Oxidation of C-H bonds
 9781119092520, 1119092523, 9781119092490

Citation preview

Oxidation of C─H Bonds

Oxidation of C─H Bonds Wenjun Lu and Lihong Zhou

Shanghai Jiao Tong University, Shanghai, China

This edition first published 2017 © 2017 by John Wiley & Sons, Inc. All rights reserved 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 Wenjun Lu and Lihong Zhou to be identified as the authors of this work and 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: Lu, Wenjun, 1966– | Zhou, Lihong, 1985– Title: Oxidation of C-H bonds / Wenjun Lu, Lihong Zhou. Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2017] | Includes bibliographical references and index. Identifiers: LCCN 2016042793 | ISBN 9781119092520 | ISBN 9781119092506 (epub) Subjects: LCSH: Organometallic compounds–Oxidation. | Oxidation. | Organometallic compounds. | Organometallic chemistry. | Carbon compounds. | Hydrogen bonding. Classification: LCC QD411 .L848 2017 | DDC 547/.23–dc23 LC record available at https://lccn.loc.gov/2016042793 Cover design by Wiley Cover Image: © Gerard Hermand/Getty Images, Inc. Set in 10/12pt Warnock by SPi Global, Pondicherry, India Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

v

Contents Preface  xi 1 Introduction  1

1.1 What Is Oxidation of C─H Bonds?  1 1.2 Chemical Synthesis and Oxidation of C─H Bonds  2 1.2.1 Transformation of Organic Compounds  2 1.2.2 Ideal Chemical Synthesis  2 1.2.3 Oxidation of C─H Bonds for Ideal Chemical Synthesis  3 1.3 C─H Bonds  6 1.3.1 Reactivity  7 1.3.2 Cleavage of Inert C─H Bonds  10 1.3.2.1 Direct Cleavage  10 1.3.2.2 Indirect Cleavage of Inert sp2C─H Bonds  12 1.3.3 Oxidation  13 1.3.3.1 Redox Processes  13 1.3.3.2 Oxidative Processes  14 Concepts in This Book  15 1.4 ­References  17 Oxidation of Methane  19 2.1 Methane  19 2.2 Methyl sp3C─H Bond  20 2.3 Oxidations of Methyl sp3C─H Bond  21 2.3.1 Syngas (CO/H2)  21 2.3.2 Methanol  23 2.3.3 Ethylene  27 2.3.4 Benzene  29 2.3.5 Acetic Acid  30 2.3.6 Methyl Halide  33 2.4 Summary  35 ­References  36

2

vi

Contents

3

Oxidation of Alkyl sp3C─H Bond  39

3.1 Alkane  39 3.2 Alkyl sp3C─H Bonds  40 3.3 Oxidations of Alkyl sp3C─H Bond  42 3.3.1 C─C Bond Formation  42 3.3.1.1 Alkenes and Arenes (Dehydrogenation)  43 3.3.1.2 Aliphatic Carboxylic Acids (Carboxylation) and Vinyl Alkanes (Alkenylation)  45 3.3.1.3 Alkylation (Metal‐Carbene‐Induced C─H Insertion)  48 3.3.2 C─N Bond Formation  51 3.3.2.1 Alkylamines (Amination)  51 3.3.2.2 Nitroalkanes (Nitration)  53 3.3.3 C─O Bond Formation  55 3.3.3.1 Alcohols (Hydroxylation)  55 3.3.4 C─Halogen Bond Formation  57 3.3.4.1 C─F Bond (Fluorination)  57 3.3.4.2 C─Cl Bond and C─Br Bond (Chlorination and Bromination)  59 3.3.4.3 C─I Bond (Iodination)  60 3.4 Summary  61 ­References  62 4

Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group  65

4.1 Directing Group  65 4.2 Alkyl sp3C─H Bonds with Directing Groups  66 4.3 Directed Oxidations of Alkyl sp3C─H Bond  67 4.3.1 C─C Bond Formation  68 4.3.1.1 Alkylation 68 4.3.1.2 Alkenylation 70 4.3.1.3 Alkynylation 73 4.3.1.4 Carbonylation 74 4.3.1.5 Arylation 76 4.3.2 C─N Bond Formation  82 4.3.2.1 Intramolecular Coupling  82 4.3.2.2 Intermolecular Coupling  87 4.3.3 C─O Bond Formation  90 4.3.4 C─Halogen Bond Formation  93 4.4 Summary  97 ­References  97 5

Oxidation of Alkyl sp3C—H Bond Adjacent to Unsaturated Carbon Atom  101

5.1 Alkyl α‐sp3C─H Bond  101 5.2 Alkyl sp3C─H Bonds Adjacent to Unsaturated Carbon Atoms  102 5.3 Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom  103

Contents

5.3.1 C─C Bond Formation  103 5.3.1.1 Alkylation 103 5.3.1.2 Arylation 109 5.3.2 C─N Bond Formation  115 5.3.2.1 Amination of Allylic and Benzylic sp3C─H Bonds  115 5.3.2.2 Amination of Active sp3C─H Bonds  118 5.3.3 C─O Bond Formation  120 5.3.4 C─Halogen Bond Formation  129 5.3.4.1 Chlorination and Bromination  129 5.3.4.2 Fluorinating Reagent and Enantioselective Fluorination  131 5.4 Summary  138 ­References  138 6

Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom  143

7

Oxidation of Alkenyl or Carbonyl sp2C─H Bond  171

6.1 Alkyl sp3C─H Bonds Adjacent to Heteroatoms  143 6.2 Oxidations of Alkyl sp3C─H Bond Adjacent to Heteroatom  144 6.2.1 C─C Bond Formation  145 6.2.1.1 Electrophilic Attack  145 6.2.1.2 Nucleophilic Attack  149 6.2.2 C─N Bond Formation  157 6.2.2.1 Nitrene Reagents  157 6.2.2.2 Other Nucleophiles as Nitrogen Sources  159 6.2.3 C─O Bond Formation  161 6.2.4 Others  166 6.3 Summary  166 ­References  167

7.1 Alkenyl and Carbonyl sp2C─H Bonds  171 7.2 Oxidations of Alkenyl and Carbonyl sp2C─H Bonds  172 7.2.1 C─C Bond Formation  173 7.2.1.1 Arylation and Alkenylation of Alkenes (The Mizoroki–Heck Coupling Reaction)  173 7.2.1.2 Alkylation of Alkenes  183 7.2.1.3 Alkylation and Alkenylation of sp2C─H Bonds on Aldehydes (Hydroacylation and Coupling Reaction)  184 7.2.1.4 Alkynylation of sp2C─H Bonds on Aldehydes  192 7.2.1.5 Arylation of sp2C─H Bonds on Aldehydes  193 7.2.2 C─Heteroatom Bond Formation  195 7.2.2.1 Oxygenation and Amination of Alkenyl sp2C─H Bonds (The Wacker and Aza‐Wacker Processes)  196 7.2.2.2 Esterification and Amidation of Carbonyl sp2C─H Bonds  200 7.3 Summary  203 ­ References  204

vii

viii

Contents

Oxidation of Alkynyl spC─H Bond  209 8.1 spC─H Bonds  209 8.2 Oxidations of spC─H Bond  210 8.2.1 Oxidations of Alkynyl spC─H Bond  210 8.2.1.1 Nucleophilic Substitution (Formation of spC─sp3C and spC─sp2C Bonds)  210 8.2.1.2 The Sonogashira Reaction (Formation of spC─sp2C and spC─sp3C Bonds)  211 8.2.1.3 Carbonylation and Carboxylation (Formation of spC─sp2C Bonds)  218 8.2.1.4 Glaser–Eglinton–Hay Homocoupling and Cadiot–Chodkiewicz Cross‐Coupling (Formation of spC─spC Bonds)  226 8.2.1.5 Formation of Alkynyl spC─Heteroatom Bonds  228 8.2.2 Oxidations of spC─H Bond of Hydrogen Cyanide  231 8.3 Summary  232 ­References  232 8

9 Oxidation of Benzene  235 9.1 Introduction  235 9.2 Oxidations of Phenyl sp2C─H Bond  237 9.2.1 Formation of C─C Bond  238 9.2.1.1 Alkylation 238 9.2.1.2 Trifluoromethylation 243 9.2.1.3 Arylation 246 9.2.1.4 Alkenylation 252 9.2.1.5 Carbonylation and Carboxylation  259 9.2.2 Formation of C─N Bond  263 9.2.3 Formation of C─O Bond  265 9.2.4 Formation of C─Halogen Bond  273 9.2.4.1 Fluorination 273 9.2.4.2 Chlorination 275 9.2.4.3 Bromination 276 9.2.4.4 Iodination 276 277 9.3 Summary  ­References  279 10

Oxidation of Aryl sp2C─H Bond on Substituted Benzene  283

10.1 Introduction  283 10.2 Formation of C─C Bond  284 10.2.1 Alkylation 284 10.2.2 Trifluoromethylation 290 10.2.3 Arylation 294 10.2.4 Alkenylation 298

Contents

10.2.5 Acylation and Carboxylation  305 10.2.6 Alkynylation 310 10.2.7 Cyanidation 312 10.3 Formation of C─N Bond  313 10.4 Formation of C─O Bond  316 10.5 Formation of C─S Bond  322 10.6 Formation of C─Halogen Bond  323 10.6.1 Fluorination 323 10.6.2 Chlorination 324 10.6.3 Bromination 327 10.6.4 Iodination 330 10.7 Summary  331 ­ References  333 11

Oxidation of Aryl sp2C─H Bond Assisted by Directing Group  337

11.1 Introduction  337 11.2 Formation of C─C Bond  337 11.2.1 Alkylation 337 11.2.2 Trifluoromethylation 348 11.2.3 Arylation 351 11.2.4 Alkenylation 369 11.2.5 Carbonylation and Carboxylation  390 11.2.6 Alkynylation 393 11.2.7 Cyanidation 399 11.3 Formation of C─N Bond  400 11.4 Formation of C─O Bond  406 11.5 Formation of C─S Bond  412 11.6 Formation of C─Halogen Bond  414 11.6.1 Fluorination 414 11.6.2 Chlorination 416 11.6.3 Bromination 419 11.6.4 Iodination 422 11.7 Summary  424 ­References  426 12

Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene  433

12.1 Introduction  433 12.2 Formation of C─C Bond  434 12.2.1 Alkylation 434 12.2.2 Trifluoromethylation 439 12.2.3 Arylation 441 12.2.4 Alkenylation 449

ix

x

Contents

12.2.5 Carbonylation and Carboxylation  454 12.2.6 Alkynylation 456 12.2.7 Cyanidation 458 12.3 Formation of C─N Bond  459 12.4 Formation of C─O Bond  461 12.5 Formation of C─Halogen Bond  462 12.5.1 Fluorination 462 12.5.2 Chlorination 464 12.5.3 Bromination 465 12.5.4 Iodination 467 12.6 Cross‐Coupling of Dual Aryl sp2C─H Bonds on Directing‐Group‐Containing Arenes, Heteroarenes, or Polyfluoroarenes  468 12.7 Summary  477 ­References  478 13

Oxidative Cross‐Coupling of Aryl sp2C─H Bond with Inert C─H Bond  483

13.1 Introduction  483 13.2 Oxidative Coupling of Simple Arenes with Alkanes (Alkylation of Arenes)  484 13.3 Oxidative Coupling of Simple Arenes with Alkenes (Alkenylation of Arenes)  486 13.4 Oxidative Cross‐Coupling of Simple Arenes (Arylation of Arenes)  490 13.4.1 Single‐Electron Transfer Processes  490 13.4.2 Aryl C─H Activation  494 13.5 Summary  498 ­References  499 Index  501

xi

Preface Functionalization of C─H bonds by oxidation reactions is one of the most convenient, powerful, and in‐demand methods in modern chemical synthesis. In the past decades, a lot of progress in this field was made due to realization of various C─H bonds and advancement of reaction methodologies based on organometallic chemistry, physical organic chemistry, catalysis, and so on. However, there are two major challenges always facing researchers: selectivity and “green” reaction systems. The former is to obtain highly chemo‐, regio‐, and stereoselective products in the oxidations of C─H bonds, especially inert C─H bonds. The latter is related to establish environmentally friendly processes with waste minimization under mild conditions such as room ­temperature and normal pressure. In the oxidations of C─H bonds, to pursue dioxygen from air as terminal oxidant is one of the symbols for the ideal transformation. There are three parts in this book. The first one is Chapter 1 describing the concepts on C─H bonds, cleavage of C─H bonds, and their oxidation reactions. The significance of oxidation of C─H bonds is also discussed. The second one is Chapters 2–8 involving oxidations of C─H bonds from methane, alkane, alkene, alkyne, etc. Some early examples and the following developments are emphasized, especially on the ways of C─H cleavage, reagents, oxidants, and reaction conditions. The third one is Chapters 9–13 focusing on the aryl sp2C─H bonds from benzene, substituted benzene, heteroarene, perfluoroarene, etc. Traditional and modern oxidations of aryl sp2C─H bonds are shown and compared. Oxidative cross‐coupling of an inert aryl sp2C─H bond with another inert C─H bond is exclusively discussed in Chapter 13, which is an important and simple method to form C─C bond in synthesis. Several successful oxidations of C─H bonds in total synthesis are also listed in some chapters. We hope that this book Oxidation of C─H Bonds will be of value to undergraduate and graduate students, researchers, and chemists who are interested in the functionalization of C─H bonds, oxidation reaction, catalysis, reaction methodology, chemical synthesis, etc. and inspire them to make breakthrough and achievement in this promising field.

xii

Preface

In this book, W. Lu contributes Chapters 1–8 and 13, and L. Zhou is in charge of Chapters 9–12. We appreciate graduate student M. Zhao for her diligent drawing and editing efforts. Additionally, we would like to thank all members in our groups for their support and encouragement. Wenjun Lu Lihong Zhou Shanghai, July 2016

1

1 Introduction 1.1 ­What Is Oxidation of C─H Bonds? Oxidation of C─H bonds is to transform the C─H bonds to various C─X bonds, in which X is a nonmetal atom with higher electronegativity than hydrogen, including carbon, nitrogen, oxygen, sulfur, selenium, fluorine, chlorine, bromine, iodine, etc. in this book [1]. In a typical oxidation process, it usually involves a cleavage of the covalent C─H bond and an oxidative functionalization of the carbon by a reagent (Scheme 1.1).

C–H

–H

C–X

+X

Electronegativity: X (2.6~4.0) > H (2.2) X = C, N, O, S, Se, F, Cl, Br, I, etc.

H 2.2

C 2.6

N 3.0

F O 3.4 4.0 Cl S 2.6 3.2 Se Br 2.6 3.0 I 2.7

Scheme 1.1  Oxidation of C─H bond.

Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

2

1 Introduction

1.2 ­Chemical Synthesis and Oxidation of C─H Bonds 1.2.1  Transformation of Organic Compounds

Organic compounds are a kind of carbon molecules containing at least one C─H, C─C, or single C─heteroatom bond, which are very important substances to provide chemical energy, to construct organisms, to act as the functional materials in human life, and so on. Actually, many transformations are happening spontaneously among these organic compounds and other carbon‐containing compounds every day, leading to a big carbon cycle on the Earth. Meanwhile, man‐made organic compounds including agrochemicals, pharmaceuticals, and various organic functional materials are prepared enormously through a series of reactions from the raw materials such as methane, ethylene, and benzene, affecting the human being’s daily life and human beings themselves remarkably. The preparation of target products (complex molecules) from substrates (simple molecules) is called chemical synthesis normally involving multiple‐step reactions in one way (Scheme 1.2). 1.2.2  Ideal Chemical Synthesis

An ideal chemical synthesis is a process with minimal impact on external environment. There are two simple aspects in the process: mass and energy. In theory, at the end of the most ideal process, there are no other substances transformed except the desired products generated from substrates and no other energy consumed except the reaction heat ΔH for product generation. Although there is a large gap between the current chemical processes and the ideal ones in most cases, it is necessary to give some concise suggestions on the estimation of a practical process. Five rules for a HELLO process are listed as follows: 1) High Yield When the product is obtained in high yield, it indicates that the utilization of substrate is highly sufficient and effective during the transformation. 2) Efficient Pathway In an efficient pathway of chemical synthesis, a multiple‐ step process is usually replaced by a one‐step reaction, a few reactions in one pot, or a cascade reaction to avoid or reduce the consumption of both Carbon cycle in Nature Carbon compound I

Carbon compound II

Chemical synthesis Substrate (simple molecule)

Target product (complex molecule)

Scheme 1.2  Carbon cycle and chemical synthesis.

1.2 ­Chemical Synthesis and Oxidation of C─H Bonds

substance and energy in the reactions and posttreatments. Furthermore, the substrates, intermediates, and products should be tolerant to the reaction systems without protection treatment on functional groups, and no external substances are consumed to initiate, accelerate, or control any reactions in the process. 3) Low Loading If it is possible, to save substance, energy, and space, quantitative reactants are employed, and other necessary materials including catalysts, additives, and solvents are used at a minimum during the whole chemical process. 4) Low Complexity in Operation It is highly required that a chemical process is carried out easily without special protection and caution, under normal pressure in air, and at an ambient temperature. In such a process, all expenses are reduced on safety, equipment, energy, and so on. 5) Only Target Products In some cases, high selectivity such as high stereoselectivity is more important than high yield. Thus, it is the key symbol for an excellent and elegant process to obtain target products only. In other words, a HELLO process could become a HELL one with a poor selectivity because the wastes or by‐products generated could decrease obviously the quantity and/or quality of products and increase largely the cost of substance and energy in the reactions as well as in the product purifications. To set up such a HELLO process, it mainly depends on the discovery and development of every single perfect reaction, that is, an ideal chemical synthesis is an ideal reaction indeed or consists of a series of ideal reactions. 1.2.3  Oxidation of C─H Bonds for Ideal Chemical Synthesis

According to the aforementioned description, oxidation of C─H bonds should be one of the most promising reactions in an ideal chemical synthesis. There are three main factors as follows to support it strongly: 1) Rich Resources Since the C─H bonds are fundamental, ubiquitous, and substantial in the saturated and unsaturated organic compounds, especially in the raw materials such as simple alkanes, olefins, and arenes, the oxidation of C─H bonds to form the C─C bonds or C─heteroatom bonds is the most popular method in organic synthesis. For example, aryl sp2C─H bonds are very common and abundant in various aromatic compounds, so it is the most convenient method for the direct oxidative coupling of two aryl sp2C─H bonds to give a new aryl sp2C─sp2C bond in the preparation of biaryls. 2) High Mass Efficiency A direct oxidation of C─H bonds to give the desired product is a process in a high mass efficiency (ME). The ME is the ratio of the mass of products to the mass of all transformed substances including reactants, reagents, oxidants or reductants, additives, etc. in

3

4

1 Introduction

the ­synthetic process. Obviously, the highest ME must be 100% in all addition or rearrangement reactions, like the atom economy [2]. In the substitution or elimination reactions, however, the highest ME can be achieved just when hydrogens, the lightest elements, are replaced or eliminated from the substrates and the wastes or by‐products are produced at a minimum. The oxidations of C─H bonds via the cleavage of C─H bonds belong to these reactions giving the highest ME values, which may be close to the ideal processes. Mass Efficiency ME

Mass of product Mass of all transformed substances

100%

When the transformed substances are just the reactants, the ME is equal to the atom efficiency (AE). For example, in the formation of biphenyl from benzene, the highest ME is 99% in the dehydrogenative coupling reaction, in which the by‐product is only H2. When dioxygen is employed as an oxidant, the ME is 90% with H2O generated in the direct oxidative coupling reaction. In contrast, the total ME is decreased sharply to just 39% because of more wastes produced in the sequentially oxidative bromination of benzene using dioxygen as the terminal oxidant and the reductive coupling (Ullmann coupling) of bromobenzene using zinc as reductant (Scheme 1.3). It is notable that the preparations of different products cannot be compared with each other by their ME values because one process in synthesis has its own highest ME values. For instance, the highest ME is 99% in the formation of biphenyl (C6H5─C6H5) from benzene (C6H6), but that is 94% in the formation of ethane (CH3─CH3) from methane (CH4). 3) High Energy Efficiency A direct oxidation of C─H bonds to give the desired product is also a process with a high energy efficiency (EE). The EE is the ratio of the reaction heat just for the products (ΔH) to all consumed energy (ΣE) in the synthetic process. The EE is a small value in a practical one due to all consumed energy including not only the reaction heat but also a large part for keeping reaction temperature, mechanical stirring, purifying substances, treating wastes, and so on though it is close to 100% in an ideal reaction. Thus, if the process is just a one‐step reaction running under mild conditions, especially to generate no or less wastes like a HELLO process, it usually shows a high EE. The aerobic oxidation of C─H bonds expresses a unique merit in EE when its by‐product is only H2O which should not be considered to deal with specially. In contrast, since the multiple‐step synthesis often requires the external energy consumption in the separation of intermediates and/or the regeneration of some important additives to enhance the ME, it is not a process in good EE.

1.2 ­Chemical Synthesis and Oxidation of C─H Bonds I. Dehydrogenative coupling of benzene H + H2

2 ME = 99% (highest) II. Oxidative coupling of benzene H

+ H2O

+ 0.5 O2

2

ME = 90% III. Oxidative bromination of benzene and reductive coupling of bromobenzene Br

H + Br2 + 0.5 O2

2

+ H2O

2

Br + Zn

2

+ ZnBr2

H + Br2 + 0.5 O2 + Zn

2

+ H2O + ZnBr2

ME = 39%

Scheme 1.3  Preparation of biphenyl from benzene and ME.

Energy Efficiency EE

Reaction heat for products H All consumed energy E

100%

For example, in the cases of biphenyl prepared from benzene mentioned earlier, if the regeneration of Zn and Br2 from ZnBr2 is carried out after the oxidative bromination/reductive coupling reaction, the total ME can be up to 90% as in the aerobic oxidative coupling reaction (Scheme 1.4). However, the three‐step process apparently requires more energy consumption for the treatments of intermediates and wastes than that one‐step process, a

5

6

1 Introduction

Br

H + Br2 + 0.5 O2

2

+ H2O

2

Br + ZnBr2

+ Zn

2

ZnBr2

Br2 + Zn

(Regeneration)

H + 0.5 O2

2

+ H2O

ME = 90%

Scheme 1.4  Oxidative bromination/reductive coupling and regeneration.

direct oxidation of C─H bonds, even though their total reaction heats for the products could be the same. Overall, it is undoubted that direct oxidation of C─H bonds is the simplest and most effective method to form the carbon backbones and to introduce a lot of functional groups or heteroatoms in the synthesis. However, at present, either the realization or the application of direct oxidation of C─H bonds is insufficient, and it is far away to be a HELLO process with high ME and EE. For example, the preparation of biphenyl by the coupling of aryl C─halogen bonds and aryl reagents is very effective and applicable, such as the Ullmann coupling [3] and the Suzuki coupling [4], but the development of the aerobic oxidative coupling of aryl C─H bonds under mild conditions is still underway because the normal aryl C─H bonds are more inert than the aryl C─halogen, C─B, and C─metal bonds in these reactions [5] (Scheme 1.5).

1.3 ­C─H Bonds In general, C─H bond is a covalent bond having one electron pair shared by the carbon and the hydrogen. According to the hybridization of carbon atom in the organic molecules, the C─H bonds can be divided into three kinds, that is, sp3C─H, sp2C─H, and spC─H bonds. The sp3C─H bonds are from the alkanes, so they are named alkyl sp3C─H bonds, correspondingly. When the sp2C─H bonds are found in olefins and arenes, they are called alkenyl (vinyl) sp2C─H bonds and aryl (phenyl) sp2C─H bonds, respectively. The spC─H bonds of alkynes are alkynyl spC─H bonds. These basic C─H bonds are normally inert

1.3 ­C─H Bonds The Ullmann coupling Br + Zn

8 mol% Pd/C

H2O/acetone rt, air, 12 h 100 mg 3 equiv.

92% (GC)

Venkatraman and Li [3b] The Suzuki coupling Br

B(OH)2 + K2CO3

+ 1 mmol

1.2 mmol

0.5 mol% PdCl2 H2O rt, air, 5 min

3 equiv.

96%

Sarmah et al. [4b] Direct oxidative coupling of aryl C–H bonds

H + Air (O2) 64 mmol

7 mol% PdCl2 2 mol% Zr(OAc)4 1.8 mol% Co(OAc)2 1.8 mol% Mn(OAc)2 3.1 mol% acac NaOAc, H2O/AcOH 105 °C, 6 h

1 MPa

89%

Mukhopadhyay et al. [5b]

Scheme 1.5  Preparation of biphenyl.

in the reactions except the alkynyl spC─H bonds. If the heteroatoms or some functional groups connect to the carbon atom or the aromatic ring, the characters of C─H bonds would be changed obviously. 1.3.1 Reactivity

It is well known that the reactivity of covalent bonds can be expressed partially by their bond strength, that is, the bond dissociation energy (BDE). A C─H bond with a high BDE value indicates it is very difficult to cleave in homolysis, such as methyl or primary sp3C─H bond, alkenyl or aryl sp2C─H bond, and alkynyl spC─H bond (BDE > 400 kJ/mol). However, if an electron‐donating group is attaching directly to the C─H bond and/or a resonance stabilization can affect the C─H bond, its BDE value decreases apparently, and the C─H bond is highly active especially in the radical reactions [6] (Scheme 1.6). For example, the

7

8

1 Introduction sp3C–H bond

BDE298 (kJ/mol) 439 420 410 400

CH3 –H C2H5–H (CH3)2CH–H (CH3)3C–H CH3C CCH2 –H PhCH2 –H CH2=CHCH2 –H

sp2C–H bond

BDE298 (kJ/mol)

Ph–H CH2=CH–H CH3C(O)–H

472 464 374

spC–H bond

BDE298 (kJ/mol)

CH3C C–H H–CN

557 528

379 375 369 357

Ph(CH3)CH–H

H–CH(CH3)CN H–CH2NH2

415 405 393 392

H–CH2OCH3 H–CH2OH

402 401

H–CH2C(O)CH3 H–CH2C(O)H

401 394

H–CH2Cl H–CHCl2 H–CCl3

419 400 392

H–CH2NO2 H–CH2CN

Scheme 1.6  Bond dissociation energies of C─H bonds. Benzylic sp3C–H bond, BDE = 357 kJ/mol H + 0.1 M

Br2

1.2 equiv.

Br

Microreactor LED lamp CCl4 rt, 8.5 s

75%

Manabe et al. [7]

Scheme 1.7  Bromination of benzylic sp3C─H bond.

bromination of a benzylic sp3C─H bond of ethylbenzene is much faster than that of alkyl sp3C─H bonds and aryl sp2C─H bonds under mild conditions [7] (Scheme 1.7). On the other hand, since a C─H bond can be broken to give a proton as an acid in heterolysis, the reactivity of a C─H bond is also determined quantitatively by its acid strength, that is, the acid dissociation constant (pKa) [8]. A C─H bond with a high pKa value (pKa > 40) is a very weak acid in the reactions, which is from the simple alkanes, alkenes, or arenes. In contrast, when the C─H bond is

1.3 ­C─H Bonds sp3C–H bond

pKa

sp2C–H bond

pKa

CH3 –H C2H5 –H

Ph–H CH2=CH–H

43 50

(CH3)2CH–H (CH3)3C–H

48 50 51 53

spC–H bond

pKa

PhCH2 –H CH2 = CHCH2 –H

41 43

CH3C C–H H–CN

24 9.4

H–CH2NO2

10

O 19~20 H O

O 11

O H

Scheme 1.8  Acid dissociate constants of C─H bonds. pKa = 11 O

O

O O

+

Cl

+

K2CO3

H 0.1 mol

0.12 mol

0.125 mol

O O

98–120 °C, 4 h 75%

Xu [9]

Scheme 1.9  Alkylation of methylene sp3C─H bond in ethyl acetoacetate.

connecting to an electron-withdrawing group, its pKa value decreases sharply, and it becomes an effective nucleophile in the presence of base in the reactions (Scheme 1.8). For example, a methylene sp3C─H bond of ethyl acetoacetate or a β‐dicarbonyl compound is very active to undergo the alkylation with an alkyl halide to afford a C─C bond just in the presence of K2CO3 as base [9] (Scheme 1.9). Based on BDE and the pKa, the C─H bonds can also be divided into two classes simply in their transformations: active and inert (Chart  1.1). For the active C─H bonds usually linking to the functional groups as mentioned earlier, they have either low BDE (600 °C) (Scheme 2.2). By use of [Pt(IV)Cl6]2− as a special oxidant, oxidation products R─OH and R─Cl were generated from alkanes R─H in the same system, and a methyl‐platinum intermediate was also confirmed to support C─H activation by Pt(II) complex. This is a pioneering work on the oxidation of sp3C─H catalyzed by transition metal under very mild conditions even though it is not an efficient and practical process in chemical synthesis. Overall, it shows that the cleavage of inert sp3C─H bonds of methane is feasible under very mild conditions. I. Superacid (at 140 °C) + CH4 H CH5+ –H2 II. C–H activation PtCl42– CH 4 D2O, DOAc ~100 °C

CH3+

3CH4 –3H2

(CH3)3C+

CH3D

Scheme 2.2  Heterolysis (cleavage of methyl sp3C─H bond).

2.3 ­Oxidations of Methyl sp3C─H Bond The simple valuable molecules including methanol, ethylene, benzene, acetic acid, etc. should be produced by oxidations of methane, which are the main materials or substrates in modern synthetic chemistry. 2.3.1  Syngas (CO/H2)

In industry, however, methane is needed to be converted into syngas (CO and H2) first at an elevated temperature (>700 °C) followed by other processes to produce ammonia, methanol, and hydrocarbons. It is called reforming of methane, a partial oxidation of methane or a complete dehydrogenation of methane. At the same time, the syngas could also be produced from coal or oil in the presence or absence of catalysts through the partial oxidation processes. There are three methods of syngas production from methane, namely, steam reforming, dry reforming, and oxy‐reforming (Scheme 2.3).

21

22

2  Oxidation of Methane

Steam reforming process is the reaction of CH4 with H2O to produce CO and H2 (3 equiv.), with a large positive enthalpy change. The main purpose of steam reforming is to provide high‐quality H2 from methane and water for ammonia synthesis. The catalytic steam reforming process in tubular furnaces was first invented in 1926–1928 by BASF and was applied in the early 1930s in the United States for commercial purposes. A current process was conducted in 40 bar pressure at 950 °C [4]. Dry reforming process is the reaction of CH4 with CO2 to afford CO (2 equiv.) and H2 (2 equiv.). The advantage of this process is the use of two greenhouse gases, and the disadvantage is the reaction enthalpy change is higher than the one of steam reforming. Oxy‐reforming process, an oxygenation of methane, is the reaction of CH4 with O2 (0.5 equiv.) to form CO and H2 (2 equiv.), with a small negative enthalpy change. Since oxy‐reforming is mildly exothermic, this process is more economical than steam reforming. Moreover, the ratio of CO with H2 is 1/2, which is suitable for methanol production. It was first established in 1929 over supporting nickel catalyst. However, due to the O2 supply, safety, and the catalyst deactivation problems, this process had not been further developed until 1990s. One early successful example was reported in 1990 by Green and coworkers [5] wherein oxy‐reforming of methane to syngas was conducted at 777 °C with 94% conversion of methane and with 97% selectivity for CO and 98% for H2, respectively, by using lanthanide ruthenium oxide catalysts. It was proposed that the oxy‐reforming process proceeded in two steps: a combustion of CH4 with O2 to give fully oxygenated products CO2 and H2O and then a reforming of CH4 with H2O and CO2 to afford CO and H2. On the basis of this mechanism, thermodynamic calculations demonstrated that higher temperature favors higher conversion of methane and higher selectivity for both CO and H2 and higher pressure in the reactor lowers either conversion of methane or selectivity for both CO and H2. I. Steam reforming CH4 + H2O

CO + 3H2 ∆H° = 206 kJ/mol

II. Dry reforming CH4 + CO2

2CO + 2H2 ∆H° = 247 kJ/mol

III. Oxy-reforming CH4 + 0.5O2

CO + 2H2 ∆H° = –36 kJ/mol

Scheme 2.3  Syngas production from methane.

The reforming of methane to syngas is not a direct method to produce valuable chemicals, and its operation is usually at high temperature. Therefore, the oxidations of methane to the basic organic compounds are highly demanded, especially under mild conditions.

2.3 ­Oxidations of Methyl sp3C─H Bond

2.3.2 Methanol

Methanol (CH3OH) is the simplest alcohol and is a volatile, colorless, and flammable liquid. Its main applications are feedstock, fuel, solvent, etc. Since its boiling point is 64.7 °C, methanol is more convenient in store, transportation, and operation than methane and other light organic compounds. IHS reported that the methanol demand will increase from 60.7 to 109 million MT/ year during 2013–2023 in the world. At present, most of methanol comes from natural gas (methane) via two steps including steam reforming of methane to syngas and catalytic conversion of syngas to methanol. Of course, methane could be oxidized selectively by oxygen to produce methanol directly through a thermodynamically favorable oxidation process. Over eight decades ago, Newitt and Haffner [6] found that methanol was formed by a high‐pressure oxidation of methane with oxygen in a static system (Scheme 2.4). The ratio of methanol/formaldehyde could be up to 40 when the yield of methanol was 14% based on the consumed methane (CH4/O2 = 8.1/1) at 10.6 MPa initial pressure and 339  °C. Since then, many efforts have been made to improve the yield, selectivity, and reaction conditions. However, high temperature (>300 °C) and low yield are not easy to overcome even though the selectivity of methanol or formaldehyde (>80%) can be increased apparently over some heterogeneous catalysts [7]. CH4 + O2

High pressure, >300 °C

CH3OH + HCHO low yield

Scheme 2.4  Oxidation of methane to methanol.

On the other hand, in the Shilov homogeneous catalytic system established in 1972, methanol could be formed in the presence of K2PtCl4 catalyst with K2PtCl6 as oxidant in HOAc aqueous solution at ~100 °C, which is a real C─H bond activation system and is called Shilov chemistry. According to the report by Bercaw and Labinger [8] in 2015, there are three major steps in the mechanism of this transformation of methane to methanol. First, methyl sp3C─H bond is cleaved by electrophilic activation with Pt(II) catalyst to afford a CH3─Pt(II) complex. In this step, PtCl2(H2O) is the active catalyst, and [PtCl3(H2O)]− is most reactive, while [PtCl4]2− and [Pt(H2O)4]2+ are totally not reactive. Second, a CH3─Pt(IV) intermediate is formed from CH3─Pt(II) species oxidized by Pt(IV) complex, not from transferring methyl group of CH3─Pt(II) species to Pt(IV) complex. Finally, the formation of CH3OH and Pt(II) species is through an intermolecular nucleophilic substitution (SN2) of H2O to the CH3─Pt(IV) intermediate, not through a reductive elimination of methyl group with H2O on Pt(IV) center (Scheme 2.5). The high chemoselectivity for methanol is confirmed in the oxidation of benzyl sp3C─H bond using soluble

23

24

2  Oxidation of Methane

4‐SO3–toluene as model substrate. The reaction rate constant of oxidizing benzyl group to benzyl alcohol is 1.5 times higher than that of oxidizing benzyl alcohol to benzaldehyde, and no further oxidation of benzaldehyde to benzoic acid is observed. It indicates that producing methanol from methane is highly practicable. The major limitation for Shilov chemistry up to date is that Pt(IV) complex is the only highly efficient stoichiometric oxidant available yet. Cat. K2PtCl4

CH4 + H2O + K2PtCl6

CH3OH

HOAc/H2O ~100 °C

CH3OH

Pt(II) CH4

SN2 H 2O

C–H activation

CH3–Pt(IV)

CH3–Pt(II)

Pt(IV) Oxidation

Scheme 2.5  Shilov chemistry.

In an indirect preparation of methanol by Shilov chemistry, methane (3.4 MPa) was converted smoothly to methyl bisulfate CH3OSO3H in the presence of catalytic bipyrimidinylplatinum(II) in oleum SO3/H2SO4 as solvent and oxidant at 220 °C (Scheme 2.6). In this work, Periana and coworkers [9] observed the selectivity was up to 81% with a methane conversion of 90%, and the only by‐product was CO2. In their following studies [10], over 300 turnovers were observed at 200–250 °C without Pt(II) catalyst deactivation. It is attributed to the catalytic cycle Pt(II)/Pt(IV)/Pt(II) and the utilization of sulfuric acid, where sulfuric acid can not only oxidize Pt(II) catalysts and CH3─Pt(II) species to their Pt(IV) complexes and intermediates, respectively, but also react with methanol to form a corresponding ester as product protectant avoiding overoxidation. Of course, the Pt(IV) complexes could also play a role of oxidant to make CH3─Pt(IV) intermediates from CH3─Pt(II) species, like in the previous Shilov system.

CH4 + SO3/H2SO4 3.4 MPa

Cat.Pt(II) 220 °C, 2.5 h

Scheme 2.6  Sulfation of methane.

N CH3OSO3H 72%

N

Pt(II) =

Pt N

N

Cl Cl

2.3 ­Oxidations of Methyl sp3C─H Bond

In this area, the main task is always to explore suitable catalysts accompanying inexpensive and effective oxidants in order to achieve both high yield and selectivity of methanol from methane under mild conditions. In 1987, Sen and coworkers [11] disclosed that methane (5.4 MPa) was oxidized by Pd(OAc)2 to methyl trifluoroacetate (CF3CO2CH3) in >60% yield based on Pd(II) in trifluoroacetic acid (TFA) CF3CO2H at 80 °C, which was a trifluoroacetoxylation of methane. It might involve an electrophilic activation to form a CH3─Pd(II) (CF3CO2) intermediate and a reductive elimination of the intermediate or an SN2 process to give CF3CO2CH3 and Pd(0). Since the ester can be hydrolyzed to the corresponding alcohol, this is an oxidation of methane to methanol mediated by Pd(II) in water under mild conditions (Scheme 2.7). After a few years [12], they also established a catalytic version by use of hydrogen peroxide H2O2 as oxidant with trifluoroacetic anhydride (TFAA) (CF3CO)2O to regenerate Pd(0) to Pd(II) catalyst during the oxidation of methane, but the turnover number (TON) was 5.3 and the yield was very low. However, the TON could be enhanced to 30 when Pd(II) complex of bridged bis(N‐heterocyclic carbenes) (NHC) was employed as catalyst with K2S2O8 as oxidant in the trifluoroacetoxylations of methane in TFAA/TFA at 90 °C [13] (Scheme 2.8). According to the detailed computational study by Strassner and coworkers [14], this reaction should run through a Pd(II)/Pd(IV)/Pd(II) catalytic cycle and involve a C─H bond activation by Pd(II). Meanwhile, other attempts involving radical processes have been reported to make the oxidation of methane to methanol running under mild conditions, especially at not high temperature (60% (based on Pd(II))

CH4 C–H activation

[O]

CH3–Pd(II)

Pd(0)

CH3OCOCF3

CF3CO2–

Reductive elimination

Scheme 2.7  Pd(II)‐mediated trifluoroacetoxylation of methane.

25

26

2  Oxidation of Methane CH4 +

CF3CO2H/(CF3CO)2O

30 bar

60/10 mL

+

0.21 mmol Pd(II)

K2S2O8

90 °C, 14 h

21 mmol

CH3OCOCF3 30% (based on K2S2O8)

CH3OCOCF3 Pd(II)

Reductive elimination

Pd(II) =

CH4

Pd

C–H activation

CF3CO2–

N N N

Br Br

N CH3–Pd(IV)

CH3–Pd(II)

K2S2O8 Oxidation

Scheme 2.8  Pd(II)/NHC‐catalyzed trifluoroacetoxylation of methane.

CH4/N2 + 5 atm/5 atm

CF3CO2H/(CF3CO)2O + K2S2O8 9 mL/10 mmol

0.022 mmol H5PV2Mo10O40 80 °C, 20 h

5 mmol

CH3OCOCF3 + CH3OCOCH3 82 : 18 95% (based on CH4) CH4

V(V) O –H

CH3

K2S2O8 –e

CH3+

CF3CO2H –H+

CH3OCOCF3

Scheme 2.9  V‐containing heteropolyacid‐catalyzed trifluoroacetoxylation of methane.

A possible mechanism suggests that methyl radical CH3⋅ is generated through abstraction of H⋅ by V(V)═O from methane followed by oxidation of methyl radical to methyl cation and formation of ester. The major limitations for its industrial relevance are the expense of K2S2O8 and the corrosive nature of CF3CO2H. In 2014, Groves, Gunnoe, and coworkers [16] reported a preparation of methyl trifluoroacetate from methane in the presence of KCl/NH4IO3/ CF3CO2H at 180 °C, with a methane conversion >20% and a selectivity >85%. Dioxygen (O2) as the terminal oxidant is always desirable in any oxidation reaction. In 1990, Moiseev and coworkers [17] reported that methyl trifluoroacetate was observed in a Co(III)‐catalyzed trifluoroactoxylation of methane with O2 in TFA at 180 °C (Scheme 2.10). In an improved version by Strassner and coworkers [18], a methyl trifluoroacetate yield of 50% based on methane was obtained from an oxidation of methane (10 bar) with O2 (5 bar) by use of 3.8 mol% Co(OAc)2·4H2O as catalyst in TFAA/TFA (6 : 1) at 180 °C. By using the redox shuttles of p‐benzoquinone/hydrobenzoquinone, NO2/NO couples,

2.3 ­Oxidations of Methyl sp3C─H Bond

and O2, Bao and coworkers [19] developed a Pd(II)‐catalyzed oxidation of methane running at 80 °C. The TON of Pd catalyst was 7, but the yield of methyl trifluoroacetate was 0.06% based on methane. CH4 +

CF3CO2H +

20 atm

0.9 × 10–4 M Co(CF3CO2)3

O2 3 atm

180 °C, 4 h

CH3OCOCF3 TON = 4

Scheme 2.10  Co(II)‐catalyzed trifluoroacetoxylation of methane using O2 as oxidant.

