O

NMe2

NMe2

OH

NHBoc

N

N H O

17.14.2

OMe O

85% 2 steps

O

OMe

KOH EtOH

CN

N

N NHBoc

CN

O

NHBoc

NH2NH2 AcOH MeOH/THF NHBoc 130 °C 90%

N Formic acid 25 °C

HN OMe

89% yield 2 steps

N H O

NH2OH•HCl EtOH

OMe O NMe2

K 2CO3, DMF 77% (2 steps)

OH

OMe O N

HN

Br

O

NHBoc N

NH2

OMe N H

N

NHBoc

Cl N N-Etmorpholine DMSO, 85 °C

O

N CN

N

N

Lactic acid distillation

HN OMe N H

THF/water 75 – 85% yield NH2

CN

N

CN

N NH3 • L-lactate

O

Heterocycles from Azido or Hydrazine Compounds

The use of continuous flow to manage the energetics of highly reactive diazo compounds is ideal for scale-up. The ability to generate and react these species in small proportions to the overall reaction scale mitigates the risk of these compounds and makes them a significantly more attractive approach to developing large-scale processes. A good example of using diazo compounds in flow to create an arylhydrazine from an aniline and subsequent generation of a pyrazole intermediate is shown below.134 Aniline BF3•THF 2-MeTHF

tBuONO 2-MeTHF

Decanter (Continuous separtion)

τ 8 min 15–20 °C

Organic phase (Waste stream)17 ~50 mL/min

Water SnCl2 2-MeTHF water

Collection vessle (Hydrazine product formed)

To adapt the batch process to flow, it was found that switching from the free phenol to its methyl ether allowed easier isolation from the tin residues created during the diazonium reduction. Although both aqueous and organic diazotization reagents worked well, the team elected to use the organic conditions. In the first process, the reagents were 134 Li, B.; Widlicka, D.; Boucher, S.; Hayward, C.; Lucas, J.; Murray, J. C.; O’Neil, B. T.; Pfisterer, D.; Samp, L.; VanAlsten, J.; Xiang, Y.; Young, J. Organic Process Research & Development 2012, 16, 2031–2035.

769

770

17 Continuous Chemistry

mixed and passed through a PFR (sonicated to prevent clogging) at 15–25 ∘ C for 10 minutes and added directly to a mixture of tin(II) chloride and enamine ketone, thus reacting the produced aryl hydrazine within minutes of its formation. In this fashion, neither the intermediate diazonium salt nor aryl hydrazine was allowed to accumulate in the process. On scale, the reagents could be pumped at a higher rate (50 mL/min vs. 5.5 mL/min) through a wider bore PFR, obviating the need to use sonication to agitate any precipitated diazonium salt. The solvent was exchanged to 2-methyltetrahydrofuran (MeTHF), and water was added to the reaction after the reactor and an inline stand-pipe decanter separator to afford a continuous separation of the phases. The aqueous phase was added to a vessel containing tin(II) chloride to afford the reduction of the diazonium to arylhydrazine. Using this protocol, the pyrazole was obtained in about 55% yield in an overall three-step process. A Fisher indole synthesis in flow to generate a kilogram quantity of 7-ethyltryptophol, an intermediate in the synthesis of etodolac, has also been exemplified.135 After describing the unsatisfactory results in a batch process, the group designed a continuous flow process in which they pumped the substrate solution at 200 mL/min for 30 minutes at 100 ∘ C, affording a 65% yield, which improved the by-product profile compared to the batch process, but still afforded significant levels (30%) of impurities. HO O CO2H

O Et

N H

NH2

aq H2SO4 Et

N H

N

OH

N H

Et

Et

N H

Me

Etodolac

A second process was implemented, wherein the arylhydrazine and dihydrofuran were heated at 60 ∘ C for five minutes, then heated with 8% sulfuric acid at 100 ∘ C for 16 minutes. This study show the intermediate hydrazone decomposed within minutes, suggesting the reaction time could be decreased. Indeed, the combination of arylhydrazine with dihydrofuran at 115 ∘ C for 20 seconds, followed by heating with 50% aqueous sulfuric acid for four minutes at 115 ∘ C afforded the desired indole. Using this process, the process performed at a rate of >230 mL/min and generated 10 kg of 7-ethyltryptophol of sufficient purity to be used directly in the next step of the synthesis of etodolac.

ArNHNH2

τ 20 s 115 °C

0.8 M DHF

τ 4 min 115 °C

τ 20 s ~ 20 °C

Collection vessle (with agitation)

50% sulfuric acid

17.15 Access to Chirality 17.15.1

Access to Chirality via Asymmetric Hydrogenations

An asymmetric hydrogenation of methyl propionylacetate in a biphasic system of ionic liquid and supercritical CO2 was demonstrated in flow.136 The research team found that a known ruthenium/(BINAP) catalyst could be immobilized in an imidazolium-based ionic liquid [dMEIm][BTA] and scCO2 used as a mobile phase for reactants and products. Acidic additives, such as HSO3 BBIm, led to enhanced reaction rates and helped stabilize the catalysts, although a slight erosion of enantiomeric excess was observed. 135 Lv, Y.; Yu, Z.; Su, W. Organic Process Research & Development 2011, 15, 471–475. 136 Theuerkauf, J.; Francio, G.; Leitner, W. Advanced Synthesis and Catalysis 2013, 355, 209–219.

17.16 Biotransformations

F CO2

60 °C 250 bar (H2/CO2)

Mass flow meter

Gas/liquid separator

[Ru]/(S)-BINAP [dMEIm][BTA] [HSO3BBIm] Window reactor O Et

OMe

F

[HSO 3BBIm] n-Bu

H2

Mass flow meter

N

Et

BPR

Window reactor: autoclave (10 mL) equipped with two thickglass windows and a magnetic stirring bar for agitation

O

OH O

N

2

SO3H

OMe

>90% conversion 82% ee 149 g/(l h)

[dMEIm][BTA] Me Me

N

N Me

O N S S F3C CF3 OO O

To assess the overall value of the continuous flow process, the authors calculated the figures to prepare 100 kg of product. Although the overall processing time was similar, the continuous process required 14 times less catalyst and 37 times less solvent while operating at a lower temperature employing a considerably smaller reactor size. A fully continuous process for a chemo- and enatioselective hydrogenation of a tetrasubstituted alkene using a high-pressure tubular reactor has also been reported.137 The reaction catalyst was prepared by mixing [Rh(COD)2 ]BF4 with the Josiphos ligand prior to addition via a pressurized feed tank. The process required higher pressure and temperature to achieve full conversion within a residence time of 10 minutes. Benefits of the process included improved safety, higher quality of product, and massive throughput improvements that resulted in the successful production of 144 kg. The entire process was continuous end-to-end, including reaction, work-up, and crystallization, all of which were performed in a fume hood. Catalyst BnO

OBn

Continuous extraction

O High pressure tubular reactor

OBn H2

Mass flow meter

Continuous crystallization

BnO OBn

Continuous distillation

Continuous filtration

O OBn Product

17.16 Biotransformations Biocatalysis is an attractive and well-established method to access enantiomerically pure chiral compounds. It has emerged as an essential tool for meeting the growing demand for green and sustainable manufacture of pharmaceutical intermediates and APIs138 and is discussed in greater detail in Chapter 15 of this book. Continuous processes using biocatalysis is industrially valuable because the merge of both important technologies brings in unique opportunities 137 Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.-M.; Miller, M. T.; Brennan, J. Organic Process Research & Development 2012, 16, 1017–1038. 138 Lorenzoni, A. S. G.; Aydos, L. F.; Klein, M. P.; Ayub, M. A. Z.; Rodrigues, R. C.; Hertz, P. F. Journal of Molecular Catalysis B: Enzymatic 2015, 111, 51–55.

771

772

17 Continuous Chemistry

to make biocatalyic reactions more viable for scale up.139 Both PBRs and fluidized bed reactors (FBRs) are used in developing continuous biocatalytic reactions using immobilized enzymes.140,141 Both types of reactors enable continuous processing by obviating the separation of the enzyme from the product stream. In general, PBRs are preferred over FBRs as they offer the advantages of lower shear stress on immobilized enzymes and therefore longer lifespan of the enzyme.142 Hajba and Guttman143 recently reviewed the developments in the field of immobilized enzymes and their applications in biocatalysis. Continuous biocatalytic reactions have been found to give better performance over batch reactions. The kinetic resolution of (R,S)-𝛼-tetralol via enzymatic transesterification using a PBR with immobilized Novozym 435 resulted in a conversion of ∼50% with ∼100% selectivity for (R)-𝛼-tetralol. The immobilized enzyme in the PBR was reusable seven times (35 hours each cycle) with no loss of catalytic activity; whereas a batch reactor under the identical conditions required eight hours to provide only 44% conversion.144 Me OH

OH

Vinyl acetate

O +

Novozyme 435 60 °C τ 3 min

In a more recent development, continuous flow kinetic resolution of a chiral amine, 4-bromo-𝛼-methylbenzylamine was accomplished with the use of immobilized 𝜔-transaminases on porous silica monoliths.145 The method made it possible to carry out enzymatic reactions in the plug flow regime without preferential flow paths under either PBR or FBR conditions. The transaminase show good activity and full enantioselectivity allowing the total kinetic resolution of a racemic mixture. O NH2

NH2

O Me

O

OH

Me OH

Me +

Me Br

139 140 141 142 143 144 145

O

NH2

ω-Transaminase

silica (HIPE) Pyridoxal phosphate

Br

Me

Br

Anderson, N. G. Organic Process Research & Development 2012, 16, 852–869. Schöffer, J. d. N.; Klein, M. P.; Rodrigues, R. C.; Hertz, P. F. Carbohydrate Polymers 2013, 98, 1311–1316. Liese, A.; Hilterhaus, L. Chemical Society Reviews 2013, 42, 6236–6249. Bornscheuer, U. T. Angewandte Chemie International Edition 2003, 42, 3336–3337. Hajba, L.; Guttman, A. Journal of Flow Chemistry 2016, 6, 8–12. Kamble, M. P.; Yadav, G. D. Industrial & Engineering Chemistry Research 2017, 56, 1750–1757. van den Biggelaar, L.; Soumillion, P.; Debecker, D. P. Catalysts 2017, 2, 54–66.