Furthermore, the ideal reaction conditions for the oxidation of methane to methanol must include neutral media, ambient temperature, atmospheric pressure, etc. In 2009, Jasra, Shukla, and Khokhar [20] reported that the selectivity of methanol was 100% when methane (12.5 atm) was oxidized by oxygen (2.5  atm) over a binuclear, bridged Ru(III) catalyst [(HSalen)2Ru2(μ‐O) (μ‐CH3COO)2] (salen = 2,2′-ethyl-enebis(nitrilomethylidene)diphenol, N,N′ethylenebis(salicylimine)) at 30 °C in a mixture of acetone/H2O (1 : 1) (Scheme 2.11). The reaction conditions in this example are very close to those ideal ones. In their typical experiment (CH4 10 atm, O2 5 atm), the methanol yield was ~9% based on methane with a TON of 54 and a selectivity of 96.6%. They suggested that the homogeneous catalyst could activate both molecular oxygen and methane in the neutral solvent followed by the insertion of oxygen atom into the C─H bond of methane through an anionic route. It is noticed that molecular oxygen activation and introduction by Ru(III) catalyst into C─H bond is a key in the oxidation of methane to methanol. In contrast, other catalysts such as cytochrome P450 (Fe(II)), Mn(III), Co(III), and Co(II) salts can also react with the oxidant O2 and bring oxygen into the methyl sp3C─H bonds through a radical process [21]. CH4

+

10 atm

O2 5 atm

5 × 10–4 M Ru(III) Acetone/H2O, 30 °C, 3 h

CH3OH TON = 54

AcO Ru(III) = Hsalen Ru(III)

O

Ru(III) Hsalen

AcO

Scheme 2.11  Ru(III)‐catalyzed oxidation of methane using O2 as oxidant.

2.3.3 Ethylene

Ethylene (CH2═CH2) is the simplest alkene, and global annual demand for ethylene exceeds 150 million tonnes in 2016 (https://marketpublishers. com/lists/20238/news.html, accessed September 16, 2016). At present, ethylene

27

28

2  Oxidation of Methane

is mostly produced from gaseous or light liquid hydrocarbons in the ­p etrochemical industry by steam cracking (750–950 °C). Theoretically, ethylene or ethane (C2H6) could be generated in an oxidative coupling of methane (OCM) or a nonoxidative coupling of methane (NOCM) (Scheme  2.12). Oxygen may play a role of an oxidant to make the OCM process thermodynamically favorable. Keller and Bhasin [22] found that methane was oxidized in oxygen to give ethylene in 1982. One of the early successful OCM reactions gave a C2 yield of 19% with its selectivity of 50%. In the OCM disclosed by Lunsford and Ito [23], the heterogeneous catalyst was Li/MgO and the operation temperature was 720 °C. It is proposed that ethane is formed by coupling of two methyl radicals after abstraction of H from methane at MgO sites, and Li as a dopant could assist in the activity and stability of the heterogeneous catalyst surface. To date, the C2 yield in OCM is still 98% at 250–375 °C, but the conversion was too low, 0

Scheme 2.12  Oxidative coupling of methane (OCM) or nonoxidative coupling of methane (NOCM).

2.3 ­Oxidations of Methyl sp3C─H Bond

a.

Ta–H

b.

Ta–H

CH4 –H2 CH4 –H2

CH3 Ta–H

Ta Ta–CH3

Ta

CH4 –C2H6

CH3 Ta

Ta–H

Ta

Scheme 2.13  Proposed mechanism of Ta‐H‐catalyzed NOCM to ethane.

Another route to synthesize ethylene from methane has been explored since the mid‐1980s by using halomethane approach, in which methane (CH4) is oxidized by halogen X2 to produce HX and CH3X followed by dehalogenation coupling to afford ethylene and HX (2 equiv.) (Scheme  2.14) [27]. After the regeneration of halogen X2 through an oxidation of HX by dioxygen (O2), the total process is ethylene produced in an oxidation of methane with O2. However, the selectivity in the initial step of monohalogenation of methane is very poor because the sp3C─H bonds of halo‐product molecules are more reactive than the starting methyl sp3C─H bond in radical process. Thus, high efficiency on this process has not been achieved up to date. In addition, the corrosive nature and environmental limitations of these halo‐compounds are also the concerning issues. CH4

+ X2

2CH3X 2HX + 0.5O2 2CH4 + O2

CH3X + HX CH2 = CH2 + 2HX X2 + H2O CH2 = CH2 + 2H2O

Scheme 2.14  Halogenation–dehalogenation coupling.

In the ethylene production from methane with high efficiency, there is still a lot of work to do either in science or in engineering. Moreover, acetylene as a by‐product is mainly prepared by the partial combustion of methane in industry annually. 2.3.4 Benzene

Benzene (C6H6) is a typical aromatic compound with unique properties, acting as one of the basic motifs in a lot of organic materials and chemicals. Essentially, oil and coal are the major sources for benzene, and it is produced by catalytic reforming, toluene hydrodealkylation, toluene disproportionation, and steam cracking in current industry. Methane can also be converted into benzene and hydrogen in the absence of oxygen, which is a thermodynamically unfavorable

29

30

2  Oxidation of Methane

process and is known as methane dehydroaromatization (MDA) (Scheme 2.15). If oxygen is present in the reaction, however, benzene would likely decompose to solid carbon “coke” or be oxidized quickly [28]. In 1989, Bragin and coworkers [29] disclosed that 78% selectivity of benzene was formed by 18% conversion of methane in the presence of a Pt–CrO3/ HZSM‐5 catalyst at 750 °C in a pulse reactor. A few years later, Xu and coworkers [30] prepared HZSM‐5 and M/ZSM‐5 (M = Zn, Mo, 2% loading) catalysts based on ZSM‐5 (SiO2/Al2O3 = 25, 50) zeolite and investigated them in the MDA reaction. At 700  °C, benzene was detected as the only hydrocarbon product in all cases of various ZSM‐5 catalysts, and Mo/ZSM‐5 gave the higher conversion, 7.2%. According to their studies, a general mechanism of the MDA on Mo/HZSM‐5 catalyst was suggested, which is a sequential bifunctional pathway. Mo is exchanged with the Brønsted acidic proton to form Mo─O─Al species first in the zeolite channels. Then, there is an induction period for formation of Mo carbide by the carbonization of Mo─O─Al species. Methyl sp3C─H bond is cleaved by Mo carbide to afford CHx. The CHx species generate aromatics through aromatization on the Brønsted acidic sites. In these MDA reactions, however, coke was observed on the active sites to deactivate the catalyst apparently with the reaction time. Thus, the yield of benzene enhancement and the lifetime of catalyst extension have been the major subjects of investigation in the MDA reactions. 6CH4

Cat. >700 °C

C6H6 + 9H2

∆H° = 531 kJ/mol

Scheme 2.15  Methane dehydroaromatization (MDA).

In a recent report on nonoxidative conversion of methane into ethylene and aromatics, by lattice‐confined single iron sites embedded within a silica matrix, methyl sp3C─H bond could be cleaved to yield methyl radicals at 1090 °C, and a conversion of methane was 48.1% with an ethylene selectivity >48.4% and total product selectivity >99% [31]. At equilibrium at 952 °C, the yields of ethylene, benzene, and naphthalene based on methane were 9, 34, and 57%, respectively. Interestingly, the catalyst was not deactivated in 60 h under the reaction conditions. It indicates that both selectivity and efficiency for these oxidations of methane may be enhanced together if a desirable catalytic system is set up. However, harsh reaction conditions, especially high operation temperature are big hindrances. 2.3.5  Acetic Acid

Acetic acid (CH3COOH) is an important chemical reagent and industrial chemical, which is produced mostly by the carbonylation of methanol involving

2.3 ­Oxidations of Methyl sp3C─H Bond

the formation of a new C─C bond, such as the rhodium‐catalyzed reaction (Monsanto process) and the iridium‐catalyzed reaction (Cativa process) in the current industry. Certainly, the direct production of acetic acid from methane is highly desired. In 1992, Fujiwara and coworkers [32] gave an early report on the carboxylation of methane with carbon monoxide to afford acetic acid directly (Scheme  2.16). This was a catalytic reaction by use of Pd(OAc)2 and/or CuSO4 as catalyst with K2S2O8 as oxidant in CF3CO2H at 80 °C. However, the yield of acetic acid based on methane was secondary > primary > methyl, which indicates that these sp3C─H bonds are completely different in chemistry. For example, in the photochemical chlorination of 2‐methylpropane ((CH3)3CH), it shows that a tertiary sp3C─H bond is substituted by Cl 5.2 times faster than each primary sp3C─H bond at 25 °C according to the distribution of monochlorinated products (Scheme 3.3). In bromination, only tertiary products are generated selectively. This means that when an alkane contains primary, secondary, and tertiary sp3C─H bonds, its primary products obtained must be accompanied with a lot of by‐products in the absence of catalysts in homolysis. Cl2

(CH3)3CCl 36% (1H)

(CH3)3CH Br2

(CH3)3CBr

+

BDE (kJ/mol)

ClCH2(CH3)2CH 64% (9H)

(CH3)3C–H

400

(H–CH2)3CH

420

~100%

Scheme 3.3  Chlorination and bromination of methylpropane.

In heterolysis, all alkyl sp3C─H bonds are very weak acids, even some of their pKa values are larger than that of methane. Meanwhile, H− as a strong base is not formed easily from a tertiary sp3C─H bond though its carbon cation is relatively stable. However, in Shilov system, primary sp3C─H bonds of ethane were also activated by Pt(II) catalyst and converted into primary sp3C─D bonds at 100–120 °C. Furthermore, in 1971, Hodges and coworkers [1] studied the H/D exchange in many alkanes including linear, branched, and cycloalkanes under the same conditions. A remarkable order of exchange rate was primary > secondary > tertiary, which gives an opposite selectivity to the radical process related to the BDE (Scheme 3.4). They explained it with the strength of M─C bonds formed and steric hindrances during the activation of alkyl sp3C─H bonds by metal complexes.

41

42

3  Oxidation of Alkyl sp3C─H Bond D in

K2PtCl4 DOAc/D2O 120 °C, 137 h

D

CH3–

–CH2–

–CH–

83%

57%

9%

Scheme 3.4  H/D exchange in alkane using Pt(II) complex.

It seems that the cleavage of alkyl sp3C─H bonds is analogous to that of methane in either radical reactions or C─H activation processes. However, as mentioned earlier, when an alkane contains various alkyl sp3C─H bonds, the chemoselectivity of these bonds with different BDEs and steric hindrances will be more complex in its possible oxidative reactions. In addition, regioselectivity and stereoselectivity have to be considered carefully if an oxidation of alkane is set up in practical chemical synthesis. For example, n‐pentane (CH3(CH2)3CH3) has two regional selections on C2 and C3, respectively, while it also has a prochiral center on C2 (Scheme 3.5). Chemoselectivity (primary and secondary sp3C–H) H X H or

X

Regioselectivity (different secondary sp3C–H) H X or H

X

Stereoselectivity (prochiral secondary sp3C–H) H X *

X

or

Scheme 3.5  Selectivity in the functionalization of sp3C─H bonds.

3.3 ­Oxidations of Alkyl sp3C─H Bond The oxidative products of alkanes contain new C─C, C─N, C─O, C─halogen bonds, etc. Since there are no functional groups on alkanes, the oxidation of alkanes is generally called the first functionalization, while high selectivity and yield are dependent on the design and combination of the cleavage route of alkyl sp3C─H bonds, catalysts, oxidants or reaction reagents, and reaction conditions. 3.3.1 C─C Bond Formation

Direct alkylation of simple alkane, alkene, alkyne, or arene is rarely found to form a C─C bond via double cleavage of C─H bonds under normal conditions.

3.3 ­Oxidations of Alkyl sp3C─H Bond

However, a lot of studies on transformations of alkanes to alkenes, arenes, and carboxylic acids have been reported for over a few decades. 3.3.1.1  Alkenes and Arenes (Dehydrogenation)

In fact, the formation of alkenes by dehydrogenation of alkanes is a strongly endothermic process with increasing entropy, as an elimination reaction. Thus, high temperature (550–750 °C) is necessary not only to cleave the inert alkyl sp3C─H bonds homolytically even in the presence of catalyst but also to overcome the limited equilibrium. The Catofin process, the Oleflex process, and other commercial dehydrogenation processes are running very well to produce isobutene, propene, and others in industry. The conversion of alkanes is >50% and the selectivity is >90%. The operation temperature is between 500 and 700 °C and supported CrOx or supported Pt–Sn catalysts are employed [2]. However, these routes are not suitable to ethane dehydrogenation because of low ethylene yield. Oxidative dehydrogenation (ODH) process may enhance the alkene yield at not high reaction temperature by introduction of oxidant such as O2 or CO2 into the heterogeneous catalytic systems. Although a few reports were found with the best performance in ethane ODH (>70% yield of ethylene) in the past years, the operation temperature has not yet been decreased apparently (most of them 400–750 °C) [3] (Scheme 3.6). Alkane + O2

Catalyst >400 °C

Alkene

Scheme 3.6  Oxidative dehydrogenation (ODH).

In comparison with heterogeneous chromium and platinum catalysts in dehydrogenation of alkanes reported by Frey, Huppke, and Haensel, respectively, over six decades ago [4], an early example of homogeneous iridium complex oxidized alkanes to alkenes or arenes was disclosed by Crabtree and coworkers in 1979 [5]. They observed that a cationic complex [Ir(H2)(acetone)2(PPh3)2] [BF4] reacted with cyclooctane (COA) to give the cyclooctadiene coordinating iridium complex in 70% yield using t‐butylethylene (TBE) as hydrogen acceptor in 1,2‐dichloroethane at 150 °C. Cyclopentane was transformed to the cyclopentadienyl complex in 30% yield under similar conditions. In their following work [6], thermal and photochemical catalytic dehydrogenation of cycloalkanes was established successfully. Later, bisphosphine and bisphosphinite iridium pincer complexes with thermal stability were employed as effective catalysts in the transfer dehydrogenation of alkanes. A more general reaction mechanism was proposed by Goldman, Brookhart, and coworkers [7]. As shown in Scheme 3.7, after insertion and reductive elimination, the initial Ir(III) dihydride catalyst is reduced to an active 14‐electron Ir(I) species with the conversion of TBE into

43

44

3  Oxidation of Alkyl sp3C─H Bond

t‐butylethane (TBA). Then, the low‐valent Ir(I) attacks an sp3C─H bond of COA by oxidative addition to form an alkyl hydrido Ir(III) complex. After β‐hydride elimination, cyclooctene (COE) is yielded and Ir(III) dihydride catalyst is regenerated. This dehydrogenation of alkane is a redox process and thermodynamically favorable, in which the substrate alkane is oxidized to a corresponding alkene with TBE as oxidant. In addition to cycloalkenes, terminal alkenes can also be obtained from linear alkanes in the Ir(III) catalytic systems under mild conditions. In a recent report by Mindiola and coworkers [8], ethane, propane, and C4–C8 linear alkanes were oxidized by a PNP (PNP = [2,6-bis(di-isopropyllphosphinomethyl) pyridine]) pincer titanium complex (PNP)Ti═CHtBu(CH2tBu) to give the corresponding terminal alkenes in high conversion (up to 90%) at room temperature. Many other homogeneous catalysts including Re, Ru, Os, and Rh have been used in alkane dehydrogenations under thermal or photochemical conditions [9]. 0.01 mmol Ir(III), tBuONa

+

30 mmol

27% TON = 806 Selectivity = 100%

30 mmol OMe

Ir(III) =

+

200 °C, 8 min

O (tBu)2P H

O Ir Cl

P(tBu)2

Ir(III)H2 β–Hydride elimination

Insertion Ir(III)H

Ir(III)H Reductive Oxidative elimination addition COA

Ir(I)

Scheme 3.7  Ir(III)‐catalyzed dehydrogenation of alkanes using olefinic hydrogen acceptors.

Dehydroaromatization of alkanes has also been reported in heterogeneous catalysis. However, high temperature (500–700 °C), low yield, and low selectivity are hampering its utilization. In 2011, Brookhart, Goldman, and coworkers

3.3 ­Oxidations of Alkyl sp3C─H Bond

gave the first catalytic conversion of n‐alkanes to benzene and alkylbenzene using various pincer iridium complexes and TBE or propene as hydrogen acceptor [10]. They proposed that 1,3,5‐cis‐hexatriene was formed through dehydrogenation of n‐hexane and olefin isomerization in the presence of iridium catalyst. After a thermal electrocyclization, 1,3‐cyclohexadiene was generated from the triene followed by iridium‐catalyzed dehydrogenation to produce benzene. At 165 °C, the yield of benzene was 44% in 120 h (Scheme 3.8). Under similar conditions, the reaction of n‐octane afforded 86% yield of aromatics including o‐xylene and ethylbenzene. +

0.005 mmol Ir(I)

4

165 °C, 120 h

1.53 mmol

Ir(I) =

i 2 PrP

+ 4 44% TON = 134

Ir

O P iPr2

Scheme 3.8  Ir(I)‐catalyzed dehydroaromatization of n‐alkanes using olefinic hydrogen acceptors.

To date, although a lot of efforts and achievements could be found in the homogeneous catalysis for dehydrogenation of alkanes, high efficiency related to low temperature, broad substrate scope, and especially normal oxidant is being pursued. 3.3.1.2  Aliphatic Carboxylic Acids (Carboxylation) and Vinyl Alkanes (Alkenylation)

Carboxylation of alkanes with carbon monoxide to form their aliphatic carboxylic acids is a direct and simple process not only to extend a chain by one more carbon but also to link a carboxylic group containing oxygen atoms. In 1992, Fujiwara and coworkers disclosed that propane (10 atm) could react with CO (20 atm) to give both isobutyric and butyric acids in the presence of Pd(OAc)2/CuSO4 as catalyst and K2S2O8 as oxidant in CF3CO2H at 80 °C [11] (Scheme 3.9). The total TON was 6.6, but the total yield was secondary > primary ≫ methyl, like in radical processes. When chiral ligands were introduced into the metal catalysts, asymmetric intermolecular alkylation of alkenes by carbene C─H insertion would be established. In 1997, Davies and Hansen used rhodium(II) (S)‐N‐ (p‐alkylphenyl)sulfonylprolinate Rh2(S‐DOSP)4 as catalyst to prepare asymmetric products in the alkylations of cycloalkenes (carbon member 5–7) with aryldiazoacetates. The yields were 55–96% with stereoselectivity 60–93% ee [19] (Scheme 3.15). Recently, Davies and coworkers [20] developed another dirhodium catalyst to achieve highly site‐selective, diastereoselective, and enantioselective C─H functionalization of n‐alkanes and terminally substituted n‐alkyl compounds (Scheme 3.15). The cleavage of C─H by metal‐carbene is an effective method to develop novel reactions probably. For now, however, scopes of substrates and reaction reagents for carbene formation and C─H insertion are too limited to be used in chemical synthesis. In addition, Ishii and coworkers reported an oxyalkylation of electron‐poor alkenes with cycloalkanes and O2 in 2001 [21], in which both C─C and C─O bonds were formed. For example, 1,3‐dimethyladamantane reacted with methyl acrylate and oxygen in the presence of catalytic NHPI/Co(acac)3 at 70 °C to afford a 7 : 3 mixture of oxyalkylated products, methyl 3‐(3,3′‐dimethyladamantyl)‐2‐ hydroxypropionate, and methyl 3‐(3,3′‐dimethyladamantyl)‐2‐oxopropionate, in 91% yield (Scheme 3.16). They proposed that the formation of PINO from NHPI could be enhanced by Co(III)‐dioxygen complex resulting from Co(II) oxidized with O2 under mild conditions, and PINO radicals still abstracted H atoms from alkanes to give alkyl radicals (Scheme 3.17). + 100 mmol

N2

CO2Et 3 mmol

Cat. Rh2(CF3CO2)4

CO2Et

22 °C, 4 h 78% TON > 1000

Scheme 3.14  Rh(II)‐catalyzed alkylation of alkanes with diazoesters.

49

Cl +

CO2Me

1 mol% Rh2(S–DOSP)4 50 °C, 90 min

MeO2C

N2 1 mmol

15 mL

H

78% (89% ee) H

Rh2(S–DOSP)4 =

Cl

Rh

O

N O SO2Ar

Rh 4

Ar = p–C12H25C6H4 Br Br +

CO2CH2CCl3

1 mol% Rh2(R–L)4 Cl3CH2CO2C H Reflux, N , 3.5 h

8 mL

95% (99% ee, 20:1 d.r.)

0.35 mmol Ph

Rh2(R–L)4 =

H

2

N2

O Rh

Ph

O Rh Ar Ar

4

Ar = p–tBuC6H4

Scheme 3.15  Rh(II)‐catalyzed selective alkylation of alkanes with diazoesters. OH

15 mmol

O

CO2Me

20 mol% NHPI 1 mol% Co(acac)2 + CO2Me + O2/N2 MeCN 75 °C, 16 h 0.5 atm/0.5 atm 3 mmol

CO2Me

+ 7:3 Total yield = 91%

Scheme 3.16  Co/NHPI‐catalyzed oxyalkylation of alkanes with alkenes using O2 as oxidant.

O Co(II)

O2

Co(III)–OO

R—H

NO

CO2Me

R

OH

O

O

O Co(III)–OOH

Co(III) NHPI

NOH O NHPI

CO2Me

+ R

R

CO2Me

Scheme 3.17  Proposed mechanism of oxyalkylation of alkanes.

R

CO2Me

3.3 ­Oxidations of Alkyl sp3C─H Bond

3.3.2 C─N Bond Formation

Oxidation of alkyl sp3C─H bonds to sp3C─N bonds is a powerful tool in chemical synthesis, especially under mild conditions because both alkylamine and nitroalkane products are important intermediates in pharmaceutical and agricultural chemical industries. 3.3.2.1  Alkylamines (Amination)

Alkylamines are derivatives of ammonia (NH3), in which one or more hydrogen atoms have been replaced by the alkyl groups. It implies that the direct formation of alkylamine by an oxidation of alkane with ammonia is a good choice. However, alkyl sp3C─H bonds, not like alkyl sp3C─X (X = Cl, Br, I) bonds, cannot proceed with NH3 as nucleophile in a nucleophilic substitution to form alkylamines, because H− is a strong base and not a good leaving group. Meanwhile, NH2─H is also a very strong bond (BDE = 452 kJ/mol) compared with sp3C─H and sp3C─sp3C bonds (C2H5─H, BDE = 423 kJ/mol and CH3─CH3, BDE = 377 kJ/mol), so radical process is not available either. Thus, to seek an effective nitrogen reagent for amination of alkane is a crucial and reasonable step. Free nitrene as an electron‐deficient nitrogen reagent can be used in aminations, but the processes are unselective and uncontrollable with less value in synthesis. In 1982, Breslow and Gellman found that manganese tetraphenylporphyrin (TPP) could catalyze the tosylamination of cyclohexane at room temperature [22]. In their reactions, hypervalent N‐tosylimino‐λ3‐iodane (the λ3 notation means the iodine exceeds its standard valence by two) as nitrogen reagent and oxidant, N‐cyclohexyltoluene‐p‐sulphonamide, was formed in 310% yield based on the Mn(III)(TPP) chloride catalyst and 6.5% based on the oxidant, respectively (Scheme 3.18). This example inspired the following researchers to develop many transition‐metal‐catalyzed aminations of alkyl sp3C─H bonds by use of imino‐λ3‐iodane nitrogen reagent under mild conditions. Actually, a transition metal might activate the alkyl sp3C─H bonds to be attacked by nitrene precursors generated in situ from hypervalent iodine reagents, or it reacted with a special nitrogen reagent such as N‐tosyloxyamide to form a metal nitrenoid complex for amination reactions. In 2011, Ochiai and coworkers reported that a metal‐free amination of various alkanes proceeded very well at ambient temperature [23]. In their studies, hypervalent aryl‐λ3‐ bromanes with higher reactivity than aryl‐λ3‐iodanes were employed as organo nitrenoid to insert into the alkyl sp3C─H bonds followed by formation of sp3C─N bonds. They thought that this process did not involve carbon cations or free radicals, and a concerted asynchronous bimolecular transition state was suggested for the C─H amination. The selectivity was preferred for tertiary and secondary sp3C─H bonds, but not primary ones. For example, based on the nitrogen reagent, amination of n‐hexane was in 51% yield with a selectivity of 100% for secondary product (C2/C3 = 43/57), and that of adamantane was in 86% yield with a selectivity of 92% for tertiary product (Scheme 3.19).

51

52

3  Oxidation of Alkyl sp3C─H Bond

I

O

O

N S

NH S O

2 mol% Mn(III)(TPP)Cl

O

+

CH2Cl2, Ar, rt, 4.5 h 125 mM in CH2Cl2

6.5%

N Cl N Mn(III)(TPP)Cl = N

Mn(III) N

Scheme 3.18  Mn(III)‐catalyzed amination of alkanes with hypervalent N‐tosylimino‐λ3‐iodane. Br—N SO2CF3 — +

Ar, rt, 24 h CF3 0.01 M

HN

SO2CF3 + HN 43 : 57 Total yield = 51%

SO2CF3

Scheme 3.19  Metal‐free amination of alkanes with hypervalent N‐tosylimino‐λ3‐bromane.

In 2014, Hartwig and coworkers developed a set of copper‐catalyzed reactions of alkanes including linear and cyclic alkanes with simple amides, sulfonamides, and imides to form the corresponding alkyl sp3C─N products [24]. The reactions were carried out in the presence of catalytic CuI/4,7‐dimethoxyphenantroline ((MeO)2phen) with t‐BuOOt‐Bu in benzene at 100 °C. In these reactions, a tert‐butoxy radical from t‐BuOOt‐Bu as radical initiator and oxidant was crucial to abstract a hydrogen atom from the alkane to form an alkyl radical intermediate. Then, the alkyl radical combined with a Cu(II)‐ amidate and Cu(II)‐imidate species generated in the reactions of Cu catalyst/ ligand with amide and imide to produce the amidation and imidation products (Scheme 3.20). The selectivity of sp3C─H bonds was secondary > tertiary > primary due to the effects of both steric hindrance and BDE. The product yields were from moderate to good, and, for example, the isolated yield of cyclohexyl‐NHCOPh was 76% based on amide.

3.3 ­Oxidations of Alkyl sp3C─H Bond O

+ H2N 5 mmol

+

tBuOOtBu

2.5 mol% CuI/(MeO)2phen C6H6, 100 °C, 24 h

Ph

0.5 mmol

NHCOPh

1 mmol

76%

(phen)Cu—NHCOPh tBuOOtBu

tBuOOtBu NH2COPh

(phen)Cu—(NHCOPh)2 (phen)Cu—(NHCOPh)2

MeO

OMe

(MeO)2phen = N

N

Scheme 3.20  Cu(I)‐catalyzed amidation of alkanes with amides.

3.3.2.2  Nitroalkanes (Nitration)

Nitroalkanes are alkanes containing one or more nitro functional groups (─NO2). The first nitration of alkanes was established by Beilstein and Kurbatov in 1880 [25]. After that, some practical processes were developed for nitrations of alkanes including propane, n‐butane, and n‐pentane in the gas phase at 350–450 °C or higher molecular weight hydrocarbons in the liquid phase at 160–200 °C [26]. Normally, at higher temperature (over 200 °C), alkyl radicals are generated by the cleavage of alkyl sp3C─H bonds during the nitration of alkanes, using nitrogen dioxide or nitric acid as a nitrating reagent. Thus, the nitrations of alkanes have been limited to several lower alkanes such as methane, ethane, and propane to avoid breaking of too many C─C bonds of alkanes. In 1971, Olah and Lin observed that nitronium salt NO2+PF6− as a nitrating reagent could make nitroalkane products from alkanes in CH2Cl2–sulfolane solution at room temperature [27] (Scheme 3.21). Adamantane was nitrated in 10% yield with the selectivity of 95% for tertiary position. However, under their reaction conditions, ethane gave nitroethane in 26% selectivity; the other was nitromethane as a major product. They suggested that this nitration was an electrophilic process involving both C─H and C─C bonds cleavage by NO2+ in strong acid solutions, and free‐radical formation was excluded.

53

54

3  Oxidation of Alkyl sp3C─H Bond NO2 +



+ NO2 PF6

+

CH2Cl2–sulfolane 25 °C, in dark

via

H

NO2

NO2

95 : 5 Total yield = 10%

+

Scheme 3.21  Nitration of alkanes with nitronium salts.

An efficient catalytic nitration of alkane was reported by Ishii and coworkers in 2001 [28]. They thought that a PINO radical was formed in situ from a catalytic NHPI with NO2 instead of O2 in carboxylation mentioned before, then PINO could abstract an H atom from the alkyl sp3C─H to give an alkyl radical and NHPI was regenerated, and finally the corresponding nitroalkane was produced by the alkyl radical attacking NO2 under mild conditions. Reactions were carried out in the presence of NHPI (24 mol%) and NO2 (1 equiv.) in the alkane solvent in air (1 atm) at 70 °C. Based on NO2 used, the yield of nitrocyclohexane was 70% in 85% selectivity, and that of nitrohexane was 54% in 84% selectivity with the ratio of C1/C2/C3, 3/53/44 (Scheme 3.22). The by‐products were alkyl nitrites and oxygenated products. Nitration of adamantane gave only tertiary product in 66% yield. They also used HNO3 to generate NO2 in situ in the same reactions. NO2 +

5 mL

NO2

2.5 mmol

24 mol% NHPI PhCF3 70 °C, 14 h

and

+

NO2

NO2 (53 + 44) : 3 Total yield = 54%

Scheme 3.22  Nitration of alkanes with NO2 using catalytic NHPI.

In the formation of alkyl sp3C─N bonds from sp3C─H bonds directly, an effective nitrogen reagent is being focused accompanying the corresponding catalytic system. However, common nitrogen sources such as NH3, KNO3, and even N2 are more convenient in utilization if breakthrough is achieved in fundamental theory and practice. Another unresolved problem is amination or nitration of primary sp3C─H bonds with high selectivity.

3.3 ­Oxidations of Alkyl sp3C─H Bond

3.3.3 C─O Bond Formation 3.3.3.1  Alcohols (Hydroxylation)

Alcohols are alkanes that contain an hydroxy group (─OH). Thus, they are also the oxidative product from an alkane or a primary functionalized alkane. Although the hydroxy group is so simple, it is very active in many transformations including substitution, elimination, oxidation, and so on. On the other hand, it is a polar and hydrophilic group to increase the boiling point and solubility for alkanes, especially for light alkanes. According to the mass efficiency, direct oxidation of alkanes with O2 should be the simplest method to prepare alcohols. In 1983, Barton and coworkers [29] observed that adamantane was oxidized to give 1‐adamantanol and a mixture of 2‐adamantanol and adamantanone in the presence of metallic iron and hydrogen sulfide in pyridine/acetic acid under 1 atm of O2 at room temperature, which was called Gif chemistry later. The results of all products related to adamantane indicated that tertiary products were still dominating (selectivity 70–80%). In these processes involving generation of radicals, H2O2 and t‐BuOOH were also effective oxidants. Although the yield and selectivity were very low, their primary work implied that Fe(II) or Fe(III) complex, like nonheme iron enzymes and O2 or H2O2, could be used as ­powerful catalyst and oxidant, respectively, in the oxygenation of inert alkyl sp3C─H bonds. For example, Miki and Furuya [30] found that only hexanol or cyclohexanol was obtained successfully in the presence of an iron carboxylate catalyst immobilized on a modified silica surface, propane‐1,3‐dithiol (PDT), CH3CO2H, and PPh3 in CH3CN under O2 at 25 °C. The TONs were 59.4 and 109.2, respectively (Scheme 3.23). + O2 3.5 mmol 1 atm

OH

0.014 mol% Fe(III) immobilized AcOH/PDT/PPh3 MeCN, 25 °C 1.6%

Scheme 3.23  Immobilized Fe‐catalyzed hydroxylation of alkanes with O2.

Selectivity is the most important aspect to a practical process in synthesis. In 2007, White and Chen [31] developed an iron‐based catalyzed oxidation of alkyl sp3C─H bond especially tertiary and secondary C─H bonds in a broad range of substrates to give the corresponding alcohols under very mild conditions. They studied the effects of the electronic and steric properties of the sp3C─H bonds and established the modes successfully to predict the selectivity in  oxidation of various alkanes without assistance of directing groups, even of complex natural products. For example, there are five tertiary sp3C─H bonds along the tetracyclic skeleton of antimalarial compound (+)‐artemisinin.

55

56

3  Oxidation of Alkyl sp3C─H Bond

According to their selectivity rules, they predicted that the tertiary sp3C─H bond at C10 would be more favorable to be oxidized than others. The oxidized product was obtained as the major one in 34% yield, which supported the reliability of their selectivity rules (Scheme 3.24). All of the reactions were carried out in the presence of iron catalyst and H2O2 as oxidant in AcOH/CH3CN at room temperature; the yield based on substrate was up to 90% when the starting material was recycled. H

H

O O O H

O

OH

H +

15 mol% Fe(S,S–PDP)

H2O2 3.6 equiv.

AcOH/MeCN rt, 30 min

O

O O O H

O O 34%

(SbF6)2 N N Fe

Fe(S,S–PDP) = N

NCCH3 NCCH3

N

Scheme 3.24  Fe‐catalyzed selective hydroxylation of alkanes with H2O2.

An interesting work by Mizuno and coworkers was reported in 2010 [32]. The selectivity of secondary sp3C─H bonds over tertiary ones was achieved in some hydroxylations of special alkanes by use of a bulky divanadium‐ substituted phosphotungstate as catalyst. They found that trans‐decalin was hydroxylated to afford almost only secondary alcohols in 51% yield based on H2O2 as oxidant in the presence of [(nC4H9)4N]4 [γ‐HPV2W10O40] catalyst and HClO4 in CH3CN/t‐BuOH at 60 °C (Scheme 3.25). However, in the case of adamantane, the selectivity of tertiary alcohol was 85%, and the yield of all alcohols was 98%. H + H 2.5 M

H2O2

50 mM

2.6 mol% [(nC4H9)4N]4[γ-HPV2W10O40] 2.6 mol% HClO4 tBuOH/MeCN,

H

60 °C, 1 h H 51%

Scheme 3.25  Regioselective hydroxylation of alkanes with H2O2 using catalytic divanadium‐substituted phosphotungstate.

OH

3.3 ­Oxidations of Alkyl sp3C─H Bond

In addition, ketones are usually produced by overoxidation of secondary sp3C─H bonds in some hydroxylations. For instance, in White’s report mentioned earlier, cyclohexanone was generated from cyclohexane in 92% yield under their standard conditions. In contrast, primary alcohols are very difficult to obtain as the major product from primary sp3C─H bonds under these hydroxylation conditions. Actually, many oxidations of simple alkanes to form alcohols in high yields have been achieved by using various catalysts at elevated temperature or using special oxidants under mild conditions. However, as mentioned earlier, it has not been established that a highly efficient preparation of alcohols from alkanes is made in both excellent yield and selectivity with atmospheric pressure air or dioxygen as terminal oxidant at ambient temperature. 3.3.4 C─Halogen Bond Formation

A monohalogenated alkane is a compound from halogenation of an alkane where one H atom of the alkane is substituted by one halogen atom (F, Cl, Br, or I). As described in Section 3.2, by radical chain reactions, chlorination and bromination are thermodynamically favorable, but iodination is not, and fluorination is uncontrollable. In these reactions, Cl2 and Br2 are the halogen sources, so safety and easy operation are concerned seriously. Thus, in addition to high product yield and selectivity, environmentally benign halogen reagents or sources and very mild operation conditions are being focused in all halogenations of alkane, especially fluorination. 3.3.4.1 C─F Bond (Fluorination)

Organic compounds containing C─F bonds play a unique role in medicines, agrochemicals, and materials, that is, C─F bonds as final functional groups are often in the target products rather than as active groups in the intermediates. However, in the fluorination of alkyl sp3C─H bonds, F2 is not a suitable fluorine reagent and oxidant because the low BDE of F─F bond (36.6 kcal/mol) with the high BDE of C─F and H─F bonds formed make the radical chain reactions extremely exothermic and unselective. Thus, it is an alternative method to use an effective fluorine reagent or to generate one in situ under mild conditions in the fluorination of alkyl sp3C─H bonds. In 2012, Lectka and coworkers [33] developed a catalytic system involving a CuI coordinating with N,N‐bis(phenylmethylene)‐1,2‐ethanediamine (BPMED) complex as catalyst, a radical precursor NHPI as cocatalyst, an anionic phase‐ transfer catalyst (KB(C6F5)4), and Selectfluor (1‐chloromethyl‐4‐fluoro‐1,4‐ diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) as fluorine reagent for fluorination of alkanes including linear and cycloalkanes running under very mild conditions. Interestingly, 1‐fluoroadamantane as major product was generated in 75% yield without KB(C6F5)4 at 25 °C (Scheme 3.26), and 2‐fluoroadamantane

57

58

3  Oxidation of Alkyl sp3C─H Bond

was in 40% yield at 0 °C. For linear alkanes, all fluorinated products were secondary, not primary. They suggested that this reaction was initiated by a single‐electron transfer (SET) from Cu(I) to Selectfluor, and PINO radical was formed from NHPI in situ with Cu(I) regenerated. One year later, Inoue and coworkers [34] discovered that an electrophilic N‐oxyl radical was oxidized directly by Selectfluor from N,N‐dihydroxypyromellitimide (NDHPI). Thus, fluorination of alkanes could be carried out without metal catalyst under mild conditions. For example, monofluoridated cyclododecane was obtained in 45% yield at 50 °C (Scheme 3.27). F +

Selectfluor

0.25 mmol

MeCN 25 °C, 24 h

0.55 mmol

N

Cat. Cu(I) = Ph

Cu I

F

10 mol% Cu(I) 10 mol% NHPI

N

+ 75% Selectivity = 89%

Selectfluor = Ph

N+

N+

CH2Cl (BF4– )2

F

Scheme 3.26  Polycomponent metal‐catalyzed fluorination of alkanes with Selectfluor. F + 0.219 mmol

Selectfluor 0.438 mmol O

NDHPI =

HO N O

2.5 mol% NDHPI MeCN, Ar 50 °C, 5 h

45%

O N OH O

Scheme 3.27  Fluorination of alkanes with Selectfluor using catalytic NDHPI.

Meanwhile, in 2012, Groves and coworkers [35] found that AgF was an effective fluorine reagent in a manganese porphyrin‐catalyzed fluorination of cycloalkanes by use of iodosylbenzene as oxidant with a catalytic amount of tetrabutylammonium fluoride (TBAF) trihydrate. Monofluorinated adamantane was in 53% yield at 50 °C, and the selectivity of 2‐fluoroadamantane was 58% (Scheme 3.28). They proposed that the reaction pathway involved a generation of O═MnV(TMP)F through oxidation of Mn(TMP)F catalyst, an

3.3 ­Oxidations of Alkyl sp3C─H Bond

abstraction of H atom from the sp3C─H bond by O═MnV(TMP)F to give an alkyl radical and a formation of monofluorinated alkane in the alkyl radical capturing fluorine from HO─MnIV─F or a trans‐difluoro‐manganese(IV) species (Scheme 3.29).

1.5 mmol

1 mol% Mn(III)(TMP)Cl 20 mol% (nBu)4N+F– • 3H2O + AgF + PhIO MeCN/CH2Cl2, N2 50 °C, 6–8 h 4.5 mmol 6–10 mmol

F

F +

1.4 : 1 Total yield = 53%

Scheme 3.28  Mn(III) porphyrin‐catalyzed fluorination of alkanes with AgF. Mn(III)(TMP)Cl R—F

Mn(III)(TMP)Cl =

Mn(III)(TMP)F PhIO

R

N Cl N

Mn(IV)(TMP)F2

— Mn(V)—O(TMP)F

N

Mn(III) N

R–H

AgOH

AgF

Mn(IV)OH(TMP)F

R

Scheme 3.29  Proposed mechanism of Mn(III) porphyrin‐catalyzed fluorination of alkanes.

On the other hand, a few photocatalytic fluorinations of alkyl sp3C─H bonds have been established recently under mild conditions and the chemo‐ and regioselectivity are good from simple alkanes to sp3C–H bonds in complex compounds [36]. 3.3.4.2 C─Cl Bond and C─Br Bond (Chlorination and Bromination)

Chlorination and bromination of alkanes can be carried out with Cl2 and Br2, respectively, through the radical chain reactions. But, HCl and HBr as by‐products decrease largely the mass efficiency of halogen source. Thus, oxidative halogenation of alkanes is more beneficial than common halogenations. Hydrogen peroxide is an effective oxidant and applied in oxidative bromination of alkanes with HBr successfully. For example, in 2000, Pombeiro, da Silva, and coworkers [37] reported that Ca[V(HIDPA)2] [HIDPA3− = basic form of (S,S)‐2,2‐(hydroxyimino)dipropionic acid] catalyzed monobromination of cyclohexane with KBr/

59

60

3  Oxidation of Alkyl sp3C─H Bond

HNO3 to give its corresponding product in  secondary ≫ primary, which was opposite to that of C─H activation. Thus, directed and nondirected intramolecular couplings of alkyl sp3C─H bonds with nitrogen reagents are highly complementary in the synthesis of N‐heterocyclic compounds. In addition, their reaction mechanisms are described by inner‐ and outersphere pathways (C─M bond formed and not), respectively.

O

O O

NH2

+ PhI(OAc)2

1.26 mmol O O S H N O 2

1.25 mmol

5 mol% Rh2(OAc)4 MgO, CH2Cl2 40 °C, 12 h

1.76 mmol

+

PhI(OAc)2

2 mol% Rh2(OAc)4 MgO, CH2Cl2 40 °C, 1–2 h

O O S O HN

87% O O S O PhI=N

PhI(OAc)2

O O S H N O 2

2 AcOH

Rh2(OAc)4

O O O O S Rh Rh N O

NH

83%

1.38 mmol

O O S O HN

O

O O O O S Rh Rh N O IPh

PhI

Scheme 4.32  Rh‐catalyzed intramolecular amidation of sp3C─H bonds.