773

18 General Solvent Properties Stéphane Caron Pfizer Worldwide R&D, Groton, CT, USA

CHAPTER MENU Introduction, 773 Definitions and Acronyms, 774 Solvent Properties, 775 Mutual Solubility of Water and Organic Solvents, 778 Other Useful Information on Solvents, 779 Solvent Safety, 780 Risk Phrases Used in the Countries of EU, 781

18.1 Introduction Solvent selection is one of the most important aspects of a chemical reaction.1 The solvent affects the solubility of starting materials, reagents, and products. It will impact the isolation and purification of the product either through precipitation/crystallization, extraction or adsorption. More importantly, the choice of solvent will often influence how a reaction proceeds through stabilization of either the ground state or transition state of reagents and intermediates. As such, solvent properties can modify the rate of most reactions, especially nonunimolecular transformations that are also affected by the reaction concentration. Another important aspect of the solvent is that it provides a heat sink for exothermic reactions, which allows for additional process safety.2 When designing a reaction sequence, solvent selection is very important, and one must establish how the solvent from one reaction might be replaced for the solvent of the second reaction or, preferably, whether two consecutive reactions can be achieved in a single solvent system. The latter could be achieved by either a telescoped batch process or by an end-to-end continuous process. In recent years, several pharmaceutical companies have published their solvent selection tools.3,4,5 Additionally, as the solvent is often the largest component of a reaction and many of them are from petroleum origins, the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable also published a solvent selection guideline, which includes information about environmental impact of several commonly used solvents. (https://www.acs.org/ content/acs/en/greenchemistry/research-innovation/tools-for-green-chemistry.html) The tables below provide useful information about common solvents. Solvents are listed in alphabetical order along with a list of general properties in tables present in Sections 18.3 and 18.4. For a more comprehensive list of solvents and solvent properties, the book entitled Organic Solvents; Physical Properties and Methods of Purification remains an excellent source of information.6 Many azeotropes can be used to facilitate the displacement of a solvent from a mixture 1 Lathbury, D. Organic Process Research & Development 2007, 11, 104. 2 Laird, T. Organic Process Research & Development 2001, 5, 543. 3 Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chemistry 2008, 10, 31–36. 4 Henderson, R. K.; Jimenez-Gonzalez, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Green Chemistry 2011, 13, 854–862. 5 Diorazio, L. J.; Hose, D. R. J.; Adlington, N. K. Organic Process Research & Development 2016, 20, 760–773. 6 Riddick, J. A.; Bunger, W. B. Techniques of Chemistry, Vol. 2: Organic Solvents: Physical Properties and Methods of Purification; 3rd ed.; Wiley-Interscience: New York, 1971. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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18 General Solvent Properties

or to achieve drying by removal of water. For a more extensive list of azeotropes, the two volume set “Azeotropic Data” is highly recommended.7 The table in Section 18.6 lists solvents in order of preference from a manufacturing point of view. It is important to consider the impact of a solvent on multiple areas, including worker exposure, safety margins in reaction processing, ease of handling, and potential for environmental impact.8 For example, n-hexane is less desirable than n-heptane due to its neurotoxicity.

Factor

Impact

Worker exposure

Known or potential toxicological impact.

Safety margin

Will the solvent serve as a heat sink or boiling point barrier?

Ease of handling

Does the solvent dissipate static charge effectively, form peroxides, have a high viscosity, or low melting point?

Environmental impact

Will the solvent persist in the environment, or have a negative effect in the atmosphere (i.e. ozone depletion), soil, or aquatic environment?

In the table, the classification based on regulatory restrictions is provided. When selecting a solvent for a given reaction, the solvent listed first in this table should be preferred based on safety and environmental impact.

18.2 Definitions and Acronyms Azeotrope: A liquid mixture of two or more components that retains the same composition in the vapor state as in the liquid state when distilled at a given pressure. Boiling point (bp): Temperature at which a liquid becomes a gas at standard atmospheric pressure. CMR: Carcinogenic/Mutagenic/Reprotox hazard potential. CMR category 1 is considered a substance with sufficient evidence to establish a causal relationship as a carcinogen, mutagen, or a reproductive hazard. Category 2 is considered a substance with sufficient evidence to establish a strong presumption of carcinogenic, mutagenic, or reproductive toxic properties. Category 3 is considered a substance that is under suspicion of having carcinogenic, mutagenic, or reproductive toxic properties. Density (d): The mass per unit volume of a substance. Dielectric constant (𝜺): A measure of the effect of a medium on the potential energy of interaction between two charges. It is a measure of the relative effect a solvent has on the force with which two oppositely charged plates attract each other. Flash point (fp): The lowest temperature at which a liquid or a solid gives off enough vapor to form a flammable air–vapor mixture near its surface. ICH: International Council on Harmonization is an alliance developed through a collaboration among the FDA and several regulatory agencies including Japan and the European Union, to “harmonize” regulatory requirements to produce marketing applications acceptable in those jurisdictions. This alliance was formed to ensure that good quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective ways. These activities are pursued to prevent unnecessary duplication of clinical trials and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. (www.ich.org) Heat capacity (C p ): The specific heat capacity of a substance is the amount of heat required to raise the temperature of 1 g of the substance 1 ∘ C at a constant pressure without change of phase. Heat of vaporization (𝚫H v ): The amount of heat required to vaporize a defined quantity of a liquid. Melting point (mp): The temperature at which a solid becomes a liquid at standard atmospheric pressure. Molecular weight (MW): The sum of the atomic weights of all the atoms in a molecule. Not. est.: Not established. TLV: Threshold limit value is an exposure standard set by a committee of the American Conference of Governmental Industrial Hygienists (ACGIH). The value defines the level of exposure and is not intended as a line between safe 7 Gmehling, J. Azeotropic Data; VCH: Weinheim, Germany, 1994. 8 Capello, C.; Fischer, U.; Hungerbuehler, K. Green Chemistry 2007, 9, 927–934.

18.3 Solvent Properties

and unsafe exposure. The objective is to minimize workers’ exposure to hazardous concentrations as much as possible. The occupational exposure limit often considers the TLV for a time-weighted average (TWA) of eight hours per day.

18.3 Solvent Properties Azeotropes (at atm. pressure) (Temp, CP Solubility % solvent (J/mol-K) in H2 O 𝚫Hv in first (kJ/mol) (25 ∘ C) (g/100 mL) column)

Solvent

Acronym/ shorthand

CAS #

Formula MW

mp (∘ C)

bp d fp (∘ C) (g/mL) (∘ C)

𝜺

Acetic acid

AcOH

64-19-7

C2 H4 O2 60.05

17

118 1.049

6.15 23.36

39

122.3

Miscible

Cyclohexane (79 ∘ C, 22%) toluene (105 ∘ C, 44%)

Acetone Acetonitrile

ACN MeCN

67-64-1

C3 H6 O

58.08

−95

56

0.791

−19

20.7 31.3

124.9

Miscible

75-05-8

C2 H3 N

41.05

−45

82

0.786

5

36.6 32.94

91.46

Miscible

heptane (92 ∘ C, 45%) MTBE (51 ∘ C, 44%) EtOH (73 ∘ C, 48%) MeOH (63 ∘ C, 19%) i-PrOH (75 ∘ C, 32%) THF (66 ∘ C, 8%) Heptane (69 ∘ C, 62%)

t-amyl alcohol [2-methyl-2-butanol]

75-85-4

C5 H12 O 88.15

−11.9 102 0.805

3

5.82 50.2

244.3

12.36 at 25 ∘ C

H2 O (76 ∘ C, 23%) Cyclohexane (79 ∘ C, 11%) i-Pr2 O (89 ∘ C, 19%)

Benzene

1-Butanol

PhH

n-BuOH

71-43-2

71-36-3

C6 H6

78.11

C4 H10 O 74.12

5.5

−90

80

0.874

116 0.811

−11

35

2.3

33.84

17.8 52.34

135.76

177.08

0.18 at 25 ∘ C

H2 O (87 ∘ C, 38%) Cyclohexane (78 ∘ C, 54%)

H2 O (69 ∘ C, 70%) 7.7 at 20 ∘ C Cyclohexane (79 ∘ C, 10%) toluene (106 ∘ C, 12%) heptane (94 ∘ C, 20%)

t-Butanol [2-methyl-2propanol] Chloroform

t-BuOH

75-65-0

67-66-3

C4 H10 O 74.12

CHCl3

28

119.38 −63

83

61

0.775

1.492

11

10.9 46.82

None 4.81 33.35

220.33

116.90

Miscible

H2 O (93 ∘ C, 24%) Cyclohexane (71 ∘ C, 27%)

H2 O (80 ∘ C, 62%) 0.8 at 20 ∘ C MeOH (53 ∘ C, 65%) EtOH (53 ∘ C, 84%)

Cyclohexane

110-82-7

C6 H12

84.16

7

81

0.779

−18

2.02 32.89

156.01

Insoluble

H2 O (56 ∘ C, 85%) H2 O (69 ∘ C, 30%)