4.3 ­Directed Oxidations of Alkyl sp3C─H Bond

4.3.2.2  Intermolecular Coupling

Based on both the C─H activation assisted by directing group and the formation of C─N bond by nitrene insertion, Che, Yu, and coworkers [40] disclosed a Pd(II)‐ catalyzed cross‐coupling of aliphatic O‐methyl oximes with amides such as sulfonamide or trifluoroacetamide to afford the corresponding β‐monoamidated products in 76–88% yield in 2006. The reactions were carried out in the presence of catalytic Pd(OAc)2 with K2S2O8 as oxidant in DCE (1,2-dichloroethane) at 80 °C. Only primary β‐sp3C─H bonds were amidated by the assistance of oxime, which indicated that five‐membered palladacycles were involved probably (Scheme 4.33). N N

O OMe + Cl

NH2 5 mol% Pd(OAc)2 S + K2S2O8 DCE O 80 °C, 20 h

1.2 equiv.

1 equiv.

O

OMe

NH

S

O

Cl

5 equiv.

88%

Scheme 4.33  Pd(II)‐catalyzed amidation of β‐sp3C─H bonds with amides directed by C═N─OMe group.

In 2014, Chang and coworkers [41] developed an Ir(III)‐catalyzed β‐amidation of sp3C─H bonds on aliphatic O‐alkyl oximes with azides as the amino source under mild conditions. For instance, 2‐methylheptan‐3‐one O‐methyl oxime underwent the amidation with p‐toluenesulfonyl azide to give its primary β‐product in 73% yield in the presence of catalytic [IrCp*Cl2]2/AgNTf2 and AgOAc in DCE at 60 °C. Since nitrogen as a single byproduct was released, no external oxidant was required in the redox reactions. In the cases of acyclic ketoximes, amidation at only primary β‐sp 3C─H bonds was observed through a possible five‐membered iridacycle pathway. This transformation involving a nitrenoid species was also proposed in their following reports [42] (Scheme 4.34). MeO

O

N

+

0.2 mmol

5 mol% [IrCp*Cl2]2 20 mol% AgNTf2 N3 10 mol% AgOAc S DCE O 60 °C, 24 h

0.4 mmol

OMe

N

O S O

NH 73%

via MeO

N

Ir+ NTs

Scheme 4.34  Ir(III)‐catalyzed amidation of β‐sp3C─H bonds with azides directed by C═N─OMe group.

87

88

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group

In 2015, by using R2N─OBz as the nitrogen source, Yu and coworkers [43] reported Pd(0)‐catalyzed β‐amidation of primary sp3C─H bonds directed by CONHAr (Ar = p‐C6F4CF3) groups. The proposed mechanism included an oxidative addition of Pd(0) with R2N─OBz to give a Pd(II)‐amido complex, a five‐membered palladacycle formation via C─H activation after the coordination of Pd(II) with the directing group, and the sp3C─N bond formation as well as Pd(0) regeneration through reductive elimination of the palladacycle. The reactions proceeded very well by use of catalytic [Pd(allyl)Cl]2/P[3,5‐ (CF3)2C6H3]3 with Cs2CO3 and 4 Å molecular sieves in CH2Cl2 at 120 °C under N2 atmosphere. The β‐amidated amides were produced in 52–78% yield, but α‐hydrogen atoms of the substrates were intolerant (Scheme 4.35). F F3C

F

F F

5 mol% [Pd(allyl)Cl]2 20 mol% P[3,5-(CF3)2C6H3]3

O

O

+

Cs2CO3, 4Å M.S. CH2Cl2 120 °C, N2, 16 h

N

N H

OBz

F

F F

0.4 mmol

0.1 mmol

F F3C

O

N H

N O

77%

O Cs2CO3 + ArF

N H

O

N O Pd(0)

CsHCO3

O

OCs ArF

N OBz

N

N

Pd(II)

Pd(II)-OBz

N O

OCs

CsOBz + CsHCO3

ArF Cs2CO3 N

N

OCs ArF

Cs2CO3

O ArF

N CsHCO3

N H

Pd(II)-OBz

O

Scheme 4.35  Pd(0)‐catalyzed amidation of β‐sp3C─H bonds with R2N─OBz directed by CONHAr group (Ar = p‐C6F4CF3).

In the aminations of C─H bonds, normal amines as nitrogen sources are highly desirable. According to the success in the Pd(0)‐catalyzed arylation of primary sp3C─H bonds of 2,4,6‐tri‐tert‐butylbromobenzene mentioned in Section  4.3.1.5, Buchwald and coworkers [44] developed an intermolecular amination version by using aryl amines as nitrogen reagents in 2011. For instance,

4.3 ­Directed Oxidations of Alkyl sp3C─H Bond

2,4,6‐tri‐tert‐butylbromobenzene underwent the amination with aniline to give the corresponding N‐(2‐methyl‐2‐phenylpropyl)aniline in 83% yield in the presence of catalytic Pd2(dba)3/SIPr·HBF4 with t‐BuONa in toluene at 110 °C. In the proposed reaction mechanism, it was assumed that aryl sp2C─Pd(II) formed in an oxidative addition of Pd(0) to aryl sp2C─Br bond, an alkyl sp3C─Pd(II) generated via the primary sp3C─H activation with the aryl sp2C─Pd(II) species at ortho‐position through a possible five‐membered palladacycle, and the sp3C─N product obtained with concomitant regeneration of Pd(0) after the transmetalation with aniline and reductive elimination processes (Scheme 4.36). Br tBu

NH2

tBu + tBu 1 mmol

+ NaOtBu

1.2 mmol

1.5 mmol

iPr

iPr N+

SIPr • HBF4 =

N

H N

5 mol% Pd2(dba)3 11 mol% SIPr • HBF4 tBu Toluene 110 °C, 4 h

tBu 83%

BF4–

iPr iPr H N

tBu

Br tBu

tBu

tBu

Pd(0)

tBu

Pd(II)-NHPh

Pd(II)-Br tBu

tBu

tBu

tBu

tBu

NaX tBuOH Pd(II)

NaOtBu

Pd(II)-X

PhNH2

HBr

tBu

tBu tBu tBu

HX

Scheme 4.36  Pd(0)‐catalyzed amination of primary sp3C─H bonds from 2,4,6‐tri‐tert‐ butylbromobenzene with aryl amines.

89

90

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group

Although aryl sp2C─Br bonds as reaction igniters and oxidants, steric bulk ligands, and multiple substitutes on phenyl ring to prevent side reactions are necessary in the ­tandem cross‐coupling reactions, it is strongly suggested that the intermolecular a­ mination of sp3C─H bonds with simple amines is feasible. 4.3.3 C─O Bond Formation

The common organic compounds containing C─O bonds are alcohols (R─OH), ethers (R─OR′), esters (R─OCOR′), etc. Thus, in the oxidations of alkyl sp3C─H bonds to sp3C─O bonds, the corresponding oxygen reagents are dioxygen, water, alcohols, carboxylic acids, carboxylic anhydrides, and so on. Moreover, in the cases of C─H activation assisted by directing groups, acyloxylation and alkyloxylation have been widely studied. In 2004, Sanford and coworkers [45a] reported the first Pd(II)‐catalyzed β‐ acyloxylation of primary sp3C─H bonds using O‐methyl oxime (C═N─OMe) or pyridine as directing group. The oxidative reactions were carried out in the presence of catalytic Pd(OAc)2 with PhI(OAc)2 as oxidant in AcOH/Ac2O at 100  °C. The acetoxylated products were obtained in 39–86% yield. They suggested the reactions included directed C─H activation to form a five‐ membered palladacyclic intermediate and oxidation to Pd(IV) followed by reductive elimination to lead the formation of C─O bond (Scheme 4.37). In their following report [45b], an aerobic Pd(OAc)2‐catalyzed version was developed by using NaNO3 (25–100 mol%) as a redox cocatalyst under 1 atm O2 or air at 100–110 °C, but multiple acetoxylated products were given usually. It is known that the acetoxy‐substituted products are converted easily into the compounds with OH group. Later, Trotta used Sanford’s method in the synthesis of oridamycin B successfully [46] (Scheme 4.38). Meanwhile, Yu and coworkers [47] gave another example of Pd(II)‐catalyzed β‐acetoxylation of primary sp3C─H bonds directed by oxazoline with Ac2O using the peroxyester t‐BuOOCOMe as oxidant. In 2006, Corey and coworkers [27] disclosed a Pd(II)‐catalyzed β‐acetoxylation of α‐amino acid derivatives with Ac2O directed by 8‐aminoquinoline (CONH‐8‐quinoline), which was the first β‐acyloxylation of amides assisted by MeO

N + PhI(OAc) 2

1.55 mmol

1.71 mmol

5 mol% Pd(OAc)2

MeO

N Pd

MeO

N OAc

AcOH/Ac2O 100 °C, 3.5 h 78%

Scheme 4.37  Pd(II)‐catalyzed acyloxylation of β‐sp3C─H bonds with PhI(OAc)2 directed by C═N─OMe group.

4.3 ­Directed Oxidations of Alkyl sp3C─H Bond MeO N

MeO N OAc

10 mol% Pd(OAc)2

CO2Me

PhI(OAc)2 AcOH/Ac2O 70 °C

N Boc

CO2Me N Boc

69%

OH OH CO2H N H

Oridamycin B

Scheme 4.38  Pd(II)‐catalyzed acyloxylation of sp3C─H bonds in the synthesis of oridamycin B.

a directing group. Their reactions proceeded by use of catalytic Pd(OAc)2, Mn(OAc)2, and Oxone (2KHSO5/KHSO4/K2SO4) in CH3NO2 at 80  °C (Scheme 4.39). After that, many reports could be found related to the directed acyloxylation of amides. For example, in 2012 Sahoo and coworkers [48] gave a Pd(II)‐catalyzed β‐acyloxylation of amides assisted by S‐methyl‐S‐2‐pyridyl‐ sulfoximine (CON═S(═O, Me)‐2‐pyridine) groups using PhI(OAc)2 as oxidant at room temperature (Scheme 4.40). In 2014, Ge and coworkers [49] disclosed that β‐acetoxylation of amides directed by 8‐aminoquinoline could proceed by using Cu(OAc)2/AgOAc (1/6) as catalyst/oxidant and with K2HPO4 in NMP (N-methyl pyrrolidone) at 170 °C (Scheme 4.41). Kanai, Kuninobu, and coworkers [50] also provided a similar report at the same time. O N

O

N H

+

N O

Ac2O +

Mn(OAc)2/Oxone

10 mmol

1.2 mmol/5 mmol

1 mmol O

20 mol% Pd(OAc)2 CH3NO2 80 °C, 22 h

N

O N

N H

O OAc 52%

Scheme 4.39  Pd(II)‐catalyzed acyloxylation of β‐sp3C─H bonds with Ac2O directed by CONH‐8‐quinoline group.

91

92

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group O O

O O S

+ PhI(OAc)2

N

5 mol% Pd(OAc)2

N 0.5 mmol

S

HOAc, rt, 14 h

N

OAc

N

0.75 mmol

80%

Scheme 4.40  Pd(II)‐catalyzed acyloxylation of β‐sp3C─H bonds with PhI(OAc)2 directed by CON═S(═O, Me)‐2‐pyridine group. O

Et

N H

N

0.15 mmol

nPr

+

AgOAc

O

50 mol% Cu(OAc)2 K2HPO4, NMP 170 °C, 24 h

N

Et

N H

nPr OAc

72%

0.45 mmol

Scheme 4.41  Cu(II)‐catalyzed acyloxylation of β‐sp3C─H bonds with AgOAc directed by CONH‐8‐quinoline group.

On the other hand, in 2012 Chen and coworkers [51] discovered a Pd(II)‐ catalyzed γ‐alkyloxylation of primary sp3C─H bonds on amides assisted by NHCO‐2‐pyridine. Various alcohols were used to give the corresponding alkoxylated products in 42–92% yield. The reactions were carried out in the presence of catalytic Pd(OAc)2 with PhI(OAc)2 in ROH/p‐xylene under argon at 110 °C (Scheme 4.42). In the following years, the Pd(II)‐catalyzed β‐alkloxylations of amides directed by CONHC(Me)2‐2‐pyridine or CONH‐8‐quinoline were also reported. The catalytic cycle was still proposed as a Pd(II)/Pd(IV)/ Pd(II) cycle. O

O N H 0.2 mmol

+ EtOH + PhI(OAc)2 0.4 mL

10 mol% Pd(OAc)2 p-Xylene 110 °C, Ar, 4 h

0.5 mmol

N H

OEt

92% 3

Scheme 4.42  Pd(II)‐catalyzed alkyloxylation of primary γ‐sp C─H bonds with alcohols directed by NHCO‐2‐pyridine group.

For the β‐functionalization of sp3C─H bonds on amides, special directing groups like 8‐aminoquinolines are always necessary even though they are removable or transformable in the previous cases. Obviously, it is interesting and highly demanded to use common functional groups such as CONHR itself as directing groups in the selective oxygenation of sp3C─H bonds. In 2014, Lu and Zhou [52] developed a Pd(II)‐catalyzed β‐acyloxylation of primary sp3C─H bonds on simple amides in the absence of any special directing groups. A variety of amides with N‐substituted linear alkanes, cyclic alkanes, and electron‐deficient

4.3 ­Directed Oxidations of Alkyl sp3C─H Bond

benzyl compounds were acyloxylated very well to give the corresponding products in 63–95% yield. The β‐hydroxy amides could be obtained easily from the acyloxylated products. However, α‐hydrogen atoms of amides were not compatible. The reactions were carried out by using Pd(OAc)2 catalyst and K2S2O8 as oxidant in CF3CO2H at 80 °C (Scheme 4.43). In their following work [53], CF3CO2H was replaced by (CH3SO2)2O (methanesulfonic anhydride) to give β‐mesylated amides. Since the mesylate (OMs) is a good leaving group, β‐mesylated amides are transformed to some valuable amides such as β‐fluoro amides and β‐lactams conveniently (Scheme 4.44). O + CF3CO2H + K2S2O8

N H 1 mmol

5 mmol

10 mol% Pd(OAc)2 80 °C, 20 h

2 mmol O N H

OCOCF3

91%

Scheme 4.43  Pd(II)‐catalyzed acyloxylation of β‐sp3C─H bonds of simple amides with CF3CO2H. O N H 1 mmol

+ Ms2O + K2S2O8 0.7 mmol

10 mol% Pd(OAc)2 CF3CH2OH 80 °C, 24 h

2 mmol

K2CO3 Ms2O = (CH3SO2)2O

N

O N H 70%

KF O

O

65% (based on amide)

OMs

N H

F

64% (based on amide)

Scheme 4.44  Pd(II)‐catalyzed mesylation of β‐sp3C─H bonds of simple amides with Ms2O and the following transformations to β‐fluoro amides and β‐lactams.

4.3.4 C─Halogen Bond Formation

Alkyl halides are often found as important intermediates in chemical transformation since alkyl sp3C─X bonds (X = Cl, Br, or I) are active groups in nucleophilic substitutions and eliminations. Meanwhile, the compounds containing C─F

93

94

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group

bonds usually have unique properties in material and medicinal chemistry. Thus, catalytic halogenation of certain sp3C─H bonds by directing groups is specially required in synthesis. In 2005, Yu and coworkers [54] developed a Pd(II)‐catalyzed β‐monoiodination of primary and secondary sp3C─H bonds assisted by oxazoline with iodine I2 under very mild conditions. The product yields were from moderate to excellent, and the diastereoselectivity was also high. The reactions took place in the presence of catalytic Pd(OAc)2 and PhI(OAc)2 as oxidant in CH2Cl2 at 24 °C (Scheme 4.45). Interestingly, Pd(II) catalyst could be recovered and reused because PdI2 precipitated in the final reaction solution. Di‐ and triiodination could happen at elevated temperature. In 2008, they gave an example of Pd(OAc)2‐catalyzed β‐chlorination of primary sp3C─H bond assisted by CONHOMe group with CuCl2 using AgOAc as oxidant in DCE at 100 °C [55]. Subsequently, the monochloride product was converted into its corresponding β‐lactam through an intramolecular nucleophilic substitution (Scheme 4.46). I N O 1 mmol

tBu

+ I2 + PhI(OAc)2

1 mmol

10 mol% Pd(OAc)2

N

CH2Cl2 24 °C, 64 h

tBu

O

1 mmol

92%

Scheme 4.45  Pd(II)‐catalyzed iodination of β‐sp3C─H bonds with I2 directed by oxazoline group. H 10 mol% Pd(OAc)2 N OMe + CuCl + AgOAc 2 DCE, 100 °C O N2, 10 h 0.75 mmol 1 mmol 0.5 mmol

Cl

H N OMe O

Cat. PhCH2(Et)3N+Cl– CsF, 100 °C, 12 h

N OMe O 68% (one-pot)

Scheme 4.46  Pd(II)‐catalyzed chlorination of β‐sp3C─H bonds with CuCl2 directed by CONHOMe group and the following transformations to β‐lactams.

In 2014, Sahoo and coworkers [56] reported that both chlorination and bromination could occur at primary β‐sp3C─H bonds of amides directed by

4.3 ­Directed Oxidations of Alkyl sp3C─H Bond

S‐methyl‐S‐2‐pyridylsulfoximine (CON═S(═O, Me)‐2‐pyridine) groups under mild conditions. N-Br/Cl‒phthalimides were crucial as either halogen sources or oxidants during the formation of Pd(IV) intermediates followed by reductive elimination to give halide products (Scheme 4.47).

O O S N N 0.3 mmol

O +

N Br O 0.45 mmol

10 mol% Pd(OAc)2 HOAc, DCE 60–65 °C,15 h

O O S L N N Pd L Br Pd(IV)

O O S N N

Br 66%

3

Scheme 4.47  Pd(II)‐catalyzed bromination of β‐sp C─H bonds with N‐Br‐phthalimides directed by CON═S(═O, Me)‐2‐pyridine group.

In the fluorination, one kind of fluorine sources are “F+” reagents, such as  NFPy (N‐fluoropyridinium salts), NFSI (N‐fluorobenzenesulfonimide), Selectfluor (1‐chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis(tetra­ fluoroborate)), and Accufluor (1‐fluoro‐4‐hydroxy‐1,4‐diazoniabicyclo‐ [2,2,2]octane bis(tetrafluoroborate)), which may play a role of oxidant to make Pd(IV) complex from Pd(II). It is also known that sp3C─F bond can be formed through a reductive elimination of Pd(IV) complex, like in Sanford’s report on Pd‐catalyzed fluorination of benzylic sp3C─H bonds in 2012 [57]. Based on the previous results related to fluorination by “F+” reagents and functionalization of alkyl sp3C─H bonds with directing groups, a series of reports from four independent groups were published successively on Pd(II)‐catalyzed β‐fluorination of secondary or primary sp3C─H bonds of amides in May–July, 2015 [58]. As shown in Scheme 4.48, Selectfluor or NFSI was the “F+” reagent, and the directing groups were CONHAr (Ar = p‐C6F4CF3), CONHC(Me)2‐2‐pyridine, and CONH‐8‐quinoline, respectively. However, most of the fluoride products were obtained in moderate yields. In addition, the formation of other C─heteroatom bonds such as sp3C─S and sp3C─Se bonds were also reported in Ni‐ or Pd‐catalyzed functionalization of inert sp3C─H bonds directed by CONH‐8‐quinoline groups [59].

95

96

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group Yu and coworkers [58a] F F3C F O N H O

F F

N

F F3C 10 mol% Pd(TFA)2 10 mol% ligand

O + Selectfluor + Ag2CO3 0.15 mmol

F

+

N + N F

Cl

N

N

O

O

F

O O + Selectfluor 0.18 mmol

10 mol% Pd(OPiv)2 20 mol% 2-Me-BAH

N

iPrCN, DCM 80 °C, N2, 24 h

0.15 mmol

N H O

N

O

46%(99% ee) O 2-Me-BAH =

O O

Ge and coworkers [58c] O N H O

N

Ligand =

2BF4–

Shi and coworkers [58b] O

N

F

53%, dr > 20 : 1

Selectfluor =

N

N H O

F

1,4-Dioxane 115 °C, air, 15 h

O

0.2 mmol

0.1 mmol

N H O

F

N

0.3 mmol

F

O 10 mol% Pd(OAc)2 30 mol% Fe(OAc)2

O + Selectfluor + Ag2CO3

0.75 mmol

iPrCN, DCE 150 °C, air

0.6 mmol

N

N H O

N

O

76%, dr = 7 : 1

Xu and coworkers [58d] O N

N H 0.2 mmol

O + NFSI 0.4 mmol

+ Ag2O

15 mol% Pd(OAc)2 PivOH, PhCl 120 °C, 1 h

N

0.2 mmol

F

N H 58%

O NFSI =

Ph

S

OO O S N Ph F

Scheme 4.48  Pd(II)‐catalyzed fluorination of β‐sp3C─H bonds with “F+” reagents directed by CONHAr (Ar = p‐C6F4CF3), CONHC(Me)2‐2‐pyridine, or CONH‐8‐quinoline group.

References

4.4 ­Summary To date, the inert sp3C─H bonds have been oxidized by the assistance of directing groups to form various C─C and C─heteroatom bonds effectively and selectively. Most of the directing groups are or are transformed from pyridine, amide, imine, amine, carboxylic acid, or ester because they can coordinate the transition‐metal catalysts to lead the formation of stable alkylmetal cycles through inert sp3C─H activation at β‐ or γ‐positions. Normally, the C─H activation is the rate‐determining step. The active reagents including halides, anions, or nucleophiles are used to form the products through oxidation or metaltransformation with the transition‐metal catalysts or alkylmetal intermediates followed by reductive elimination. Thus, there are several limitations to this method today. 1) Substrates with special directing groups or with a few kinds of functional groups 2) C─H bonds at β‐ or γ‐positions 3) Cyclization to usually form N‐containing compounds 4) C─C bond formation by mainly using halides 5) C─heteroatom bond formation by using special reagents 6) Racemic mixtures in the case of chiral carbon (secondary sp3C─H bonds) 7) High precious catalyst loading (~10%) 8) Dioxygen (air) not as oxidant Attempts are underway to remove some or all of these, and other, limitations, but with satisfactory examples are reported scarcely. Overall, effective oxidation of inert sp3C─H bonds is still in its infancy.

­References [1] Carr, K.; Sutherland, J. K. J. Chem. Soc. Chem. Commun. 1984, 1227–1228. [2] Constable, A. G.; McDonald, W. S.; Sawkins, L. C.; Shaw, B. L. J. Chem. Soc.

Chem. Commun. 1978, 1061–1062.

[3] (a) Rousseau, G.; Breit, B. Angew. Chem. Int. Ed. 2011, 50, 2450–2494;

[4]

[5] [6] [7]

(b) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743; (c) Zhou, L.; Lu, W. Acta Chim. Sinica 2015, 73, 1250–1274. (a) House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128–3141; (b) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911–3912. Chen, X.; Goodhue, C. E.; Yu, J.‐Q. J. Am. Chem. Soc. 2006, 128, 12634–12635. Wang, D.‐H.; Wasa, M.; Giri, R.; Yu, J.‐Q. J. Am. Chem. Soc. 2008, 130, 7190–7191. Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965–3972.

97

98

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group

[8] Zhang, S.‐Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc.

2013, 135, 2124–2127.

[ 9] Chen, K.; Hu, F.; Zhang, S.‐Q.; Shi, B.‐F. Chem. Sci. 2013, 4, 3906–3911. [ 10] (a) Zhang, S.‐Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013,

[11] [12] [13] [14] [15]

[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]

135, 12135–12141; (b) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789–1792. Wasa, M.; Engle, K. M.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 3680–3681. Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541–6544. He, G.; Chen, G. Angew. Chem. Int. Ed. 2011, 50, 5192–5196. Wang, B.; Lu, C.; Zhang, S.‐Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett. 2014, 16, 6260–6263. (a) Liu, Y.‐J.; Zhang, Z.‐Z.; Yan, S.‐Y.; Liu, Y.‐H.; Shi, B.‐F. Chem. Commun. 2015, 51, 7899–7902; (b) Shan, G.; Huang, G.; Rao, Y. Org. Biomol. Chem. 2015, 13, 697–701. Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.‐Q. J. Am. Chem. Soc. 2011, 133, 19598–19601. Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.‐Q. Organometallics 2008, 27, 1667–1670. Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984–12986. He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.‐Q. J. Am. Chem. Soc. 2013, 135, 3387–3390. Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2002, 124, 11856–11857. Yoo, E. J.; Wasa, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 17378–17380. Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070–8073. Baudoin, O.; Herrbach, A.; Guéritte, F. Angew. Chem. Int. Ed. 2003, 42, 5736–5740. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696. Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155. (a) Daugulis, O.; Do, H.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086; (b) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem. Res. 2015, 48, 1053–1064. Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391–3394. Giri, R.; Maugel, N.; Li, J.‐J.; Wang, D.‐H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.‐Q. J. Am. Chem. Soc. 2007, 129, 3510–3511. Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030–6032. Gu, Q.; Al Mamari, H. H.; Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53, 3868–3871. Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076–19079.

References

[32] Renaudat, A.; Jean‐Gérard, L.; Jazzar, R.; Kefalidis, C. E.; Clot, E.; Baudoin, O.

Angew. Chem. Int. Ed. 2010, 49, 7261–7265.

[33] Neumann, J. J.; Rakshit, S.; Dröge, T.; Glorius, F. Angew. Chem. Int. Ed. 2009,

48, 6892–6895.

[34] He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3–6. [35] He, G.; Zhang, S.‐Y.; Nack, W. A.; Li, Q.; Chen, G. Angew. Chem. Int. Ed.

2013, 52, 11124–11128.

[36] Sun, W.‐W.; Cao, P.; Mei, R.‐Q.; Li, Y.; Ma, Y.‐L.; Wu, B. Org. Lett. 2014, 16,

480–483.

[37] (a) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem. Int. Ed. 2014, 53,

[38] [39]

[40] [41] [42] [43] [44] [45]

[46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56]

3496–3499; (b) Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem. Int. Ed. 2014, 53, 3706–3710; (c) Wu, X.; Zhao, Y.; Ge, H. Chem. Eur. J. 2014, 20, 9530–9533; (d) Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Nat. Commun. 2015, 6, article 6462. McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129–133. (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935–6936; (b) Espino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598–600. Thu, H.‐Y.; Yu, W.‐Y.; Che, C.‐M. J. Am. Chem. Soc. 2006, 128, 9048–9049. Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136, 4141–4144. Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040–1052. He, J.; Shigenari, T.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2015, 54, 6545–6549. Pan, J.; Su, M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 8647–8651. (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542–9543; (b) Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci. 2012, 3, 3192–3195. Trotta, A. H. Org. Lett. 2015, 17, 3358–3361. Giri, R.; Liang, J.; Lei, J.‐G.; Li, J.‐J.; Wang, D.‐H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2005, 44, 7420–7424. Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2012, 14, 3724–3727. Wu, X.; Zhao, Y.; Ge, H. Chem. Asian J. 2014, 9, 2736–2739. Wang, Z.; Kuninobu, Y.; Kanai, M. Org. Lett. 2014, 16, 4790–4793. Zhang, S.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313–7316. Zhou, L.; Lu, W. Org. Lett. 2014, 16, 508–511. Zhao, R.; Zhou, L.; Lu, W. In The 18th National Symposium on Organometallic Chemistry, Lanzhou, China, August 2014, P1–104, p. 182. Giri, R.; Chen, X.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2005, 44, 2112–2115. Wasa, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2008, 130, 14058–14059. Rit, R. K.; Yadav, M. R.; Ghosh, K.; Shankar, M.; Sahoo, A. K. Org. Lett. 2014, 16, 5258–5261.

99

100

4  Oxidation of Alkyl sp3C─H Bond Assisted by Directing Group

[57] McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett. 2012, 14,

4094–4097.

[58] (a) Zhu, R.‐Y.; Tanaka, K.; Li, G.‐C.; He, J.; Fu, H.‐Y.; Li, S.‐H.; Yu, J.‐Q. J. Am.

Chem. Soc. 2015, 137, 7067–7070; (b) Zhang, Q.; Yin, X.‐S.; Chen, K.; Zhang, S.‐Q.; Shi, B.‐F. J. Am. Chem. Soc. 2015, 137, 8219–8226; (c) Miao, J.; Yang, K.; Kurek, M.; Ge, H. Org. Lett. 2015, 17, 3738–3741; (d) Zhu, Q.; Ji, D.; Liang, T.; Wang, X.; Xu, Y. Org. Lett. 2015, 17, 3798–3801. [59] (a) Lin, C.; Yu, W.; Yao, J.; Wang, B.; Liu, Z.; Zhang, Y. Org. Lett. 2015, 17, 1340–1343; (b) Yan, S.‐Y.; Liu, Y.‐J.; Liu, B.; Liu, Y.‐H.; Zhang, Z.‐Z.; Shi, B.‐F. Chem. Commun. 2015, 51, 7341–7344; (c) Wang, X.; Qiu, R.; Yan, C.; Reddy, V. P.; Zhu, L.; Xu, X.; Yin, S.‐F. Org. Lett. 2015, 17, 1970–1973; (d) Ye, X.; Petersen, J. L.; Shi, X. Chem. Commun. 2015, 51, 7863–7866; (e) Xiong, H.‐Y.; Besset, T.; Cahard, D.; Pannecoucke, X. J. Org. Chem. 2015, 80, 4204–4212.

101

5 Oxidation of Alkyl sp3C—H Bond Adjacent to Unsaturated Carbon Atom 5.1 ­Alkyl α‐sp3C─H Bond A pure alkyl sp3C─H bond is an “isolated” one not influenced by other functional groups or heteroatoms, while it is inert in either hemolysis or heterolysis due to its both high BDE (>400 kJ/mol) and pKa (>40). Methane, simple alkanes and some sp3C─H bonds not linking to functional groups or heteroatoms, have been described in Chapters 2–4, and it is definitely found that effective functionalization of them is always a big challenge, especially under mild conditions. Besides the inert alkyl sp3C─H bonds, however, the others are not inert and even active in either hemolysis or heterolysis, which are normally adjacent to functional groups or heteroatoms and affected by them enormously. To be more simple and accurate, the noninert α‐sp3C─H bonds can be divided into two categories. One is to connect with unsaturated carbon atoms and the other is to connect with various heteroatoms, which will be discussed in this chapter and the next one, respectively (Scheme 5.1). Inert alkyl sp3C–H bonds (BDE > 400 kJ/mol and pKa > 40): CH4, CH3CH2CH(CH3)2, CH3CH2

DG (DG = directing functional group)

Noninert alkyl α-sp3C–H bonds: I. Connecting to unsaturated carbon atom X CH3

Ar–CH3

CH3

CH3 (X = N, O)

N

II. Connecting to heteroatom CH3–X (X = N, O, halogen)

Scheme 5.1  Inert and noninert alkyl sp3C─H bonds.

Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

CH3

102

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

5.2 ­Alkyl sp3C─H Bonds Adjacent to Unsaturated Carbon Atoms Unsaturated carbon atoms are the sp2C and spC atoms. Their related functional groups include vinyl, aryl, carbonyl, imine, alkynyl, nitrile, etc. in which the most useful and common groups are vinyl, aryl, and carbonyl groups. Moreover, all of these groups can change the reactivity of their alkyl α‐sp3C─H bonds as shown by BDE and pKa values, respectively, due to their electronic and/or resonance effects. For example, propene CH3─CH═CH2 has methyl sp3C─H bonds adjacent to the vinyl group. The BDE of α‐sp3C─H bond is only 364 kJ/mol, which means it is not a strong bond compared with other common sp3C─H bonds, such as primary sp3C─H bonds of propane CH3─C2H5 with a BDE of 423 kJ/mol. In fact, it is not very difficult to be broken homolytically, and its allyl radical is conjugate and stabilized by resonance effect of the vinyl group. On the other hand, the formation of a stable π‐allyl complex is the unique and crucial step to cleave α‐sp3C─H bonds by a transition‐metal catalyst such as palladium(II) catalyst. Many oxidations of allyl compounds are based on the π‐allyl complexes via C─H activation. Certainly, selectivity must be considered seriously since the vinyl C═C bond is often attacked by reagents or catalysts during the transformations of alkyl α‐sp3C─H bonds (Scheme 5.2). However, although its pKa is ~40 (CH3─C2H5 pKa = 50), it is still a very weak acid and not easy to be cleaved by ordinary bases. Other similar C─H bonds are benzylic and propynyl sp3C─H bonds linking to aryl C═C and alkynyl C≡C groups, respectively. Overall, they are more active than normal alkyl sp3C─H bonds, but C─H ­activation with or without directing groups is often necessary besides radical processes in their oxidations. In contrast, acetone CH3─COCH3 has a lower pKa value (26.5) at its α‐ sp3C─H bonds because the carbonyl group is strongly electron deficient to Radical process: +

X2

ROOR or hν

X

(X = Cl, Br) C–H activation: R–

Cat. M

R

M

Scheme 5.2  Functionalizations of allyl sp3C─H bond.

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

polarize α‐sp3C─H bonds and to stabilize the carbanion intermediates. Other ketones, imines, nitriles, and similar compounds containing C═O, C═N, and C≡N groups make their α‐sp3C─H bonds more acidic. Hence, in the presence of certain bases, alkylation of acidic α‐sp3C─H bonds (pKa  65

N Cr+

O

O Cl–

Scheme 5.29  Pd(II)/(salen)Cr(III)‐catalyzed amination of allylic sp3C─H bond with N‐(methoxycarbonyl)‐p‐toluenesulfonamide. (L= linear, B= branched)

C8H17

+ MeOCONHTs + O2

0.6 mmol

0.1 mmol

6 atm

10 mol% Pd(OAc)2 40 mol% maleic anhydride 25 mol% NaOAc C8H17 DMA, 4 Å MS, 35 °C, 12 h

Ts N

OMe

O 63% Selectivity = 69%

Scheme 5.30  Pd(II)‐catalyzed amination of allylic sp3C─H bond with N‐(methoxycarbonyl)‐ p‐toluenesulfonamide using O2 as oxidant.

+ TsNH2 + PhI(OAc)2 3 mmol

0.3 mmol

I

NHTs

I2, 50 °C, 48 h

0.9 mmol

95% 3

Scheme 5.31  Iodine‐mediated amination of benzylic sp C─H bond with TsNH2.

­ iphenylmethanes with sulfonamides or carboxamides by using 2,3‐dichloro‐5,6‐ d dicyano‐p‐benzoquinone (DDQ) as oxidant in DCE at 100  °C (Scheme  5.32). On  the other hand, in 2012 Muñiz and coworkers [37] reported a metal‐free allylic amination of alkenes with bistosylimides by using hypervalent iodine(III) reagent as oxidant in CH2Cl2 at room temperature. PhI(OAc)NTs2 was a good reagent to enhance the yield up to 99% by increasing the ­concentration of NTs2−,

117

118

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom O +

TsNH2

Cl

CN

Cl

CN

+ O 0.6 mmol

1 mmol

0.5 mmol

DCE, 3 Å MS 100 °C, 24 h

NHTs

+

82%

Scheme 5.32  Amination of benzylic sp3C─H bond with TsNH2.

+ NHTs2 0.5 mmol

0.75 mmol

+

PhI(OAc)(NTs2) 0.7 mmol

NTs2 CH2Cl2 25 °C, 20 h

94% NTs2–

I(III)

I(III) + –I–

Scheme 5.33  Amination of allylic sp3C─H bond with NHTs2.

and it was also suggested that NTs2− as nucleophile attacked the allylic intermediates oxidized by hypervalent iodine(III) (Scheme 5.33). 5.3.2.2  Amination of Active sp3C─H Bonds

Amination of active sp3C─H bonds with low pKa faces two aspects, which are the selection of nitrogen reagent and the control of enantioselectivity. In 2002, the groups of Jørgensen and List [38] independently gave the first successful enantio­selective α‐amination of aldehydes using l‐proline as organocatalyst and azodicarboxylate esters as electrophiles. For example, propanal reacted with tert‐butyl azodicarboxylate to afford α‐aminated product in 99% yield and with 89% ee in the presence of catalytic l‐proline in CH2Cl2 at room temperature (Scheme 5.34). Meanwhile, Jørgensen and coworkers [39] also reported a direct l‐proline‐catalyzed asymmetric α‐amination of ketones in MeCN under similar conditions, and the ee value was up to 99%. In these reactions, a generalized enamine catalysis cycle was involved, and dialkyl azodicarboxylates (RO2CN═NCO2R) were useful electrophiles to attack on enamines (Scheme 5.35).

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

O

N

+

H

tBuO C 2

CO2tBu

O

10 mol% L-proline

N

CH2Cl2 rt, 205 min

H

1 mmol

1.5 mmol

CO2tBu

HN N

CO2tBu

99% (89% ee)

Scheme 5.34  l‐Proline‐catalyzed asymmetric α‐amination of aldehyde with dialkyl azodicarboxylate.

O

N

+ EtO2C

CO2Et

N

10 mol% L-proline

O

MeCN, rt, 10 h

CO2Et CO2Et

N

N H

N H2O

+

HN N

O

CO2Et CO2Et

9:1 Total yield = 80% (93% ee)

2 mmol

10 mmol

HN N

N

N+

N– N

N H H2O

Scheme 5.35  l‐Proline‐catalyzed asymmetric α‐amination of ketone with dialkyl azodicarboxylate.

On the other hand, a tandem reaction combining α‐halogenation of ketones and nucleophilic attacking on the intermediates with amines sequentially is another feasible method for amination of active sp3C─H bonds. MacMillan and coworkers [40] disclosed a Cu(II)‐catalyzed coupling of α‐sp3C─H bonds of ketones, aldehydes, and esters with cyclic or acyclic dialkylamines in 2013. The amination took place in the presence of catalytic CuBr2 in DMSO under O2 or air (1 atm) at 5–60 °C, and the product yields were 41–93%. The crucial step was the α‐bromo carbonyl species generated from the reaction of CuBr2 with an active sp3C─H bond. After a nucleophilic substitution of the bromide with the amine, the α‐amino carbonyl adduct was produced. Oxygen was the terminal oxidant to regenerate Cu(II) from Cu(I) during bromination (Scheme 5.36). One year later, Guo and coworkers [41] developed a transition‐ metal‐free α‐C─H amination of ketones with primary/secondary amines, anilines, or amides. The reactions were carried out by using NH4I as catalyst with Na2CO3 and H2O2 or t‐BuOOH as oxidants in MeCN at 50 °C, and the yield was up to 94%. The key intermediate was an iodo carbonyl species formed through a radical iodination process involving an iodine cycle with oxidant. These two examples indicate again that halogen could be used as catalyst in a tandem process (Scheme 5.37).

119

120

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom O OMe

H N

O OMe

10 mol% CuBr2 + O2 DMSO rt, 24 h

+

Cl

S

0.75 mmol

O

N

Cl OMe

Cl

Br

Plavix

S

2.23 mmol 1 atm

87%

Scheme 5.36  CuBr2‐catalyzed α‐amination of ester with dialkylamine using O2 as oxidant.

O

O

H N +

1 mmol

3 mmol I

15 mol% NH4I

+ tBuOOH

[O]

N

Na2CO3, MeCN 50 °C, 18 h

2 mmol

83%

I–

HI

H N

HI O

O

O

[O] +

I



I

Scheme 5.37  Metal‐free α‐amination of ketone with dialkylamine.

5.3.3 C─O Bond Formation

The traditional strategy is to employ a powerful metal reagent as an oxidant in the transformation of sp3C─H bonds to sp3C─O bonds. For instance, in 1928 Treibs and Schmidt [42] described the first example of allylic oxidation by using stoichiometric amounts of chromium(VI) oxide as a metal oxidant. Since then, the oxidative systems including either metal catalysts or organocatalysts with oxygen reagents such as dioxygen, H2O2, and t‐BuOOH (TBHP) have been developed. Certainly, high yield and selectivity (chemo‐ and stereoselectivity), environment‐friendly reaction processes, and mild reaction conditions (at ambient temperature) are always been a demand in this area. An early example of aerobic allylic oxygenation of cyclohexene to cyclohexen‐3‐one was reported by Collman and coworkers in 1967 [43].

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

In  their reactions, the products were obtained in 20–50% yield in the presence of catalytic Ir, Pt, or Rh complex in benzene or methylene dichloride under O2 (14–36 psi) at 25–60 °C (Scheme 5.38). Based on the work of Schenck and coworkers [44], a photochemical aerobic allylic oxygenation was disclosed by Mihelich and Eickhoff in 1983 [45]. The yield of cyclohexen‐3‐enone from cyclohexene was 78% in the presence of catalytic pyridine/meso‐tetraphenylporphine (TPP)/4‐(dimethylamino)pyridine (DMAP) with Ac2O under a 400 W sodium vapor lamp in methylene dichloride (Scheme  5.39). In the oxidations of Δ5‐steroids to the corresponding 7‑keto‐Δ5‐steroids, it was found that t‐BuOOH was a very effective oxidant compared with various metal catalysts such as V, Cr, Mn, Fe, Co, Cu, Mo, Ru, and Bi. For example, in 2006 Nikolaropoulos, Muzart, and coworkers [46] developed a CrO3/pyridine‐catalyzed allylic ­oxygenation of cholesteryl acetate to give 3β‐acetoxy‐5‐cholesten‐7‐one in 74 or 76% yield by using t‑BuOOH as oxidant in CH2Cl2 or PhCF3 at room temperature (Scheme 5.40). Actually, Lardy and coworkers [47] disclosed a transition‐metal‐free oxygenation of steroidal olefins and benzylic compounds to α,β‐enones just by using NaOCl with t‐BuOOH as oxidant in EtOAc at 2–10  °C in 2004. In their reactions, the t‐BuOO· radicals generated from TBHP with NaOCl were suggested as the crucial species to undergo hydrogen abstraction of allylic and benzylic sp3C─H bonds (Scheme 5.41). Scheme 5.38  Transition‐ metal‐catalyzed oxygenation of allylic sp3C─H bond with O2.