775

776

18 General Solvent Properties

Solvent

Acronym/ shorthand

CAS #

Formula MW

mp bp d fp (∘ C) (∘ C) (g/mL) (∘ C) 𝜺

1,2-Dichloroethane

DCE

107-06-2

C2 H4 Cl2 98.96

−35

83

1.256

15

Azeotropes (at atm. pressure) (Temp, CP Solubility % solvent (J/mol-K) in H2 O 𝚫Hv in first (kJ/mol) (25 ∘ C) (g/100 mL) column)

16.7 35.15

128.99

0.87

EtOAc (70 ∘ C, 49%) i-PrOH (75 ∘ C, 49%) cyclohexane (74 ∘ C, 46%)

Dichloromethane

DCM

75-09-2

CH2 Cl2

84.93

−97

40

1.320

none 9.08 28.56

100.88

H2 O (71 ∘ C, 68%) 1.3 at 20 ∘ C MeOH (38 ∘ C, 86%) EtOH (39 ∘ C, 98%)

Diethyl ether

Et2 O

60-29-7

C4 H10 O

74.12

Diisopropyl ether

IPE, i-Pr2 O

108-20-3

C6 H14 O

102.17 −87

Dimethoxyethane [ethylene elycol dimethyl ether] Dimethylacetamide

DME

110-71-4

C4 H10 O2 90.12

DMAC DMAc DMAA DMF

127-19-5

DMSO

Dimethylformamide Dimethyl sulfoxide 1,4-Dioxane

−116 35

H2 O (38 ∘ C, 93%) 6.9 at 20 ∘ C H2 O (34 ∘ C, 95%) Low H2 O (63 ∘ C, 78%) Miscible H2 O (77 ∘ C, 90%)

0.706

−40 4.34 27.2

172.5

68

0.725

−12 3.88 32.0

216.1

−58

85

0.867

0

193.3

C4 H9 NO 87.12

−20

165 0.937

77.2 47.8 49.15

176

Miscible

68-12-2

C3 H7 NO 73.09

−61

152 0.944

58

38.3 47.51

148.36

Miscible

67-68-5 123-91-1

C2 H6 OS 78.13 C4 H8 O2 88.11

6 11.8

189 1.101 100 1.034

95 12

47.2 52.88 2.21 35.59

153.18 150.65

Miscible Miscible

7.2

36.39

Heptane (97 ∘ C, 8%) Heptane (92 ∘ C, 47%) EtOH (77 ∘ C, 28%)

Ethanol

EtOH

64-17-5

C2 H6 O

46.07

−144 78

0.790

12

24.3 42.309

112.34

Miscible

H2 O (88 ∘ C, 48%) THF (66 ∘ C, 9%) EtOAc (71 ∘ C, 46%) cyclohexane (65 ∘ C, 44%)

Ethyl acetate

EtOAc

141-78-6

C4 H8 O2

88.11

−83

77

0.902

−4

6.02 35.62

169.0

9.0

H2 O (78 ∘ C, 90%) Cyclohexane (72 ∘ C, 55%) hexane (66 ∘ C, 34%)

Ethylene glycol

104-21-1

C2 H6 O2

62.07

−13

196 1.113

110

37.0 67.8

149.4

Miscible

Formic acid

64-18-6

CH2 O2

46.03

8.2

101 1.220

65

58

99.04

Miscible

20.10

Heptane

142-82-5

C7 H16

100.20 −91

98

0.684

−3

Hexane

110-54-3

C6 H14

86.18

69

0.659

−21 2.02 31.552

−95

1.9

36.55

224.98

Insoluble

195.48

Insoluble

H2 O (71 ∘ C, 30%) Toluene (110 ∘ C, 9%) 1,2-Dichloroethane (77 ∘ C, 43%) heptane (78 ∘ C, 63%) H2 O (79 ∘ C, 55%) H2 O (62 ∘ C, 78%)

18.3 Solvent Properties

Solvent

Acronym/ shorthand

Isoamyl alcohol

CAS #

Formula MW

mp bp d fp (∘ C) (∘ C) (g/mL) (∘ C) 𝜺

123-51-3

C5 H12 O

−117 131 0.809

88.15

43

Azeotropes (at atm. pressure) (Temp, CP Solubility % solvent (J/mol-K) in H2 O 𝚫Hv in first (kJ/mol) (25 ∘ C) (g/100 mL) column)

14.7 55.6

211.3

3 at 30 ∘ C

[3-methyl-1-butanol]

Isopropyl acetate

Isoropyl alcohol [2-propanol]

Toluene (110 ∘ C, 12%) heptane (98 ∘ C, 8%)

i-PrOAc

i-PrOH, IPA, IPO, i-PrOH

108-21-4

67-63-0

C5 H10 O2 102.13 −73

C3 H8 O

60.10

−86

89

83

0.874

0.785

2

12

NA 37.20

18.3 45.52

222.6

154.60

H2 O (95 ∘ C, 17%) 4.3 at 27 ∘ C Hexane (68 ∘ C, 8%)

Miscible

H2 O (76 ∘ C, 59%) EtOAc (75 ∘ C, 34%) cyclohexane (69 ∘ C, 41%) hexane (62 ∘ C, 28%) heptane (76 ∘ C, 60%)

Methanol

MeOH

67-56-1

CH4 O

32.04

−98

65

0.791

11

33

37.43

81.47

Miscible

H2 O (80 ∘ C, 69%) Acetone (56 ∘ C, 20%) THF (59 ∘ C, 51%) MTBE (51 ∘ C, 35%) cyclohexane (54 ∘ C, 60%) hexane (50 ∘ C, 49%)

Methyl-t-butyl ether

MTBE

1634-04-4 C5 H12 O

Methyl ethyl ketone [2-butanone]

MEK

78-93-3

C4 H8 O

88.15

−4

55.2 0.740

−28

72.11

−86

80

−1

0.805

18.5 34.51

158.91

heptane (59 ∘ C, 73%) ∘ 4.2 at 20 C H2 O (52 ∘ C, 83%) 29 at 20 ∘ C EtOAc (76 ∘ C, 17%) cyclohexane (71 ∘ C, 50%) hexane (64 ∘ C, 33%) H2 O (673 ∘ C, 66%)

2-Methyl tetrahydrofuran9 N-methyl pyrrolidinone Nitromethane Pyridine

86.13

78

96-47-9

C5 H10 O

NMP

872-50-4

C5 H9 NO 99.13

−24

202 1.027

86

32.2 52.80

166.1

Miscible

MeNO2

75-52-5

C3 NO2

82.04

−29

101 1.127

35

35.9 38.27

105.77

12 at 25 ∘ C

Py

110-86-1

C5 H5 N

79.10

−42

115 0.978

20

12.3 40.41

135.6

Miscible

pyr

0.860

16 at 25 ∘ C

MeTHF

−11 6.97 32.34

H2 O (84 ∘ C, 76%) Toluene (110 ∘ C, 22%) heptane (95 ∘ C, 30%) H2 O (94 ∘ C, 25%)

9 Aycock, D. F. Organic Process Research & Development 2007, 11, 156–159.

777

778

18 General Solvent Properties

mp bp d fp (∘ C) (∘ C) (g/mL) (∘ C)

Azeotropes (at atm. pressure) (Temp, CP Solubility % solvent (J/mol-K) in H2 O 𝚫Hv in first (kJ/mol) (25 ∘ C) (g/100 mL) column)

Acronym/ shorthand

CAS #

Formula MW

Sulfolane Tetrahydrofuran

THF

126-33-0 109-99-9

C4 H8 O2 S 120.17 28 285 1.261 C4 H8 O 72.11 −108 64 0.889

165 −17

43.3 62.8 7.52 32.0

180 123.9

Miscible Miscible

Toluene

PhMe

108-88-3

C7 H8

111 0.865

6

2.44 37.99

157.29

Insoluble

100 1.000 137 0.860

None 80 45.04 29 2.37 ∼42.6

75.98 ∼183.4

Insoluble

Solvent 10

Water Xylenes

7732-18-5 H2 O 1330-20-7 C8 H10

92.14

−95

18.02 0 106.16

𝜺

(60/14/9/17 mixture of m/p/o/Ethyl benzene)

18.4 Mutual Solubility of Water and Organic Solvents Solvent

CAS #

H2 O solubility (%w/w)

Solubility in H2 O (g/100 mL)

Acetic acid

64-19-7

Miscible

Miscible

Acetone

67-64-1

Miscible

Miscible

Acetonitrile

75-05-8

Miscible

Miscible

t-Amyl alcohol

75-85-4

23.47%

12.36 at 25 ∘ C

71-43-2

0.06

[2-methyl-2-butanol] 1-Butanol

71-36-3

20.5

0.18 at 25 ∘ C 7.7 at 20 ∘ C

t-Butanol

75-65-0

Miscible

Miscible

Chloroform

67-66-3

0.09

0.8 at 20 ∘ C

Cyclohexane

110-82-7

0.01

Insoluble

Benzene

[2-methyl-2-propanol]

1,2-Dichloroethane

107-06-2

0.81

0.87

Dichloromethane

75-09-2

1.30

Diethyl ether

60-29-7

6.05

1.3 at 20 ∘ C 6.9 at 20 ∘ C

Diisopropyl ether

108-20-3

1.2

Low

Dimethoxyethane [ethylene elycol dimethyl ether]

110-71-4

Miscible

Miscible

Dimethylacetamide

127-19-5

Miscible

Miscible

Dimethylformamide

68-12-2

Miscible

Miscible

Dimethyl sulfoxide

67-68-5

Miscible

Miscible

1,4-Dioxane

123-91-1

Miscible

Miscible

Ethanol

64-17-5

Miscible

Miscible

Ethyl acetate

141-78-6

8.08

9.0

Ethylene glycol

104-21-1

Miscible

Miscible

Formic acid

64-18-6

Miscible

Miscible

Heptane

142-82-5

5000

100 100

Reacts with acids, active H+

R11-20

C3 H8 O

1

200

Active H+

R11-36-67

3

>5000

2-propanol Acetone 1-Butanol Ethanol Ethyl acetate Heptane Methanol

C3 H6 O C4 H10 O C2 H6 O C4 H8 O2 C7 H16 CH4 O

1 1 1

Reacts with bases Active H+ Active H+ Reacts with bases

1 1

500 20 1000 400 400 200

3 3 3 3 3 2

>5000 >5000 >5000 >5000 >5000 3000

Methyl ethyl ketone

C4 H8 O

1

200

Reacts with bases

R11-36-66-67 R10-22-37/38-41-67 R11 R11-36-66-67 R11-38-50/53-65-67 R11-23/24/25-39/23/ 24/25 R11-36-66-67

3

>5000

C5 H9 NO

1

Not est.

Reacts with bases

R36/38

2

530

C5 H10 O

1

C5 H10 O2 C4 H8 O C2 H4 O2

1 1 1

100 50 10

C2 H3 N C2 H6 OS C6 H12 C2 H6 O2

1 1 and 2 1 1 and 2

20 Not est. 100 X 100

2-butanone N-methyl pyrrolidinone 2-Methyl tetrahydrofuran Isopropyl acetate Tetrahydrofuran Acetic acid

Acetonitrile Dimethyl sulfoxide Cyclohexane Ethylene glycol

X Active H+

X

Can form peroxides

X

Reacts with bases Can form peroxides Active H+

Reacts with bases Reacts with bases Active H+

Not est. R11-36-66-67 R11-19-36/37 R10-35 Harmful to aquatic organisms R11-20/21/22-36 R11-38-65-67-50/53 R22

3 2 3

>5000 720 >5000

2 3 2 2

410 >5000 3880 620

18.7 Risk Phrases Used in the Countries of EU

Skin absorption (1) or sensitizing potential TLV CMR category (2) (ppm)

Potential for static charge Potential buildup reactivity

Solvent

Formula

Methyl-t-butyl ether

C4 H12 O

1

50

Toluene

C7 H8

1

50

Xylenes (mixtures of isomers) Chloroform 1,2-Dichloroethane Dichloromethane

C8 H10

1 and 2

100

3

1 1 1

10 10 50

Reacts with bases Alkylating agent Reacts with bases alkylating agent

CHCl3 C2 H4 Cl2 CH2 Cl2

3

X

Reactive arene X

Reactive arene

Diisopropyl ether Dimethoxyethane ethylene glycol dimethyl ether Dimethylacetamide Dimethylformamide Hexanes

C6 H14 O C4 H10 O2

2

1

250 X Not est.

can form peroxides Can form peroxides

C4 H9 NO C3 H7 NO C6 H14

2 2 3

1 1 1

10 10 50

Reacts with bases Reacts with bases

Pyridine

C5 H5 N

3

2

5

Sulfolane Benzene

C4 H8 O2 S C6 H6 1

1 2

Not est. 0.5

1,4-Dioxane Diethyl ether Nitromethane

C4 H8 O2 C4 H10 O CH3 NO2

1&2 1 1

20 400 20

1

X Reacts with acids and electrophiles Reacts with bases Reactive arene X X

Can form peroxides Can form peroxides Shock sensitive. reacts with acids and bases

18.7 Risk Phrases Used in the Countries of EU Nature of special risks attributed to dangerous substances and preparations

Category

Nature of risk

R1

Explosive when dry

R2

Risk of explosion by shock, friction, fire, or other sources of ignition

R3

Extreme risk of explosion by shock, friction, fire, or other sources of ignition

R4

Forms very sensitive explosive metallic compounds

R5

Heating may cause an explosion

R6

Explosive with or without contact with air

R7

May cause fire

R8

Contact with combustible material may cause fire

R9

Explosive when mixed with combustible material

R10

Flammable

R11

Highly flammable

R12

Extremely flammable

EU classification R11-38 Persists in environment R11-38-48/20-6365-67 R10-20/21-38

ICH Q3C [ ] limit classifi- in API cation (ppm) 3

Not est.

2

890

2

2170

R22-38-40-48/20/22 R45-11-22-36/37/38 R40 Potential ground water contaminant R11-19-66-67 R60-61-11-19-20

2 1 2

60 5 600

2

not est. 100

R61-20/21 R61-20/21-36 R11-38-48/20-62-6567-51/53 R11-20/21/22

2 2 2

1090 380 290

2

200

R22-36-60 R45-46-11-36/38-48/ 23/24/25-65 R11-19-36/37-40-66 R12-19-22-66-67 R5-10-22

2 1

160 2

2 3 2

380

781

782

18 General Solvent Properties

Category

Nature of risk

R14

Reacts violently with water

R15

Contact with water liberates highly flammable gases

R16

Explosive when mixed with oxidizing substances

R17

Spontaneously flammable in air

R18

In use, may form flammable/explosive vapor–air mixture

R19

May form explosive peroxides

R20

Harmful by inhalation

R21

Harmful in contact with skin

R22

Harmful if swallowed

R23

Toxic by inhalation

R24

Toxic in contact with skin

R25

Toxic if swallowed

R26

Very toxic by inhalation

R27

Very toxic in contact with skin

R28

Very toxic if swallowed

R29

Contact with water liberates toxic gases

R30

Can become highly flammable in use

R31

Contact with acids liberates toxic gas

R32

Contact with acids liberates very toxic gas

R33

Danger of cumulative effects

R34

Causes burns

R35

Causes severe burns

R36

Irritating to eyes

R37

Irritating to respiratory system

R38

Irritating to skin

R39

Danger of very serious irreversible effects

R40

Possible risks of irreversible effects

R41

Risk of serious damage to eyes

R42

May cause sensitization by inhalation

R43

May cause sensitization by skin contact

R44

Risk of explosion if heated under confinement

R45

May cause cancer

R46

May cause heritable genetic damage

R48

Danger of serious damage to health by prolonged exposure

R49

May cause cancer by inhalation

R50

Very toxic to aquatic organisms

R51

Toxic to aquatic organisms

R52

Harmful to aquatic organisms

R53

May cause long-term adverse effects in the aquatic environment

R54

Toxic to flora

R55

Toxic to fauna

R56

Toxic to soil organisms

R57

Toxic to bees

R58

May cause long-term adverse effects in the environment

R59

Dangerous for the ozone layer

18.7 Risk Phrases Used in the Countries of EU

Category

Nature of risk

R60

May impair fertility

R61

May cause harm to the unborn child

R62

Possible risk of impaired fertility

R63

Possible risk of harm to the unborn child

R64

May cause harm to breastfed babies

R65

Harmful: may cause lung damage if swallowed

R66

Repeated exposure may cause skin dryness or cracking

R67

Vapors may cause drowsiness and dizziness

R68

Possible risk of irreversible effects

R14/15

Reacts violently with water liberating highly flammable gases

R15/29

Contact with water liberates toxic, highly flammable gas.

R20/21

Harmful by inhalation and in contact with skin

R20/22

Harmful by inhalation and if swallowed

R20/21/22

Harmful by inhalation, in contact with skin and if swallowed

R21/22

Harmful in contact with skin and if swallowed

R23/24

Toxic by inhalation and in contact with skin

R23/25

Toxic by inhalation and if swallowed

R23/24/25

Toxic by inhalation, in contact with skin and if swallowed

R24/25

Toxic in contact with skin and if swallowed

R26/27

Very toxic by inhalation and in contact with skin

R26/28

Very toxic by inhalation and if swallowed

R26/27/28

Very toxic by inhalation, in contact with skin and if swallowed

R27/28

Very toxic in contact with skin and if swallowed

R36/37

Irritating to eyes and respiratory system

R36/38

Irritating to eyes and skin

R36/37/38

Irritating to eyes, respiratory system, and skin

R37/38

Irritating to respiratory system and skin

R39/23

Toxic: danger of very serious irreversible effects through inhalation

R39/24

Toxic: danger of very serious irreversible effects in contact with skin

R39/25

Toxic: danger of very serious irreversible effects if swallowed

R39/23/24

Toxic: danger of very serious irreversible effects through inhalation and in contact with skin

R39/23/25

Toxic: danger of very serious irreversible effects through inhalation and if swallowed

R39/24/25

Toxic: danger of very serious irreversible effects in contact with skin and if swallowed

R39/23/24/25

Toxic: danger of very serious irreversible effects through inhalation, in contact with skin and if swallowed

R39/26

Very toxic: danger of very serious irreversible effects through inhalation

R39/27

Very toxic: danger of very serious irreversible effects in contact with skin

R39/28

Very toxic: danger of very serious irreversible effects if swallowed

R39/26/27

Very toxic: danger of very serious irreversible effects through inhalation and in contact with skin

R39/26/28

Very toxic: danger of very serious irreversible effects through inhalation and if swallowed

R39/27/28

Very toxic: danger of very serious irreversible effects in contact with skin and if swallowed

R39/26/27/28

Very toxic: danger of very serious irreversible effects through inhalation, in contact with skin and if swallowed

R40/20

Harmful: possible risk of irreversible effects through inhalation

R40/21

Harmful: possible risk of irreversible effects in contact with skin

783

784

18 General Solvent Properties

Category

Nature of risk

R40/22

Harmful: possible risk of irreversible effects if swallowed

R40/20/21

Harmful: possible risk of irreversible effects through inhalation and in contact with skin