+ O2 14–36 psi

Cat. IrI(CO)(PPh3)2 or PtO2(PPh3)2 or RhCl(PPh3)3

O

Benzene or CH2Cl2 25–60 °C, 24 h 20–50%

Meanwhile, aerobic benzylic oxygenation was also studied widely. For example, in 1997, Ishii and coworkers [48] developed a catalytic method to convert alkylbenzenes into the corresponding carboxylic acids by using catalytic N‐hydroxyphthalimide (NHPI) and Co(OAc)2 under atmospheric dioxygen at room temperature. They suggested that a PINO was generated by the reaction of the NHPI with the cobalt(III)‐oxygen complex under ambient conditions, then the hydrogen was abstracted by the PINO to give a benzyl radical, and finally it was trapped by dioxygen to form a benzylperoxyl radical followed by the hydrogen abstraction of NHPI to produce the benzylic acid and PINO (Scheme  5.42). One year later, they extended successfully the Co(II), Cu(II), or Mn(II) catalytic system to oxygenation of alkynes to α,β‐acetylenic ketones with dioxygen at room temperature [49] (Scheme 5.43).

121

+

+

O2/light

0.3 mol

Ac2O

O

0.147 mL pyridine 0.021 g TPP 0.006 mol DMAP CH2Cl2, 2 h

0.3 mol

1O 2

OOH

78%

OOAc

HOAc

Ac2O –HOAc

N NH

HN N

N N

TPP = meso-tetraphenylporphine

DMAP = 4-(dimethylamino)pyridine

Scheme 5.39  Photochemical oxygenation of allylic sp3C─H bond with O2.

C8H17

+ tBuOOH(aq)

C8H17 5 mol% CrO3 10 mol% pyridine PhCF3, rt, 31 h

AcO

AcO 7 mmol

1 mmol

O 76% Selectivity = 80%

Scheme 5.40  CrO3/pyridine‐catalyzed oxygenation of allylic sp3C─H bond of cholesteryl acetate. O

O

+ tBuOOH(aq) + NaOCl AcO 0.01 mmol

0.06 mmol

DCE 2–5 °C AcO O 10 h 0.02 mmol 65% (Selectivity 98%) O

tBuOOH, NaOCl EtOAc, 2–5 °C 98%

Scheme 5.41  Oxygenation of allylic or benzylic sp3C─H bond using t‐BuOOH and NaOCl.

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom 0.5 mol% Co(OAc)2 10 mol% NHPI HOAc, 25 °C, 20 h

+ O2 3 mmol

1 atm

COOH

O NHPI =

NOH O

81% Selectivity = 96% O

Co(II)

O2

NHPI

Co(III)OO

Co(III)OOH +

NO O PINO

CH2

CH3

CH2OO O2

PINO –NHPI

CH2OOH

COOH

Co(III) –Co(II)

NHPI –PINO

Scheme 5.42  Co(II)/NHPI‐catalyzed transformation of toluene to benzoic acid using O2.

Et

Et 2 mmol

+

O2 1 atm

0.5 mol% Cu(acac)2 10 mol% NHPI MeCN, 25 °C, 30 h

O Et

Et

53% Selectivity = 77%

Scheme 5.43  Cu/NHPI‐catalyzed oxygenation of alkyne to α,β‐acetylenic ketone using O2.

Obviously, in the case of toluene, the oxygenation products could be benzyl alcohol, benzaldehyde, and/or benzoic acid [50]. Thus, the chemoselectivity is more important, and the effectively catalytic systems should be established correspondingly. For example, Bhattacharyya and coworkers [51] used MoO(O2)(QO)2 (QO = 8‐quinolinolate anion) as catalyst and H2O2/O2 as oxidant to produce benzoic acid in 95% with TON of 1310 in refluxing MeCN. Chen and Pan [52] reported that benzaldehyde was obtained in >85% yield in the presence of 5 mol% Mn(OAc)2 · 4H2O with TBHP as oxidant in CH2Cl2 at room temperature. Ali and coworkers [53] improved the selectivity of benzyl alcohol up to 80% with a yield of 66% by use of a special catalytic Cu(II) complex (0.2 mol%) and H2O2/O2 as oxidant in the refluxing MeCN. On the other hand, the conversion of sp3C─H bonds into esters is a method to prevent overoxidation of alcohols in the oxygenations. In 1995, Pfaltz and coworkers [54] reported a Cu(I)‐catalyzed enantioselective allylic acyloxylation of cycloalkenes with peresters (Scheme 5.44). Over 10 years later, White and Covell [55] developed a chiral Pd(II)/Cr(III) catalytic system for allylic acyloxylation of linear terminal alkenes with acetic acid (Scheme 5.45). They also found

123

124

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

that (E)‐allylic acetates could be prepared from terminal olefins and acetic acid in the presence of catalytic Pd(OAc)2 using BQ as oxidant in DMSO at 40 °C [56] (Scheme 5.46). O

+ PhCO3tBu 40 mmol

O

5 mol% CuOTf 8 mol% ligand

Ph

CH3CN/CH2Cl2 23 °C, 4 day

10 mmol

68% (74% ee)

Scheme 5.44  Cu(I)‐catalyzed asymmetric acyloxylation of allylic sp3C─H bond of cyclopentene with PhCO3tBu. O C8H17

1 mmol

10 mol% Pd(II) 10 mol% Cr(III)

+ HOAc +

1.1 mmol

Pd(II) =

O 2 mmol

EtOAc, 4Å MS rt, 48 h

O S Ph Pd(OAc)2

O Ph S

C8H17

* OAc

77% (57% ee)

Cr(III) =

N

N Cr

tBu

O F tBu

tBu

O tBu

Scheme 5.45  Pd(II)/Cr(III)‐catalyzed asymmetric acyloxylation of allylic sp3C─H bond of terminal alkene with HOAc. O + HOAc

1 mmol

3 mL

+ O 2 mmol

10 mol% Pd(OAc)2 DMSO, 4Å MS 40 °C, 48 h

OAc

65%, L : B > 99, E : Z = 13 : 1

Scheme 5.46  Pd(II)‐catalyzed acyloxylation of allylic sp3C─H bond of terminal alkene with HOAc.

Meanwhile, Sanford and coworkers [57] also found that benzylic sp3C─H bonds of 8‐methylquinoline underwent oxidations to give acyloxylated or

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

methyloxylated products in the presence of Pd(OAc)2 with PhI(OAc)2 as oxidant in AcOH or MeOH at 100 °C. This was a directed oxygenation via C─H activation with a Pd(II)/Pd(IV)/Pd(II) catalytic cycle (Scheme 5.47).

N 1.4 mmol

+ PhI(OAc)2

1 mol% Pd(OAc)2 AcOH 100 °C, 22 h

N N

Pd(IV)

OAc

1.3 mmol

88%

Scheme 5.47  Pd(II)‐catalyzed acyloxylation of benzylic sp3C─H bond with PhI(OAc)2 assisted by pyridine.

Hypervalent iodine is not only an effective oxidant but also a powerful electrophile in α‐functionalization of carbonyl compounds without metal catalysts, even in asymmetric versions [58]. The first example of the hypervalent iodine‐ mediated α‐oxygenation was reported by Mizukami and coworkers in 1978 [59]. They found that acetophenones and β‐diketones underwent α‐acetoxylation with PhI(OAc)2 to give the products in 22–63% yield in H2SO4 and Ac2O/AcOH at 30 °C (Scheme 5.48). After 3 years, Moriarty and coworkers [60] developed an α‐hydroxylation of ketones by using PhIO as oxidant with NaOH in MeOH at 10 °C (Scheme 5.49). They also reported an α‐methyloxylation of esters by using PhI(OAc)2 as oxidant with NaOMe in MeOH in the same year [61]. Compared with −OAC, −OH, or −OMe groups, the −OTs group is a more useful leaving group in substitution reactions. In 1982, Koser and coworkers [62] found that hydroxy(tosyloxy)iodo benzene (Koser’s reagent PhI(OH)OTs) was a useful reagent in the α‐tosyloxylation of ketones in  MeCN. Simple ketones and β‐diketones were tosyloxylated to their ­corresponding products in 40–100% yield at room temperature to 82  °C (Scheme 5.50). In their following work [63], the reaction was also extended to α‐mesyloxylation of ketones using hydroxy(mesyloxy)iodo benzene (PhI(OH)OMs) as the reagent. O

O + PhI(OAc)2

0.06 mmol

0.05 mmol

OAc H2SO4, Ac2O/HOAc 30 °C, 10 h 25%

Scheme 5.48  α‐Acetoxylation of ketone with PhI(OAc)2 in the presence of catalytic H2SO4.

125

126

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom O–

O

O

PhIO OH–

OH–

O

OH– I

OH

Ph

OH

Scheme 5.49  α‐Hydroxylation of ketone using PhIO.

O

O +

PhI(OH)OTs 10 mmol Koser’s reagent

OTs

MeCN, reflux 10 min 94%

Scheme 5.50  α‐Tosyloxylation of ketone with PhI(OH)OTs.

An early asymmetric α‐tosyloxylation of ketones was disclosed by Wirth and Hirt in 1997 [64]. Their strategy was implemented by chiral Koser’s reagents in the tosyloxylations, and the ee value was 15% (Scheme  5.51). Córdova and ­coworkers [65] gave an asymmetric α‐hydroxylation of ketones in 2005. The reactions were carried out in the presence of catalytic l‐proline with PhIO as an oxidant in DMSO or DMF at room temperature. The ee value was up to 76% with 48% yield in the case of cyclohexanone (Scheme 5.52). O

Et

O

OMe

+ I HO

OTs

CH2Cl2, –10 °C

OTs

15% ee

Scheme 5.51  Asymmetric α‐tosyloxylation of ketone with chiral Koser’s reagent. O

O +

3 mmol

PhIO 1 mmol

30 mol% L-proline

OH

Scheme 5.52  l‐Proline‐ catalyzed α‐hydroxylation of ketone using PhIO.

DMF/H2O rt, 24 h 48% (76% ee)

A very important attempt is to employ catalytic hypervalent iodine or iodine with other general oxidants in α‐oxygenations. In 2005, Ochiai and coworkers [66] reported an iodobenzene‐catalyzed α‐acetoxylation of ketones by use of m‐chloroperoxybenzoic acid (m‐CPBA) as oxidant and BF3·Et2O/H2O in AcOH at 25–30 °C. The isolated yields of acetoxylated ketones were 43–63%.

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

They found BF3·Et2O accelerated the oxidation of iodobenzene with m‐CPBA to PhI(OAc)2. It was suggested that an α‐λ3‐iodanyl ketone was formed by a ligand exchange of PhI(OAc)2 with an enol derived from a ketone followed by an SN2 process with acetic acid to produce an α‐acetoxy ketone and liberation of an PhI (Scheme 5.53). One year later, Togo and Yamamoto [67] developed an iodobenzene‐catalyzed α‐tosyloxylation of ketones with TsOH still using m‐CPBA as an oxidant in MeCN at 50 °C.

Cl O

+ COOH O 0.42 mmol

0.21 mmol

O

10 mol% PhI BF3·Et2O, H2O HOAc, rt, 20 h

OAc 46% (GC 79%)

m-CPBA O m-CPBA HOAc

OAc

R1

PhI

R2

AcOH O

OAc I

R1

PhI(OAc)2

Ph

R2 OH R2

R1

O R2

R1

Scheme 5.53  α‐Acyloxylation of ketone using catalytic PhI and m‐CPBA in HOAc.

Moreover, in 2007 Wirth and coworkers [68] used chiral iodoarenes instead of iodobenzene in this catalytic α‐tosyloxylation of ketones to give the enantio­ selective products. For instance, the α‐tosyloxylated propiophenone was obtained in 59% yield with 27% ee (Scheme 5.54). Meanwhile, intramolecular α‐oxygenations were also studied by many researchers. For example, in 2014 Ishihara and coworkers [69] reported that chiral ammonium hypoiodite salts catalyzed an oxidative cyclization of γ‐(2‐hydroxyphenyl) ketones to 2‐acylchromans, which were the intermediates for tocopherols. These reactions were intramolecular enantioselective α‐phenyloxylations of ketones and proceeded

127

128

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

very well in the presence of catalytic an ammonium iodide with H2O2 as ­ xidant in methyl tert‐butyl ether (MTBE) at room temperature. In their o report, a five‐membered ring dihydrobenzofuran was obtained in 95% yield with 93% ee (Scheme 5.55). Cl

O +

O 10 mol% Ar*I

+

TsOH

COOH 1 equiv

1.5 equiv

MeCN, rt, 48 h

O 1.5 equiv

Ar =

OTs 59% (27% ee)

CF3

F3C

CF3

CF3

Scheme 5.54  Asymmetric α‐tosyloxylation of ketone with TsOH using catalytic chiral ArI and m‐CPBA.

O

Ph N

TBSO H OH

N

0.05 mmol

+ H2O2(aq)

tBuOMe, rt, 30 min

0.1 mmol

(R,R)-R4N+I– =

O

TBSO 10 mol% (R,R)-R4N+I– O

Ph N N

95% (93% ee) Ar I– N+ Ar

Scheme 5.55  Intramolecular asymmetric α‐phenyloxylations of ketone with phenol using catalytic chiral ammonium hypoiodite salt and H2O2.

Although a lot of development of α‐oxygenation especially under metal‐free conditions has been achieved, the exploration of more efficient catalytic systems using normal oxidants to provide highly chemo‐ and stereoselective products is underway.

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

5.3.4 C─Halogen Bond Formation

According to the previously described text, it is known that both allylic and benzylic sp3C─H bonds can be cleaved through either free radical process or C─H activation in their transformations. On the other hand, the acidic α‐sp3C─H bonds of carbonyl compounds can be attacked directly by electrophilic species. These approaches are still available in their halogenations. 5.3.4.1  Chlorination and Bromination

In 1942 Ziegler and coworkers [70] found that N‐bromosuccinimide (NBS) was a convenient brominating agent in formation of allylic bromides from ­olefins, which is a free radical chain process and used as a standard synthetic procedure by now (Scheme 5.56). Radical allylic chlorination can proceed by using chlorine at high temperature in industry (Scheme 5.57). In contrast, in 1959, the groups of Hüttel and Hafner [71] independently reported the first preparation of the η3‐allylpalladium chloride dimer via a C─H allylic activation of a simple olefin by PdCl2. An allylic chloride could be produced with Pd(0) formed after a reductive elimination of the dimeric complex. Although it was not a practical method, it implied that Cl− could be a chlorine source when an effective oxidant was employed in the chlorination (Scheme 5.58). Scheme 5.56  Bromination of allylic sp3C─H bond with NBS.

Br

O N–Br

+

hν, CCl4

O NBS

Scheme 5.57  Chlorination of allylic sp3C─H bond with Cl2 at high temperature.

+ PdCl2

+ Cl2

Pd(II) HOAc, NaOAc 90 °C

Cl 400 °C

Cl

Scheme 5.58  Chlorination of allylic sp3C─H bond with PdCl2.

The most ideal oxidant is dioxygen (air) because it is so convenient, and the only byproduct is water in the oxidations of C─H bonds. Another similar ­oxidant widely used in industry is hydrogen peroxide (H2O2). In 1998, Minisci and coworkers [72] reported that a benzylic bromination was carried out by

129

130

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

using Br2 or NaBr/H2SO4 reagents and H2O2 as oxidant in H2O/CH2Cl2. Monobrominated products were obtained in 85–95% yield (Scheme  5.59). In  the following work, Mestres and Palenzuela [73] made this bromination reaction running in ester solvents instead of chlorinated solvents under ­illumination with a 100 W incandescent lamp, and Iskra and coworkers [74] developed a visible light‐induced benzylic bromination with HBr (1.1 equiv.)/ H2O2 in H2O (Scheme 5.60). Br + 5 mmol

Br2

+

3.5 mmol

H2O2(aq) 2.5 mmol

CH2Cl2/H2O Reflux, 4 h

92%

Scheme 5.59  Bromination of benzylic sp3C─H bond with Br2 using H2O2 as oxidant. Br + 1 mmol

HBr

+

1.1 mmol

H2O2(aq) 2 mmol

Visible light H 2O 27 °C, 10 h 79%

Scheme 5.60  Bromination of benzylic sp3C─H bond with HBr using H2O2 as oxidant.

For α‐bromination of ketones, in 2003 Wakharkar and coworkers [75] reported that acetophenones were brominated with HBr/H2O2 or TBHP in dioxane to give the corresponding monobromo products in 75–98% yield (Scheme 5.61). Other 1,3‐diketones, β‐ketoesters, cyclic ketones, and aryl alkyl and dialkyl ketones could be brominated by HBr/H2O2 in H2O even at room temperature [76]. In the chlorination and iodination of ketones, the HCl/H2O2 and I2/acid/H2O2 were also effective reagents to give α‐halogenated products [77]. O

O Br + HBr + H2O2(aq)

2 mmol

3 mmol

2.2 mmol

Dioxane Reflux, 20 h

95%

Scheme 5.61  α‐Bromination of ketone with HBr using H2O2 as oxidant.

Compared with hydrogen peroxide as oxidant, dioxygen used directly in α‐halogenations is rarely reported. However, it was found that some catalytic

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

s­ ystems including NO2− or NO3− for aerobic oxidative halogenations were very effective. For example, in 2006 Liang, Liu, and coworkers [78] reported an NaNO2‐catalyzed α‐bromination of aryl ketones with HBr under O2 in EtOH at 60 °C. The α‐monobromo products were obtained in 68–92% yield. Two key steps in the catalytic cycle included the oxidation of HBr by NO2− or NO2 to provide Br2, NO, and H2O and the regeneration of NO2 through oxidation of NO with O2 under mild conditions (Scheme 5.62). In 2014, Stavber and Prebil [79] developed an aerobic oxidative α‐chlorination of aryl or alkyl ketones with HCl to give the corresponding products in 42–90% yield in the presence of catalytic NH4NO3/I2 under air in MeCN at 60 °C. They suggested that NO2 from decomposition of HNO3 (HCl/NH4NO3) was the actual catalyst and oxidant to participate in both I−/I2 and NO2/NO/NO2 with air cycles, and the final α‐chlorinated products were generated from α‐iodinated products during the substitution reactions (Scheme 5.63). O

O

10 mmol

13 mmol

Br

20 mol% NaNO2

+ HBr + O2

EtOH/H2O 60 °C, 5 h

1 atm

90%

O2 NaNO2

HBr

NO

NO2

Br2

HBr

Scheme 5.62  α‐Bromination of ketone with HBr using catalytic NaNO2 in O2. O + HCl + Air

1 mmol

25 mol% NH4NO2 5 mol% I2 MeCN/H2O 60 °C, 24 h

O

O I

1.5 mmol 1 atm

Cl

66%

Scheme 5.63  α‐Chlorination of ketone with HCl using catalytic NH4NO2/I2 in air.

5.3.4.2  Fluorinating Reagent and Enantioselective Fluorination

Both nucleophilic and electrophilic fluorinating reagents are employed to make fluorinations happen according to the properties of substrates and products. An electrophilic fluorinating reagent “F+” acts as not only the fluorine source but also the oxidant in oxidations of C─H bonds to C─F bonds. For

131

132

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

example, in 2002 Nakagawa and coworkers [80] reported an example of Yb(OTf )3‐catalyzed allylic C─H fluorination of α‐methylstyrene with an electrophilic fluorinating reagent, N‐fluoro‐5‐(trifluoromethyl)pyridinium‐2‐ sulfonate. The allylic‐fluorinated product was obtained in 63% yield in CH2Cl2/ THF at room temperature (Scheme 5.64). Another electrophilic fluorinating reagent, Selectfluor (1‐chloromethyl‐4‐fluorodiazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), was very widely used with or without transition‐metal catalysts in allylic C─H fluorinations. F3C +

N+

F

25 mol% Yb(OTf)3

SO3–

CH2Cl2/THF rt, 9 h

F

63%

Scheme 5.64  Yb(III)‐catalyzed fluorination of allylic sp3C─H bond with N‐fluoro‐5‐ (trifluoromethyl)pyridinium‐2‐sulfonate.

In contrast, the application of nucleophilic fluorinating reagents was rarely reported in this field. In 2013, Doyle and Braun [81] disclosed an allylic C─H fluorination of olefins with Et3N∙HF to give major branched products in the presence of catalytic Pd/Cr with ligands and BQ as oxidant in DCE at 23 °C. The yields were 16–68%, and the ratios of branched and linear products were 2 : 1 to 7.8 : 1 (Scheme 5.65). Interestingly, in 2014 Lectka and coworkers [82] reported that cyclic and acyclic alkenes underwent a transition‐metal‐free allylic fluorination with both nucleophilic and electrophilic fluorinating reagents, AgF/PhSeCl and NFPy∙BF4 under N2 in CH2Cl2 at room temperature. A proposed reaction mechanism involved an electrophilic addition of PhSeF to the alkene to afford an intermediate and an oxidation of selenium on the intermediate by NFPy∙BF4 followed by an elimination of phenylselenium fluoride to produce the allylic fluoride (Scheme 5.66). O 5

+

Et3N • HF +

DCE, 23 °C, 72 h

O 0.2 mmol

1.2 mmol

15 mol% Pd(CF3CO2)2/ligand 10 mol% (R,R)-(salen)CrCl

0.4 mmol F

Ligand = Bn S O

O S

5

Bn

+

5

F

7.3 : 1 Total yield = 70%

Scheme 5.65  Pd(II)/(salen)Cr(III)‐catalyzed fluorination of allylic sp3C─H bond with Et3N·HF.

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom F + AgF + PhSeCl + NFPy • BF4

CH2Cl2 N2, rt, 24 h

0.25 mmol 0.25 mmol 0.3 mmol 0.55 mmol AgF

+

PhSeCl

66%

PhSeF F

PhSeF

F

F+

F –PhSeF, H+

Se+ Ph

SePh

F

Scheme 5.66  Fluorination of allylic sp3C─H bond with AgF/PhSeCl and NFPy·BF4.

An enantioselective version by Toste and coworkers [83] was established in 2013. It was crucial that the chiral phosphate anions carrying “F+” could make or cause the abstraction of hydrogen atom from allylic sp3C─H bond in the aid of the directing groups of substrate through hydrogen bonding. In these reactions, the electrophilic fluorinating reagent was Selectfluor, and the directing group for allylic fluorination of alkene was the amide or 2‐hydroxyphenyl group. The yields of β‐amino and β‐phenolic allylic fluorides were 56–92% with 76–97% ee (Scheme 5.67). O

O N H 0.1 mmol

Ph

+

Cl 10 mol% (R)-STRIP 2BF4– Na2CO3, toluene F rt, 18 h 0.135 mmol N N+

+

(R)-STRIP =

iPr

N F H

Ph

88% (92% ee)

iPr

iPr O O P O OH iPr

iPr

iPr

3

Scheme 5.67  Asymmetric fluorination of allylic sp C─H bond with Selectfluor using catalytic chiral phosphate anion.

Actually, in 2006 Sanford and coworkers [84] disclosed a Pd(OAc)2‐­catalyzed benzylic fluorination of 8‐methylquinoline by using N‐fluoro‐2,4,6‐trimethylpyridinium

133

134

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

+ N

N+

10 mol% Pd(OAc)2 Benzene, microwave 110 °C, 1 h –

F BF4

0.69 mmol

N F 75% Selectivity = 77%

1.07 mmol

Scheme 5.68  Pd(II)‐catalyzed fluorination of benzylic sp3C─H bond with N‐fluoro‐2,4,6‐ trimethylpyridinium tetrafluoroborate assisted by pyridine.

+ AgF + PhI(OPiv)2 N 0.19 mmol

0.96 mmol 0.38 mmol

10 mol% Pd(OAc)2 MgSO4, CH2Cl2 60 °C, 16 h

N

F

N

Pd

F 67%

Scheme 5.69  Pd(II)‐catalyzed fluorination of benzylic sp3C─H bond with AgF assisted by pyridine.

tetrafluoroborate as “F+” source. This was a quinoline‐directed ­oxidation via benzylic sp3C─H activation, and the catalytic cycle was a Pd(II)/Pd(IV)/Pd(II) with the “F+” oxidant. The yields were 49–75% in benzene under microwave irradiation at 100–110 °C (Scheme 5.68). In 2012, they used a nucleophilic fluorinating reagent AgF with PhI(OPiv)2 as oxidant instead of the expensive “F+” reagent in the Pd(II)‐ catalyzed benzylic fluorination of 8‐methylquinoline derivatives [85]. The yields were 30–70% in CH2Cl2 at 60 °C (Scheme 5.69). The hypervalent iodine PhI(OPiv)2 probably oxidized Pd(II) to Pd(IV) or AgF to PhIF2. Groves and Liu [86] developed an Mn(salen)‐catalyzed radical benzylic fluorination by using a nucleophilic fluorinating reagent, triethylamine ­trihydrofluoride (Et3N·3HF) or Et3N·3HF/AgF with iodosylbenzene (PhIO) as an oxidant. They suggested that the starting Mn(III)(salen)F catalyst was oxidized by PhIO to Mn(V)(O)(salen)F, then a benzyl radical and an Mn(IV) species were formed through the abstraction of hydrogen atom from the alkylbenzene substrate by Mn(V)(O)(salen)F, and finally the benzyl radical reacted with an Mn(IV)(salen)F2 complex to provide the fluorinated product and the Mn(III) catalyst. These reactions proceeded in CH3CN at 50 °C to give the corresponding products in 44–70% yield (Scheme 5.70). Meanwhile, it was also found that the Selectfluor was very effective in Fe‐ or photocatalyzed benzylic fluorinations. In the presence of chiral fluorinating reagents, metal catalysts with chiral ligands or chiral organocatalysts, enantioselective α‐fluorinations of carbonyl compounds have also been established. For example, in 1988 Lang and Differding

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom F + Et3N·3HF + PhIO AcO 1.2 mmol

0.8 mmol

20 mol% Mn(salen)Cl MeCN, 50 °C, 9 h

AcO

4.8 mmol

58%

F Mn(III)(salen)

PhIO

F PhI F

O Mn(V)(salen)

Mn(IV)(salen)

F

F OH

H2O

Mn(IV)(salen) HF

F

Scheme 5.70  (Salen)Mn(III)‐catalyzed fluorination of benzylic sp3C─H bond with Et3N·3HF.

[87] reported that optically pure N‐fluoro sultams could react with various prochiral metal enolates to afford the enantioselective α‐fluorinated ketones in up to 70% ee (Scheme 5.71). Takeuchi and coworkers [88] developed an approach to enantioselective fluorination of active sp3C─H bonds from cyclic and acyclic carbonyl compounds by using the combination of Selectfluor and cinchona alkaloid derivatives including dihydroquinine 4‐chlorobenzoate (DHQB) and dihydroquinidine acetate (DHQDA) as chiral sources in 2000. The reactions were carried out in MeCN/CH2Cl2 at −80 °C, and the products were obtained in  80–92% yield with 76–87% ee (Scheme  5.72). In the same year, Togni and Hintermann [89] reported an asymmetric α‐fluorination of β‐keto esters that was achieved in the presence of catalytic TiCl2‐TADDOLato complex in MeCN at room temperature, and the ee values were 62–90% (Scheme  5.73). Other transition‐metal catalysts including Ni, Pd, Ru, Fe, Co, Cu, etc. were also applied in the asymmetric α‐fluorination of β‐keto esters [90]. In 2005, the groups of Enders, Jørgensen, Barbas, and MacMillan [91] independently disclosed the organocatalytic enantioselective α‐fluorination of aldehydes, and the highest stereoselectivity was up to 99%. For example, Enders and Hüttl reported that both α‐fluoro aldehydes and α‐fluoro ketones could be prepared in the yields of 47–78% in the presence of catalytic (S)‐proline with

135

136

5  Oxidation of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom

OM

Scheme 5.71  Asymmetric α‐fluorination of ketone.

O

+

N F F up to 70% ee

SO2

N MeO

AcO H

H and

O

N+ Cl N+ 2BF4–

O

N F DHQDA/ Selectfluor

CO2Et

* CO2Et F

MeCN, –80 °C, overnight

89% (78% ee)

Scheme 5.72  Asymmetric α‐fluorination of β‐keto ester with Selectfluor/dihydroquinidine acetate (DHQDA).

O

O

O OEt

N+ N+

+ F

[ Ti ] =

Cl –

2BF4

O

Cat. [ Ti ]

*

MeCN, rt, 40 min

F

OEt

(62% ee)

R R R R

Cl O Ti NCMe NCMe Cl

R = 1-naphthyl

O

Scheme 5.73  Asymmetric α‐fluorination of β‐keto ester with Selectfluor using catalytic TiCl2‐TADDOLato complex.

Selectfluor in MeCN/CF3CO2H at room temperature. This was one of the early examples of enantioselective α‐fluorination of aldehydes and ketones even though the ee values were below 36% (Scheme 5.74). However, it was still hardly found that nucleophilic fluorinating reagents were used in the enantioselective α‐fluorinations. In 2014, Kita, Shibata, and coworkers [92] reported that the chiral hypervalent iodine catalyst ArIF 2 could be generated in situ by HF·pyridine,

5.3 ­Oxidations of Alkyl sp3C─H Bond Adjacent to Unsaturated Carbon Atom Enders and Hüttl [91a] O

O Cl

N+

+

N+

Cat. (S)-proline

2BF4–

F

F

*

MeCN, CF3CO2H rt

98% (Scheme  6.29). Compared with PhI=NTs, the inexpensive and commercially available chlora­ mine‐T (TsNClNa) just gave NaCl and N2 as the sole by‐products in the reac­ tions, which was a more green reagent. Yu and coworkers [42] also found that α‐tosylamino THF was obtained in 86% yield in the presence of catalytic copper(II) trifluoromethanesulfonate and PhI(OAc)2/p‐toluenesulfonamide as nitrene source in CH2Cl2 at 40 °C. O

+ TsNClNa · 3H2O

1 mmol

10 mol% CuCl MeCN, N2 rt, overnight

NHTs

O

1.3 mmol

62%

Scheme 6.28  Cu(I)‐catalyzed α‐amidation of tetrahydrofuran with chloramine‐T. Br TpBr3 = Br Br TpBr3Cu(NCMe)

N H N N N B N Br N Br

Scheme 6.29  TpBr3Cu(NCMe) complex.

Br

Br

Br

Br

However, in 2012 Ochiai and coworkers [43] developed a transition‐metal‐ free α‐amidation of cyclic and acyclic ethers with hypervalent N‐triflylimino‐λ3‐ bromane under Ar at room temperature. When THF was used as solvent, its α‐amidated product was obtained in 85% isolated yield. Surprisingly, even N‐tosylimino‐λ3‐iodane (PhI=NTs) underwent the metal‐free amidation with THF to afford its corresponding product in 70%. Two possible reaction ­pathways were suggested, in which imino‐λ3‐bromane acted as an active nitre­ noid species. One was a direct C─H insertion via a concerted asynchronous transition state the same as in the amidation of alkanes, and another was a stepwise insertion involving the formation of oxonium ylide (Scheme  6.30). After investigation of relative reactivities for amidation of THF and cyclohex­ ane, the results indicated that the rate of α‐amidation of THF was faster than that of cyclohexane by a factor of 110.

O

+ PhI=NTs

123 equiv.

1 equiv.

rt, Ar

O

Ts H N– I+H Ph

or

O+

N– Ts

Scheme 6.30  Metal‐free α‐amidation of tetrahydrofuran with PhI=NTs.

O 70%

NHTs

6.2  Oxidations of Alkyl sp3C─H Bond Adjacent to Heteroatom

6.2.2.2  Other Nucleophiles as Nitrogen Sources

Since α‐carbon radicals or α‐carbocations can be generated from simple amines and ethers, it is possible to form C─N bonds by using nucleophiles such as amides, anilines, or other N‐heterocyclic compounds with acidic hydrogen atoms as nitrogen sources. In 2007, Fu and coworkers [44] reported that primary and secondary amides underwent oxidative coupling reactions with phenyl‐substituted tertiary amines to produce the corresponding α‐amidated amines in 20–78% isolated yield in the presence of catalytic CuBr and t‐BuOOH (in decane) as oxidant under N2 at 80 °C. A crucial intermediate was the iminium ion generated from an amine substrate through sequential SET processes with t‐BuOOH and CuBr, followed by nucleophilic attack of an amide to lead to the formation of final product (Scheme 6.31). After 1 year, they [45] also used N‐halosuccinim­ ides as the oxidants in the same amidations. The reactions proceeded in ethyl acetate at room temperature and the yields were 40–64%. N

N+ +

H2N

+ tBuOOH O

4 mmol

2 mmol

5 mol% CuBr 80 °C, N2, 6 h

H N

N

O

3 mmol

76%

Scheme 6.31  Cu(I)‐catalyzed α‐amidation of tertiary amines with amide.

On the other hand, the formation of α‐C─N bonds of ethers has been achieved by oxidative coupling reactions in several groups. For example, in 2010 Li and coworkers [46] reported an FeCl3‐catalyzed coupling of α‐sp3C–H bonds of THF and simple acyclic ethers with N─H bonds of various azoles by using t‐BuOOH as oxidant and 4 Å MS in EtOAc at 80 °C. The yields of azole derivatives were 65–93%. In their proposed mechanism, Fe(III), t‐BuO·, and OH− were formed from the Fe(II) catalyst with t‐BuOOH first; then through sequential SET processes, an oxonium ion and Fe(II) were generated from an ether with t‐BuO· and Fe(III); and finally a nucleophilic azole attacked the ­oxonium ion to give the desired C─N coupling product (Scheme 6.32).

+ O 5 mmol

N

NH + tBuOOH

0.5 mmol

2.5 mol% FeCl3 · 6H2O DCE, 80 °C, 1 h

O+

1.5 mmol

Scheme 6.32  Fe(III)‐catalyzed α‐amination of tetrahydrofuran with azole.

O

N 88%

N

159

160

6  Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom

In 2011, Guo, Qu, and coworkers [47] used various purines as nitrogen sources to couple with simple ethers just in the presence of PhI(OAc)2 and iodine under nitrogen and irradiation with a 200‐W tungsten filament lamp at 70 °C. Notably, the reactions were carried out very well in the absence of any metal catalysts, and the yields were 43–96% (Scheme 6.33). They suggested that an oxonium ion was generated from an ether through radical processes under irradiation with light and PhI(OAc)2, and it was trapped subsequently by the nucleophilic purine to afford the corresponding product. Later, Hu and Buslov [48] developed a transition‐metal‐free α‐amination of simple cyclic and acyclic ethers with a variety of amides, imides, and amines by using a hypervalent iodine reagent Ph2IPF6 as oxidant at room temperature. Actually, the transfor­ mation was a one‐pot tandem reaction. Firstly, a strong base NaH was used to abstract acidic hydrogen of a nitrogen compound such as amide to form a sodium amide. Secondly, the sodium amide reacted with Ph2IPF6 to afford an ionic complex of diphenyliodonium and amide. After an SET process and a radical decomposition, a phenyl radical was formed to cleave the α‐sp3C─H bond of ether. The final coupling product was yielded via amide ion undergoing a nucleophilic reaction with the α‐ethereal radical or carbocation (Scheme 6.34). Cl N

+

O

Cl 1 mL

N N N H

N 1 mmol

+ PhI(OAc)2

I2 (trace) DCE, N2 hν, 70 °C, 4.5 h

N N

Cl

2 mmol

O

N Cl 96%

Scheme 6.33  Metal‐free α‐amination of ether with purine under light.

O O 1 mL

+

N H

1. NaH (0.5 mmol), rt, N2, 3 h 2. Ph2IPF6 (0.75 mmol) rt, N2, 6 h

0.5 mmol

O N O 71%

Scheme 6.34  Metal‐free α‐amidation of tetrahydrofuran with amide.

In addition, normal arylamines could be also employed successfully as nitrogen sources in the coupling reactions with α‐sp3C─H bonds of isochroman deriva­ tives and cyclic amides, which was reported by the Yang and Bao groups, ­respectively [49]. All of the reactions were carried out in the presence of cata­ lytic FeCl3 and TBHP as oxidant under nitrogen at 75 °C (Scheme 6.35).

6.2  Oxidations of Alkyl sp3C─H Bond Adjacent to Heteroatom Yang and coworkers [49a] HN NH2

O

+

0.5 mmol

+ tBuOOH 1 mmol

0.5 mmol

10 mol% FeCl2 · 4H2O

Bao and coworkers [49b] O N

0.5 mmol

61% O

NH2 + tBuOOH

+

O

Toluene, N2 75 °C, 24 h

2 mL

0.75 mmol

10 mol% FeCl3 75 °C, N2, 8 h

N HN 76%

Scheme 6.35  Fe‐catalyzed α‐amination of benzylic ether or cyclic amide with arylamine.

6.2.3 C─O Bond Formation

The common oxygen resources are alcohols and carboxylic acids in the α‐ oxygenation of simple amines, amides, and ethers because they are con­ venient and safe for operation in laboratories. Moreover, since they are nucleophiles, it is certainly feasible to introduce the alkoxy and acyloxy groups to the amines, amides, and ethers after carbon radicals or carbocations are generated via the cleavage of α‐sp3C─H bond. An early report by Weinberg and Brown [50] was an electrochemical α‐ alkoxylation of tertiary amines with methanol in 1966. Recently, Aubé and coworkers [51] developed an anodic oxidation in MeOH to prepare α‐meth­ oxylated lactams (a methoxy group adjacent to nitrogen) (Scheme  6.36). In fact, Murahashi and coworkers [52] reported a pioneering work on the RuCl2(PPh3)3‐catalyzed α‐oxidation of phenyl‐substituted tertiary amines with t‐BuOOH to afford the corresponding tert‐butyldioxy amines under mild con­ ditions in 1988. In the following work [53], they found that tert‐butyldioxy amides were also produced when the catalytic oxidation of amides with t‐BuOOH proceeded in benzene at room temperature, and β‐acetoxy β‐lactams were obtained with AcOOH in acetic acid at room temperature. They suggested that a ruthenium(II) complex reacted with t‐BuOOH to form Ru(II)OOt‐Bu, and then it was converted into a Ru(IV)═O species by cleavage of the O─O bond by protonolysis. An iminium ion complex was generated by electron transfer and subsequent proton transfer, which was an oxidative process accompanying the reduction of Ru(IV)═O species to Ru(II). Finally, another t‐BuOOH as a nucleophile attacked the iminium ion to produce the product. Since AcOH was more nucleophilic than AcOOH, acetoxy products were dominant in the oxidation of β‐lactams (Scheme 6.37).

161

162

6  Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom

O

N O

OMe Undivided cell C anode/cathode Et4NOTs, MeOH

O

N O

H 0.43 mmol

H 78%

Scheme 6.36  Electrochemical α‐alkoxylation of tertiary amine with methanol.

N + tBuOOH 2 mmol

OOBut

N

3 mol% RuCl2(PPh3)3 Benzene, rt, Ar, 3 h

4.4 mmol

93%

5 mol% Ru on carbon + AcOOH/AcOEt NH AcONa, HOAc O rt, 2.5 h 4.37 mmol 9.61 mmol

OAc O

NH 94%

OOBut

N

tBuOOH Ru(II) tBuOOH

N+

Ru(II)OOBut + Ru(II)OH Ru(IV) = O

N

Scheme 6.37  Ru(II)‐catalyzed α‐oxygenation of tertiary amine with t‐BuOOH.

In 2006, Yu and coworkers [54] established a Pd(OAc)2‐catalyzed acetoxyla­ tion of Boc‐protected amines. The reactions proceeded very well in the pres­ ence of I2 and PhI(OAc)2 as oxidant in DCE at 40–60 °C, and only methyl C─H bonds of amines were acetoxylated in 74–96% yield. They proposed that the reaction involved a Boc‐directed C─H activation process to give a Pd(II)–C complex, followed by a Pd(IV)–C complex formed in the oxidation of the

6.2  Oxidations of Alkyl sp3C─H Bond Adjacent to Heteroatom

Pd(II)–C complex with IOAc from I2 and PhI(OAc)2.. After a direct reductive elimination or substitution of α‐iodo amines with OAc−, the product was obtained and Pd(II) catalyst was regenerated (Scheme  6.38). In the case of 1‐phenylpiperidine, Liang and coworkers [55] found that cis‐diacetoxylation took place to afford its cis‐2,3‐diacetoxylated product in 42% yield just by using PhI(OAc)2 as oxidant in i‐PrOH with 5 Å MS at room temperature. The possi­ ble reaction pathway involved an oxidation of 1‐phenylpiperidine by PhI(OAc)2 to give its iminium ion, and an α,β‐unsaturated compound formed after β‐hydrogen elimination followed by oxidation and substitution with PhI(OAc)2 to lead the formation of the final product (Scheme 6.39). Boc N + PhI(OAc)2/I2

1 mmol

10 mol% Pd(OAc)2 DCE, 60 °C, 40 h

tBuO

Boc

AcO

OAc N Pd I O

N

1.6 mmol/1.6 mmol

83%

Scheme 6.38  Pd(II)‐catalyzed α‐acetoxylation of N‐Boc amine with PhI(OAc)2. OAc + PhI(OAc)2 N Ph 0.2 mmol

0.8 mmol

iPrOH,

5Å MS rt, 6 h

N Ph

N

OAc

Ph 42%

Scheme 6.39  Metal‐free α,β‐diacetoxylation of N‐phenyl amine with PhI(OAc)2.