R40/20/22

Harmful: possible risk of irreversible effects through inhalation and if swallowed

R40/21/22

Harmful: possible risk of irreversible effects in contact with skin and if swallowed

R40/20/21/22

Harmful: possible risk of irreversible effects through inhalation, in contact with skin and if swallowed

R42/43

May cause sensitization by inhalation and skin contact

R48/20

Harmful: danger of serious damage to health by prolonged exposure through inhalation

R48/21

Harmful: danger of serious damage to health by prolonged exposure in contact with skin

R48/22

Harmful: danger of serious damage to health by prolonged exposure if swallowed

R48/20/21

Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin

R48/20/22

Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed

R48/21/22

Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed

R48/20/21/22

Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed

R48/20/21/22

Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed

R48/23

Toxic: danger of serious damage to health by prolonged exposure through inhalation

R48/24

Toxic: danger of serious damage to health by prolonged exposure in contact with skin

R48/25

Toxic: danger of serious damage to health by prolonged exposure if swallowed

R48/23/24

Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin

R48/23/25

Toxic: danger of serious damage to health by prolonged exposure through inhalation and if swallowed

R48/24/25

Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed

R48/23/24/25

Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed

R50/53

Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment

R51/53

Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment

R52/53

Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment

R68/20

Harmful: possible risk of irreversible effects through inhalation

R68/21

Harmful: possible risk of irreversible effects in contact with skin

R68/22

Harmful: possible risk of irreversible effects if swallowed

R68/20/21

Harmful: possible risk of irreversible effects through inhalation and in contact with skin

R68/21/22

Harmful: possible risk of irreversible effects in contact with skin and if swallowed

R68/20/21/22

Harmful: possible risk of irreversible effects through inhalation, in contact with skin and if swallowed

785

19 Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School Sally Gut Ruggeri Pfizer Worldwide R&D, Groton, CT, USA (retired)

CHAPTER MENU Introduction, 785 Reaction Execution, 785 Solvents and Reagents, 788 Isolation, 793 Analysis, 797

19.1 Introduction During the course of undergraduate study, chemists are taught the basics of carrying out organic reactions through lab courses and, sometimes, by carrying out undergraduate research. The fundamentals absorbed at this level generally include how to set up a simple reaction safely, how to work it up (usually by extraction), and how to isolate the product by crystallization, distillation, or chromatography. As a chemist progresses through graduate school, these techniques are refined and more technically challenging ones are introduced. Given the nature of academic research, most reactions are run on small to very small scale, and may require increasingly skilled techniques during the course of study. This approach is at the opposite end of the spectrum from what is considered practical in an industrial setting, especially in process groups. Here the intent is to design processes that are safe, robust, reproducible, and flexible enough to be carried out in any type of manufacturing equipment by operators not trained as chemists.1 This chapter describes the collective learnings of the Pfizer process group on how to approach reaching this ideal and common pitfalls or issues to be avoided.

19.2 Reaction Execution 19.2.1

Heat Transfer

The success of a reaction that is influenced by temperature is dependent on the ability to control the temperature or heat flow. This is especially true for reactions where heat needs to be removed. The ability to control the temperature is relatively easy on the small scale normal to an academic setting, where ice baths are used for cooling and oil baths or heating mantles for heating. As a reaction is scaled up in glassware, control of the heat transfer becomes increasingly difficult. Assuming all spherical reactors, for every 10-fold increase in volume, the surface area:volume ratio is roughly halved.2 This means that when scaling up a reaction a 1000-fold (1 ml to 1 l), the surface area: volume ratio is approximately one-tenth its original value, and equivalent means of temperature control will be much less efficient. Large reactors are usually nonspherical but may suffer from the same scaling effects. They are invariably jacketed, both for practical considerations (you can’t lift one up and put it in a bath!) and because the flow through the jacket is a more efficient means of heat transfer than the static system found in a bath. Internal temperature probes should be used 1 Weizmann, C.; Sulzbacher, M.; Bergmann, E. Journal of the American Chemical Society 1948, 70, 1153–1158. 2 Sebahar, P. R.; Williams, R. M. Journal of the American Chemical Society 2000, 122, 5666–5667. Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Second Edition. Edited by Stéphane Caron. © 2020 John Wiley & Sons, Inc. Published 2020 by John Wiley & Sons, Inc.

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19 Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School

to monitor reaction temperature, as external readings can often be >10 ∘ C at variance with the actual temperature. Continuous processing instead of batch processing can be an advantage in this regard, as the ratio may be similar or even identical in scaling up (see Chapter 17). 19.2.2

Heat Profiles

Monitoring the internal temperature of a reaction is the only way to ensure that the desired temperature control is being maintained (vide supra). The data generated can also be mined for valuable insights into the reaction mechanism, reaction completion, and safety margins. Polymorph control or particle size can sometimes be influenced by the precipitation temperature and the rate of cooling – parameters that are best measured by an internal temperature probe. Important safety data can also be collected by monitoring for spikes in the heat profile. 19.2.3

Stirring

Mixing can have a large influence on reactions, especially heterogeneous ones. How the mixing is performed can also have a large impact on the reaction outcome. For example, the stirring achieved with a magnetic stir bar vs. an overhead stirrer is not the same. In most cases, overhead stirring is more efficient and is far more representative of a large-scale reaction. However, stir bars can have a grinding effect on heterogeneous reactions, and an accelerating effect may be observed that is not reproducible on different scales. For example, when using an insoluble base such as cesium carbonate in tetrahydrofuran (THF), the rate may be accelerated with a magnetic stir bar because its action reduces the particle size of the solid, thereby increasing its surface area. This effect is typically not observed when using an overhead stirrer. A special case where different mixing methods can have striking effects occurs during hydrogenations: results can vary drastically depending on whether the reactor is shaken or stirred, and in extreme examples will give no product in one case and a good yield in the other. This is most pronounced in reactions where the mass flow of hydrogen gas into solution is rate-limiting. Again, the stirred reactor is far more predictive of large-scale reactors. 19.2.4

Homogeneous vs. Heterogeneous Reactions

Homogeneous reactions are generally less sensitive to scale than heterogeneous reactions, for obvious reasons: the rate of homogeneous reactions is controlled by diffusion, while heterogeneous reactions are dependent on mixing, surface area (for solids), absorption (for gases), and a host of other factors. Stir rate can have an enormous influence on heterogeneous reactions, and its effect should be studied to fully understand a reaction. The effective stir rate can also be affected by the size and shape of the reaction vessel. The particle size and shape of solids also has a large influence on the reaction rate. For slow reactions, the surface area of the solids should be maximized. A typical situation arises in the use of carbonate bases in organic solvents, where particle size reduction will greatly accelerate the reactions. In the lab, this can be accomplished with a mortar and pestle; in an industrial setting, milling is a more standard technique. 19.2.5

Electrophilic vs. Nucleophilic Substitution Reactions

As a very gross generalization, electrophilic substitution reactions are often more reproducible and will scale up better than nucleophilic substitution reactions. In this context, an electrophilic reaction is defined as one in which the high-energy species is cationic, and in a nucleophilic reaction, it is anionic. One explanation that may account for this is a consideration of the decomposition pathways of the high-energy intermediate. As an example, consider the acylation of a phenyl ring. This can be accomplished in the electrophilic sense by a Friedel–Crafts acylation, and in the nucleophilic sense by a metalation/acylation. In the Friedel–Crafts acylation, the reagent being used to generate the acylium species is the high-energy intermediate and is often used in excess to account for its decomposition. Note that in this case, the “decomposition” pathway may be hydrolysis to the acid, and since this may have been the precursor to the acylium ion, it may not be lost from the productive pathway. Moreover, since the acylium ion is generated in the presence of the aromatic trap, there is little buildup during the course of the reaction. The substrate being acylated is by far the less reactive species of the two components and is usually stable to decomposition pathways. That these reactions usually need to be carried out at elevated temperatures is a further indication of component stability.

19.2 Reaction Execution

O M

Ar-Br

R

A r-M

O

X

R

O

Ar-H

Ar

O

R

R

X

O

Ar-H R

OH

In the corresponding nucleophilic reaction, the substrate being metalated is now high-energy, and often highly reactive. The reactions are usually carried out at low to cryogenic temperatures (330 min CO2-free

This result highlights the importance of testing different methods of inerting a reaction to see if they have an effect. 19.2.7

Execution of Energetic Reactions

Many reactions in organic chemistry are extremely energetic, usually evidenced by the generation of large exotherms and/or pressure development. The classic way that most chemists have been taught to deal with this situation is to cool the reaction down. This is one of the riskier ways to carry out such reactions since it increases the potential to build up reactive intermediates that are the source of the high energy. Additionally, as noted above, the ability to control heat transfer decreases as the scale increases, leading to the situation where a reaction that seemed safe in a 10 ml flask can be disastrous at 1 l. The preferred way to carry out energetic reactions is to run them at the highest temperature possible coupled with slow addition of a reactive component so that high-energy intermediates are consumed as soon as they are formed. In the reaction shown below, acryloyl azide reacts via a Curtius rearrangement and is trapped with 3 Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas, S. P. The Journal of Organic Chemistry 2004, 69, 2565–2568.

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19 Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School

benzyl alcohol to give the corresponding urethane.4 Both the starting azide and intermediate isocyanate are thermally unstable and decompose at low onset temperatures. To address the safety issues, the reaction is carried out at a high enough temperature that the rearrangement and trap occur instantaneously as the azide is added to the rest of the reagents. There is no buildup of the isocyanate, and the generation of gas is controlled by the rate of addition.

N3

BnOH, pyr K 2CO3, toluene hydroquinone

O

100 °C

O C N

O BnO

NH

Even if heating is not possible, dose-control of one of the reactive components can still be used to control the energetics of a reaction. As in the previous case, the preferred method is to add the reagent that leads to the high-energy intermediate to the rest of the reagents in the pot at a rate such that all of the high-energy intermediate is consumed prior to the next dose. During the synthesis of varenicline tartrate, an aide to smoking cessation, a very exothermic dinitration was required. The reaction was carried out by mixing the starting material and triflic acid in dichloromethane. Nitric acid was then added portion wise at a rate that maintained the internal temperature slightly above ambient. Under these conditions, the nitronium ion being generated was consumed as it was formed.5 O N

CF3

O2N

HNO3, CF3SO3H CH2Cl2, 25–30 °C

O2N

O N

CF3

A completely different approach to running energetic reactions is based on a strategy of minimizing the quantity of the reaction at a given time, thus the total energy output possible, by running it under flow conditions (see Chapter 17). This approach is somewhat reminiscent of the earlier flash vacuum pyrolysis (FVP) method that was used to achieve ultra-high temperatures not otherwise attainable in normal glassware. Several reviews are available on the use of flow reactors,6,7 and this technique has been used in the successful scale-up of many energetic8 or otherwise problematic to scale reactions, such as the Newman–Kwart rearrangement shown below.9 NMe2 S

O

NMe2 Me Me Me

TEGDME 300 °C

Me

O

S

Me CHO

CHO

Me Me Me

(i) NaBH4, MeOH, H2O (ii) NaOH (iii) C7H7SO2Cl, pyridine LiBr, toluene, EtOAc 72% over 4 steps

C7H7O2S

S

Me Me Me

Me OH

TEGDME = tetraethylene glycol dimethyl ether

19.3 Solvents and Reagents 19.3.1

Solvent Selection

Be creative and thoughtful when selecting an appropriate solvent for your reaction (see Chapter 18). Choice of the proper solvent can enhance desired reactivity, minimize by-product formation, and simplify or even eliminate workups.10 Reactions can be classified into four general categories that will impact the choice of solvent: 4 am Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Organic Process Research & Development 1998, 2, 382–392. 5 Coe, J. W.; Watson, H. A., Jr.; Singer, R. A. Varenicline: Discovery Synthesis and Process Chemistry Developments; CRC Press, LLC: Boca Raton, FL, 2008. 6 Anderson, N. G. Organic Process Research & Development 2001, 5, 613–621. 7 Pennemann, H.; Watts, P.; Haswell, S. J.; Hessel, V.; Loewe, H. Organic Process Research & Development 2004, 8, 422–439. 8 Proctor, L. D.; Warr, A. J. Organic Process Research & Development 2002, 6, 884–892. 9 Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Organic Preparations and Procedures International 2000, 32, 547–555. 10 Chen, C.-K.; Singh, A. K. Organic Process Research & Development 2001, 5, 508–513.

19.3 Solvents and Reagents

• Solid to solid: a heterogeneous reaction that either doesn’t go through a homogeneous phase or does so temporarily. These reactions may be more challenging to monitor for reaction completion, but can be simpler to work up. • Solid to solution: a heterogeneous reaction that is homogeneous at reaction completion. The solubility differences can help drive reactions that might stall. • Solution to solid: a homogeneous reaction that is heterogeneous at reaction completion. In the best case, the precipitate is the product, which will facilitate isolation, but it may also be a byproduct. These types of reaction can also help drive equilibria. • Solution to solution: a homogeneous reaction throughout. These are probably the types of reactions most chemists are familiar with, but do not drive equilibria and require the most manipulations for work up. However, they are the simplest to monitor and track both product and by-product formation. Following are some general guidelines and things to keep in mind: 1. Avoid solvents that react with your materials a. Ethyl acetate frequently reacts with amines to form the corresponding acyl amides; use of isopropyl acetate can reduce this side reaction. Ethyl acetate also decomposes very rapidly in the presence of hydroxide to acetic acid and ethanol. Therefore, it is a poor choice of organic solvent when an extraction is planned with sodium or potassium hydroxide, as the pH drop can impact partitioning. Aqueous solutions of carbonate bases can be used if a basic extraction is needed, with minimal decomposition of the ethyl acetate. It should be noted that CO2 may be liberated in this approach and proper venting should be ensured. b. Ester exchange in alcohol solvents can be very rapid. For example, if a substrate containing a methyl ester is allowed to react in a solvent such as ethanol, a mixture of methyl and ethyl esters may be obtained. The exchange can occur under acidic, basic, or neutral conditions. From a strategic view, this may not matter to the overall sequence being pursued, but it can cause analytical issues. Whenever possible, the alcohol solvent should be chosen to match the alkyl group of the ester. c. Dichloromethane will react with nucleophilic amines or alcohols to form chloromethyl amines and ethers or methylene-bridged dimers.11 This can be a very competitive process, and it is generally prudent to avoid the combination. Dichloromethane should also be avoided when using azide ions, as it can form diazidomethane, an explosive compound.12 d. Ethereal solvents can form peroxides in oxidation reactions and should be avoided if possible.13,14 The flash point of low molecular weight dialkyl ethers also increases to the hazards associated with their use. Toluene, water, dichloromethane, and other related halogenated solvents are safer alternatives. e. Cyclic ethers such as THF can undergo ring opening in the presence of strong protic or Lewis acids, and by-products from the corresponding open-chain alcohols may be observed. f. Polyether solvents such as glyme or diglyme can sometimes be used in place of crown ethers and are usually much easier to handle and less toxic. g. Ketone solvents can react with many different kinds of reagents and should generally be avoided with amines or reagents like POCl3 .15 Acetone can condense or polymerize in the presence of strong acids or bases. h. Alcohol solvents have the potential to react with strong acids such as HCl or p-TsOH to form the corresponding chlorides or sulfonate esters. While these are not high-yielding reactions, it can become an issue if a nucleophile is present in the reaction. In the pharmaceutical industry, the presence of alkyl sulfonates or chlorides is a potential issue from a regulatory perspective because of their potential mutagenicity or carcinogenicity. 2. Consider safety first. Some combinations of reagents and solvents are known to be unstable. For example, sodium hydride is known to decompose violently and auto-catalytically in the presence of solvents such as N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), or dimethyl sulfoxide (DMSO),16 so avoid the combination. DMSO is also incompatible with a number of other reagents, such as perchloric acid and bromides.17 Sulfolane may be a viable alternative. 3. t-Amyl alcohol is a good choice for a high-polarity, water-immiscible solvent. It is also an excellent solvent to screen in palladium-catalyzed couplings. 11 12 13 14 15 16 17

Mills, J. E.; Maryanoff, C. A.; McComsey, D. F.; Stanzione, R. C.; Scott, L. The Journal of Organic Chemistry 1987, 52, 1857–1859. Hassner, A.; Stern, M.; Gottlieb, H. E.; Frolow, F. The Journal of Organic Chemistry 1990, 55, 2304–2306. Williams, E. C. Chemistry & Industry 1936, 580–581. Aycock, D. F. Organic Process Research & Development 2007, 11, 156–159. Brenek, S. J.; am Ende, D. J.; Clifford, P. J. Organic Process Research & Development 2000, 4, 585–586. French, F. A. Chemical & Engineering News 1966, 44, 48. Urben, P. G. Chemical Health & Safety 1994, 1, 30, 47.

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4. If a reaction is exothermic, consider the boiling point of the solvent you select: a lower boiling point offers a potential barrier to a runaway reaction, or acts as a buffer to absorb the heat being produced. 5. If a solvent change is needed in the course of a reaction, either for isolation purposes or to telescope two reactions, consider the relative boiling points or existence of azeotropes of the solvents being used. When possible, a higher-boiling or favorable azeotrope solvent should be used to displace the first solvent. 6. Wet solvents can have much better solubilizing properties than dry solvents, so addition of a small amount of water can greatly increase the solubility of compounds. For example, wet 2-methyltetrahydrofuran (2-MeTHF) can be much better at solubilizing organic substrates than when it is dry. 7. Some higher homologues of water-miscible solvents are immiscible, such as 1-butanol and 2-MeTHF. This may make them preferable for reactions in which aqueous extractions are planned. Even some normally water-miscible solvents can become immiscible depending on conditions such as pH, temperature, and ionic strength of the medium. For example, THF is immiscible with water at high pH, and acetonitrile separates from water at subzero temperatures. 8. Some organic solvents are immiscible with other organics. For example, hexanes or heptanes are immiscible with acetonitrile or N,N-dimethylacetamide (DMAc) and can be used to extract nonpolar impurities. Also, expensive specialty solvents, such as hexafluoroisopropanol, can be readily recovered when used in biphasic mixtures with nonpolar solvents. 9. Use less solvent than you think you need; unless there is a reason for higher dilution, keep reactions concentrated. A rough rule of thumb is to try reactions first at 5–7 volumes (mL/g). In addition to being a more environmentally conscientious approach, your reaction may be accelerated as long as it is greater than first-order. 10. Try to avoid solvents that are chlorinated, toxic, or have very low flash points. Use heptane instead of hexanes. Older literature syntheses that use benzene usually work with toluene. If a chlorinated solvent is necessary, use dichloromethane or 1,2-dichloroethane instead of chloroform or carbon tetrachloride. 11. Try water as a reaction solvent; it often gives surprisingly good reactivity,18 especially when the reaction mixture is not soluble in it. 12. If the solubility of the starting material is much higher than the product in a given solvent, the reaction can be designed such that the product precipitates in the course of the reaction therefore avoiding the need for a complicated workup and purification. This method is sometimes referred to as a direct drop process. 13. When transferring large amounts of solvent, a grounding strap or line should be used. It is very easy to generate “lightning” in a reaction vessel via static discharge, a situation obviously to be avoided when using flammable solvents.19 14. When using mixed solvents, choose those that can be recycled by distillation in a solvent recovery unit or by separation during workup. 15. Many of the most popular polar aprotic solvents (DMSO, DMAc, and DMF) are on the REACH list (https:// chemicalwatch.com/66647/nmp-added-to-reach-restricted-substances-list), which may limit their availability and use in the EU in the future. These solvents should be avoided if possible when planning large-scale syntheses. 19.3.2