The α‐alkoxylation of simple ethers such as THF with alcohols is a method for protection of hydroxy groups since hydrolysis of THF ethers can occur under milder acidic conditions. A general preparation of 2‐tetrahydrofuranyl ethers in high yield was reported by van der Gen in 1976 [56]. The reactions of THF with various alcohols were carried out very well just by the use of SO2Cl2 as oxidant in the presence of Et3N at room temperature. After that, many reac­ tion systems were established, such as THF in combination with cerium(IV) ammonium nitrate (CAN), TsCl/NaH, CrCl2/CCl4, peroxy‐λ3‐iodane/CCl4, Mn(0)/CCl4, O2/CH2═CHCH2Cl, etc. [57]. A common pathway in these reac­ tions involved the formation of 2‐tetrahydrofuranyl radical or cation, and then the radical undergoing halogenation followed by a nucleophilic substitution with the alcohol or the cation is trapped directly by the alcohol to give the THF‐ether (Scheme 6.40). Meanwhile, the OH bonds of o‐carbonyl-substituted phenols could couple with α‐sp3C─H bonds of cyclic ethers in the presence of transition‐metal

163

164

6  Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom

Scheme 6.40  α‐Alkoxylation of tetrahydrofuran with alcohols.

CCl4 Oxidant

O or

O

ROH

O O

Cl

+

ROH O

OR

catalysts and oxidants to produce acetals. For example, in 2012 Reddy, Kappe, and coworkers [58] found that Cu(OAc)2‐catalyzed coupling of THF with 2‐hydroxyacetophenone gave the α‐aryloxy THF in 74% yield by using TBHP as oxidant in decane at 100 °C (Scheme 6.41). Two years later, Wang, Chang, and coworkers [59] developed an Fe2(CO)9‐catalyzed cross‐coupling of cyclic ethers with 2‐formyl‐substituted phenols. In the case of THF with salicy­ laldehyde, their coupling product was obtained in 61% still yield by using TBHP as oxidant in decane at 110 °C (Scheme 6.42). They proposed that salicylalde­ hyde might form a coordination complex with iron catalyst followed by the complex undergoing nucleophilic attacking on the ethereal radical generated by abstraction of hydrogen from ether with TBHP. OH

O

O + tBuOOH (in decane)

+ O 2mL

1 mmol

O

5 mol% Cu(OAc)2 100 °C, 3 h

2.2 mmol

O 74%

Scheme 6.41  Cu(II)‐catalyzed α‐aryloxylation of tetrahydrofuran with 2‐hydroxyacetophenone. OH

O 2 mL

O

O + tBuOOH (in decane) 10 mol% Fe2(CO)9 110 °C, 90 min

+ 0.2 mmol

1.2 mmol

O O 61%

Scheme 6.42  Fe‐catalyzed α‐aryloxylation of tetrahydrofuran with 2‐hydroxyacetophenone.

In addition, Yuan, Xiang, and Guo [60] disclosed an α‐thiolation of ethers and amides (tertiary amines) with diaryl disulfides just by using di‐tert‐butyl ­peroxide (DTBP) as oxidant in 2013. This metal‐free coupling reaction proceeded very well in dioxane or DMA at 120 °C, and the alkyl aryl sulfides were obtained in 52–89% isolated yield. A radical process pathway was proposed, in which the crucial step was alkoxy radical intermediates generated via abstraction of hydrogen atoms from ethers by tert‐butoxyl radicals of DTBP (Scheme 6.43).

6.2  Oxidations of Alkyl sp3C─H Bond Adjacent to Heteroatom Ph

+

O

S S Ph

2 mL

0.5 mmol

+ (tBuO) 2

S 120 °C,12 h

O

O

4 mmol

76%

Scheme 6.43  Metal‐free α‐thiolation of tetrahydrofuran with diaryl disulfide.

On the other hand, in 2011, Wan and coworkers reported [61] a metal‐free cross‐coupling of simple cyclic and acyclic ethers with various carboxylic acids to prepare α‐acyloxy ethers. The products were obtained in 54–98% yield by using Bu4NI as a catalyst and TBHP as oxidant in EtOAc at 80 °C. In their ­suggested mechanism, TBHP could not only abstract a hydrogen atom from α‐sp3C─H bond of the ether to form an alkoxy radical intermediate but also oxidize I− to I2 via SET processes. Subsequently, the intermediate was oxidized by I2 to generate an oxonium ion which was trapped by a nucleophile, carboxy­ late ion to give the coupling product. Thus, I− was the real catalyst during the acyloxylation of ether (Scheme 6.44). Three years later, the Patel and Nagaiah groups [62] developed a Cu(OAc)2‐catalyzed acyloxylation of cyclic ethers with benzoic acids generated in situ from methylarenes or benzyl alcohols by using TBHP as oxidant (Scheme 6.45). O COOH + tBuOOH (in H2O)

+

O 10 mmol

20 mol% Bu4NI EtOAc, 80 °C, 12 h

O O

1.1 mmol

0.5 mmol

86%

Pathway: tBuOOH

I–

0.5I2

+

tBuO

+

OH–



PhCO2H

OH

PhCO2–

tBuO

O

O

+

H2O I2

O –

O+

PhCO2

O O

Scheme 6.44  Bu4NI‐catalyzed α‐acyloxylation of ether with benzoic acid. OH +

+ tBuOOH (in decane)

O 2 mL

1 mmol

4 mmol

O

5 mol% Cu(OAc)2 100 °C, 8 h

O

O 68%

Scheme 6.45  Cu(II)‐catalyzed α‐acyloxylation of tetrahydropyran with benzyl alcohol.

165

166

6  Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom

6.2.4 Others

Since α‐halogenated products from ethers are more unstable under normal conditions, halogenations are not going to be described. However, some other acidic sp3C─H bonds adjacent to heteroatoms, such as nitroalkanes, can be fluorinated smoothly. For example, Shreeve and Peng [63] reported that several nitroalkanes were α‐monofluorinated in 70–98% yield (four examples) by Selectfluor in the presence of a strong base, tetrabutylammonium hydroxide (TBAH), in CH3CN/H2O (Scheme 6.46).

C11H23

NO2

1. tBu4N+(OH)– (1.5 equiv.) MeCN/H2O 2. Selectfluor (1.5 equiv.)

F C11H23

NO2

98%

Scheme 6.46  α‐Fluorination of nitroalkane with Selectfluor.

6.3 ­Summary In this chapter, it is described that oxidation of alkyl sp3C─H bonds adjacent to heteroatoms is mainly to form new C─C, C─N and C─O bonds. According to the properties of these sp3C─H bonds affected by heteroatoms such as O and N atoms, they can be cleaved by strong bases, transition metals, or radi­ cal initiators to generate the corresponding intermediates including carbon anions, C─M bonds, carbon‐free radicals, or carbocations, respectively. Moreover, C─H insertion by carbenoid species can also occur under certain conditions. However, tertiary amines, protected amines, and ethers are more available in most cases because there are no acidic hydrogen atoms attached to N or O atoms, which are strongly susceptible to strong bases and other reagents. Except electrophiles attacking on carbon anions to give the prod­ ucts directly, nucleophiles can undergo either radical‐chain processes or combinations with carbocations probably formed from carbon radicals through SET processes to complete functionalizations. Compared with elec­ trophiles such as halides (C─X bonds), nucleophiles are a big family includ­ ing various salts, organometallic reagents, amines (N─H bonds), alcohols (O─H bonds), acidic C─H compounds, etc. Normally, the oxidative coupling reaction of α‐sp3C─H bonds with other N─H, O─H or C─H bonds is desir­ able based on mass efficiency. C─H activation by transition‐metal catalysts is one of several powerful and promising methods to achieve α‐functionali­ zation of amines and ethers with common nucleophiles. Meanwhile, effec­ tive and selective SET processes with or without other catalysts are also highly demanded and suitable for α‐oxidation of sp3C─H bonds linked to heter­ oatoms. Of course, oxidants, additives, solvents, and reaction conditions should be convenient, safe, and environmentally friendly in these reactions.

­References

During the cleavage of sp3C─H bonds adjacent to heteroatoms, selectivity is still a challenge in many functionalized compounds. For example, the chem­ oselectivity is not good for α‐oxidations of alcohols and amines with N─H bonds, and the stereoselectivity is just achieved by using chiral complex ­catalysts very well in the limited examples. Therefore, new concepts, princi­ ples, and strategies on the balance between reactivity and selectivity or even a reversal of the common orders of reactivity and selectivity are worth exploring and establishing for the future.

­References [1] Beak, P.; Lee, W. Tetrahedron Lett. 1989, 30, 1197–1200. [2] Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109–1117. [3] Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708–9710. [4] Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K. J. Am. Chem. Soc.

2001, 123, 5132–5133.

[5] Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. J. Am.

Chem. Soc. 2006, 128, 3538–3539.

[6] Millet, A.; Dailler, D.; Larini, P.; Baudoin, O. Angew. Chem. Int. Ed. 2014, 53,

2678–2682.

[7] Cordier, C. J.; Lundgren, R. J.; Fu, G. C. J. Am. Chem. Soc. 2013, 135,

10946–10949.

[8] McGrath, M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378–16379. [9] Gelardi, G.; Barker, G.; O’Brien, P.; Blakemore, D. C. Org. Lett. 2013, 15,

5424–5427.

[10] Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc.

1999, 121, 6509–6510.

[11] Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075–9076. [12] Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122,

3063–3070.

[13] Díaz‐Requejo, M. M.; Belderraín, T. R.; Nicasio, M. C.; Trofimenko, S.; Pérez,

P. J. J. Am. Chem. Soc. 2002, 124, 896–897.

[14] Fraile, J. M.; García, J. I.; Mayoral, J. A.; Roldán, M. Org. Lett. 2007, 9, 731–733. [15] Urry, W. H.; Juveland, O. O.; Stacey, F. W. J. Am. Chem. Soc. 1952, 74, 6155. [16] Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K.

J. Am. Chem. Soc. 1999, 121, 9546–9549.

[17] Suga, S.; Suzuki, S.; Yoshida, J.‐I. J. Am. Chem. Soc. 2002, 124, 30–31. [18] Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi, F.; Murai,

S. J. Am. Chem. Soc. 2000, 122, 12882–12883.

[19] Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am.

Chem. Soc. 2001, 123, 10935–10941.

[20] Murahashi, S.‐I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003,

125, 15312–15313.

167

168

6  Oxidation of Alkyl sp3C─H Bond Adjacent to Heteroatom

[21] Li, Z.; Li, C.‐J. J. Am. Chem. Soc. 2004, 126, 11810–11811. [22] Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005, 127,

11610–11611.

[23] Li, Z.; Bohle, D. S.; Li, C. Proc. Natl. Acad. Sci. 2006, 103, 8928–8933. [24] McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114–1117. [25] (a) Hanford, W. E.; US 2411158; 1946; (b) Hanford, W. E.; US 2411159; 1946;

[26] [27] [28] [29] [30] [31] [32]

[33] [34] [35] [36] [37] [38] [39] [40]

[41] [42] [43] [44] [45] [46]

(c) Hanford, W. E.; US 2433844; 1948; (d) Hanford, W. E.; Joyce, R. M.; US 2559638; 1951. Wallace, T.; Gritter, R. J. Org. Chem. 1961, 26, 5256. Wallace, T. J.; Gritter, R. J. J. Org. Chem. 1962, 27, 3067–3071. Jacobs, R. L.; Ecke, G. G. J. Org. Chem. 1963, 28, 3036–3038. Hirano, K.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 3617–3620. Oka, R.; Nakayama, M.; Sakaguchi, S.; Ishii, Y. Chem. Lett. 2006, 35, 1104–1105. Liu, Z.‐Q.; Sun, L.; Wang, J.‐G.; Han, J.; Zhao, Y.‐K.; Zhou, B. Org. Lett. 2009, 11, 1437–1439. (a) Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066–2067; (b) Shi, L.; Tu, Y.‐Q.; Wang, M.; Zhang, F.‐M.; Fan, C.‐A.; Zhao, Y.‐M.; Xia, W.‐J. J. Am. Chem. Soc. 2005, 127, 10836–10837; (c) Zhang, S.‐Y.; Tu, Y.‐Q.; Fan, C.‐A.; Zhang, F.‐M.; Shi, L. Angew. Chem. Int. Ed. 2009, 48, 8761–8765. Kamitanaka, T.; Hikida, T.; Hayashi, S.; Kishida, N.; Matsuda, T.; Harada, T. Tetrahedron Lett. 2007, 48, 8460–8463. Li, Z.; Yu, R.; Li, H. Angew. Chem. Int. Ed. 2008, 47, 7497–7500. Huang, X.‐F.; Zhu, Z.‐Q.; Huang, Z.‐Z. Tetrahedron 2013, 69, 8579–8582. He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011, 13, 5016–5019. Xie, Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.; Wang, L.; Pan, Y. Org. Lett. 2013, 15, 4600–4603. Liu, D.; Liu, C.; Li, H.; Lei, A. Chem. Commun. 2014, 50, 3623–3626. Xiang, S.; Zhang, B.; Zhang, L.; Cui, Y.; Jiao, N. Sci. China: Chem. 2012, 55, 50–54. Albone, D. P.; Challenger, S.; Derrick, A. M.; Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson, D. J. Org. Biomol. Chem. 2005, 3, 107–111. Fructos, M. R.; Trofimenko, S.; Díaz‐Requejo, M. M.; Pérez, P. J. J. Am. Chem. Soc. 2006, 128, 11784–11791. He, L.; Yu, J.; Zhang, J.; Yu, X.‐Q. Org. Lett. 2007, 9, 2277–2280. Ochiai, M.; Yamane, S.; Hoque, M. M.; Saito, M.; Miyamoto, K. Chem. Commun. 2012, 48, 5280–5282. Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813–3816. Liu, X.; Zhang, Y.; Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 6207–6212. Pan, S.; Liu, J.; Li, H.; Wang, Z.; Guo, X.; Li, Z. Org. Lett. 2010, 12, 1932–1935.

R ­ eferences

[47] Guo, H.‐M.; Xia, C.; Niu, H.‐Y.; Zhang, X.‐T.; Kong, S.‐N.; Wang, D.‐C.; Qu,

G.‐R. Adv. Synth. Catal. 2011, 353, 53–56.

[48] Buslov, I.; Hu, X. Adv. Synth. Catal. 2014, 356, 3325–3330. [49] (a) Chen, D.; Pan, F.; Gao, J.; Yang, J. Synlett 2013, 24, 2085–2088; (b) Sun, M.;

Zhang, T.; Bao, W. Tetrahedron Lett. 2014, 55, 893–896.

[50] Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31, 4058–4061. [51] Frankowski, K. J.; Liu, R.; Milligan, G. L.; Moeller, K. D.; Aubé, J. Angew.

Chem. Int. Ed. 2015, 54, 10555–10558.

[52] Murahashi, S.‐I.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988, 110,

8256–8258.

[53] (a) Murahashi, S.‐I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.;

[54] [55] [56] [57]

[58] [59] [60] [61] [62]

[63]

Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820–7822; (b) Murahashi, S.‐I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490–1501. Wang, D.‐H.; Hao, X.‐S.; Wu, D.‐F.; Yu, J.‐Q. Org. Lett. 2006, 8, 3387–3390. Shu, X.‐Z.; Xia, X.‐F.; Yang, Y.‐F.; Ji, K.‐G.; Liu, X.‐Y.; Liang, Y.‐M. J. Org. Chem. 2009, 74, 7464–7469. Kruse, C. G.; Broekhof, N. L. J. M.; van der Gen, A. Tetrahedron Lett. 1976, 17, 1725–1728. (a) Maione, A. M.; Romeo, A. Synthesis 1987, 1987, 250–251; (b) Yu, B.; Hui, Y. Synth. Commun. 1995, 25, 2037–2042; (c) Baati, R.; Valleix, A.; Mioskowski, C.; Barma, D. K.; Falck, J. R. Org. Lett. 2000, 2, 485–487; (d) Ochiai, M.; Sueda, T. Tetrahedron Lett. 2004, 45, 3557–3559; (e) Falck, J. R.; Li, D. R.; Bejot, R.; Mioskowski, C. Tetrahedron Lett. 2006, 47, 5111–5113; (f) Troisi, L.; Granito, C.; Ronzini, L.; Rosato, F.; Videtta, V. Tetrahedron Lett. 2010, 51, 5980–5983. Kumar, G. S.; Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem. Eur. J. 2012, 18, 6124–6128. Barve, B. D.; Wu, Y.; El‐Shazly, M.; Korinek, M.; Cheng, Y.‐B.; Wang, J.‐J.; Chang, F.‐R. Org. Lett. 2014, 16, 1912–1915. Guo, S.‐R.; Yuan, Y.‐Q.; Xiang, J.‐N. Org. Lett. 2013, 15, 4654–4657. Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J. 2011, 17, 4085–4089. (a) Rout, S. K.; Guin, S.; Ali, W.; Gogoi, A.; Patel, B. K. Org. Lett. 2014, 16, 3086–3089; (b) Raju, K. B.; Kumar, B. N.; Nagaiah, K. RSC Adv. 2014, 4, 50795–50800. Peng, W.; Shreeve, J. N. M. Tetrahedron Lett. 2005, 46, 4905–4909.

169

171

7 Oxidation of Alkenyl or Carbonyl sp2C─H Bond 7.1 ­Alkenyl and Carbonyl sp2C─H Bonds In organic chemistry, there are three geometries of carbon atom connecting with other atoms, which are tetrahedral, trigonal planar, and linear. According to the orbital hybridization, these structures of carbon compounds are related to sp3C, sp2C, and spC, respectively. Moreover, the tetrahedral sp3C compounds are saturated, and the other compounds containing sp2C or spC atom are unsaturated, where double or triple bonds as the functional groups are involved. These unsaturated bonds can be produced from the saturated bonds through oxidative processes, dehydrogenations or eliminations, etc. Certainly, sp2C─H and spC─H bonds are affected tremendously by the unsaturated bonds in their own transformations. Moreover, the sp2C─H bonds can be divided into two types: one is aromatic sp2C─H bond being on an aromatic ring, and another is nonaromatic sp2C─H bond, which can be found in alkenes, aldehydes, imines, etc. In this chapter, the sp2C─H bonds of alkene and aldehyde are focused upon, and the oxidations of them will be described (Scheme 7.1). Saturated H

Unsaturated H X

H

H

(X = C, N, O, etc.) sp3C–H

Aromatic sp2C–H

Nonaromatic sp2C–H

spC–H

Scheme 7.1  Saturated and unsaturated C─H bonds.

Alkenyl sp2C─H bonds are highly inert due to their both high BDEs (464 kJ/mol) and pKa values (~44). Compared with alkyl sp3C─H bonds described in the previous chapters, alkenyl sp2C─H bonds are not easy to break directly through radical process or proton abstraction. In contrast, the C═C bonds of alkenes Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

172

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

are more reactive especially in the electrophilic additions with cations or free radicals to give the corresponding carbon cations or carbon radicals or undergo the insertions into metal─H (C) bonds to form M─C─C─H(C) complexes. However, the C═C bonds could be regenerated from the carbon radicals through oxidation and subsequent elimination or from the M─C─C─H (C) complexes after β‐hydride elimination. Thus, an oxidation of alkenyl sp2C─H bonds can be established through multiple steps, and transition‐metal catalysts are normally necessary to complete the functionalizations of these C─H bonds, such as in the classical Mizoroki–Heck coupling reaction (Scheme 7.2). In addition, the selectivity is a challenge especially for the functionalization of an alkene with more than one sp2C─H bond. For example, propene CH3CH═CH2 has three sp2C─H bonds at different positions, and the corresponding three isomers may be yielded after functionalization of its sp2C─H bonds. Ar H

Ar-M

H

Ar

– M–H

M

Scheme 7.2  The Mizoroki–Heck reaction.

On the other hand, the C═O bonds of aldehydes are attacked readily by nucleophiles to undergo addition reactions. Similarly, after eliminations, the carbonyl sp2C─H bonds can be functionalized along with the C═O bonds regenerated, such as in the Cannizzaro reaction (Scheme 7.3). Meanwhile, the carbonyl sp2C─H bonds are not inert; for example, the BDE of sp2C─H bond from acetaldehyde CH3CHO is 374 kJ/mol, which is close to that of a benzylic sp3C─H bond of toluene (375 kJ/mol). Therefore, oxidations of carbonyl sp2C─H bonds are feasible and practical through radical processes. O O

OH– H

O–

H OH

O

H

OH O–

H H

Scheme 7.3  The Cannizzaro reaction.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds The C═C and C═O double bonds are the very important and useful motifs in natural products, pharmaceuticals, and materials, which can be formed by oxidations of saturated sp3C─H bonds through eliminations including

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

dehydrogenation, dehydration or dehydrohalogenation, and oxygenations, respectively. Meanwhile, directly introducing these double bonds into the target products is a powerful method in synthesis by using unsaturated reagents mainly including alkenes, alkynes, carbon monoxide, acyl halides, and so on, in which the oxidation of sp2C─H bonds from simple alkenes and aldehydes is one of the most convenient and green methods. 7.2.1 C─C Bond Formation

Transformation of alkenyl sp2C─H bonds to new C─C bonds can be achieved through coupling reactions normally using aryl halides as reagents in the presence of transition‐metal catalysts under mild conditions, which is called the Mizoroki–Heck coupling involving a cleavage of C─H bond by β‐hydride elimination. On the other hand, various ketones can be prepared by hydroacylations of alkenes or alkynes with aldehydes through a homolytic cleavage of the carbonyl sp2C─H bonds or an oxidative addition of transition metals to these C─H bonds. 7.2.1.1  Arylation and Alkenylation of Alkenes (The Mizoroki–Heck Coupling Reaction)

Actually, an oxidative coupling of aryl sp2C─H bonds with alkenyl sp2C─H bonds is the simplest approach to give alkenylated arenes, and its first example was reported by Fujiwara and Moritani in 1967 [1]. Since the key step is the activation of aryl sp2C─H bond by a transition‐metal complex, it will be described in detail in Chapters 9–13. At the same time, however, Heck found that olefins could undergo arylation, methylation, or carboxyalkylation with organomercury, ‐lead, and ‐tin compounds in the presence of Pd(II), Rh(III), or Ru(III) salts [2]. Remarkably, Pd(II)‐catalyzed arylation of olefins with arylmercuric salts was established by using CuCl2 as oxidant in CH3OH at room temperature. A reaction mechanism was proposed that an olefin could insert into the arylpalladium(II) intermediate resulting from the metal transformation between a palladium(II) salt and an arylmercuric reagent to afford alkylpalladium(II) complexes. After β‐hydride elimination from the complexes, an arylated olefin and a Pd(II)–H species were generated. The Pd(II)–H was reduced easily to Pd(0), and it was oxidized by CuCl2 to the Pd(II) complex for the next catalytic cycle (Scheme 7.4). In 1968, Fitton and coworkers [3] disclosed that Pd(0)‐phosphine complexes could undergo oxidative additions to various C─halogen bonds to give organopalladium(II) compounds such as methyl‐ and phenyl-palladium(II) compounds (Scheme 7.5). Based on these results, Mizoroki and coworkers [4] developed an effective Pd(II)‐catalyzed arylation of olefins such as ethylene and styrene with aryl iodides in 1971. For example, trans‐stilbene was obtained in 90% yield in the

173

174

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond Pd(II)Cl2

CuCl2 Pd(0)

Scheme 7.4  Pd(II)‐catalyzed arylation of olefin with arylmercuric reagent.

Ar-Hg(II)Cl

Ar-Pd(II)Cl H

Pd(II)–H

H Ar C C Pd(II)Cl

Ar

R

Ph3P Pd(PPh3)3

+ R–X

+ PPh3

Pd(II) X

PPh3

R = Me, Ph X = I

Scheme 7.5  Oxidative addition of C─halogen bonds to Pd(0) complex.

PdCl2 (1 mol%)‐catalyzed coupling of styrene with iodobenzene in the presence of KOAc in CH3OH under N2 at 120 °C (Scheme 7.6). One year later, Heck and Nolley [5] used Pd(OAc)2 as catalyst and n‐Bu3N instead of KOAc very well in the same coupling reactions of olefins with iodobenzenes. Furthermore, they found that benzylic chloride and β‐bromostyrene were available to give the corresponding benzylated and vinylated alkenes in good or moderate yields even though longer reaction time was needed. I + 50 mmol

100 mmol

1 mol% PdCl2 MeOH, KOAc 120 °C, N2, 2 h

90%

Scheme 7.6  Pd(II)‐catalyzed arylation of styrene with phenyl iodide.

A general reaction pathway included a step where an organopalladium(II) intermediate resulted from an oxidative addition of Pd(0) to a C─halogen bond, then an alkylpalladium(II) complex formed through an insertion of an ­olefin into the intermediate, and finally the functionalized olefin was ­produced and Pd(0) regenerated after a β‐hydride elimination of the Pd(II) complex (Scheme 7.7). Since then, the Mizoroki–Heck coupling reaction or Heck reaction was established.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds I

Pd(0)

Pd(II)I

Pd(II)–H

Pd(II) H

Scheme 7.7  Proposed mechanism of the Mizoroki–Heck coupling reaction.

In the coupling reactions related to alkenes, halides as coupling partners are much more convenient and safe than organometallic compounds such as organomercury, ‐lead, and ‐tin compounds initially employed by Heck. Especially, the formation of C─C bonds from C─H and C─halogen bonds is a redox process without any external oxidants. Among various aryl sp2C─halogen bonds, the order of reactivity is Ar–I > Ar–Br ≫ Ar–Cl to form aryl sp2C─M─halogen bonds through oxidative additions, which corresponds to the BDEs of 65, 81, and 96 kcal/mol, respectively. However, aryl chlorides are more convenient and economical compounds than other aryl halides in chemical synthesis. Thus, many researchers attempted to enhance the ability of Pd(0) complex with efficient ligands in activation of Ar─Cl bonds, especially those unactivated aryl chlorides without electron‐withdrawing groups. In 1984, two reports were found about the aryl chlorides in the Heck reaction [6]. One of them by Davison and coworkers disclosed that Pd(OAc)2‐catalyzed coupling of styrene with chlorobenzene produced trans‐stilbene in 53% yield at 130 °C. It was crucial that a bulky electron‐rich bidentate ligand, 1,2‐ bis(diphenylphosphino)ethane (dppe), was employed first in the Heck reaction (Scheme 7.8). 2 mol% Pd(OAc)2 2 mol% dppe

Cl +

dppe = Ph2P

NaOAc, DMF/H2O 130 °C PPh2

53%

Scheme 7.8  Pd(II)/dppe‐catalyzed arylation of styrene with phenyl chloride.

175

176

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

In 1992, Milstein and coworkers [7] used successfully the dippb ligand (dippb = 1,4‐bis(diisopropylphosphino)butane) in the arylation of olefins with aryl chlorides. For example, trans‐stilbene was obtained in 80% yield from styrene and chlorobenzene in the presence of catalytic Pd(OAc)2 (1 mol%)/dippb and NaOAc in DMF under N2 at 150 °C (Scheme 7.9). Cl

1 mol% Pd(OAc)2 2 mol% dippb

+

NaOAc, DMF 150 °C, N2, 24 h

12 mmol

10 mmol

80%

dippb = P

P

Scheme 7.9  Pd(II)/dippb‐catalyzed arylation of styrene with phenyl chloride.

More interestingly [8], when the rigid dippp ligand (dippp = 1,3‐bis(diisopropyl­ phosphino)propane) and a reducing agent Zn powder were employed instead of dippb and NaOAc in the same reaction, cis‐stilbene was obtained in 81% yield at 140 °C (Scheme 7.10). It was suggested that (dippp)PdCl2 was reduced by Zn to be the active Pd(0) catalyst. Cl

+

+

12 mmol

10 mmol

Zn

5 mmol

1 mol% Pd(OAc)2 2 mol% dippp DMF, 140 °C, Ar, 24 h 81%

dippp = P

P

Scheme 7.10  Pd(II)/dippp‐catalyzed arylation of styrene with phenyl chloride in the presence of Zn.

In 2001, Fu and Littke [9] reported that Pd2(dba)3/P(t‐Bu)3 effectively catalyzed the coupling of styrene with electron‐poor 4‐chloroacetophenone to afford the trans‐arylated product in 76% yield in the presence of Cy2NMe as base in dioxane at room temperature. In contrast, in the case of electron‐rich 4‐chloroanisole, its corresponding product was obtained in 72% at 120 °C. Meanwhile, a vinylation version also proceeded smoothly, as when 1‐chloro‐ 4‐tert‐butylcyclohexene reacted with styrene to lead to the formation of their coupled product in 66% yield at 110 °C (Scheme 7.11).

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

1.5 mol% Pd2(dba)3 3 mol% P(tBu)3

Cl +

Cy2NMe, dioxane rt, Ar, 32 h

O 0.887 mmol

76%

1.5 mol% Pd2(dba)3 6 mol% P(tBu)3

Cl +

Cy2NMe, dioxane 110 °C, Ar, 46 h

tBu

1.17 mmol

O

0.96 mmol

1.26 mmol

tBu

66%

Scheme 7.11  Pd(0)/P(t‐Bu)3‐catalyzed arylation or alkenylation of styrene with aryl or alkenyl chloride.

In fact, a lot of Pd(0), Pd(II), and other transition‐metal catalysts with or without ligands or additives in homogeneous and even in heterogeneous systems have been developed not only for enlarging scopes of olefins and coupling partners but also for enhancing turnover numbers and turnover frequencies in inter‐ and intra-molecular Heck reactions [10]. One of the unusual mechanisms of the Heck reaction relating to the Pd(II)/Pd(IV)/Pd(II) catalytic cycle was proposed by Jensen and coworkers in 2000 [11]. They found that the phosphinito palladium PCP pincer complex [PdCl{C6H3(OPPri2)2‐2,6}] (0.67 mol%) could catalyze the Heck reaction of styrene and chlorobenzene to give trans‐stilbene in >99% yield in the presence of CsOAc at 120 °C for 5 days or 180 °C for 24 h. Based on the excellent yield and the high thermal stability of the catalyst, they suggested that the catalytic process was initiated by the oxidative addition of the phosphinito PCP pincer Pd(II) catalyst with an alkenyl sp2C─H bond to form the first Pd(IV) complex, like an alkenyl sp2C─H activation process. After a reductive elimination of the intermediate and releasing HCl, the second Pd(IV) complex was yielded by the oxidative addition with Ar–Cl. Finally, the coupling product was obtained through the second reductive elimination of the Pd(IV) complex and the Pd(II) catalyst was regenerated (Scheme 7.12). In 2011, Shirakawa, Zhang, and Hayashi [12] revealed a transition‐metal‐free Mizoroki–Heck‐type arylation of styrene derivatives with aryl halides through a radical process. For example, trans‐stilbene was obtained in 66% yield from the coupling of styrene with iodobenzene just in the presence of catalytic EtOH and t‐BuOK in DMF under N2 at 80 °C. They proposed that an aryl halide was transformed to an aryl radical by a single‐electron transfer (SET) process with t‐BuOK, and then the aryl radical added with a styrene to form a benzylic radical; after direct elimination or elimination of a benzylic cation resulting from oxidation of the benzylic radical, the coupling product was obtained at last

177

178

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond O PPr i2

Ar

Ph

Ph

Pd Cl O PPr i2

O PPr i2

O PPr i2

Ph

Pd Ar Cl O PPr i2

Ph

Pd H Cl O PPr i2 O PPr i2 Pd

ArCl

O PPr i2

Ph

HCl

Scheme 7.12  Proposed mechanism of [PdCl{C6H3(OPPri2)2‐2,6}]‐catalyzed arylation of olefin with aryl chloride.

(Scheme 7.13). Neither aryl chlorides nor styrene derivatives with CF3 group, an electron‐withdrawing substituted group, were available in these reactions. However, the role of EtOH was unclear. I +

+ tBuOK

EtOH (20 mol%) DMF, 80 °C, N2, 2 h

0.23 mmol 1.2 mmol 0.69 mmol

66%

Scheme 7.13  tBuOK‐mediated arylation of styrene with phenyl iodide.

At the same time, Shi and coworkers [13] reported that 1,1‐diphenylethylenes underwent arylation with aryl iodides or bromides very well in the presence of catalytic bathophen and t‐BuOK in benzene at 110 °C (Scheme 7.14). They also suggested that these Heck‐type reactions involved radical intermediates, and the complex of t‐BuOK with bathophen, a dinitrogen ligand, was the radical precursor. In 2014, Rossi and coworkers [14] developed a t‐BuOK‐promoted Heck‐type arylation of styrene derivatives with aryl halides in DMSO or 18‐crown‐6 ether at room temperature. They found that the reactions were photoinduced. For example, the yield of (E)‐1‐methoxy‐4‐styrylbenzene was 87% in the coupling of styrene with 4‐iodoanisole under irradiation conducted by Philips HPI‐T 400‐W lamps, but it was decreased to 59% in the dark (Scheme 7.15). These transition‐metal‐free arylations of alkenes with aryl halides provide the complementary approaches to the traditional Heck coupling reactions.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

I + tBuOK

+ 0.5 mmol

1.5 mmol

Bathophen (30 mol%) Benzene, 110 °C, 36 h

1.5 mmol

78%

Ph

Bathophen = Ph N

N

Scheme 7.14  t‐BuOK‐mediated arylation of 1,1‐diphenylethylene with phenyl iodide using catalytic bathophen.

I +

+ tBuOK

MeO 0.5 mmol

5 mmol

1.5 mmol

18-crown-6 ether hν, rt, N2, 15 min

MeO

87%

Scheme 7.15  t‐BuOK‐mediated arylation of styrene with 4‐iodoanisole under irradiation at room temperature.

On the other hand, the selectivity of alkenyl sp2C─H functionalization in the Heck reaction has been studied as another important subject by many researchers. In the early Heck reactions, phenyl groups of aryl halides normally coupled to the less substituted carbons of the alkenyl double bonds. For example, in 1981, Hallberg and coworkers [15] found that methyl vinyl ether underwent the Heck reaction with 4‐nitrohalobenzene to give β‐aryl alkene in 52% total yield in the presence of catalytic Pd(OAc)2 with Et3N at 120 °C. However, only α‐aryl product, 4‐methoxyacetophenone, was isolated in 55% yield when 4‐iodoanisole was employed in the coupling reaction under identical conditions, which indicated that aryl reagents could change the regioselectivity in the arylations of alkenes (Scheme 7.16). After 9 years, Cabri and coworkers [16] established a highly regioselective palladium‐catalyzed α‐arylation of butyl vinyl ether with aryl triflates. It was found that acetophenone as the sole product was obtained in 92% yield from butyl vinyl ether and phenyl triflate in the presence of catalytic Pd(OAc)2/dppp (dppp = 1,3‐bis(diphenylphosphino)propane) with Et3N at 100 °C (Scheme 7.17). Later, they also reported [17] that aryl bromides or aryl iodides could undergo α‐arylation of olefins when a stoichiometric silver or thallium salt was added. It is now known well that there are two competing reaction pathways related to α‐ and β‐arylation in the Heck reaction. In the pathway A, after the dissociation

179

180

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond Br OMe O2N

+ O2N

52% (E/Z= 1 : 1)

Cat. Pd(OAc)2 Et3N, 120 °C, 5 h

OMe

OMe

O2N

O

OMe

I MeO

MeO

MeO

55%

Scheme 7.16  Regioselectivity in the Pd(II)‐catalyzed arylation of olefin with aryl halide.

OTf OnBu

+

3 mmol dppp = Ph2P

0.6 mmol

2.5 mol% Pd(OAc)2 2.75 mol% dppp Et3N, DMF 100 °C, 2 h

H+ OnBu

O 92%

PPh2

Scheme 7.17  Pd(II)/dppp‐catalyzed β‐arylation of olefin with phenyl triflate.

of an anion X (halide or triflate) from Ar–Pd–X, an ionic Ar–Pd(II)‐olefin complex is formed followed by the Ar group attacking on the positive α carbon to give the α product. In contrast, in the pathway B, an Ar–Pd(II)–X complex completes the insertion of alkene to afford β product as in the early Heck reactions (Scheme 7.18). Based on this principle, some regioselective and convenient Heck reactions using aryl halides as reagents have been developed. For example, in 2008, Xiao and coworkers [18] established a highly regioselective Pd(II)‐catalyzed α‐arylation of electron‐rich olefins including vinyl ethers, hydroxyvinyl ethers, enamides, and so on with a variety of aryl bromides just in 2‐propanol and particularly in ethylene glycol without any halide scavengers or salt additives. In their report, acetophenone was obtained in 81% yield from butyl vinyl ether and bromobenzene in the presence of catalytic Pd(OAc)2/dppp with Et3N in i‐PrOH at 115 °C. They also found that α‐regioselective arylation products could be produced in almost all of the protic solvents, and the α‐arylation rates were accelerated with the increase of parameter ETN expressing the hydrogen‐ bond‐donating capability of a solvent, which suggested that the formation of α product was favorably through an ionic reaction pathway A. In their one following work on extension of scope [19], it was reported that 4‐chloroanisole

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds R +

P Ar

P

X–

Ar

P

Pd

R

Pathway A

Pd

R

P

P

X

P Ar

ArX

R

P

Pd

P

Pd

P

P

Pd

X R

Pathway B

Base P

X

Ar

P H

Pd

R

P

α R

P X

Ar

X

Ar

Pd

Ar β

R

Scheme 7.18  Proposed mechanism of Pd‐catalyzed α,β‐arylation of olefin with aryl reagent.

reacted with 4‐methoxystyrene to afford α coupling product in 72% yield (α/β = 9/1) in the presence of catalytic Pd(OAc)2/4‐MeO‐dppp with KOH in ethylene glycol at 145 °C (Scheme 7.19). OMe Cl

2 mol% Pd(OAc)2 3 mol% 4-MeO-dppp KOH, ethylene glycol 145 °C, 10 h

+ OMe

MeO

+

OMe OMe

1 mmol

1.5 mmol

OMe

9:1 Total yield = 80%

Scheme 7.19  Pd(II)/4‐MeO‐dppp‐catalyzed β‐arylation of 4‐methoxystyrene with 4‐chloroanisole.

In addition, alkenylation of alkenes can also be achieved by the oxidative cross‐coupling of two different alkenes via dual C─H bond cleavage. In 2004, Ishii and coworkers [20] disclosed that an effective Pd(OAc)2 (10 mol%)‐catalyzed cross‐coupling of acrylates with vinyl carboxylates give their corresponding

181

182

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

coupling products in the presence of catalytic H4PMo11VO40 (2 mol%) in acetic acid under O2 (1 atm) at 70 °C. For example, the reaction of n‐butyl acrylate with vinyl acetate (1 : 5) could produce n‐butyl 5‐(acetoxy)‐2,4‐pentadienoate, in 70% yield (E/Z = 65/35). Since no dimerization of acrylate was observed, it was proposed that the formation of a vinyl Pd species from the more electron‐ rich alkene, vinyl acetate, and Pd(OAc)2 was the first step. Then σ‐Pd complex was formed by coordination and insertion of the electron‐deficient alkene, acrylate to the vinyl Pd species. After β‐hydride elimination, the corresponding diene and H–Pd–OAc were given. Finally, the H–Pd–OAc was oxidized by H4PMo11VO40/O2 to regenerate Pd(II) catalyst (Scheme 7.20).

CO2nBu 1 mmol

+

OAc + O2 5 mmol

10 mol% Pd(OAc)2 2 mol% H4PMo11V40

1 atm

NaOAc, HOAc 90 °C, 12 h

AcO

CO2nBu

70% (E/Z = 65/35) H-Pd-OAc

Pd(OAc)2 AcOPd

CO2nBu OAc

AcOPd

OAc CO2

nBu

Scheme 7.20  Pd(II)/H4PMo11VO40‐catalyzed cross‐coupling of olefins using O2 as oxidant.

In the following years, in this area many catalytic systems were established successfully by employing Pd, Rh, or Ru as catalyst with various oxidants such as Cu(II), Cu(II)/O2, Ag(I), O2, etc. [21]. In 2013, Bäckvall and Gigant [22] reported that various linear, cyclic, and heterocyclic alkenes could undergo alkenylation with other alkenes such as acrylate ester, styrene, allyl acetate, diethyl vinyl­ phosphonate, phenyl vinyl sulfone, etc. very well in the presence of catalytic Pd(OAc)2/p‐benzoquinone (BQ)/iron phthalocyanine (Fe(Pc)) (2.5–5/5–20/1– 2.5 mol%) in acetic acid/dimethylacetamide (1 : 1) or PivOH under O2 (balloon) at 70–120 °C (Scheme 7.21). Their biomimetic approach was effective in the regeneration of Pd(II) from Pd(0) through the oxidation process by using O2 as the terminal oxidant under the assistance of catalytic quantity of p‐BQ and Fe(Pc) as electron‐transfer mediators.

+ O2

CO2nBu + 1 mmol

2 mmol

1 atm

5 mol% Pd(OAc)2 2.5 mol% Fe(Pc) 20 mol% p-benzoquinone HOAc, 90 °C, 24 h

CO2nBu 56% (E/Z= 86/14)

Scheme 7.21  Pd(II)/Fe(Pc)/BQ‐catalyzed cross‐coupling of olefins using O2 as oxidant.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

7.2.1.2  Alkylation of Alkenes

An example of direct oxidative coupling of alkenyl sp2C─H bonds from styrenes with simple alkyl sp3C─H bonds was described in Chapter 3, which was a radical process by using DTBP as both oxidant and radical initiator in a Cu(II) catalytic system, and it was reported by Wei and Zhu in 2014 [23]. Actually, as early as 1998, Waegell, de Meijere, and Bräse [24] found that 1‐bromoadamantane could react with styrene to give exclusively (E)‐1‐styryladamantane in 41%  yield in the presence of catalytic Pd/C and K2CO3 in DMF at 120 °C (Scheme 7.22). According to the studies by Alexanian and Zhou [25] separately on palladium‐catalyzed intra‐ and inter-molecular alkylation of various olefins with alkyl iodides, the reaction pathways were proposed as follows: (i) an alkyl radical was formed through a homolytic breaking of the alkyl sp3C─I bond along with Pd(0) oxidized to Pd(I) species, (ii) the alkyl radical was added to the alkene to afford a coupled radical, and (iii) after a sequent oxidation and elimination with the Pd(I) species, the alkylation alkene was produced and the Pd(0) catalyst was regenerated (Scheme 7.23).