Removal of Water from Solvents or Reactions

Many types of reactions can be sensitive to the presence of water. During screening of reaction conditions, it is prudent to exclude water when its effect may be unknown. The standard method for removing water on an academic scale is to use solvent that has been distilled over a drying agent or passed through a solvent drying system. This process is convenient on a small scale, but is impractical, wasteful, and costly as the scale rises. The easiest and most economical method to achieve a dry solvent is to azeotropically remove the water. For a reaction mixture, this is achieved by an addition of excess reaction solvent, followed by vacuum or atmospheric distillation to the desired volume. For lab use, fresh, anhydrous solvents poured from a bottle contain little or no more water than distilled solvents handled with syringe and needle. A practical way to dry a flask prior to use is to rinse once with anhydrous solvent. After screening has been completed, and a given reaction is being optimized, the assumed negative impact of water should be challenged. Many reactions, such as palladium-mediated couplings, will tolerate or even be enhanced by low levels of water. Experiments should be carried out during optimization to determine allowable and optimal ranges for water content. 18 Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Letters 1994, 35, 7947–7948. 19 Giles, M. R. Organic Process Research & Development 2003, 7, 1048–1050.

19.3 Solvents and Reagents

An alternative way to dry or remove water from a reaction is the Dean–Stark method. It requires the use of a water-immiscible solvent that is less dense than water. In a lab, a Dean–Stark trap attached to a reaction set-up will accomplish the water removal. On a kilo-lab or pilot plant scale, condensers are usually offset from reactors, so the requisite set-up is a natural part of the system. There are also inverse Dean–Stark traps known, where a solvent heavier than water can be removed. To dry an organic solution after an aqueous workup, azeotropic removal of the water is again the preferred method. The use of drying agents, such as magnesium or sodium sulfate, is unwieldy and costly on a large scale. Other techniques, such as membrane pervaporation, may be more practical for sensitive substrates (see Chapter 17).20 19.3.3

Solvent Contamination

Several commercially available solvents may be contaminated with compounds that can interfere or react competitively with desired transformations. • DMF often contains some level of dimethylamine, or will decompose under reaction conditions to produce it. In nucleophilic substitution reactions, it can add competitively to give the dimethylamino product. DMAc or NMP are less prone to decomposition and are often comparable to DMF as a solvent. • Solvents that are prone to air oxidation, such as ethers, are often stabilized with 2,6-di-t-butyl-4-methylphenol (BHT). If large volumes of solvents are used in a process and then removed by distillation, the residual BHT can sometimes be a significant contaminant in the isolated product. • There are many grades of ethanol, most of which contain a cosolvent to decrease the potential for misuse (i.e. denatured alcohol, see Section 19.5). For example, 2B ethanol contains ∼5% toluene and 3A ethanol contains ∼5% methanol. During concentrations, these cosolvents can have a large effect on crystallizations or purifications, and should be taken into consideration. • Chloroform is stabilized with either ethanol or amylenes. The amylenes rarely cause a compatibility issue in reactions and are easily removed, but the ethanol can cause problems. • Straight chain alkane solvents are often contaminated with higher boiling hydrocarbons (branched and cyclic analogues) that can become an issue during concentrations. • Some solvents readily leach plasticizers or other organic-soluble components from plastic or rubber. For example, the phthalate esters in TygonTM tubing readily dissolve in dichloromethane and can easily contaminate reaction mixtures. Similarly, rubber septa can degrade in the presence of some solvents or strong acids and contaminate reactions. Check the manufacturers’ websites for solvent compatibility. 19.3.4 19.3.4.1

Reagent Selection and Compatibility Replacements for NaH

As mentioned in the solvent selection section, NaH can react violently with some organic solvents and can be even more of an issue when reactions are run cold, since it can react vigorously when warmed. While this risk can be lessened by the proper choice of a solvent, it is better to avoid its use when possible. If the product of the reaction is to be isolated by crystallization, adding the NaH as a mineral oil suspension might not cause problems in the isolation and is the safest handling alternative. Potassium t-butoxide in THF is a good combination to try as a replacement, and usually gives equivalent results. It can be conveniently purchased as an anhydrous solution. If sodium is desired as a counter ion, sodium t-amylate is a good choice as a replacement. Phase transfer conditions are often successful replacements as well. 19.3.4.2

Use of Hydrides

Sodium borohydride can selectively reduce ketones and aldehydes in the presence of esters, but it will reduce esters at room temperature given sufficient time (and no competing functionality) (see Section 19.4.1.3 for workups). Its reactivity in alcohol solvents follows the order MeOH>EtOH>2-PrOH, however, the rate of decomposition is also fastest in MeOH, so a larger excess may be required. As with other hydrides, it should not be used with polar, high-boiling 20 Li, B.; Guinness, S. M.; Hoagland, S.; Fichtner, M.; Kim, H.; Li, S.; Maguire, R. J.; McWilliams, J. C.; Mustakis, J.; Raggon, J.; Campos, D.; Voss, C. R.; Sohodski, E.; Feyock, B.; Murnen, H.; Gonzalez, M.; Johnson, M.; Lu, J.; Feng, X.; Sun, X.; Zheng, S.; Wu, B. Organic Process Research & Development 2018, 22, 707–720.

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solvents such as DMF.21 Sodium triacetoxyborohydride (STAB) is also an excellent source of hydride for appropriate reactions, such as reductive aminations, and is easier to handle and quench. LiAlH4 (LAH) is more stable to air in THF-toluene mixtures than THF alone and is sometimes more reactive toward organic substrates in them as well. A minimum of two moles of THF are required to solubilize the LAH, and a solution of this complex is commercially available. The reactivity can also be tuned by the addition of other ethers. Borane is usually purchased as a complex with THF or SMe2 to avoid having to crack the dimer. The THF complex is thermally unstable, especially as the concentration rises,22 and is not recommended above 1 M for safety reasons, especially at a large scale. The stability of the THF complex is claimed to be affected by the choice of stabilizer, with amines being preferred to NaBH4 .23 Borane amine complexes are also known and may be preferred, as they are typically shelf-stable solids. 19.3.4.3

Metal Catalysts

Dry metal catalysts such as Pd/C are extremely hazardous and can ignite in air and/or in the presence of organic solvents. Water-wet catalysts should be used instead and are typically available as 1 : 1 mixtures by weight with water to stabilize them. In most cases, the water-wet catalysts perform equally well as the dry catalysts and do not spark when mixed with organic solvents. If the reaction does not tolerate water, a suspension of the catalyst can be dried azeotropically under nitrogen to minimize the fire hazard, prior to introduction of hydrogen. The reaction should be kept under an inert atmosphere until the catalyst has been removed by filtration, at which point it should be suspended in water for disposal. In addition to the safety issue, many substrates are efficiently oxidized in the presence of a palladium catalyst and oxygen, giving another reason for keeping the reaction inert. Many different types of the same catalyst are available. The difference in the catalyst often stems from the source of the solid support. For example, the carbon in Pd/C can come from plant or animal sources, which can have a profound effect on reactivity. The catalysts can be acidic or basic enough to affect labile groups in the substrate. Different lots of the same catalyst can also vary in reactivity and should be checked in a test reaction prior to large-scale use. The reactivity of homogeneous metal catalysts varies widely depending on the source and purity. The most reliable results will often be obtained by freshly preparing the catalyst, but this may not always be feasible for scale up. If a commercial catalyst is used, it should always be use-tested prior to scaling up. It can be almost impossible to analytically detect small changes that result in gross effects on the reaction. Raney nickel, sometimes referred to as sponge nickel, is an excellent reagent for reducing a variety of functional groups, but there are issues with its use, such as its pyrophoric nature. Nickel is a carcinogen, and most reagents based on it are assumed to be the same. As with many other catalysts, there are different types of Raney nickel that have varying reactivity. It is usually manufactured in the presence of hydroxide, and residual base may need to be washed out prior to use. Raney nickel loses activity with time, which usually necessitates the use of large excesses. Nickel boride24 can be used as a replacement for Raney nickel for sufficiently reactive substrates. 19.3.4.4

Generation of HCl

For reactions requiring anhydrous HCl, gaseous acid is often used. This may not be easy or convenient if the stoichiometry of the acid needs to be carefully controlled. A more convenient and safer practical alternative is to generate the HCl in situ from an alcohol and acetyl chloride.25 Another method involves mixing of sulfuric acid and sodium chloride. 19.3.4.5

HF

The hazards of hydrofluoric acid (HF) (reactivity with bone, etching of glass) are well known, and its use should be avoided when possible. If HF must be used, reactions should be carried out in compatible plastics, such as polyethylene, or Hastelloy reactors. For additional worker safety, care should be taken to keep the pH basic after the reaction is complete. It should be realized that HF or its equivalent can be generated during reactions such as nucleophilic aromatic displacements of fluorides, and that these reactions can be as hazardous as using the reagent itself. When using HF, a solution of calcium gluconate should be available since this will readily deactivate HF by the formation of insoluble CaF2 . The antidote for skin contact is subcutaneous injection of the solution. 21 22 23 24 25

Lu, T. J.; Liu, S. W.; Wang, S. H. The Journal of Organic Chemistry 1993, 58, 7945–7947. Laird, T. Organic Process Research & Development 2003, 7, 1028. Vogt, P. F.; Am Ende, D. J. Organic Process Research & Development 2005, 9, 952–955. Back, T. G.; Baron, D. L.; Yang, K. The Journal of Organic Chemistry 1993, 58, 2407–2413. Yadav, V. K.; Babu, K. G. European Journal of Organic Chemistry 2005, 452–456.