Br

+

Cat. Pd/C K2CO3, DMF 120 °C, 24 h

41%

Scheme 7.22  Pd(0)‐catalyzed alkylation of styrene with bromoadamantane. Scheme 7.23  Proposed mechanism of Pd(0)‐catalyzed alkylation of olefin with alkyl halide.

HX

R–X

Pd(0)

R R′

H–Pd(II)X R

R

R′

Pd(I)X R′

Pd(II)X R

R′

In 2002, Oshima and coworkers [26] used catalytic CoCl2(dpph) (dpph = 1,6‐ bis(diphenyl­phosphino)hexane) and Me3SiCH2MgCl as additive successfully in the alkylation of styrenes with various alkyl iodides, bromides, and chlorides. For example, (E)‐1‐styryladamantane was obtained in 90% from styrene and 1‐chloroadamantane in ether at 35 °C (Scheme 7.24). Other primary, secondary, and tertiary

183

184

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

alkyl halides gave the desired products in 55–95% yield. They also reported an intramolecular version in the same year and a mechanism study in 2006 [27]. They suggested that this was an SET process, and Me3SiCH2MgCl was very important to generate Co(I) and Co(II) species for the formation of intermediates and the catalytic cycle. C12H25 nC H Cl 12 25

+

1.5 mmol

Co(II)CH2SiMe3

C12H25

5 mol% CoCl2(dpph) Me3SiCH2MgCl Ether, 35 °C, 3 h 1 mmol

74%

Scheme 7.24  Co(II)‐catalyzed alkylation of styrene with alkyl chloride.

After that, many alkyl reagents such as α‐carbonyl, cyano, ester or benzyl alkyl bromides, alkyltrifluoroborates, and trifluoromethylation reagents were employed successfully in the Ni‐, Ru‐, Ir‐, or Cu‐catalyzed alkylation of olefins [28]. In some cases, the coupling of special alkenes with activated alkyl halides can proceed even in the absence of any transition‐metal catalysts under very mild conditions. For example, in 2014, Tang and coworkers [29] revealed an alkylation of di‐ and trisubstituted alkenes with 2‐chloro‐1,3-dithiane just by using a catalytic amount of BF3∙Et2O or in the absence of any catalysts. In their system, 1,1‐diphenylethene could couple with 2‐chloro‐1,3‐dithiane smoothly to produce 2‐(2,2‐diphenylvinyl)‐1,3‐ dithiane in 69% yield in DCE under air at room temperature (Scheme 7.25). S S Air DCE, rt, 48 h

S +

S Cl

0.25mmol

0.225 mmol

69%

Scheme 7.25  Metal‐free alkylation of 1,1‐diphenylethene with 2‐chloro‐dithiane.

7.2.1.3  Alkylation and Alkenylation of sp2C─H Bonds on Aldehydes (Hydroacylation and Coupling Reaction)

In 1949, Kharasch and coworkers [30] revealed that ketones were formed by the addition of aldehydes to 1‐alkenes, which might be initiated by photolysis or by acyl peroxides and involved an acyl radical formation via homolytic cleavage of the carbonyl sp2C─H bond. For example, 4‐dodecanone was obtained in 57% from butanal (excess) and 1‐octene in the presence of acetyl peroxide under reflux (Scheme  7.26). Unfortunately, besides the addition of long‐chain aldehydes to long‐chain 1‐alkenes through the radical chain process,

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

other hydroacylations of alkenes with aldehydes such as styrene and acetaldehyde gave the target ketone products in very low yields since polymerization took place easily in these cases. Three years later, Patrick [31] found that benzoyl peroxide could initiate the addition of acetaldehyde to diethyl maleate to give 2‐acetylsuccinate in 53% yield at 82–89 °C. After that, many reports based on free radical chemistry can be found, which indicate that various electron‐deficient alkenes and strained double bonds are particularly good acyl radical acceptors under irradiation or thermal conditions. O H

AcOOAc Reflux, 7h

+

0.846mol

O

0.162 mol

57%

AcOOAc O

O

Scheme 7.26  Alkylation of sp2C─H bond on butanal with 1‐octene.

In 1972, a transition‐metal complex, RhCl(PPh3)3 (Wilkinson’s complex), was introduced into an intramolecular alkene hydroacylation with aldehyde to give its cycloketone by Sakai and coworkers [32]. A catalytic version was established by Miller and Lochow in 1976 [33]. They found that 4‐pentenal could be cyclized to afford cyclopentanone in 72% yield by using 10 mol% Wilkinson’s complex in C2H4/CHCl3 at room temperature. It was suggested that an acyl‐ Rh(III)‐H species was formed by an oxidative addition of Rh(I) catalyst to the sp2C─H bond of aldehyde, subsequently the alkene inserted into the Rh(III) species followed by a reductive elimination to give both the desired ketone and the regenerated Rh(I) catalyst (Scheme 7.27). 10 mol% RhCl(PPh3)3

O H

CHCl3, C2H4 rt, 88 h

O

O Rh(III)–H 72%

Scheme 7.27  Rh(I)‐catalyzed cyclization of 4‐pentenal to cyclopentanone.

When Rh(acac)(C2H4)2 was used instead of Wilkinson’s complex, some intermolecular hydroacylation products were also detected. However, saturated aldehydes did not undergo the hydroacylation, indicating that the C═C might act as an effective ligand to stabilize the Rh(III) species. In 1979, Suggs [34] established a catalytic intermolecular hydroacylation of ethylene with 3‐methyl‐ 2‐aminopyridyl aldimines transformed from aldehydes. He still used Wilkinson’s

185

186

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

complex (5 mol%) in the reaction of the imines with an alkene to give the alkylated imines in THF at 160 °C. The pyridine motif was crucial to play a role of directing group during the reactions. After hydrolysis, the corresponding ketones were prepared finally (Scheme 7.28). This is an example on hydroacylation of alkenes with aldehydes (imines) in the presence of chelation assistance.

N Ph

N

+ C2H4

5 mol% RhCl(PPh3)3

N

THF, 160 °C, 6 h Ph

150 psi (1.03 Mpa)

H

N Rh(III)–H

N

N

Ph Moist silica gel O Ph 45%

Scheme 7.28  Rh(I)‐catalyzed alkylation of sp2C─H bond on imine with ethylene assisted by pyridine group.

When a chiral rhodium catalyst, [Rh(S,S‐chiraphos)2]Cl (chiraphos = 2S,3S‐ bis(diphenylphosphino)butane), was introduced into an intramolecular hydro­ acylation of racemic DL‐2‐phenylpropionaldehyde by James and Young in 1983 [35], the corresponding cyclopentanone was obtained in 40–50% yield with a maximum of 52% ee at 160 °C (Scheme 7.29). O H Ph

Cat.Rh(S,S-chiraphos)2Cl 160 °C, N2, 10 h

Ph O

1 mL

40% (52% ee) TON = 240

(S,S)-chiraphos = Ph2P

PPh2

Scheme 7.29  [Rh(S,S‐chiraphos)2]Cl‐catalyzed asymmetric cyclization of 4‐pentenal to cyclopentanone.

Later, Sakai and coworkers [36] reported that the cyclization of achiral 4‐ pentenals could provide a cyclopentanone product in 71% yield with 76% ee by use of Rh(dipmc)Cl catalyst (dipmc = trans‐1,2‐bis[(diphenylphosphino)methyl]cyclohexane) in CH2Cl2 at room temperature (Scheme 7.30). In their work [37], the enantioselectivity could be up to 99% in the cyclization of certain substrates when [Rh(BINAP)]ClO4 was employed as the catalyst. In 2007, Bolm and Stemmler [38] gave an example on the enantioselective intermolecular

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

hydroacylation of norbornenes with salicylaldehydes. In the presence of catalytic Rh(acac)(C2H4)2, they found that monodentate phosphoramidite ligands gave an endo product in 98% yield with 54% ee, and bidentate phosphine ligands led to the formation of an exo product in 95% yield with 82% ee (Scheme 7.31). Ph

O

25 mol% Rh(dipmc)Cl CH2Cl2, rt, 4 h

H Ph

O 71% (76% ee)

dipmc =

PPh2 PPh2

Scheme 7.30  Rh(dipmc)Cl‐catalyzed asymmetric cyclization of 4‐pentenal to cyclopentanone.

OH

H

O

HO

5 mol% Rh(acac)(C2H4)2 10 mol% (S)-MonoPhos

H +

O

DCE, 80 °C, 1 h

OH OH

0.3 mmol

1.8 mmol

98% (95 : 5 dr, 54% ee)

(S)-MonoPhos = O P–NMe2 O

OH

OH

O 5 mol%Rh(acac)(C2H4)2 5.5 mol% diphosphine DCE, 80 °C, 0.5 h

H + NO2 0.3 mmol

1.8 mmol

Diphosphine =

O H

NO2 95% (99 : 1 dr, 82% ee)

PR′2 PR2 Fe

R = 3,5-Me2-4-MeOC6H2 R′ = 3,5-(CF3)2C6H3

Scheme 7.31  Rh(acac)(C2H4)2‐catalyzed asymmetric alkylation of sp2C─H bond on salicylaldehyde with norbornene.

187

188

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

One year later, Willis and coworkers [39] developed an enantioselective hydroacylation of 1,3‐disubstituted allenes with β‐S‐substituted aldehydes by using a MeDuPhos‐derived cationic rhodium catalyst. In some cases, both high yield (95%) and ee value (94%) were obtained (Scheme 7.32). SMe O H

CF3 + Hex

0.15 mmol



10 mol% [Rh((R,R)-Me-DuPhos)]ClO4 Acetone, 40 °C, N2, 24 h

0.3 mmol

CF3

SMe O Hex 95% (94% ee)

(R,R)-Me-DuPhos = P

P

Scheme 7.32  [Rh((R,R)‐MeDuPhos)]ClO4‐catalyzed asymmetric alkylation of sp2C─H bond on β‐S‐substituted aldehyde with 1,3‐disubstituted allene.

In 2009, Tanaka and Shibata [40] disclosed that 1,1‐disubstituted alkenes and acrylamides could undergo enantioselective hydroacylation successfully with unfunctionalized aldehydes such as hydrocinnamaldehyde in (CH2Cl)2 at 80 °C. They suggested that strong bidentate coordination of substituted acrylamides to the cationic Rh(I) with (R,R)‐QuinoxP* ligand was favorable to give both high product yields (73–87%) and ee values (96–99%) (Scheme 7.33). O

5 mol% Ph [Rh((R,R)–QuinoxP*)]BF4 N Ph (CH2Cl)2, 80 °C, 16 h

H+ 0.55 mmol

O 0.5 mmol

Ph N Ph

O O 87% (98% ee)

tBu

(R,R)-QuinoxP* = N

P

N

P tBu

Scheme 7.33  [Rh((R,R)‐QuinoxP*)]BF4‐catalyzed asymmetric alkylation of sp2C─H bond on aldehyde with 1,1‐disubstituted alkene.

Alkyne hydroacylation was also established by researchers to give α,β‐unsaturated carbonyl compounds. For example, in 1990 Tsuda, Saegusa, and Kiyoi [41] reported that an Ni(cod)2/P(n‐C8H17)3‐catalyzed addition of simple aryl and alkyl aldehydes with symmetrical internal alkynes could afford the α,β‐enones with main E‐form. In the reaction of isobutyraldehyde with 4‐octyne, the

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

corresponding enone was obtained in 93% yield in THF at 100 °C, and the stereoselectivity was 93 : 7 (E : Z) (Scheme 7.34). They proposed that the formation of acyl‐Ni‐H complex was involved in their reactions.

+

H

O

5 mol% Ni(cod)2 10 mol% P(nC8H17)3

O

THF, 100 °C, 20 h 1 mmol

1.5 mmol

93% (E : Z = 93 : 7)

Scheme 7.34  Ni‐catalyzed alkenylation of sp2C─H bond on aldehyde with symmetrical internal alkyne.

After that, other transition‐metal catalysts such as Rh and Ru were employed successfully in the alkyne hydroacylations with simple aldehydes and O‐ or S‐chelation aldehydes [42]. In 2002, Jun and coworkers [43] used 2‐amino‐3‐ picoline as an added chelating auxiliary to develop an Rh(I)‐catalyzed hydro­ acylation of terminal alkynes with aryl and alkyl aldehydes. It was found that aryl aldehydes reacted with terminal alkynes to produce branched α,β‐enones exclusively using Wilkinson’s complex as catalyst in the presence of catalytic amount of benzoic acid in toluene at 80 °C. In contrast, only E‐ α,β‐enone product was isolated in 74% yield without any branched adducts in the reaction of hexanal with tert‐butylacetylene under identical conditions (Scheme 7.35). O Ph

+ H H

O C5H11

H

0.216 mmol

+ H

C4H9

tC

4H9

0.432 mmol

5 mol% Rh(PPh3)Cl 40 mol% 2-amino-3-picoline 20 mol% benzoic acid Toluene, 80 °C,12 h

O C4H9

Ph

92% O C5H11

tC

4H9

74%

Scheme 7.35  Rh(I)/2‐amino‐3‐picoline‐catalyzed alkenylation of sp2C─H bond on aldehyde with terminal alkyne.

For intramolecular alkyne hydroacylation, Fu and Tanaka [44] demonstrated that cyclopentenones could be prepared very well in an [Rh(dppe)]2(BF4)2‐catalyzed hydroacylation of 4‐alkynals in acetone at room temperature in 2001. It was found that the combination of Rh catalyst with ligand and solvent was crucial to the success of their reactions. Interestingly, when a chiral catalyst, [Rh((R)‐Tol‐BINAP)](BF4), was employed in the hydroacylation of racemic 4‐alkynes with 3‐methoxy group, not only cyclopentenones but also cyclobutenones were obtained with high ee values (up to 99%) in CH2Cl2 at room

189

190

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

temperature, which was a catalytic parallel kinetic resolution. They suggested that the acyl‐Rh(III)‐H species could undergo either trans‐ or cis‐addition to the triple bonds to lead the formation of five‐membered rings and four‐ membered rings, respectively, under these conditions [45] (Scheme 7.36). O

10 mol% [Rh(dppe)]2(BF4)2

H

O

Acetone, rt, Ar, 48 h

Ph

Ph 0.581 mmol O

OMe

H

88% O CH2Cl2,rt, Ar, 21 h

Ph

Ph 47% (84% ee) O

H

ion

Rh

OMe 45% (88% ee)

O

R

R s–a

Ph

Rh

ddit

a Cis– Tran

R

+ OMe

0.398 mmol

O

O

5 mol% [Rh((R)-Tol-BINAP)](BF4)

O

ddit

ion

Rh

O R

R

Scheme 7.36  [Rh(dppe)]2(BF4)2‐catalyzed cyclization of 4‐alkynals.

Meanwhile, α,β‐unsaturated carbonyl compounds should also be prepared directly from the oxidative cross‐coupling of carbonyl sp2C─H bonds with alkenyl sp2C─H bonds. Based on Satoh and Miura’s [46] previous work on the Rh‐catalyzed oxidative coupling of salicylaldehydes with internal alkynes to produce chromone derivatives, Glorius and coworkers [47] reported a Rh(III)‐catalyzed coupling of salicylaldehydes with olefins to give 2′‐hydroxychalcones and/or aurones in 2012. In their reactions, [(Cp*RhCl2)2] /C5H2Ph4 was employed as catalyst, and Cu(OAc)2 was selected as an effective oxidant. Salicylaldehyde reacted with styrene to afford the coupling product in 66% yield in DCE at 120 °C, and it coupled with ethyl acrylate to give the cyclization product in 76% yield (E/Z = 98/2) under the same conditions (Scheme 7.37). It was presumed that the successive oxidative cyclization was inhibited since styrene was less electrophilic than ethyl acrylate. They suggested that this coupling was an oxidative Heck‐type reaction involving acyl‐Rh(III) species formation with the assistance of OH group, alkene insertion, β‐hydride elimination, and reoxidation of Rh(I) to Rh(III) using Cu(II) salt, etc.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds O

O H + OH 0.2 mmol

CO2Et + Cu(OAc)2 0.4 mmol 0.8 mmol 2.5 mol% (Cp*RhCl2)2 10 mol% C5H2Ph4 or DCE, 120 °C, Ar, 18 h Ph 0.4 mmol

O CO2Et 76% (Z/E = 98 : 2) O Ph

+ Cu(OAc) 2 0.4 mmol

OH 66%

Scheme 7.37  Rh(III)‐catalyzed coupling of sp2C─H bond on aldehyde with alkene.

One year later, Lei and coworkers [48] revealed a CuCl2‐catalyzed coupling of simple aryl aldehydes with styrenes to afford E‐α,β‐enones by using TBHP as oxidant. Under N2 at 80 °C, (E)‐chalcone was obtained in 63% yield from the coupling of benzaldehyde with styrene, and 2‐naphthaldehyde gave its desired product in 80% yield. It was proposed that t‐BuO· and a highly valent Cu species were formed after an SET between t‐BuOOH and Cu catalyst. Then, an acyl radical was generated from the aldehyde through hydrogen abstraction with t‐BuO· followed by an addition of the acyl radical to styrene to give a benzylic radical. Finally, after oxidation and deprotonation with the highly valent Cu species, the benzylic radical was transformed to the α,β‐enone product, and the Cu catalyst was regenerated (Scheme 7.38). O

O H

2.5 mmol

tBuO

+

+ tBuOOH 0.5 mmol O

20 mol% CuCl2 80 °C, N2, 12 h

1.25 mmol

63% O

Scheme 7.38  Cu(II)‐catalyzed coupling of sp2C─H bond on aldehyde with styrene.

In addition, N‐heterocyclic carbenes (NHCs) can be used as organocatalysts in the transformation of aldehydes, which is the functionalization of acyl sp2C─H bonds [49]. The mechanism is that an acyl anion equivalent, the Breslow intermediate, is generated in the nucleophilic addition of the NHC to  the aldehyde; subsequently, the intermediate can undergo nucleophilic ­addition to another aldehyde to afford a benzoin condensation product or can participate in the addition with an unsaturated bond such as alkene or alkyne, etc. to give an acylated product even with high enantioselectivity in a Stetter

191

192

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

reaction and hydroacylation (Scheme 7.39). Based on the unique properties of NHCs in the nucleophilic addition of C═O double bonds of aldehydes, it is worthwhile exploring the reactions proceeding through an indirect cleavage of carbonyl sp2C─H bonds to achieve the alkylation or alkenylation of aldehydes in the absence of any transition metals (Scheme 7.40). 1

R Ar N

O R1

O– H

+ Ar N

Y

Y

R2

R1

OH

R2

R1

H

OH Benzoin condensation

O

H R1

O

O



O

Acyl anion Y

O R2

Ar N

R1 R3

R3

R2 O Stetter reaction

Breslow intermediate

Scheme 7.39  Benzoin condensation and the Stetter reaction. O R2

O R1

H

+

R3

or R3 R2

R1 NHC

or

R3 R2 O

R1

R3 R2

Scheme 7.40  N‐heterocyclic carbene (NHC)‐catalyzed alkylation or alkenylation of aldehydes.

7.2.1.4  Alkynylation of sp2C─H Bonds on Aldehydes

Not only enones but also ynones can be prepared by coupling reactions via the cleavage of sp2C─H bonds on aldehydes. For example, in 1997, Fuchs and Gong [50] reported that ynones were produced as major products in a radical coupling of some aldehydes with acetylenic trifluoromethyl sulfones. The reactions were carried out in the presence of azoisobutyronitrile (AIBN) in CH3CN at reflux. However it was suggested that acyl radicals were generated through a hydrogen abstraction by CF3∙ from acetylenic trifluoromethyl sulfones in the chain propagation sequence, and a byproduct, decarbonylation alkyne, was not avoided (Scheme  7.41). Obviously, a suitable alkynylation reagent, acetylenic trifluoromethyl sulfone, was very important in their reactions. In the following reports by other researchers, it was also found that ethynyl benziodoxolones (EBX) as the effective alkynylation reagents could be successfully employed in transition‐metal (Ir, Rh, etc.)‐catalyzed or even metal‐free carbonyl sp2C─H oxidative alkynylation of aldehydes.

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds O SO2CF3 O

20 mol% AIBN

+

O

MeCN, Reflux, 1.5 h

H 1 equiv.

1.3–1.5 equiv.

82% 2

Scheme 7.41  Alkynylation of sp C─H bond on aldehyde with acetylenic trifluoromethyl sulfone.

In the case of terminal alkyne, in 2015 Lei and coworkers [51] demonstrated that simple aryl aldehydes could undergo alkylation very well with terminal aryl or alkyl alkynes in the presence of catalytic Zn(OTf )2/In(OTF)3, NEt3, and PhCOCF3 (α,α,α‐trifluoroacetophenone) as oxidant, which is an oxidative cross‐ coupling of carbonyl sp2C─H bonds with alkynyl spC─H bonds. For example, 1,3‐diphenylprop‐2‐yn‐1‐one was obtained in 73% yield from the coupling of benzaldehyde with ethynylbenzene (1 : 1) in toluene at 80 °C. The reaction pathway was suggested to involve an alkynyl zinc species formed from the terminal alkyne with zinc salt and NEt3, a propargylic alcohol complex generated through a nucleophilic addition of the alkynyl zinc to the zinc‐coordinated aldehyde, and the alkynylated aldehyde prepared after a hydrogen transfer process between the propargylic alcohol complex and PhCOCF3 (Scheme  7.42). This is also an example of the indirect cleavage of carbonyl sp2C─H bonds by nucleophilic addition and elimination related to carbonyl groups. H

O H

+

0.5 mmol

0.5 mmol

0.6 mmol

Ph

–H+

Zn Ph Ph

73% Zn

O H [Zn], Et3N

O

15 mol% Zn(OTf)2 5 mol% In(OTf)3 + PhCOCF3 Et3N, toluene 80 °C, 27 h

H

O

O H

Ph

Ph Ph

CF3

H+

[Zn],

O Ph Ph OH

Ph

CF3

Scheme 7.42  Zn(II)/In(III)‐catalyzed coupling of aldehyde with terminal alkyne.

7.2.1.5  Arylation of sp2C─H Bonds on Aldehydes

A direct method of arylation of aldehydes is the oxidative cross‐coupling of carbonyl sp2C─H bonds with aryl sp2C─H bonds, like the Fujiwara–Moritani reaction. Other approaches are related to the use of effective arylation reagents

193

194

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

under certain reaction conditions. In 1985, Hirao and coworkers [52] successfully used organovanadium reagents generated in situ in dichloromethane from vanadium trichloride and organo-lithium or magnesium compounds (1 : 1) in the formation of ketones from aldehydes through a sequent nucleophilic addition and elimination. For example, benzophenone was prepared in 66% yield from benzaldehyde and PhMgBr in toluene at reflux (Scheme  7.43). Other alkylation and arylation reactions of aldehydes could also proceed under the same conditions. Ishiyama and Hartwig [53] developed an RhCl(cod)/P(n‐Pr)3‐catalyzed coupling of aryl iodides or bromides with N‐pyrazyl aryl aldimines to form the corresponding diaryl ketimines through a Heck‐type process in 2000 (Scheme 7.44). Since aldimines and ketimines are analogues of aldehydes and ketones, respectively, this is a method for arylation of sp2C–H bonds on imines or aldehydes with chelation assistance. Two years later, Cheng and coworkers [54] established a direct Ni(dppe)Br2‐catalyzed coupling of aryl iodides with simple aryl aldehydes. In the presence of Zn in THF at 110 °C, benzophenone was prepared in 84% yield from benzaldehyde and PhI. It was proposed that a nucleophilic addition of aryl‐Ni species with C═O groups was involved, and Zn or its salts could abstract or supply halide ions from or to Ni complexes during the reactions (Scheme 7.45). In 2008 and 2010, Xiao and coworkers [55] reported that alkyl aryl ketones could be prepared very well by a bis(dibenzylideneacetone)palladium complex (Pd(dba)2)‐ catalyzed coupling of aryl bromides or chlorides with alkyl aldehydes (RCH2CHO) in the presence of ligands, pyrrolidine, and 4 Å MS. In the cases of aryl bromides, dppp, dppf [(1,1-bisdiphenylphosphino)ferrocene], PPh3, or BINAP were effective as ligands in DMF at 110 °C. However, a bulky, electron‐rich monophosphine was necessary in acylation of aryl chlorides in DMA at 110 °C. Pyrrolidine was a crucial substance for the formation of an enamine with the aldehyde and the neutralization with the acid HX (Scheme 7.46). In fact, their reactions were the couplings of enamines with aryl halides, like the Heck‐type way. O

O H

1 mmol

+ PhMgBr + VCl3 1 mmol

CH2Cl2, Toluene Reflux, 16 h

1 mmol

66% 2

Scheme 7.43  V(III)‐mediated arylation of sp C─H bond on benzaldehyde with PhMgBr.

N N

+ Ar2–I, Br

N H

Ar1

5 mol% RhCl(cod) 5 mol% P(n-Pr)3 Base, 135–160 °C

N N Ar2

O

H3O+

N Ar1

Ar1

Scheme 7.44  Rh(I)‐catalyzed arylation of sp2C─H bond on imine with aryl iodide or bromide assisted by pyrazine group.

Ar2

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds +

O

O

10 mol% H + Ph I + Zn Ni(dppe)Br2 THF 110 °C, 30 h 1 mmol 1.5 mmol 2.75 mmol

P P

Ni

O H

84%

Scheme 7.45  Ni(II)‐catalyzed arylation of sp2C─H bond on benzaldehyde with PhI.

O

+

1.2 mmol

+

N H

H

2 mmol

O

+ H

2 mmol

Br 2 mol% Pd(dba)2 3 mol% dppp

O N

H3O

+

4 Å MS, DMF 115 °C, N2, 6 h 1 mmol

N H 1.5 mmol

81%

+ MeO

Cl 2 mol% Pd(dba) 2 6 mol% ligand H3O+ 4 Å MS, DMA 140 °C, 4 h

1 mmol

O

OMe 60%

Ligand = N

P(tBu)2 OMe

Scheme 7.46  Pd(0)‐catalyzed arylation of sp2C─H bond on aldehyde with aryl bromide or chloride in the presence of pyrrolidine.

7.2.2 C─Heteroatom Bond Formation

Transformations of alkenyl or carbonyl sp2C─H bonds to their corresponding C─O and C─N bonds are very important and useful both in laboratory and in industry. For example, olefins can be oxidized directly to afford aldehydes or ketones by the Wacker process. The intramolecular amination of olefins provides an approach to prepare heterocycles such as indoles. The formation of esters and amides from simple aldehydes is a convenient and complementary method in the synthesis of carboxylic acid derivatives.

195

196

7  Oxidation of Alkenyl or Carbonyl sp2C─H Bond

7.2.2.1  Oxygenation and Amination of Alkenyl sp2C─H Bonds (The Wacker and Aza‐Wacker Processes)

In 1959, Smidt and coworkers [56] working for Wacker Chemie disclosed that methyl ketones could be prepared from normal 1‐alkenes with water in the presence of catalytic PdCl2 and stoichiometric CuCl2 under acidic, aqueous, and aerobic conditions. This is an early example to employ a transition‐metal catalyst and a milestone for palladium catalysis, which was called the Wacker process later. In 1964, Clement and Selwitz [57] improved this process by using catalytic PdCl2/CuCl2 (10/10 mol%) in DMF(dimethylformamide)/H2O (7 : 1) with bubbling O2 at 60–70 °C, and 2‐dodecanone was obtained in 87% yield from 1‐dodecene in this catalytic system. Twenty years later, Tsuji and coworkers [58] found that the reaction could proceed very well to give 2‐decanone in 73% yield (gram scale) from 1‐decene at room temperature when 1 equiv. of CuCl was used instead of CuCl2 under balloon pressure of dioxygen. In the classical Wacker process, olefin is oxidized by Pd(II) with water to give an enol and Pd(0) through insertion and β‐hydride elimination, and then the enol is transformed to its stable keto form, a methyl ketone. Moreover, Pd(II) is regenerated from Pd(0) by Cu(II) oxidant, and dioxygen is the terminal oxidant to oxidize Cu(I) to Cu(II) effectively during the Pd(II) regeneration (Scheme 7.47). PdCl2

+

OH

R + H2O

Pd(0) + 2CuCl2

Pd(II)

+ Pd(0) + 2HCl R

PdCl2 + 2CuCl

2CuCl + 1/2O2 + 2HCl

R + 1/2O2

R

O

2CuCl2 + H2O O R

Scheme 7.47  The Wacker process.

Obviously, it is an important task to explore an effective oxidation of Pd(0) to Pd(II) by dioxygen under mild conditions in the development of the Wacker process. In 1990, Bäckvall and coworkers [59] established successfully a triple catalytic system including Pd(OAc)2/hydroquinone/Fe(Pc) (5/15/5 mol%) for aerobic oxidation of olefins to ketones. For example, 2‐decanone was obtained in 73% yield from 1‐decene in the presence of HClO4 (5 mol%) in DMF/H2O (9 : 1) under oxygen (1 atm) at room temperature (Scheme 7.48). In 2006, Kaneda and coworkers [60] found that 2‐decanone could be produced in 85% yield just by using catalytic PdCl2 (0.5 mol%) in DMA (dimethylacetamide)/H2O (6 : 1) under pressured oxygen (6 atm) at 80 °C (Scheme 7.49). Meanwhile, Sigman and Cornell [61] also used Pd[(−)‐sparteine]Cl2 as catalyst (1 mol%) without any additives effectively in the Wacker process under balloon pressure of O2 or air at 70 °C (Scheme 7.50).

7.2 ­Oxidations of Alkenyl and Carbonyl sp2C─H Bonds

C8H17 + O2 1.5 mmol

5 mol% Pd(OAc)2 5 mol% Fe(Pc) 15 mol% hydroquinone

HClO4, DMF/H2O rt, 3 h 1 atm

N

O

N

C8H17 73%

N N

Fe

Fe(Pc) = N

N

N N

Scheme 7.48  Pd(II)/Fe(Pc)/hydroquinone‐catalyzed oxygenation of alkene with O2 at room temperature. Scheme 7.49  PdCl2‐catalyzed oxygenation of alkene with O2.

+ O2

C8H17 1 mmol

C10H21 + Air 0.8 mmol

1 mol% Pd[(–)-sparteine]Cl2

DMA/H2O 80 °C, 3 h

C8H17

6 atm

83%

O

DMA/H2O, 70 °C, 18 h

Balloon

O

0.5 mol% PdCl2

C10H21 71%

Scheme 7.50  Pd[(−)‐sparteine]Cl2‐catalyzed oxygenation of alkene with air.

In the Wacker process, another challenge is about selectivity, that is, the transformation of 1‐alkenes to aldehydes through anti‐Markovnikov (AM) addition. In 1986, Feringa [62] reported that a mixture of decanal and 2‐decanone with a ratio of 60/40 was obtained in 27% yield in the PdCi(NO2)(MeCN)2/ CuCl2‐catalyzed oxidation of 1‐decene in t‐BuOH under dioxygen at 30 °C (Scheme  7.51). No aldehyde was found in the absence of CuCl2 or t‐BuOH. However, only phenylacetaldehyde was found in 90%), but the amount of homocoupling products still dominated. In 2014, Shi and coworkers [49] revealed that the high selectivity for the unsymmetrical diynes (>10 : 1) could be achieved very well when dppm(AuBr)2 catalyst (2.5 mol%) was used in the presence of Phen (phenanthroline) ligand (10 mol%) and PhI(OAc)2 (2 equiv.) as oxidant in the oxidative cross‐coupling of terminal alkynes. For instance, 1‐ethynyl‐4‐ fluorobenzene and 2‐methylbut‐3‐yn‐2‐ol (1.3 : 1) underwent the catalytic coupling to give the corresponding unsymmetrical diyne in 85% yield (selectivity of hetero/homo = 12 : 1) in CH3CN/dioxane (3 : 1) at 50  °C (Scheme  8.40). According to the test results, they suggest that PhI(OAc)2 and the N,N‐ligand (1,10‐Phen) were crucial in the formation of a gold(III) acetylide from the gold(I) acetylide and in the reductive elimination of dialkynylgold(III) species to give the unsymmetrical product.

227

228

8  Oxidation of Alkynyl spC─H Bond

R

H + CuCl

R

NH2OH • HCl

Br

Cu

R′ MeOH

EtNH2, MeOH, N2

R

R′

Scheme 8.38  The Cadiot–Chodkiewicz cross‐coupling.

H

+

2 mmol

I 1 mmol

10 mol% CuI Pyrrolidine rt, 30 min

C5H11 95%

Scheme 8.39  CuI‐catalyzed cross‐coupling of terminal alkyne with alkynyl iodide at room temperature.

H + PhI(OAc)

H + HO

F

0.13 mmol

0.1 mmol

2.5 mol% dppm(AuBr)2 10 mol% phenanthroline MeCN/dioxane 50 °C, 15 min

2

0.2 mmol F

OH 83% (hetero/homo = 12 : 1)

dppm = Ph2P

PPh2

Scheme 8.40  Au‐catalyzed cross‐coupling of two different terminal alkynes.

8.2.1.5  Formation of Alkynyl spC─Heteroatom Bonds

Heteroatom‐substituted alkynes (heteroatom = N, O, Cl, Br, or I, etc.) can be prepared directly through the oxidation of alkynyl spC─H bonds with the heteroatom reagents under corresponding conditions. A synthesis of a β‐lactam ynamide from t‐butyl ester of propiolic acid and 4‐iodomethylazetidin‐2‐one was disclosed by Domiano and coworkers in 1985 [50], the first example on the oxidative amidation of terminal alkynes with amides to form the spC─N bonds. This coupling reaction was carried out in the presence of stoichiometric CuCl under O2 in hexamethylphosphoramide (HMPA) at 0 °C (Scheme 8.41). In 2008, Stahl and coworkers [51] established the first Cu‐catalyzed aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles including cyclic or acyclic carbamate, amide, urea, and indole. For instance, phenylacetylene reacted with β‐lactam (1 : 5) to give the coupling product in 89% yield by using CuCl2 as catalyst (20 mol%) with pyridine and Na2CO3 as base under O2 (1 atm) in toluene at 70  °C. They proposed a catalytic mechanism involving sequential abstractions of hydrogen from the terminal alkyne and nitrogen nucleophile with the bases, a C─N reductive elimination of the alkynyl amidate Cu(II) intermediate, and an aerobic reoxidation of the Cu catalyst (Scheme 8.42). Later, Evano and coworkers [52] prepared ynimines from terminal alkynes and

8.2  Oxidations of spC─H Bond

diaryl imines successfully in the same catalytic system. Another route to amination of 1‐alkynes was to employ the hypervalent iodine reagent PhI(OAc)NTs2 as nitrogen source in the absence of any metal complex, which was reported by Muñiz and coworkers in 2012 [53]. A variety of terminal arylalkynes underwent very well the coupling reactions with PhI(OAc)NTs2 to afford the corresponding ynamides in 59–93% yield in DCE at 80  °C. In the proposed mechanism, it was suggested that the hypervalent iodine reagent PhI(OAc)NTs2 coordinated to the aryl acetylene to form a σ‐alkynyl iodine(III) species after loss of acetic acid. Subsequently, an addition of the free bistosylimide nucleophile to the triple bond took place to give an alkylidenecarbene while releasing iodobenzene. Finally, the ynamide was produced via a rearrangement of the alkylidenecarbene (Scheme 8.43). Actually, in 1987 Stang and coworkers [54] disclosed that the synthesis of alkynyl tosylates and mesylates could be achieved smoothly through the corresponding σ‐alkynyl iodine(III) species with a catalytic Cu(I) salt at room temperature, in which the spC─O bonds were formed (Scheme 8.44). CH2I

CH2I H

CO2tBu +

+

NH

O

CuCl

O2

CO2tBu

N

HMPA, 0 °C O

40%

Scheme 8.41  CuCl‐mediated amination of terminal alkyne with amide. O O H +

+ NH

0.1 mmol

R

O2 1 atm

0.5 mmol

20 mol% CuCl2

R

LnCu(II)X2

NR′Z O2 HX/base

89%

H Base

R

LnCu(II)

N

Pyridine, Na2CO3 Toluene, 70 °C, 4 h

R LnCu(II)

NR′Z

X H–NR′Z Base

Scheme 8.42  CuCl2‐catalyzed amination of terminal alkyne with amide using O2 as oxidant.

229

230

8  Oxidation of Alkynyl spC─H Bond

H + PhI(OAc)(NTs2) 10 mmol

NTs2

DCE, 80 °C, 20 min

9.8 mmol

78%

PhI(OAc)(NTs2) Ts2N– H

–HOAc

Ts2

–PhI

Ph

I+(OAc)

N–

Ts2N

I+

Ph

Scheme 8.43  Amination of terminal alkyne with PhI(OAc)(NTs2). +

H

H3C

PhI(OH)OTs

10 mL

+

I+Ph–OTs

H3C

7.9 mmol I+Ph–OTs

H3C

DCM, rt, 20 h

19%

CuOTf

MeCN, rt, 2 h

H3C

1 mmol

1.45 mmol

OTs 38%

Scheme 8.44  Oxygenation of terminal alkyne with PhI(OH)(OTs) at room temperature.

In 2012, Qing and coworkers [55] demonstrated a metal‐free oxidative trifluoromethylthiolation of terminal arylalkynes to afford spC─SCF3 bonds just by use of CF3SiMe3 and elemental sulfur. For example, phenylacetylene coupled with S8 (6 equiv.) and CF3SiMe3 (5 equiv.) to give the trifluoromethylthiolated product in 96% yield in the presence of KF under air in DMF at room temperature. They suggested that the active SCF3 anion was a crucial species generated from CF3SiMe3 and elemental sulfur, and that elemental sulfur also played a role of oxidant in this trifluoromethylthiolation of terminal alkynes (Scheme 8.45). H

+

0.2 mmol

CF3SiMe3

CF3SiMe3

+

1 mmol

1.2 mmol

KF

S8

KSCF3

S

S8 + DMF H

SCF3

KF, DMF rt, air, 6 h

Ph

96% H

S8 + DMF NMe2

Ph

SCF3

S H

NMe2

Scheme 8.45  Metal‐free trifluoromethylthiolation of terminal alkyne with CF3SiMe3 and S8 at room temperature.

8.2  Oxidations of spC─H Bond

Based on many previous methods for the formation of spC─halo bonds using various halogen reagents, especially N‐bromosuccinimide (NBS), in 2014, Liang, Jin, and coworkers [56] developed an effective metal‐free halogenation of spC─H bonds by using NBS, N‐iodosuccinimide (NIS), or N‐chlorophthalimide (NCP) as the halogen source (1.1 equiv.) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene, DBU (1.1 equiv.) in MeCN at room temperature. For example, the yields of 1‐chloro‐4‐(haloethynyl)benzenes were 96, 99, and 86% (halo = I, Br, and Cl), respectively. In the reaction mechanism, it was proposed that an electrophilic bromine species was generated from the NBS and DBU followed by the formation of a π‐coordinated complex of the alkyne with the bromine species. Finally, the complex was transformed to the alkynyl halide with the release of succinimide after abstraction of hydrogen from the spC─H bond (Scheme 8.46). O Br + O

R

O

N H

N Br

N

O

N

R

H

O O

Br N+

N–

O

O

N Br N

N O

R

H

O

N– Br N+

N

N

Scheme 8.46  Proposed mechanism of metal‐free bromination of terminal alkyne with NBS.

8.2.2  Oxidations of spC─H Bond of Hydrogen Cyanide

In fact, the formal oxidation products of hydrogen cyanide HCN are R─CN or Ar─CN, which are also the cyanation products containing the C─spCN bonds. However, although the heterolytic cleavage of the spC─H bond of HCN, a weak acid (pKa = 9.4), is not difficult, the equivalents such as KCN, NaCN, and (CH3)3SiCN are more often employed as the effective cyanation reagents to replace the HCN itself having a low boiling point (26 °C) and a high toxicity in synthesis. Therefore, the cyanation reaction is not described in this book.

231

232

8  Oxidation of Alkynyl spC─H Bond

8.3 ­Summary Since spC─H bonds of terminal alkynes are acidic, the spC− anions or spC─M species can be generated by bases, even by weak bases in the presence of transition‐ metal complexes such as copper salts. Thus, terminal alkynes normally act as alkynylation reagents in chemical synthesis. They can undergo either the nucleophilic substitution/addition with primary alkyl halides/carbonyl compounds or the catalytic coupling reactions including the Sonogashira coupling and the Cadiot–Chodkiewicz coupling with alkyl, aryl, alkenyl, and alkynyl halides to prepare various internal alkynes. In some cases, oxidative couplings via dual C─H bonds cleavage can also be achieved very well by use of dioxygen or even air as the terminal oxidant, like the Glaser coupling of terminal alkynes. However, catalytic oxidative cross‐coupling involving the activation of inert alkyl sp3C─H or aryl sp2C─H bonds is not convenient, which is described in other chapters. Notably, not only carbon monoxide but also carbon dioxide is available to play a role of carbonylation, carboxylation reagent in the preparation of alkynyl esters, amides, and carboxylic acids. The coinage metal catalysts such as Cu and Ag can make these reactions happen under very mild conditions. In addition, spC─heteroatom bonds (N, O, S, Cl, Br, I, etc.) can also be formed from alkynyl spC─H bonds with some special reagents under certain conditions. Overall, alkynyl spC─H bonds are more active than alkyl sp3C─H, aryl sp2C─H, and alkenyl sp2C─H bonds to be transformed to C─C and C─heteroatom bonds in synthesis. By now, it is emphasized to develop the catalytic oxidations of spC─H bonds with normal partners in the absence of noble metals and halides under mild conditions.

­References [1] Andrussow, L. Ber. Dtsch. Chem. Ges. A/B 1927, 60, 2005–2018. [2] DeRoy, P. L.; Surprenant, S.; Bertrand‐Laperle, M.; Yoakim, C. Org. Lett. 2007,

9, 2741–2743.

[3] Truong, T.; Daugulis, O. Org. Lett. 2011, 13, 4172–4175. [4] (a) Cassar, L. J. Organomet. Chem. 1975, 93, 253–257; (b) Dieck, H. A.; Heck,

F. R. J. Organomet. Chem. 1975, 93, 259–263.

[5] Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315. [6] Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,

4467–4470.

[7] Ogawa, T.; Kusume, K.; Tanaka, M.; Hayami, K.; Suzuki, H. Synth. Commun.

1989, 19, 2199–2207.

[8] Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. Tetrahedron Lett. 1992, 33,

5363–5364.

­Reference

[9] Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem.

1993, 58, 4716–4721.

[10] Thomas, A. M.; Sujatha, A.; Anilkumar, G. RSC Adv. 2014, 4, 21688–21698. [11] Li, J.‐H.; Li, J.‐L.; Wang, D.‐P.; Pi, S.‐F.; Xie, Y.‐X.; Zhang, M.‐B.; Hu, X.‐C.

J. Org. Chem. 2007, 72, 2053–2057.

[12] (a) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem. 2004, 6, [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]

215–218; (b) He, H.; Wu, Y.‐J. Tetrahedron Lett. 2004, 45, 3237–3239. Jiang, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synthesis 2008, 2417–2426. Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642–13643. Altenhoff, G.; Würtz, S.; Glorius, F. Tetrahedron Lett. 2006, 47, 2925–2928. Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078–12079. Pérez García, P. M.; Ren, P.; Scopelliti, R.; Hu, X. ACS Catal. 2015, 5, 1164–1171. Yi, J.; Lu, X.; Sun, Y.‐Y.; Xiao, B.; Liu, L. Angew. Chem. Int. Ed. 2013, 52, 12409–12413. Kobayashi, T.; Tanaka, M. J. Chem. Soc. Chem. Commun. 1981, 333–334. Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057–3060. Hao, W.; Sha, J.; Sheng, S.; Cai, M. J. Mol. Catal. A: Chem. 2009, 298, 94–98. Neumann, K. T.; Laursen, S. R.; Lindhardt, A. T.; Bang‐Andersen, B.; Skrydstrup, T. Org. Lett. 2014, 16, 2216–2219. Tsuji, J.; Takahashi, M.; Takahashi, T. Tetrahedron Lett. 1980, 21, 849–850. Sakurai, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1999, 40, 1701–1704. Izawa, Y.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2004, 77, 2033–2045. Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M. J. Organomet. Chem. 2001, 622, 84–88. Gadge, S. T.; Khedkar, M. V.; Lanke, S. R.; Bhanage, B. M. Adv. Synth. Catal. 2012, 354, 2049–2056. Tsuda, T.; Ueda, K.; Saegusa, T. J. Chem. Soc. Chem. Commun. 1974, 380–381. Tsuda, T.; Chujo, Y.; Saegusa, T. J. Chem. Soc. Chem. Commun. 1975, 963–964. Fukue, Y.; Oi, S.; Inoue, Y. J. Chem. Soc. Chem. Commun. 1994, 2091. Zhang, W.‐Z.; Li, W.‐J.; Zhang, X.; Zhou, H.; Lu, X.‐B. Org. Lett. 2010, 12, 4748–4751. Inamoto, K.; Asano, N.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. Org. Biomol. Chem. 2012, 10, 1514–1516. Yu, B.; Diao, Z.‐F.; Guo, C.‐X.; Zhong, C.‐L.; He, L.‐N.; Zhao, Y.‐N.; Song, Q.‐W.; Liu, A.‐H.; Wang, J.‐Q. Green Chem. 2013, 15, 2401–2407. Yu, B.; Xie, J.‐N.; Zhong, C.‐L.; Li, W.; He, L.‐N. ACS Catal. 2015, 5, 3940–3944. Gooßen, L. J.; Rodríguez, N.; Manjolinho, F.; Lange, P. P. Adv. Synth. Catal. 2010, 352, 2913–2917.

233

234

8  Oxidation of Alkynyl spC─H Bond

[36] [37] [38] [39] [40]

[41] [42] [43] [44] [45] [46]

[47] [48] [49] [50] [51] [52] [53] [54] [55] [56]

Yu, D.; Zhang, Y. Proc. Natl. Acad. Sci. 2010, 107, 20184–20189. Yu, D.; Tan, M. X.; Zhang, Y. Adv. Synth. Catal. 2012, 354, 969–974. Yu, D.; Zhang, Y. Green Chem. 2011, 13, 1275–1279. Zhang, X.; Zhang, W.; Ren, X.; Zhang, L.‐L.; Lu, X.‐B. Org. Lett. 2011, 13, 2402–2405. (a) Kim, S. H.; Kim, K. H.; Hong, S. H. Angew. Chem. Int. Ed. 2014, 53, 771–774; (b) Arndt, M.; Risto, E.; Krause, T.; Gooßen, L. J. ChemCatChem 2012, 4, 484–487; (c) Liu, X.‐H.; Ma, J.; Niu, Z.; Yang, G.; Cheng, P. Angew. Chem. Int. Ed. 2015, 54, 988–991. (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422–424; (b) Glaser, C. Ann. Chem. Pharm. 1870, 154, 137–171. Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737–738. Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321. Stefani, H. A.; Guarezemini, A. S.; Cella, R. Tetrahedron 2010, 66, 7871–7918. Cheng, G.; Zhang, H.; Cui, X. RSC Adv. 2014, 4, 1849–1852. (a) Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819–869; (b) Cadiot, P.; Chodkiewicz, W. Chemistry of Acetylenes. Viehe, H.‐G., Ed.; New York: Marcel Dekker. 1969, 597–647. Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763–2766. Yin, W.; He, C.; Chen, M.; Zhang, H.; Lei, A. Org. Lett. 2009, 11, 709–712. Peng, H.; Xi, Y.; Ronaghi, N.; Dong, B.; Akhmedov, N. G.; Shi, X. J. Am. Chem. Soc. 2014, 136, 13174–13177. Balsamo, A.; Macchia, B.; Macchia, F.; Rossello, A.; Domiano, P. Tetrahedron Lett. 1985, 26, 4141–4144. Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835. Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14, 6–9. Souto, J. A.; Becker, P.; Iglesias, Á.; Muñiz, K. J. Am. Chem. Soc. 2012, 134, 15505–15511. Stang, P. J.; Surber, B. W.; Chen, Z.‐C.; Roberts, K. A.; Anderson, A. G. J. Am. Chem. Soc. 1987, 109, 228–235. Chen, C.; Chu, L.; Qing, F.‐L. J. Am. Chem. Soc. 2012, 134, 12454–12457. Li, M.; Li, Y.; Zhao, B.; Liang, F.; Jin, L. RSC Adv. 2014, 4, 30046–30049.

235

9 Oxidation of Benzene 9.1 ­Introduction Benzene (C6H6) is the basic aromatic compound having six identical aryl sp2C─H bonds, that is, phenyl sp2C─H bonds. Currently benzene is mainly produced from petroleum oils as raw materials through refining, catalytic reforming, or pyrolysis of gasoline [1] (Scheme 9.1). Benzene is used to synthesize ethylbenzene, followed by dehydrogenation to styrene monomer exclusively, leading ultimately to various materials including polystyrene, styrene–acrylonitrile copolymer (SAN), acrylonitrile–butadiene–styrene terpolymers (ABS), etc. Besides, some benzene is used to produce cumene, which is converted into phenol and acetone through cumene oxidation process and is hydrogenated to cyclohexane, followed by oxidation to adipic acid, caprolactam, hexamethylenediamine, etc. in the manufacture of nylon. Other major applications of benzene include production of nitrobenzene for aniline synthesis and linear alkylbenzenes (LABs) used as detergents, chlorobenzene, maleic anhydride (MAH), etc. However, although the commercial utilization of benzene to supply bulk chemicals such as styrene, phenol, aniline, etc. has been conducted for decades, these processes are often indirect and need multisteps. Thus, direct oxidation of phenyl sp2C─H bond to produce important chemicals in one step is still of commercial interest currently. On the other hand, due to the prevalence of benzene core in natural products, pharmaceuticals, and functional materials, etc., efficient methods of converting benzene into universal synthetic building blocks are also highly desired. Different from cleavage of methyl or alkyl sp3C─H bonds described in previous chapters, generally there are two ways, namely, direct and indirect methods to cleave a phenyl sp2C─H bond on the benzene ring. In the direct way, a phenyl sp2C─H bond may be cleaved either homolytically or heterolytically. However, the phenyl sp2C─H bond, with a high BDE value of 472 kJ/mol, is even more stable than the methyl sp3C─H bond (BDE = 439 kJ/mol). Thus, it is more reluctant for phenyl sp2C─H bond to break homolytically. Moreover, the pKa value of phenyl sp2C─H bond is 43, slightly more acidic than methyl sp3C─H bond (pKa = 48), but it is still not acidic enough for phenyl sp2C─H bond to be Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

236

9  Oxidation of Benzene Petroleum oils

NO2

OH

O

Alkyl

Cl

NH2

CO2H CO2H

Scheme 9.1  Production and application of benzene.

deprotonated readily for further utilization in organic synthesis. Fortunately, some electrophilic transition‐metal complexes could attack on the phenyl sp2C─H bonds to form phenyl sp2C─M species via C─H activation process under mild conditions. For example, in 1965, Van Helden and Verberg reported formation of biphenyl through oxidative homocoupling of benzene mediated by palladium complex to cleave phenyl sp2C─H bonds [2]. A cross‐coupling of benzene and alkene to produce styrene derivatives was established in 1969 by Fujiwara, Moritani, et al. using catalytic palladium to cleave phenyl C─H bond and applying copper or silver salt combined with O2 as oxidant to regenerate palladium to fulfill the catalytic cycle [3]. In these direct oxidation cases, inert phenyl sp2C─H bond is cleaved by palladium complex to form phenyl–palladium species, and further oxidative functionalization of this phenyl–palladium species completes the oxidation of phenyl sp2C─H bond (Scheme 9.2). H + PdII

PdII

FG

PdII

FG

FG + Pd0

Scheme 9.2  Cleavage of phenyl C─H bond through C─H activation process. FG - Functional groups.

In the indirect way, phenyl sp2C─H bond can be cleaved during dearomatization and rearomatization of benzene ring attacked by certain electrophiles in the electrophilic aromatic substitution (SEAr) process. For example, as early as 1845, systematic work by Hofmann and Muspratt on nitration of benzene to

9.2  Oxidations of Phenyl sp2C─H Bond

afford mono‐ and di-nitrobenzene by using mixtures of nitric and sulfuric acids was reported [4]. Furthermore, formation of a carbon–carbon skeleton on a benzene ring was achieved in 1877 by Friedel and Crafts through alkylation or acylation of benzene with alkyl or acyl halides mediated by Lewis acids to produce alkylbenzene or phenyl ketone, named as Friedel–Crafts alkylation or acylation later [5]. In this SEAr process of phenyl C─H bond oxidation, an electrophile substitutes a hydrogen atom on benzene ring through dearomatizing the electron‐rich aromatic ring followed by rearomatizing with rapid loss of a proton to recover aromaticity. Cleavage and oxidation of phenyl C─H bond occur simultaneously at the step of rearomatization of benzene ring (Scheme 9.3). H + E

E

+

E + H

H

+

+

Scheme 9.3  Cleavage of phenyl C─H bond through SEAr process.

It is notable that the substituted product generated from phenyl sp2C─H bond oxidation is an electron‐rich or electron‐poor aromatic compound compared with benzene. When the oxidation product is more electron rich than benzene, generally it is more reactive than benzene in either SEAr or C─H activation processes, and thus overoxidations usually occur unless reaction kinetics are controlled, such as keeping the benzene substrate in large excess (often used as solvent). When the oxidation product is more electron poor than benzene, monooxidative‐functionalized product is usually obtained in high selectivity. Comprehensive judgment and balance on reactivity and selectivity are very important in the synthesis of target products by oxidation of phenyl sp2C─H bond. In addition, in some cases, a benzene radical cation could also be generated by a single‐electron accepter followed by nucleophilic addition, oxidation, and deprotonation to give a substituted product (Scheme 9.4). –e

+

Nu



Nu H

–e

Nu + H

+

Scheme 9.4  Cleavage of phenyl C─H bond through single‐electron-transfer process.

9.2 ­Oxidations of Phenyl sp2C─H Bond This chapter describes the oxidation of phenyl sp2C─H bond according to the type of bond formation (e.g., C─C or C─N bond), structures of oxidation product (e.g., alkylbenzene or trifluoromethylbenzene), and type of reagent (e.g., alkyl halide, alkyl alcohol, or alkene). In each case, description is based on the major reaction type, namely, SEAr process or C─H activation. Representative application of the oxidation reaction in either bulk or fine chemical is described

237

238

9  Oxidation of Benzene

if possible. The chapter is focused on the discovery of the new reactive species and reaction mechanism and the following further exploitation leading to the new type of oxidation with high efficiency under mild conditions. 9.2.1  Formation of C─C Bond 9.2.1.1 Alkylation

Alkylation of benzene to form a phenyl–alkyl bond is highly desired because it is a basic structure core widely found in natural products, pharmaceuticals, functional materials, and bulk chemicals such as LAB and exists in various very important industrial intermediates including ethylbenzene, i‐propylbenzene (cumene), etc. Construction of phenyl–alkyl motif is achieved by either substitution of a hydrogen atom on benzene with an alkyl surrogate such as alkyl halide, alkyl alcohol, etc. or addition of an alkene to the benzene ring. This type of reaction is usually attributed to Friedel–Crafts alkylation, which is the classical and the still powerful method to afford phenyl–alkyl bonds in current organic synthesis [5]. The Friedel–Crafts alkylation is a standard SEAr process. Traditionally, it is conducted by treatment of benzene with alkyl halide in the presence of stoichiometric Lewis acid such as AlCl3 (Scheme 9.5). The alkyl cation generated in situ from reaction of alkyl halide with AlCl3 adds on benzene by dearomatizing the aromatic ring followed by rearomatization with rapid loss of a proton to afford the alkylbenzene product. + Cl

AlCl3

Scheme 9.5  Friedel–Crafts alkylation.

A typical Friedel–Crafts alkylation has the following characteristics. First, electron‐rich arenes perform well and electron‐poor arenes normally do not react. Second, the in situ generated alkyl cation favors rearrangement to more stable secondary or tertiary alkyl cation if possible. Third, multialkylation products are obtained since an alkylbenzene is more reactive than benzene. Besides, current environmental concerns demand avoiding stoichiometric consumption and disposal of metal halide acting as Lewis acid. Therefore, the use of catalytic amount of Lewis acid or reusable catalyst after aqueous work‐up of the reaction is highly desired. Besides, use of more environmentally benign alkyl alcohol instead of alkyl halide is also preferred, if deactivation of Lewis acids by either alkyl alcohol or H2O generated in situ during alkylation is overcome. In 1986, Fujiwara et al. found that rare earth Lewis acids LnCl3 especially the late lanthanoids such as DyCl3, TmCl3, LaCl3, etc. were reusable catalysts for alkylation of benzene with benzyl halides [6]. For example, treatment of benzyl chloride (1.34 mmol) with benzene (2.0 mL) in the presence of DyCl3 (0.5 mmol)

9.2  Oxidations of Phenyl sp2C─H Bond

at 75 °C for 1 h affords diphenylmethane in 74% yield based on benzyl chloride (Scheme 9.6). After quenching, extraction, evaporation, and treatment with conc. HCl, the recovered DyCl3 is active for two more runs of the reaction maintaining its performance. In addition to benzyl halides, n‐propyl bromide reacted with benzene under LuCl3 catalysis to produce cumene and n‐propylbenzene in 24 and 8% yield, respectively. +

CH2Cl

0.5 mmol DyCl3 75 °C, 1 h

1.34 mmol

2.0 mL

74%,TON = 2

Scheme 9.6  Reusable LnCl3 catalyst for Friedel–Crafts alkylation.

Also in 1986, in the research of SeCl4‐ or TeCl4‐mediated conversion of alkyl alcohol into alkyl halides, Uemura and coworkers observed that 1‐phenylethanol (30 mmol) reacted with benzene (30 mL) to afford mixtures of mono‐ and di-benzylated benzene products in moderate yield in the presence of stoichiometric TeCl4 (1.2 equiv.) at 5 °C for 1 h [7] (Scheme 9.7). More surprisingly, when the more reactive toluene (30 mL) was used as reactant, a 93% yield of benzylation products was obtained at 25 °C for 3 h even in catalytic amount of TeCl4 (10 mol%). The reaction mechanism was proposed that TeCl4 served as both the chlorinating reagent and the Lewis acid catalyst, converting benzyl alcohol into benzyl chloride, followed by alkylation of benzene to afford benzylated product. This was indicated by the fact that the same reaction at −50 °C afforded mainly the benzyl chloride and the product ratio of alkylation of benzene with benzyl chloride is the same as that obtained from benzyl alcohol as reactant. Me + 30 mL

OH

Me 1.2 equiv. TeCl4

+

5 °C, 1 h 30 mmol

Me

3%

Me 44% (o/p = 24/76)

Scheme 9.7  TeCl4‐mediated alkylation of benzene with benzyl alcohol.

Catalytic alkylation of benzene with benzyl alcohols was achieved by Fukuzawa et al. in 1997 using Sc(OTf)3 as efficient Lewis acid [8, 9]. For example, treatment of benzyl alcohol (1.0 mmol) with benzene (5.0 mL) catalyzed by Sc(OTf)3 (0.1 mmol) at 115–120 °C for 6 h affords a 91% yield of diphenylmethane based on benzyl alcohol. Besides, 4‐methyl‐ or 4‐chloro‐substituted benzyl alcohol is also available to give the corresponding diarylmethane in 85 or 93% yield for 3 h (Scheme 9.8). The recovered Sc(OTf)3 from evaporation of the aqueous phase of the reaction mixture was active for another run to obtain diphenylmethane in 89% yield. ScCl3 is not active in this reaction probably due to its weaker Lewis acidity than Sc(OTf)3.

239

240

9  Oxidation of Benzene

+ 5.0 mL

CH2OH

10 mol% Sc(OTf)3 115–120 °C, 6 h

1.0 mmol

91%

Scheme 9.8  Sc(OTf )3‐catalyzed alkylation of benzene with benzyl alcohol.

The catalytic alkylation of benzene with benzyl alcohols was further developed using more economic and environmentally benign FeCl3 or Bi(OTf )3 as effective catalyst. In 2005, Beller and coworkers demonstrated that treatment of 1‐phenylethyl acetate (0.5 mmol) with benzene (5.0 mL) in the presence of FeCl3 (10 mol%) at 140  °C for 20 h afforded a 50% yield the corresponding diphenylmethane [10] (Scheme  9.9). In 2006, Rueping et  al. reported that ­benzyl acetate (1.0 mmol) reacted with benzene (3.0 mmol) in the presence of 1 mol% of Bi(OTf )3 to give diphenylmethane in 79% yield for 5 h [11]. Benzene is not in large excess as solvent and the catalytic efficiency is high with TON of up to 79 (Scheme 9.10). In addition, benzyl alcohol is also available for benzylation, affording diphenylmethane in 59% yield for 2 h. Me + 5.0 mL

Me OAc

10 mol% FeCl3 140 °C, 20 h

0.5 mmol

50%

Scheme 9.9  FeCl3‐catalyzed alkylation of benzene with 1-phenylethyl acetate.

+ 3.0 mmol

OAc 1.0 mmol

1mol% Bi(OTf)3 5h 79%, TON = 79

Scheme 9.10  Bi(OTf )3‐catalyzed alkylation of benzene with benzyl acetate.

In the previous examples, only activated alkyl alcohols such as benzylic alcohols were used as reactants. Expansion of the substrate scope to normal alkyl alcohols was highly desired. In 2014, Cook and Jefferies found that FeCl3/ AgSbF6 (15%/45%) combination was an effective catalyst in alkylation of benzene (15 equiv.) with unactivated secondary alcohol cyclohexanol (0.8 mmol) in DCE (8 mL) at 80 °C for 20 h to afford cyclohexylbenzene in 58% yield [12] (Scheme 9.11). It was proposed that a more active cationic iron complex for the dehydration generated from addition of AgSbF6 to FeCl3 was critical to the use of normal secondary alkyl alcohols successfully. In addition to alkyl halides and alcohols, alkenes are also available partners for  Friedel–Crafts alkylation reaction especially in the industry since very

9.2  Oxidations of Phenyl sp2C─H Bond OH + 15 equiv.

15 mol% FeCl3 45 mol% AgSbF6 DCE (8 mL), 80 °C, 24 h

0.8 mmol

58%

Scheme 9.11  FeCl3/AgSbF6‐catalyzed alkylation of benzene with alkyl alcohol.

important bulk chemicals including ethylbenzene, cumene, etc. are produced from alkylation of benzene with alkenes. The common problem in these processes is that the Lewis acid catalysts used are not reusable after the aqueous work‐up of the reaction. Rare earth metal complexes were demonstrated to be efficient and reusable catalysts in the alkylation of benzene with either benzyl halides or benzyl alcohols, but treatment of benzene with 1‐hexene in the presence of rare earth metal complexes such as Sc(OTf)3 did not afford any alkylation product, as observed by Song, Choi, et al. in 2000 [13]. However, the reaction becomes available when Sc(OTf)3 is immobilized in ionic liquids consisting of 1,3-dialkylimidazolium cations and their counter anions. For example, alkylation of benzene (2.0 mL) with 1‐hexene (1.0 mmol) in the presence of [emim][SbF6] (1.0  mL) (emim= 1-ethyl-3-methylimidazolium cation) that immobilized Sc(OTf)3 catalyst (0.2 mmol) at 20 °C for 12 h affords branched alkylation mixtures of 2‐phenylhexane and 3‐phenylhexane in 96% yield with ratio of 1.5/1 (Scheme  9.12). Other ionic liquids including [bmim][PF6], [bmim][SbF6] (bmim = 1-butyl-3-methylimidazolium cation) [pmim][PF6] (pmim = 1-pentyl3-methylimidazolium cation), and [hmim][PF6] (hmim = 1-hexyl-3-methylimidazolium cation) are also available for this reaction. Besides linear alkenes, cyclic alkenes such as cyclohexene also give alkylation products in high yield. Moreover, the previous reaction of two more runs using recovered ionic liquid‐containing catalyst also produces cyclohexylbenzene in high yield.

+ 2.0 mL

20 mol% Sc(OTf)3 n-Pr 1.0 mmol

[emin][SbF6] (1.0 mL) 20 °C,12h

n-Pr

+

a

n-Pr b

93% (a/b = 1.5/1)

Scheme 9.12  Immobilized Sc(OTf )3‐catalyzed addition of alkene to benzene.

Normally, it is almost impossible for Friedel–Crafts alkylation to afford linear alkylbenzene product due to the nature of carbon cation generated in situ from olefin and Lewis acid, even when shape selective, acidic zeolites are employed [5]. Typical procedure of synthesizing linear alkylbenzenes is through an indirect process involving two tandem reactions, namely, Friedel– Crafts acylation of benzene to give phenyl ketones followed by decarbonylation

241

242

9  Oxidation of Benzene

of the ketone group by reduction methods such as Clemmensen reduction. In 2000, Matsumoto and coworkers reported an anti‐Markovnikov olefin arylation to afford linear alkylbenzene as major product under iridium catalysis [14]. For example, reaction of benzene (3.0 mL) with 1‐hexene at 180 °C for 20 min affords 1‐phenylhexane in 69% selectivity, along with 2‐phenylhexane in 31% selectivity (1‐phenylhexane/2‐phenylhexane = 2.2/1), and no 3‐phenylhexane is produced (Scheme 9.13). Other than alkenes such as propylene, i‐butene also gives linear alkylbenzenes as major products. Control experiment of benzene with 1‐hexene in the presence of AlCl3 gives mixtures of 2‐phenylhexane and 3‐phenylhexane in 66 and 34% selectivity, without formation of 1‐phenylhexane, demonstrating the branched selectivity in Lewis acid‐mediated Friedel–Crafts alkylation. A C─H activation followed by olefin insertion mechanism was proposed to explain the anti‐Markovnikov selectivity. An iridium complex cleaves the phenyl sp2C─H bond through either electrophilic activation or oxidative addition to produce phenyl–iridium intermediate. This phenyl–iridium intermediate is inserted by alkene to give phenylalkyl–iridium species with the least steric hindrance, which is the origin of the anti‐Markovnikov selectivity. Iridium center fulfills the catalytic cycle after loss of product. +

3 mL

n-Bu

1.0 mg Ir complex 29 atm N2 180 °C, 20 min

0.8 mL

a

n-Bu

+

n-Bu b

TON = 8, a/b = 2.2/1

Ir complex: [Ir(μ-acac-O,O,C3)(acac-O,O)(acac-C3)]2

Scheme 9.13  Ir‐catalyzed linear alkylation of benzene with alkene.

The linear selectivity in alkylation of benzene with olefins was further developed by Hartwig and coworkers in 2014 [15]. For example, reaction of benzene (60 equiv.) with 1‐octene (0.15 mmol, 1 equiv.) in the presence of 20 mol% [Ni(COD)2], (COD= cycloocta-1,4-diene) 40 mol% IPr carbene ligand [IPr=1,3bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene], and t‐BuONa at 100 °C for 16 h affords 1‐phenyloctane in 17% yield with 19/1 ratio for linear‐ to‐branched selectivity (Scheme 9.14). Combined experimental and computational studies reveal reversible formation of alkyl–Ni–Ph intermediate and rate‐determining reductive elimination to afford a linear alkylbenzene mechanism, in which lower barrier for formation of linear alkylbenzene from reductive elimination leads to the high linear selectivity. + 60 equiv.

20 mol% [Ni(COD)2] n-hex 0.15 mmol

40 mol% IPrHCl NaOtBu,100 °C,16h

n-hex

+

a 17%, a/b ≥ 19/1

Scheme 9.14  Ni‐catalyzed linear alkylation of benzene with alkene.

n-hex b

9.2  Oxidations of Phenyl sp2C─H Bond

9.2.1.2 Trifluoromethylation

Owing to the unique character of fluorine atom which owns the highest electronegativity and similar atomic radius to hydrogen atom, the trifluoromethyl group is sharply different from an alkyl group in properties and receives growing attentions due to its powerful ability to regulate the characteristics of the functional molecules including pharmaceuticals, medicinal drugs, agrochemicals, etc. [16]. However, only a few methods are available for introducing ­trifluoromethyl groups to aromatic compounds, even prefunctionalized aromatic compounds such as phenyl iodides are used as substrates, exhibiting the ­difficulties in formation of phenyl–trifluoromethyl bond. For example, Chen and Wu disclosed an early example of transition‐metal‐catalyzed trifluoromethylation of phenyl halides in 1989. Iodo‐ or bromo-benzene is converted into trifluoromethylbenzene efficiently in the presence of 12 mol% copper(I) iodide using methyl fluorosulfonyl­difluoroacetate as the trifluoromethylating reagent [17] (Scheme 9.15). I

+ FO2SCF2CO2Me

2.0 equiv.

12 mol% CuI

CF3

DMSO, 60 °C, 2.5 h

1 equiv.

84%

Scheme 9.15  Cu‐catalyzed trifluoromethylation of phenyl halides.

Current industrial production of trifluoromethylbenzene is through a two‐ step process (Swarts reaction) using toluene as raw material, in which toluene is converted into benzyl trichlorides by radical chlorination first and then followed by halogen exchange with HF to afford the target product (Scheme 9.16). Although Swarts reaction owns some obvious weak points including use and generation of hazardous reagent and intermediate, it is the only industrially viable process to synthesize trifluoromethylbenzene currently. Thus, an alternative method especially direct trifluoromethylation of benzene with loss of a hydrogen atom is highly desired. CH3

Cl2

CCl3

HF

CF3

Scheme 9.16  Current production of benzotrifluoride (Swarts reaction).

Basically, there are three types of trifluoromethylating reagents; namely, radical reagents, such as CF3I, CF3SO2Cl, and CF3SO2Na, nucleophilic ­reagents, for example, CF3H, FSO2CF2CO2Et, and TMSCF3 (trifluoromethylsilane; Ruppert’s reagent), and electrophilic reagents including 5‐(trifluoromethyl) dibenzothiophenium salts, 3,3‐dimethyl‐1‐(trifluoromethyl)‐1,2‐benzodioxole (Togni reagent), etc. Reaction pathway for trifluoromethylation of benzene stays close to the trifluoromethylating reagents and reaction conditions previously conducted. Traditionally, CF3I has been used for trifluoromethylation of

243

244

9  Oxidation of Benzene

benzene. However, it is a gas at atmospheric pressure (−23 °C bp) and thus is difficult to handle in the laboratory. In 1990, Kamigata and coworkers reported trifluoromethylation of benzene (5.0 mL) with CF3SO2Cl (2.0 mmol) using 1 mol% Ru(PPh)3Cl2 at 120 °C for 18 h to afford benzotrifluoride in 41% yield [18] (Scheme 9.17). Liquid and easy to treat CF3SO2Cl (32 °C bp) was used as trifluoromethyl source. A radical mechanism was proposed by them in 1994 [19]. Redox transfer between CF3SO2Cl and Ru(II) catalyst produces Ru(III) species and CF3SO2Cl radical anion, followed by loss of chloride anion and SO2 to generate CF3 radical. Homolytic addition of CF3 radical to benzene gives cyclohexadienyl radical, which is converted into cyclohexadienyl cation by donating one single electron to Ru(III), which is reduced to Ru(II) to fulfill the catalytic cycle. On the other hand, re-aromatization of cyclohexadienyl cation with loss of a proton affords trifluoromethylbenzene product (Scheme 9.18). + 5.0 mL

CF3SO2Cl

1 mol% RuCl2(PPh3)3

CF3

120 °C, 18 h 41%

2.0 mmol

Scheme 9.17  Ru‐catalyzed homolytic trifluoromethylation of benzene. H

CF3 –H

+ +

H CF3

CF3

RuII CF3SO2Cl

RuIII

RuIII

H

CF3 RuIII

CF3SO2Cl

Cl–, SO2

Scheme 9.18  Mechanism of homolytic trifluoromethylation of benzene.

This redox radical phenyl C─H trifluoromethylation strategy was further developed by MacMillan in 2011 using photocatalysis [20]. For example, a 74% yield of benzotrifluoride is afforded by treatment of benzene (0.5 mmol, 1 equiv.) with CF3SO2Cl (2.0 equiv.) in the presence of 1 mol% Ir(Fppy)3 photocatalyst [Fppy = tris[2-(4,6-difluorophenyl)pyridinato-C2,N]iridium(III)] and K2HPO4 (3.0 equiv.) in CH3CN (4 mL) at room temperature for 24 h (Scheme 9.19). The

9.2  Oxidations of Phenyl sp2C─H Bond

reaction mechanism is generally similar to the previous Kamigata’s report except that in this case trifluoromethyl radical is generated from CF3SO2Cl and Ir(Fppy)3 through SET process. + 0.5 mmol

CF3SO2Cl 1.0 mmol

1 mol% Ir(Fppy)3

CF3

3 equiv. K2HPO4 MeCN-d3 (4 mL) 26 W light, rt, 24 h

74 %

Scheme 9.19  Ir‐catalyzed homolytic trifluoromethylation of benzene.

Alternatively, adduct of CF3I with tetramethylguanidine (TMG) was found as an effective liquid‐trifluoromethylating reagent by Ritter and coworkers in 2015 [21]. For example, treatment of benzene (0.25 mmol, 1 equiv.) with TMG∙CF3I (0.5 mmol) in the presence of Cu(OAc)2∙H2O (0.5 mmol) and K2S2O8 (1.0 mmol) in HOAc (2 mL) at 90 °C for 24 h affords benzotrifluoride in 77% yield (Scheme 9.20). + TMG CF I 3 0.25 mmol

0.5 mmol

0.5 mmol Cu(OAc)2 H2O 1.0 mmol K2S2O8 HOAc (2 mL), 90 °C, 24 h

CF3 77%

Scheme 9.20  Trifluoromethylation of benzene with TMG∙CF3I.

Trifluoromethyltrimethylsilane (TMSCF3, Ruppert’s reagent) is another effective trifluoromethylating reagent; for example, in the copper‐mediated synthesis of benzotrifluoride from phenyl iodide through well‐defined CuCF3 complex as reported by Vicic and coworkers in 2008 [22]. Further exploration on the reactivity of phenyl iodide with AgCF3 instead of CuCF3 generated in situ from AgF with TMSCF3 revealed that trifluoromethylation occurred on phenyl C─H bond rather than C─I bond as reported by Sanford and coworkers in 2011 [23]. Under optimal conditions, benzene (20 equiv.) is converted into benzotrifluoride in 87% yield at 85  °C for 24 h in the presence of TMSCF3 (0.081 mmol, 1 equiv.), AgOTf (4.0 equiv.), and KF (4.0 equiv.) (Scheme  9.21). The reaction mechanism was proposed that AgCF3 generated in situ decomposed homolytically to produce Ag(0) and CF3 radical, followed by radical aromatic substitution to afford trifluoromethylation product. + 20 equiv.

TMSCF3 0.081 mmol

4.0 equiv. AgOTf 4.0 equiv. KF DCE (0.2 mL) 85 °C, 24 h, dark

CF3 87%

Scheme 9.21  Ag‐mediated trifluoromethylation of benzene with TMSCF3.

245

246

9  Oxidation of Benzene

This silver‐mediated trifluoromethylation reaction was improved to silver catalysis as reported by Greaney and coworkers in 2013 using PhI(OAc)2 as oxidant and DMSO as critical solvent [24]. The reaction is rather solvent sensitive since other common solvents produce no product except CH3CN, but the yield is low. A 60% yield of benzotrifluoride is afforded by treatment of benzene (0.3 mmol, 1 equiv.) with TMSCF3 (2.0 equiv.) in the presence of AgF (25 mol%) and PhI(OAc)2 (2.0 equiv.) in DMSO (1 mL) at 70 °C for 20 h (Scheme 9.22). + 5.0 mmol

TMSCF3 0.5 mmol

0.125 mmol AgF 1.0 mmol PhI(OAc)2 DMSO (0.5 mL), 70 °C, 20 h

CF3 60%

Scheme 9.22  Ag‐catalyzed trifluoromethylation of benzene with TMSCF3.

The more commercially available and economical trifluoroacetic acid (TFA) was applied as the trifluoromethylation reagent by loss of CO2 in the trifluoromethylation of benzene under silver catalysis using K2S2O8 as oxidant as reported by Zhang and coworkers in 2015 [25]. Treatment of benzene (0.25 mmol, 1 equiv.) with TFA (6.1 equiv.) in the presence of Ag2CO3 (40 mol%), K2S2O8 (2.0 equiv.), Na2CO3 (2.5 equiv.), and H2SO4 (0.2 equiv.) in CH2Cl2 (0.7 mL) at 120 °C for 10 h affords trifluoromethylbenzene in 69% yield along with 10% of bis(trifluoromethyl) product (Scheme 9.23). Isotopic experiment with benzene and benzene‐d6 reveals kinetic isotope effect (KIE) value of 1.0, indicating that phenyl C─H cleavage is not the rate‐determining step. It was proposed that CF3CO2H was transformed to CF3CO2 radical by Ag(II) generated from Ag(I) and K2S2O8 in situ. CF3CO2 radical decomposed to CF3 radical by release of CO2, followed by radical aromatic trifluoromethylation to afford the target product. On the other hand, the Ag(I) species reduced by CF3CO2H is reoxidized to Ag(II) by K2S2O8 to fulfill the catalytic cycle.

+ 0.25 mmol

CF3CO2H 6.1 equiv.

40 mol% Ag2CO3 2.0 equiv. K2S2O8 2.5 equiv. Na2CO3 0.2 equiv. H2SO4 DCM (0.7 mL), 120 °C, 10 h

CF3 69%

Scheme 9.23  Ag‐catalyzed trifluoromethylation of benzene with CF3CO2H.

9.2.1.3 Arylation

Phenyl–aryl linkage is the core structure of biaryls, which are prevalent in natural products, pharmaceuticals, etc. Current strategies to synthesize biaryl

9.2  Oxidations of Phenyl sp2C─H Bond

structures are the state‐of‐the‐art transition‐metal‐catalyzed cross‐coupling reactions of aryl halides with aryl metal reagents, for example, the Suzuki– Miyaura reaction using aryl halides and aryl boronic acid as coupling partners catalyzed by Pd(0) species. These methodologies share features of diverse substrate scope, mild conditions, high catalytic efficiency, etc. and have been widely applied in large‐scale production already [26] (Scheme 9.24). The major limitation of cross‐coupling reaction is the use of both prefunctionalized aryl halides and aryl metal reagents as substrates. These halides or metals attached on aromatic ring need additional step(s) to prepare and are disposed of stoichiometrically after the reaction. Therefore, direct use of simple arenes instead of aryl halides and aryl metal reagents to synthesize biaryls is of high demand especially for pharmaceutical manufacturers [27]. CN Cl + (HO)2B

Me

Pd(OAc)2

TPPTS, 120 °C

CN

Me

N NH N N

HO

O Me H

O

Me

Valsartan (Diovan) Me $2.12 billion, rank 23 (US sales, 2013)

Scheme 9.24  Biaryl production by the Suzuki–Miyaura cross‐coupling in industry.

One strategy to fulfill such transformation is coupling of one arene with one prefunctionalized arene such as aryl iodide or bromide, which is called direct arylation [28]. In 2006, Fagnou and Lafrance reported direct arylation of benzene with aryl bromides to afford biaryls [29]. For example, treatment of ­benzene (3.0 mL) with 4‐bromotoluene (0.64 mmol, 1 equiv.) in the presence of Pd(OAc)2 (3 mol%) DavePhos (3 mol%) [DavePhos = 2-cyclohexylphosphino2′-(N,N-dimethylamino)biphenyl], PivOH (0.3 equiv.), and K2CO3 (2.5 equiv.) in DMA at 120 °C for 12 h affords 4‐phenyltoluene in 82% yield. Isotopic experiment of 4‑bromoanisole with benzene and benzene‐d6 elucidates a large KIE value of 5.5, which indicates that cleavage of phenyl C─H bond is the rate‐ determining step. In the proposed Pd(0)/Pd(II) mechanism, oxidative addition of Pd(0) generated in situ from Pd(OAc)2 and phosphine ligand DavePhos to aryl–Br bond forms aryl‐Pd(II)–Br intermediate, which exchanges with PivOH to give aryl‐Pd(II)–OPiv species. This aryl‐Pd(II)–OPiv species cleaves phenyl C─H bond through concerted metalation–deprotonation (CMD) process to produce aryl‐Pd(II)‐phenyl key intermediate, followed by reductive elimination of aryl and phenyl group to afford biaryl product and Pd(0) species to fulfill the catalytic cycle. PivOH facilitates the rate‐determining cleavage of phenyl C─H bond significantly by abstracting the proton and thus is crucial to the success of this reaction (Scheme 9.25).

247

248

9  Oxidation of Benzene

+

Br

Me 0.64 mmol

3.0 mL

3 mol% Pd(OAc)2 3 mol% DavePhos 2.5 equiv. K2CO3 0.3 equiv. tBuCO2H DMA (3.5 mL), 120 °C,12 h

Oxidative addition PdII

PdII

PivOH

82%

Br

Pd0 Reductive elimination

Me

C H activation

Ligand exchange PdII

OPiv

Br PivO–

Br –

Scheme 9.25  Pd(0)/Pd(II)‐catalyzed arylation of benzene with aryl bromides.

Alternatively, to avoid using phosphine ligands, a Pd(II)/Pd(IV) catalytic cycle was established for cross‐coupling benzene with aryl iodide in 2008 by Lu and Qin [30]. For example, treatment of benzene (25 equiv.) with 4‐iodonitrobenzene (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%), AgOCOCF3 (1.2 equiv.), and CF3CO2H (2.5 equiv.) in CF3CH2OH (35 equiv.) at 140 °C for 20 h to afforded 4‐nitrobiphenyl in 64% yield. Isotopic experiment of 4‐iodoanisole with benzene and benzene‐d6 gave a KIE value of 2.5 that indicates phenyl C─H bond cleavage is the rate‐determining step. In the proposed mechanism, Pd(II) cleaves phenyl C─H bond first to form phenyl‐Pd(II) species. Oxidative addition of this phenyl‐Pd(II) species to aryl iodide gives phenyl‐Pd(IV)‐aryl intermediate. The following reductive elimination of phenyl and aryl groups produces biaryl and Pd(II) iodide. Stoichiometric AgOCOCF3 is consumed to regenerate Pd(OCOCF3)2 to fulfill the catalytic cycle from the deactivated Pd(II) iodide by capturing iodides (Scheme 9.26). The question is whether the key phenyl‐Pd(IV)‐aryl species is available from intermolecular oxidative addition of phenyl‐Pd(II) species to aryl iodide. It is partly supported by the synthesis of alkyl‐Pd(IV)‐aryl complex from intramolecular oxidative addition of alkyl‐Pd(II) complex to

9.2  Oxidations of Phenyl sp2C─H Bond

aryl iodide as reported by Vicente and coworkers in 2011, in which the alkyl‐ Pd(IV)‐aryl complex is isolated and fully characterized by X‐ray diffraction, NMR spectroscopy, and elemental analyses [31].