19.4 Isolation

19.3.4.6

NBS

N-bromosuccinimide (NBS) and, more generally, other brominating agents, may be incompatible with a wide variety of organic solvents. A study of NBS revealed that it has good compatibility with acetonitrile, dichloromethane, and ethyl acetate, but not many other commonly used solvents.26 Bromine will also react with many solvents, often with very high exothermicity. 19.3.4.7

Use of POCl3

Phosphorus oxychloride (POCl3 ) is a reagent commonly used for dehydrations, chlorinations, etc., and is often used in combination with DMF to generate the Vilsmeier reagent. Less well known is that this combination also generates dimethylcarbamoyl chloride (DMCC) as a by-product.27 DMCC is a known animal carcinogen. An assessment to a very low level is required if this combination is used to make material of pharmaceutical grade. 19.3.4.8

KOH Contamination

Solid KOH may be contaminated with nickel and other metals. This can be an issue if it is used as a base in palladiumor other metal-mediated reactions. Check the label for its presence. 19.3.4.9

Material Compatibility

Equipment should be inspected for materials of construction and appraised for compatibility with reagents and solvents being used. The incompatibility of Tygon tubing with some solvents is well known, resulting in leaching of phthalate esters. O-rings may also be susceptible to degradation in the presence of organics, causing leakage and/or contamination. Stainless steel is not inert in the presence of halides. This can be a problem when drying compounds such as HCl salts in drying ovens, which are frequently constructed from stainless steel. The decomposition of the stainless steel can result in the contamination of the solids being dried. Reactors constructed of Hastelloy are often used for reactive chemistry, but even in this case, fittings or smaller components may be made of different materials. For example, some equipment uses brass fittings, which will decompose in the presence of ammonia, creating a dangerous situation. Coupons made of various metals are available and can be tested against reaction conditions, if this is a potential concern.

19.4 Isolation The workup and purification of a newly made compound can often be as challenging as the synthesis. This is especially true for large-scale chemistry, where multiple extractions are costly and chromatographic purifications are discouraged or even prohibitive. The art of crystallization is the preferred method for isolation and purification of compounds that are solids. For compounds that are oils, formation of a salt to render them crystalline is the preferred option on a large scale. If no salt can be formed, carrying forward the intermediate as a solution is the next best option, if the subsequent chemistry will tolerate the potential contaminants. Listed below is some general and specific guidance on workup and purification.

19.4.1

Reaction Workups

In the ideal process, the product precipitates directly from the reaction mixture as it is formed and is isolated by simple filtration. This ideal is not often realized, however. Many reactions are subjected to aqueous workups to quench reactive intermediates and reagents or to wash by-products away from the desired material. While these workups often cannot be avoided, they should be kept to the absolute minimum, i.e. not done simply because they seem like a good idea, but because there is hard data that they are necessary. This is especially true if the product of the reaction is a solid, in which case precipitation of the solid by addition of an anti-solvent or displacement into a nonsolubilizing solvent is preferred. 26 Shimizu, S.; Imamura, Y.; Ueki, T. Organic Process Research & Development 2014, 18, 354–358. 27 Levin, D. Organic Process Research & Development 1997, 1, 182.

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19.4.1.1

Extractions

As stated in the introduction, extractions should be minimized in any workup, and only carried out because there is data that suggests they are necessary. If extractions are required, the options for acid and base solutions should be considered. The most commonly used are probably aqueous HCl and NaOH. These are certainly sensible choices for cost and availability reasons, but may not be suitable for all reactions. If aqueous HCl is incompatible with a reaction stream, a solution of 10% citric acid is a very mild way of washing out basic impurities. It is also useful for extracting amines whose HCl salts are insoluble in water and tend to precipitate. Carbonate or bicarbonate washes can be substituted for NaOH extractions, depending on the pH required to remove the impurities. These are especially useful when extracting from organic solvents that decompose in the presence of NaOH, such as EtOAc. A caution must be observed in their use, as they can generate CO2 rapidly when quenching strongly acidic reaction mixtures. Other salts may also be employed, and in some instances, have been shown to have profound effects on the partitioning between organic and aqueous phases.28 For some extractions, the phase split can be difficult to visualize, especially if both layers are very dark. Applying a stronger light source, such as a flashlight as a backlight can help find the boundary. A small amount of Celite can also be added, as it usually settles at the interface. 19.4.1.2

Emulsions

If an emulsion forms during an aqueous workup, the simplest way to resolve it is to add more water and organic solvents. If this technique does not work, brine may be added to encourage separation of the layers. This approach works only with organic solvents that are less dense than water; with higher-density solvents, the addition of brine worsens the emulsion. If dilution is not desired or possible, the emulsion can be filtered through diatomaceous earth, which often resolves the layers. Heating the mixture can also break up an emulsion. 19.4.1.3

Workup of Hydrides

Hydride reagents based on aluminum, boron, or titanium can be challenging to work up. These metals tend to result in gels and slow-to-filter solids that can cause hopeless emulsions during extractive workups on a large scale. Some strategies for removing these metals include • Nonextractive workups that rely on precipitation of salts. Control of the stoichiometry of water and/or hydroxide can result in a well-filtering solid. For aluminum reagents, this can be carried out by simple addition of the correct amount of water (4–5 M equivalents per aluminum) to precipitate aluminum oxide. It is preferable to premix the water for quenching with a water-miscible solvent to more accurately control the rate of addition and dispersal into the reaction. If the solids are somewhat gelatinous, heating and cooling cycles in the organic reaction solvent can “dry” the solids. • Alternatively, the Fieser workup (Fieser and Fieser, “Reagents for Organic Synthesis,” Volume 1, 1967, p. 584) also usually gives filterable solids. A delayed exotherm is sometimes observed in these quenches, so care should be employed when running them for the first time. • Another trick to avoid the gelatinous solids that can form is the addition of diatomaceous earth or another solid support to the reaction mixture. The solids adsorb onto the support without the usual blinding effect observed when the gelatinous solids are poured directly onto a filter aid. This works very well for quenches that generate titanium dioxide. • If quenching with water is too exothermic, try 2-propanol instead. However, be watchful for a delayed exotherm. Other solvents that have been used include acetone or ethyl acetate, especially for diisobutylaluminum hydride (DIBAL-H) reactions. • For extractive workups, try varying the pH of the aqueous phase. For some reactions, there is an optimal pH where the inorganic by-products dissolve more readily, and emulsions can sometimes be avoided by identifying it. For example, when working up mixtures containing zinc salts, a gelatinous white precipitate forms around pH 9. This issue may be resolved by adding more base to a pH of 14. • Borane can be quenched with aqueous HCl, amines, or acetone. Methanol can also be used and is useful when a distillation is planned, since the resulting trimethylborate ester has a very low boiling point (68–69 ∘ C). 28 Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng, F. Organic Process Research & Development 2017, 21, 1355–1370.

19.4 Isolation

19.4.1.4

Workup of POCl3

While most chemists are aware that POCl3 needs to be quenched cautiously, it is not as widely known that the reagent will react with some organic solvents in a potentially hazardous fashion. The greatest risk probably occurs with acetone, since it is commonly used as a rinse or a wash solvent. Acetone and POCl3 react at room temperature to produce heat and gas in a runaway reaction that can lead to a dangerous situation.29 The POCl3 should always be quenched after the desired reaction and prior to mixing with other organic waste (this includes reagent that may have been distilled into rotavap bump traps). There is a long induction period when water is used as a quench as they are not miscible; ammonium hydroxide is a better choice, since it reacts much more quickly. 19.4.1.5

Reduction of Iodine

Several inorganic salts are known to reduce excess iodine in a reaction, such as sodium bisulfite or sodium thiosulfate. However, the latter reagent may cause sulfur contamination of the product, which can lead to issues downstream.30 Ascorbic acid can also be used as a reducing agent. 19.4.1.6

Removal of Ph3 PO

Triphenylphosphine oxide (TPPO) can be very difficult to purge from reaction mixtures by nonchromatographic methods. Occasionally, crystallization solvents can be identified that separate it from the product, but this is not a reliable approach. TPPO can be selectively extracted into methyl t-butyl ether (MTBE) if the product can be extracted into an aqueous phase, either through inherent solubility or by pH adjustment. 19.4.1.7

Removal of Triethylamine

Triethylamine (TEA) will often co-distill with organics solvents, so concentrations may be effective at removing it. If it was used as a proton scavenger, triethylammonium chloride is insoluble in acetonitrile and THF and can be removed by filtration. Primary and secondary amines will also exchange protonation with TEA, so with the appropriate choice of solvent, the equilibrium can be driven by precipitation and removal of the salt. 19.4.2 19.4.2.1

Purification Crystallization

How many times have chemists been heard to curse because a compound starts to precipitate while they are preparing it for chromatographic purification? This is the best possible sign that the compound “wants” to crystallize, which is by far the preferred method for isolation and purification on a larger scale. Until the advent of flash chromatography, crystallization was the practice of choice for isolation. Since that time, the over-reliance on chromatographic purifications in the academic setting has made this somewhat of a lost art, and one that has to be relearned in industry. Chromatography is still the method of choice for small (