+ I

NO2 0.2 mmol

5.0 mmol

AgI

NO2

0.5 mmol CF3CO2H 7.0 mmol CF3CH2OH 140 °C, 20 h

64%

CF3CO2–PdII C H activation

Ligand exchane

CF3CO2Ag I

5 mol% Pd(OAc)2 0.24 mmol CF3CO2Ag

CF3CO2H PdII

PdII Reductive elimination

Oxidative addition I

I

IV

Pd

Scheme 9.26  Pd(II)/Pd(IV)‐catalyzed arylation of benzene with aryl iodides.

The previous examples of direct arylation of benzene with aryl halides are based on the direct cleavage of phenyl C─H bond through a Pd(II)‐involved CMD process. Alternatively, such transformations are available through indirect cleavage of phenyl C─H bond by a homolytic aromatic substitution process. In 2004, Fujita and coworkers reported direct arylation of benzene (20 mmol) with phenyl iodide (0.5 mmol) in the presence of [Cp*IrHCl]2 (5 mol%) and t‐BuOK (3.3 equiv.) at 80  °C for 30 h to afford biphenyl in 72% yield [32] (Scheme  9.27). Various electron‐rich aryl iodides such as 4‐iodoanisole, 4‐iodotoluene, etc. are available in this reaction. When anisole or toluene is arylated with phenyl iodide under optimal conditions, ortho‐arylation product is obtained as the major product. The regioselectivity observed is very similar to that in homolytic aromatic substitution, indicating that radical intermediate is ­probably involved during the reaction pathway. In the proposed mechanism, Ir(III) catalyst is reduced by t‐BuOK to form Ir(II) species, which transfers one

249

250

9  Oxidation of Benzene

single electron to aryl iodide to regenerate Ir(III). The formed aryl iodide radical anion loses iodide to give aryl radical, which reacts with benzene to afford the biaryl product. 5 mol% [Cp*IrHCl]2

+ I 0.5 mmol

20 mmol

1.65 mmol KOtBu 80 °C, 30 h

72%

Scheme 9.27  Ir‐catalyzed homolytic arylation of benzene with aryl iodides.

In 2006, Curran and Keller reported a very mild arylation of benzene with aryl iodide through homolytic aromatic substitution [33]. For example, treatment of benzene (50 mL) with phenyl iodide (0.2 mmol, 1 equiv.) in the presence of (TMS)3SiH (1.2 equiv.) and pyridine (5.0 equiv.) at room temperature for 3 h affords biphenyl in 75% yield (Scheme 9.28). Aryl iodide attached with either electron‐withdrawing or electron‐donating group such as methyl 4‐iodobenzoate or 4‐iodoanisole produces the corresponding biaryl in high yield. In the ­ proposed mechanism, initiator (TMS)3SiH loses a hydrogen to form (TMS)3Si radical, which abstracts iodine from aryl iodide to give (TMS)3SiI and aryl radical. The formed aryl radical adds to benzene through homolytic aromatic substitution to give cyclohexadienyl radical, which reacts with O2 to give biaryl product and hydroperoxyl radical, which abstracts hydrogen atom from (TMS)3SiH to transfer the chain. O2 is critical for rearomatization of cyclohexadienyl radical to produce biaryl product, and the reaction does not work when degassed benzene is used. 1.2 equiv. (TMS)3SiH

+ I 50 mL

5.0 equiv. pyridine, rt, 3 h 0.2 mmol

75%

Scheme 9.28  Silane‐mediated homolytic arylation of benzene with aryl iodides.

In 2010, further improved homolytic aromatic substitution reactions of benzene with aryl iodide or aryl bromide were established by using catalytic amount of bidentate nitrogen ligand and stoichiometric amount of base at three independent research groups, which are Kwong, Lei and coworkers [34], Shi and co­workers [35], and Shirakawa, Hayashi and coworkers[36]. In the example of Kwong and coworkers [34], treatment of benzene (4.0 mL) with phenyl iodide (0.5 mmol, 1 equiv.) in the presence of N,N′‐dimethylethane‐1,2‐diamine (DMEDA, 20 mol%) and t‐BuOK (3.0 equiv.) at 80 °C affords biphenyl in 81%. In the reaction of Shi and coworkers [35], 1,10‐phenanthroline (Phen, 40 mol%) and t‐BuOK (3.0 equiv.) are applied in the mixture of benzene (4.0 mL) and phenyl bromide

9.2  Oxidations of Phenyl sp2C─H Bond

(0.5 mmol, 1 equiv.) at 100 °C for 18 h to give 74% yield of biphenyl. As for the work of Shirakawa, Hayashi, et  al. [36], a­ rylation of benzene (27 mmol) with phenyl iodide (0.225  mmol) under 4,7‐diphenyl‐1,10‐phenanthroline (Ph‐phen, 10 mol%) and t‐BuONa (2.0 equiv.) at 155 °C for 6 h produces biphenyl in 65% yield (Scheme 9.29). Various unsymmetrical biaryls are obtained in high yield. Though the conditions applied in these reactions differ slightly from each other, namely, aryl halide (aryl iodide vs. aryl bromide), bidentate nitrogen ligand (DMEDA, Phen, Ph‐phen), base (t‐BuOK vs. t‐BuONa), and temperature, some common features are shared. Benzene is used in large excess as solvent. Cleavage of phenyl C─H bond is not the rate‐determining step, as confirmed by low KIE value obtained from arylation of benzene and benzene‐ d6 with aryl halide (1.3, 1.1, and 1.1). No reaction occurs when radical scavenger is added. Ortho‐selectivity is observed when monosubstituted benzene is arylated with aryl halide. Kwong and coworkers [34] +

20 mol% DMEDA

I

4.0 mL

0.5 mmol

3.0 equiv. KOtBu 80 °C

81%

Shi and coworkers [35] +

40 mol% Phen

Br

4.0 mL

0.5 mmol

3.0 equiv. KOtBu 100 °C,18 h

74%

Shirakawa, Hayashi, and coworkers [36] + 27 mmol

I 0.225 mmol

10 mol% Ph-phen 2.0 equiv. NaOtBu 155 °C, 6 h

65%

Scheme 9.29  Base‐promoted homolytic aromatic substitution of benzene.

The reaction mechanism was ambiguous and controversial initially and was elucidated later by Studer and Curran, defined as base‐promoted homolytic aromatic substitution (BHAS) described in the form of either radical chain process [37] or electron catalytic cycle [38]. In the form of radical chain process [37], aryl halide is converted into aryl halide radical anion by transfer of one single electron more likely indirectly from a bidentate nitrogen ligand complexed t‐BuOK or t‐BuONa. The aryl halide radical anion is decomposed to aryl radical by loss of iodide. Aryl radical adds to benzene through homolytic

251

252

9  Oxidation of Benzene

aromatic substitution to produce cyclohexadienyl radical, followed by deprotonation by t‐BuOK or t‐BuONa to generate cyclohexadienyl radical anion key intermediate. This cyclohexadienyl radical anion is highly reductive, transferring one single electron to substrate aryl halide to afford biaryl product and aryl halide radical anion to fulfill the propagation (Scheme 9.30). Alternatively, when an electron is considered as the catalyst [38], an electron is injected into the catalytic cycle from the initiator complexed t‐BuOK or t‐BuONa. This ­single electron adds to aryl halide to give aryl halide radical anion, which is decomposed to aryl radical by loss of iodide. Aryl radical adds to benzene through homolytic aromatic substitution to produce cyclohexadienyl radical, followed by deprotonation by t‐BuOK or t‐BuONa to generate cyclohexadienyl radical anion key intermediate. Rearomatization of this highly reductive cyclohexadienyl radical anion affords biaryl product and one single electron to fulfill the electron catalytic cycle (Scheme 9.31). X ET X X–

X –

tBuOH H tBuO–

Scheme 9.30  Mechanism of BHAS in the form of radical chain process.

9.2.1.4 Alkenylation

Phenyl–alkenyl bond is the core structure of styrene. Styrene is one of the most important industrial intermediates with worldwide production of ~25 million t/a in 2010 [39], mainly used in manufacture of polystyrene, SAN, ABS, styrene–butadiene rubber, latex, polyester resins, etc. [40]. Commercially, 85% of styrene is produced at ~620 °C through catalytic dehydrogenation of ethylbenzene, which is prepared from addition of ethylene to benzene.

9.2  Oxidations of Phenyl sp2C─H Bond

Scheme 9.31  Mechanism of BHAS in the form of electron catalysis.

X e–

X

X–

tBuOH

tBuO–

H

The other 15% production is through the styrene–propylene oxide process also starting from ethylbenzene. On the other hand, the powerful tool to produce styrene structure in modern organic synthesis is the classic Mizoroki–Heck reaction, which is the cross‐coupling of aryl halide and alkene under Pd(0) catalysis developed in the 1970s. The Mizoroki–Heck cross‐coupling shares advantages of mild reaction conditions, high catalytic efficiency, wide substrate scope, etc. and has been widely used for the synthesis of pharmaceuticals, natural products, etc. as well as for industrial applications. The major limitation of the Mizoroki–Heck reaction is the use of prefunctionalized aryl halide as starting material, in which halogen is added on benzene with additional step(s) and is disposed of after reaction stoichiometrically. Therefore, production of styrene directly from cross‐coupling of phenyl C─H bond and alkene is highly desired [41]. In fact, a prototype of this ideal method to produce styrene was established even earlier than the Mizoroki–Heck cross‐coupling. In 1967, Moritani and Fujiwara found that treatment of benzene (340 mL) with styrene∙PdCl2 complex (9.10 g) in the presence of HOAc (80 mL) at reflux for 8 h afforded trans‐stilbene in 26% yield based on styrene∙PdCl2 complex [42] (Scheme 9.32). Control experiments clearly demonstrated that reaction of benzene with styrene∙PdCl2 complex afforded trans‐stilbene product. Acetic acid plays an important role on this reaction, and no trans‐stilbene is formed when HOAc is absent or replaced by HCl. + 340 mL

PdCl2

HOAc (80 mL) Reflux, 8 h

9.10 g

Scheme 9.32  Cross‐coupling of benzene with styrene∙PdCl2 complex.

26%

253

254

9  Oxidation of Benzene

Moreover, direct cross‐coupling of benzene with alkenes to produce styrene derivatives was achieved shortly afterward [3]. For example, treatment of benzene (340 mL) with styrene (32 mmol, 1 equiv.) in the presence of Pd(OAc)2 (7.21 g, 1.0 equiv.) in HOAc (80 mL) at reflux for 8 h affords trans‐stilbene in 90% yield (Scheme 9.33). Various other alkenes including ethylene, 1‐butene, 1,1‐diphenylethylene, trans‐stilbene, triphenylethylene, acrylonitrile, etc. are also available for this reaction. Furthermore, catalytic cross‐coupling of benzene with alkenes was established in 1969 under palladium catalysis using Cu(OAc)2/O2 or AgOAc/ O2 oxidative system [3]. For example, treatment of benzene (20 mL) with styrene (5.0 mmol) in the presence of Pd(OAc)2 (0.5 mmol), Cu(OAc)2 (0.5 mmol), and O2 (50 atm) in HOAc (5 mL) at reflux for 8 h affords trans‐stilbene in 45% yield, and the TON is 4 (Scheme 9.34). This is an early example of transition‐metal‐ catalyzed formation of carbon─carbon bond through C─H bond activation and cross‐coupling reaction, which was named as the Fujiwara–Moritani reaction later. The unique chemoselectivity exhibited in this reaction is also of particular interest in the reaction of Pd(OAc)2, alkene, and benzene in HOAc at reflux affords cross‐ coupling product styrene exclusively since homocoupling of either alkene to give butadiene or benzene to give phenyl in the similar conditions was known at that time. They also proposed the reaction mechanism in palladium catalytic cycle, which is still available today. Pd(II) catalyst cleaves phenyl C─H bond to form phenyl‐Pd(II) intermediate, which is inserted by alkene to give phenylethyl‐Pd(II) intermediate. β‐Hydrogen elimination affords styrene product and Pd(II)–H species, which decomposed to Pd(0) species and proton. Pd(II) catalyst is regenerated by oxidation of Pd(0) species with Cu(OAc)2 and O2 to fulfill the catalytic cycle (Scheme 9.35). The reaction mechanism is closely related to the Mizoroki–Heck cross‐coupling except that phenyl‐Pd(II) intermediate is formed through direct cleavage of phenyl C─H bond by Pd(II) complex instead of oxidative addition of Pd(0) species to phenyl halide. Oxidation of phenyl C─H bond occurs when phenyl‐Pd(II) intermediate is inserted by alkene followed by β‐hydrogen elimination. 1.0 equiv. Pd(OAc)2

+ 340 mL

HOAc (80 mL), reflux, 8 h 32 mmol

90%

Scheme 9.33  Pd(II)‐mediated cross‐coupling of benzene with styrene.

0.5 mmol Pd(OAc)2 0.5 mmol Cu(OAc)2, O2 (50 atm) HOAc (5 mL), reflux, 8 h

+ 20 mL

5.0 mmol

Scheme 9.34  Pd(II)‐catalyzed cross‐coupling of benzene with styrene.

45%, TON = 4

9.2  Oxidations of Phenyl sp2C─H Bond PdII

Cu(OAc)2 O2

C H Activation

Oxidation

H+ Pd(0)

PdII

Reductive β–H elimination H+

Insertion H H

PdII H

Scheme 9.35  Proposed mechanism of the Fujiwara–Moritani cross‐coupling.

The initial Fujiwara–Moritani reaction has obvious limitations including using benzene in large excess (often as solvent), low catalytic efficiency, harsh oxidation conditions, etc. and is not ready for synthetic applications. It takes decades for Fujiwara et al. and other groups to improve this reaction. In 1999, Fujiwara and coworkers provided a highly mild and efficient cross‐coupling of benzene with alkene to produce styrene under palladium catalysis in their last report on the Fujiwara–Moritani reaction [43]. For example, treatment of ­benzene (15 mmol) with ethyl (2E)‐cinnamate (3.0 mmol) in the presence of Pd(OAc)2 (0.03 mmol, 1 mol%), benzoquinone (BQ, 0.3 mmol), t‐BuOOH (3.9 mmol), HOAc (3 mL), and Ac2O (1 mL) at 90 °C for 12 h affords 3‐phenylcinnamate in 81% yield, and the TON is 81 (Scheme 9.36). The TON is up to 280 by further enlarging the ratio of substrate to catalyst. BQ is believed to stabilize Pd(0) species preventing aggregation to Pd black by formation of Pd(0)∙BQ complex in situ followed by oxidation of Pd(0) to Pd(II). Addition of Ac2O to remove water from t‐BuOOH as well as to facilitate formation of tert‐ butyl peracetate also improves the yield.

CO2Et +

15 mmol

1 mol% Pd(OAc)2,10 mol% BQ 3.9 mmol tBuOOH, Ac2O (1 mL) HOAc (3 mL), 90 °C, 12 h

3.0 mmol

Scheme 9.36  A highly efficient Fujiwara–Moritani cross‐coupling.

CO2Et

81%, TON = 81

255

256

9  Oxidation of Benzene

Though t‐BuOOH is economical, use of low‐pressured or atmospheric O2 or air as oxidant is always the pursuit of an ideal oxidation of C─H bonds. In 2000, Matsumoto and Yoshida reported rhodium‐catalyzed coupling of benzene with ethylene to produce styrene using 5.4 atm of O2 as oxidant with TON of 23 [44] (Scheme 9.37). In 2001, Milstein and coworkers reported ruthenium‐ catalyzed coupling of benzene with methyl acrylate using 2 atm of O2 as oxidant with TON of 88 [45] (Scheme 9.38). These are also the early examples of rhodium or ruthenium catalyzing the Fujiwara–Moritani‐type reactions. 0.003 mmol Rh(acac)(CO)2

+ 31.8 mmol

15.3 atm

2.0 mmol acacH O2 (5.4 atm), 180 °C, 20 min

TON = 23

Scheme 9.37  Rh‐catalyzed Fujiwara–Moritani‐type cross‐coupling.

+ 8.0 mL

CO2Me 5.0 mmol

CO2Me

0.4 mol% RuCl3 • 3H2O CO (6.1 atm),O2 (2 atm) 180 °C, 48 h

35%, TON = 88

Scheme 9.38  Ru‐catalyzed Fujiwara–Moritani‐type cross‐coupling.

In 2003, use of atmospheric O2 (1 atm) as terminal oxidant was achieved by Ishii and coworkers using heteropoly acid as cocatalyst [46]. For example, treatment of benzene (30 mmol) with ethyl acrylate (1.5 mmol) in the presence of Pd(OAc)2 (0.1 mmol), H7PMo8V4O40 (43 mg, ~0.02 mmol), acacH (0.1 mmol), NaOAc (0.08 mmol), and O2 (1 atm) in CH3CH2CO2H (5 mL) at 90 °C for 3 h affords ethyl(2E)‐cinnamate in 72% yield. Particularly, air (1 atm) is also available instead of O2 under the same conditions, which is important from the practical synthetic viewpoint, to produce ethyl(2E)‐cinnamate in 72% yield as well by prolonging the reaction time to 6 h (Scheme 9.39).

+ 30 mmol

1.5 mmol

+ 30 mmol

CO2Et

CO2Et 1.5 mmol

0.1 mmol Pd(OAc)2, 0.02 mmol H7PMo8V4O40 0.1 mmol acacH, 0.08 mmol NaOAc O2 (1 atm), EtCO2H (5 mL), 90 °C,3 h

CO2Et 72%

0.1 mmol Pd(OAc)2, 0.02 mmol H7PMo8V4O40 0.1 mmol acacH, 0.08 mmol NaOAc air (1 atm), EtCO2H (5 mL), 90 °C, 6 h

CO2Et 72%

Scheme 9.39  The Fujiwara–Moritani cross‐coupling using atmospheric O2 or air as oxidant.

9.2  Oxidations of Phenyl sp2C─H Bond

Use of atmospheric O2 as oxidant in palladium‐catalyzed cross‐coupling of benzene with alkene is also available by the use of bulky 2,6‐di‐alkyl‐substituted pyridine ligand (2,6‐bis(2‐ethylhexyl)pyridine) as reported in 2009 by Yu and coworkers [47] (Scheme 9.40) or combination of iron phthalocyanine ([Fe(Pc)]) and BQ reported by Bäckvall and coworkers [48] in 2013 (Scheme 9.41). +

CO2Et

10 mol% Pd(OAc)2 20 mol% 2,6-bis(2-ethylhexyl)pyridine

0.6 mmol

2.0 mL

CO2Et

1.0 equiv. Ac2O, O2 (1 atm), 90 °C, 24 h 77%

Scheme 9.40  The Fujiwara–Moritani cross‐coupling using atmospheric O2 as oxidant (i). + 10 mmol

CO2nBu 1.0 mmol

CO2nBu

5 mol% Pd(OAc)2 2 mol% [Fe(Pc)], 20.0 mol% BQ O2 (1 atm), HOAc (1 mL), 80 °C, 24 h

56%

Scheme 9.41  The Fujiwara–Moritani cross‐coupling using atmospheric O2 as oxidant (ii).

On the other hand, in addition to cross‐coupling of benzene with alkene, phenyl–alkenyl bond is also formed through addition of alkyne to benzene. In 1979, Hong and coworkers reported addition of internal alkyne to benzene in rhodium catalysis [49]. For example, treatment of benzene (30 mL) with diphenylacetylene (1 g) in the presence of Rh4(CO)12 (0.04 g) and CO (25 kg/cm2) at 220 °C for 7 h affords triphenylacetylene in 45% yield and other side products (Scheme 9.42). It was proposed that [Rh] catalyst cleaves phenyl C─H bond by oxidative addition to form phenyl–[Rh]–H intermediate, which is inserted by acetylene to give phenylvinyl–[Rh]–H species. Reductive elimination of vinyl and hydride group produces styrene and [Rh] to fulfill the catalytic cycle.

0.05 mmol Rh4(CO)12

+ 30 mL

CO (25 kg/cm2), 220 °C, 7 h 5.6 mmol

45%

Scheme 9.42  Rh‐catalyzed addition of internal alkyne to benzene.

In 2000, Fujiwara and coworkers gave examples of platinum‐ or palladium‐ catalyzed addition of internal alkyne to benzene under mild conditions [50]. For example, treatment of benzene (10 mmol) with diphenylacetylene (5.0 mmol) in the presence of PtCl2 (0.25 mmol) and AgOAc (0.5 mmol) in mixtures of CF3CO2H (4 mL) and CH2Cl2 (1 mL) at room temperature for 42 h gives triphenylethylene in 56% yield (Scheme 9.43). Pd(OAc)2 is also available despite the lower yield (36%).

257

258

9  Oxidation of Benzene

0.25 mmol PtCl2, 0.5 mmol AgOAc

+ 10 mmol

5.0 mmol

CF3CO2H (4 mL), CH2Cl2(1 mL), rt, 42 h

56% TON = 11

Scheme 9.43  Pt‐catalyzed addition of internal alkyne to benzene.

In the proposed mechanism, Pd(II) catalyst cleaves phenyl C─H bond to from phenyl‐Pd(II) intermediate, which is trans‐inserted by alkyne to give phenylvinyl‐Pd(II) species. Protonation of this species produces styrene and Pd(II) catalyst to fulfill the catalytic cycle [51] (Scheme 9.44). Alternatively, addition of Pd(II) cation or proton to alkyne to form vinyl cation in situ, which reacts with benzene through SEAr process to afford styrene, is also possible [52]. The latter situation is partly supported by the fact that formation of triphenylethylene is also available through FeCl3 (Scheme 9.45) promoting addition of diphenylacetylene to benzene, though the yield is very low [53] (Scheme 9.46). Isotopic experiment of phenylacetylene with p‐xylene and p‐xylene‐d10 gives a KIE value of 1, confirming that it is a Friedel–Crafts-type reaction.

H

PdII

H+ H+ Pd(II) Pd(II)

Scheme 9.44  Proposed mechanism of Pd‐catalyzed addition of alkyne to benzene.

9.2  Oxidations of Phenyl sp2C─H Bond

H

FeIII

H+

FeIII

FeIII

H+

Scheme 9.45  Proposed mechanism of addition of internal alkyne to benzene through SEAr process.

0.2 mmol FeCl3

+

CH3NO2 (0.5 mL), 80 °C, 17 h

3.0 mmol

11%

1.0 mmol

Scheme 9.46  Fe‐mediated addition of internal alkyne to benzene.

9.2.1.5  Carbonylation and Carboxylation

Phenyl carbonyl compounds including phenyl ketone, benzaldehyde, benzoic acid and its derivatives, etc. are fundamental aromatic intermediates of considerable industrial interest for production of pharmaceuticals, insecticides, plasticizers, dyes, perfumes, and other commercial specialty products. Currently, preparation of phenyl ketone derivatives and benzaldehyde is mainly through the Friedel–Crafts acylation, which is the reaction of aromatic compounds with acyl halides in the presence of stoichiometric amount of Lewis acid traditionally [5] (Scheme 9.47). +

O Cl

AlCl3

Scheme 9.47  Friedel–Crafts acylation.

O

259

260

9  Oxidation of Benzene

Compared with the Friedel–Crafts alkylation, the Friedel–Crafts acylation is usually conducted under quite mild conditions since acyl halides react more readily than alkyl halides in general. However, owing to environmental demand, use of acyl anhydride or acid instead of acyl halide as acylating reagent is highly desired. Besides, stoichiometric or overstoichiometric amount of corrosive Lewis acid, most commonly AlCl3, is usually required to obtain acylation product in high yield due to the consumption of Lewis acid coordinating with carbonyl compound to form a complex. Search for environmentally benign and reusable catalyst, mainly solid acid including zeolite, modified clay, solid superacid, heteropoly acid, Nafion‐H, etc., is under active consideration [5]. Among them, heteropoly acids (HPA) attract considerable interest because of their high surface area, high acidity, and insolubility. For example, a halogen‐ free Friedel–Crafts acylation of benzene with benzoic anhydride on insoluble HPA catalyst was reported by Tagawa et al. in 2004 [54]. Quantitative yield of benzophenone is achieved by treatment of benzene (1.17 mol) with benzoic anhydride (6.6 mmol) in the presence of H0.5Cs2.5PW12O40 (0.33 mmol) at 150 °C for 120 min (Scheme 9.48). The recovered HPA catalyst is reused and active for a second run, but the reactivity decreases gradually at third run due to the adsorption of ketone and benzoic acid on catalyst. In 2008, Shimizu and coworkers reported that treatment of benzene (5.0 mmol) with nC11H23CO2H (1.0 mmol) in the presence of Ti0.75PW12O40 (14 mol%) at 180  °C for 72 h afforded the acylation product in 53% yield [55] (Scheme 9.49). O +

1.17 mol

O O

O

0.33 mmol H0.5Cs2.5PW12O40 150 °C, 120 min

6.6 mmol

Quantitative

Scheme 9.48  Acylation of benzene with benzoic anhydride.

+ 5.0 mmol

nC H CO H 11 23 2

14 mol% Ti0.75PW12O40 180 °C, 72 h

1.0 mmol

O nC H 11 23

53%

Scheme 9.49  Acylation of benzene with carboxylic acid.

As for benzoic acid, current industrial production mainly relies on liquid‐ phase oxidation of toluene with O2 [56]. In a typical modern process at 165 °C and 0.9 MPa, benzoic acid is afforded in ~90% yield. Alternatively, benzoic acid is synthesized through carboxylation of benzene through CO insertion. Based on previous work of phenyl C─H vinylation through alkene insertion under

9.2  Oxidations of Phenyl sp2C─H Bond

palladium catalysis, Fujiwara et al. reported in 1980 that treatment of benzene (20 mL) with CO (15 atm) in the presence of Pd(OAc)2 (1.0 mmol) at 100 °C for 20 h afforded 26% yield of benzoic acid based on Pd(OAc)2 [57] (Scheme 9.50). The facts that no benzaldehyde is detected in the resulting mixture and that benzoic acid is also formed in deoxygenated benzene do not favor the mechanism involving benzaldehyde as intermediate followed by further oxidation to benzoic acid by O2 dissolved in benzene. Catalytic reaction with 1 atm of CO using t‐BuOOH as oxidant was established in 1983 at the same group [58] (Scheme 9.51). It is proposed that Pd(II) catalyst cleaves phenyl C─H bond to form phenyl‐Pd(II) intermediate, which is inserted by CO to give phenylcarbonyl‐Pd(II) species. Reductive elimination of phenylcarbonyl and acetate group attached on Pd(II) complex followed by hydrolysis affords benzoic acid (Scheme 9.52). + 20 mL

1.0 mmol Pd(OAc)2

CO

CO2H

100 °C, 20 h

15 atm

26%

Scheme 9.50  Palladium‐mediated carboxylation of benzene with CO.

+ 12 mL

CO 1 atm

0.1 mmol Pd(OAc)2

CO2H

0.05–1.0 mmol allyl chloride 35–50 mmol tBuOOH HOAc (3.0 mL), 75 °C, 2 h

TON = 12–13

Scheme 9.51  Palladium‐catalyzed carboxylation of benzene with CO (1 atm).

PdII(OAc)2 tBuOOH C H activation

Oxidation

HOAc Pd(0)

PdII Reductive elimination

O

Insertion

OAc

CO

O OAc

PdIIOAc

Scheme 9.52  Proposed mechanism of carboxylation of benzene with CO.

261

262

9  Oxidation of Benzene

In 1995, Fujiwara and coworkers provided a highly efficient and mild method for carboxylation of benzene with CO [59]. For example, treatment of benzene (56 mmol) with CO (1 atm, balloon) in the presence of Pd(OAc)2 (0.1 mmol) and K2S2O8 (5.0 mmol) in CF3CO2H (5 mL) at room temperature for 120 h affords benzoic acid in 3300% yield based on Pd(OAc)2, and the TON is 33. Moreover, quantitative yield of benzoic is obtained when benzene (1.0 mmol) is treated with CO (1 atm, balloon), Pd(OAc)2 (0.1 mmol), and K2S2O8 (2.5 mmol) in CF3CO2H (1 mL) at room temperature (Scheme 9.53). The mechanism is similar with the initial work, but the reaction is more efficient and under milder conditions due to formation of more electrophilic Pd(OCOCF3)+ cation in situ from Pd(OAc)2 and trifluoroacetic acid (CF3CO2H) instead of acetic acid (HOAc). +

CO 1 atm

56 mmol

+ 1.0 mmol

CO 1 atm

0.1 mmol Pd(OAc)2 5.0 mmol K2S2O8 CF3CO2H (5 mL), rt, 120 h 0.1 mmol Pd(OAc)2 2.5 mmol K2S2O8 CF3CO2H (1 mL), rt

CO2H TON = 33 CO2H Quantitative

Scheme 9.53  Pd(II)‐catalyzed carboxylation of benzene with CO in CF3CO2H.

Carbon dioxide (CO2) is also available in carboxylation of benzene. In 1984, Fujiwara et al. reported that treatment of benzene (16 mL) with CO2 (1 atm) in the presence of Pd(OAc)2 (0.2 mmol) and t‐BuOOH (8.0 mmol) in HOAc (4 mL) at 70 °C for 3 days afforded benzoic acid in 127% yield based on Pd(OAc)2 [60] (Scheme 9.54). The reaction mechanism is closely related to that of CO insertion of benzene under palladium catalysis. + 16 mL

CO2 1 atm

0.2 mmol Pd(OAc)2 8.0 mmol tBuOOH HOAc (4 mL), 70 °C, 3 days

CO2H TON = 1

Scheme 9.54  Pd(II)‐mediated carboxylation of benzene with CO2.

The catalytic efficiency was improved under rhodium catalysis by Iwasawa and coworkers in 2014 [61]. Treatment of benzene (2.0 mL) with CO2 (1 atm) in the presence of rhodium complex (1,2‐bis(dialkylphosphino)ethane-rhodium(I) chloride, 0.005 mmol), AlMe1.5(OEt)1.5 (1.0 mmol), and DMA (0.1 mL) at 85 °C for 6 h affords benzoic acid in TON of 33 (Scheme 9.55). The tentative mechanism starts with reaction of rhodium(I) chloride with AlMe1.5(OEt)1.5 to form

9.2  Oxidations of Phenyl sp2C─H Bond

methyl-Rh(I) complex, which cleaves phenyl C─H bond through oxidative addition to form Rh(III) species. Reductive of methyl and hydride group from Rh(III) species gives phenyl‐Rh(I) species, which is inserted by CO2 to form phenylcarbonyl‐Rh(I) species. Transmetalation of this phenylcarbonyl‐Rh(I) species with AlMe1.5(OEt)1.5 affords methyl-Rh(I) complex to fulfill the ­catalytic cycle and phenylcarbonyl-Al complex followed by hydrolysis to produce benzoic acid. Isotopic experiment of CO2 with benzene and benzene‐ d6 gives a KIE value of 5.5, which indicates that cleavage of phenyl C─H bond is the rate‐determining step. +

CO2 1 atm

2.0 mL

0.005 mmol Rh complex 1.0 mmol AlMe1.5(OEt)1.5 DMA (0.1mL), 85 °C, 6 h

CO2H TON = 33

Scheme 9.55  Rh‐catalyzed carboxylation of benzene with CO2.

9.2.2  Formation of C─N Bond

Important compound with a phenyl-nitrogen bond include nitrobenzene and aniline. Major industrial application of nitrobenzene is to produce aniline. As early as in 1845, systematic work on nitration of benzene by mixtures of nitric and sulfuric acids was reported by Hofmann and Muspratt, which is still the dominant method for introducing a nitro group into aromatic system nowadays. For example, current large‐scale nitration of benzene usually uses mixtures of nitric acid (20%), sulfuric acid (60%), and water (20%) at 50 to 100 °C by continuous process [4]. Since nitronium ion (NO2+) is confirmed as the active species, nitration of benzene with more environmentally benign nitronium ion reagents is demanded. For example, Waller, Barrett, et al. reported that treatment of benzene (3.0 mmol) with 69% nitric acid (3.0 mmol) in the presence of Yb(OTf)3 (10 mol%) in DCE (5 mL) at reflux for 12 h afforded nitrobenzene in 75% yield, and no dinitrated products were observed [62] (Scheme 9.56). Other lanthanide(III) triflates were screened and Sc(OTf )3 exhibited similar reactivity while others were less effective. Different rates with various lanthanide triflates indicate that complex of metal center with nitric acid is involved, which produces active nitronium ion. Yb(OTf )3 catalyst is recovered by simple evaporation and is active for another three runs of nitration with no reduction in rate or yield and no change in selectivity. + 3.0 mmol

HNO3 (69%) 3.0 mmol

10 mol% Yb(OTf)3

NO2

DCE (5 mL), reflux, 12 h 75%

Scheme 9.56  Yb(OTf )3‐catalyzed nitration of benzene with HNO3.

263

264

9  Oxidation of Benzene

Aniline is also an important industrial intermediate, and the aniline market was estimated to be worth 3.8 million t/a in 2008 [63]. Major applications of aniline involve synthesis of isocyanates primarily 4,4′‐methylenebis(phenyl isocyanate) (MDI) for polyurethanes production (67% of total 1984 consumption and over 5 million t/a worldwide production in 2011), manufacture of antioxidants in rubber industry, herbicides, fungicide, insecticides, animal repellents, dyes, etc. Current industrial production of aniline is through catalytic hydrogenation of nitrobenzene with H2; for example, liquid‐phase hydrogenation performed at 100–170 °C and 10–150 bar H2. In laboratory synthesis, amination of aryl halide by Ullmann or Buchwald–Hartwig reaction is the common method. In either industrial production or laboratory synthesis, prefunctionalized nitrobenzene or aryl halide is used as substrate. Thus, direct synthesis of aniline by amination of benzene is of considerable interest. Nitrene insertion to phenyl C─H bond is available for phenyl–nitrogen bond formation. For example, treatment of benzene (10  mL) with PhI=NTs (0.5 mmol) in the presence of TpBr3Cu(NCMe) catalyst (0.025 mmol) at room temperature afforded aniline derivative in 40% yield as reported by Pérez and coworkers in 2003 [64]. The yield is further increased to 80% when the reaction is conducted at 85 °C (Scheme 9.57). + 10 mL

PhI NTs 0.5 mmol

5 mol% TpBr3 Cu(NCMe) 85 °C

NHTs 80%

Scheme 9.57  Amination of benzene by copper‐catalyzed nitrene insertion.

Besides, transition‐metal‐free preparation of aniline derivatives by imidation of benzene with imides was reported independently by two groups, namely, Cho and Changs [65] and DeBoef [66] in 2011. In the work of Cho and Changs, group treatment of benzene (1.5 mL) with succinimide (0.3 mmol) in the presence of PhI(OAc)2 (5.0 equiv.) at 140 °C for 4 h affords the desired aniline derivative in 90% yield [65] (Scheme 9.58). Other imides including glutarimide, phthalimide, 1,8‐naphthalimide, saccharin, etc. are also available. An SEAr process‐involved mechanism is proposed, in which imide reacts with PhI(OAc)2 to form N‐(phenylacetoxyiodo)imido (NPhth{I(OAc)Ph}) species, followed by SEAr process on benzene to afford the aniline derivative. The proposed mechanism is supported by the observation that the KIE value is 1.0, p‐xylene reacts 13 times faster than 1,4‐dichlorobenzene, and [NPhth{I(OAc)Ph}–Na] is detected by ESI (electrospray ionization) mass spectrometry. In the example of DeBoef and coworkers, treatment of benzene (4.0 mL) with phthalimide (0.68 mmol) in the presence of  PhI(OAc)2 (1.7 mmol) at 145  °C for 3 h under microwave heating affords

9.2  Oxidations of Phenyl sp2C─H Bond O

O +

HN

5.0 equiv. PhI(OAc)2 140 °C, 4 h

O

O 0.5 mmol

1.5 mL

N

90%

Scheme 9.58  Imidation of benzene with succinimide. O

O +

4.0 mL

HN

1.7 mmol PhI(OAc)2 145 °C, mw, 3 h

O 0.68 mmol

N O 88%

Scheme 9.59  Imidation of benzene with phthalimide.

a­ niline derivative in 88% yield [66] (Scheme 9.59). Succinimide is also available, while other imides give low yields. An SET process‐involved mechanism is preferred, in which benzene is oxidized by PhI(OAc)2 to phenyl radical ­cation followed by reaction with imide to afford aniline derivative. This tentative mechanism is supported by the fact that the reaction is inhibited by TEMPO [2,2,6,6-(Tetramethylpiperidine-1-yl)1-oxyl], a common radical inhibitor, observation of arene radical cation formed by I(III) oxidant in ­others work, and regioselectivity for amination of monosubstituted arenes. 9.2.3  Formation of C─O Bond

Phenol and its derivatives have phenyl─oxygen bonds. For phenol, 37% of global output is used for production of bisphenol A, whose applications include manufacture of polycarbonates and epoxy resins. Thirty‐three percent of phenol is consumed for production of phenolic resins, which are mainly used for under‐ seal applications. The rest is used for production of caprolactam through cyclohexanol, aniline, alkylphenols, diphenols, and salicylic acid. Currently, 95% of phenol is produced industrially through three steps from benzene, namely, addition of propene to benzene to form cumene at 200–250 °C in ~20% conversion of benzene, oxidation of cumene with O2 to cumene hydroperoxide (CHP) operated under either overpressure at 90–120  °C or atmospheric pressure at 95% selectivity (2) HF/O2, 350–400 °C, CuF2 regeneration

F

Scheme 9.78  CuF2‐mediated fluorination of benzene.

In 2013, Fukuzumi and coworkers reported fluorination of benzene in photocatalysis [89]. For example, treatment of benzene (20 mM) with tetraethylammonium fluoride tetra(hydrogen fluoride) salt (TEAF∙4HF, 50 mM) in the presence of photocatalyst QuCN+ClO4− (2 mM) in oxygen‐saturated MeCN with photoirradiation for 50 min affords fluorobenzene in 20% yield with 40% conversion (Scheme 9.79). It is proposed that activation of QuCN+ with photoirradiation produces QuCN+*, which abstracts one single electron from benzene to give phenyl radical cation followed by reaction with HF to afford fluorobenzene product. + 20 mM

TEAF 4HF

2 mM QuCN+ClO4–

F

O2-saturated CD3CN (0.6 mL), hν, rt, 50 min

50 mM

20%

Scheme 9.79  QuCN+‐catalyzed fluorination of benzene with TEAF/HF.

9.2.4.2 Chlorination

Chlorobenzene is an important starting material and additive in the production of high‐quality insecticides, fungicides, herbicides, dyes, pharmaceuticals, etc. [90]. Current large‐scale production of chlorobenzene is through reaction of benzene with chlorine gas in the presence of Lewis acid through SEAr process with loss of an equal equivalent hydrogen chloride as side product. Alternatively, chlorination of phenyl C─H bond using chloride anion as chlorine source under oxidative conditions avoids involvement of hazardous chlorine gas and stoichiometric disposal of hydrogen chloride and is of great interest in the demand of green chemistry. For example, Ledwith and Russell reported chlorination of benzene with Cl− using Na2S2O8 as terminal oxidant in 1974 [91]. Treatment of benzene (0.22 M) with LiCl (1.15 M) in the presence of CuCl2∙2H2O (0.02 M), Na2S2O8 (0.05 M), and HCl (0.2 M) in mixtures of MeCN/H2O (1/4, v/v) affords chlorobenzene in 60% yield (Scheme  9.80). It is proposed that decomposition of S2O82− generates SO4∙−, which abstracts one single electron from benzene to form phenyl radical cation followed by reaction with CuCl2 to give chlorobenzene and CuCl. Oxidation of CuCl with S2O82− and Cl− regenerates CuCl2 to fulfill the catalytic cycle.

275

276

9  Oxidation of Benzene + 0.22 M

LiCl

0.02 M CuCl2 • 2H2O, 0.05 M Na2S2O8

Cl

0.2 M HCl, MeCN/H2O (1/4, v/v)

1.15 M

60%

Scheme 9.80  Oxidative chlorination of benzene with LiCl using CuCl2/Na2S2O8.

This type of transformation just using K2S2O8 as oxidant was further developed by Zhang and coworkers in 2013 [92]. For example, treatment of benzene (0.25 mmol) with K2S2O8 (1.0 mmol) in 1.0 mL of MeCN/saturated NaCl solution (1/1, v/v) at 100 °C for 1 h affords chlorobenzene in quantitative yield (Scheme 9.81). +

NaCl

0.25 mmol

1.0 mmol K2S2O8 MeCN/saturated NaCl (1.0 mL, 1/1, v/v) 100 °C, 1 h

Cl Quantitative

Scheme 9.81  Oxidative chlorination of benzene with NaCl using K2S2O8.

9.2.4.3 Bromination

Bromobenzene is a useful intermediate in current organic synthesis. Industrial preparation of bromobenzene is through reaction of benzene with liquid bromine in the presence of Lewis acid via SEAr process, which is similar to the synthesis of chlorobenzene. Thus, bromination of benzene with safer bromide anion under oxidative conditions avoids using hazardous Br2 and disposing of stoichiometric HBr as side product and is highly demanded. One example was reported by Kumar and coworkers in 2012 in that bromination of benzene was achieved using NaBr/NaIO4 system under mild acidic conditions [93]. Treatment of benzene (10 mmol) with NaBr (10 mmol) in the presence of NaIO4 (5.0 mmol) in mixtures of H2SO4 (4 mL) and H2O (5 mL) at 50 °C for 3 h affords bromobenzene in 89% yield (Scheme 9.82). It is proposed that oxidation of NaBr by NaIO4 generates Br+ in situ, which reacts with benzene to give bromobenzene product. + 10 mmol

NaBr 10 mmol

5.0 mmol NaIO4

Br

H2SO4 (4 mL), H2O (5 mL), 50 °C, 3 h 89%

Scheme 9.82  Oxidative bromination of benzene with NaBr using NaIO4.

9.2.4.4 Iodination

Iodobenzene serves as an important intermediate in current organic synthesis. However, more extensive progress has been retarded due to the lack of simple and reliable methods for its preparation. Among them, iodination of benzene with iodide anion under O2 atmosphere is an ideal reaction to synthesize iodobenzene. In 1988, Radner reported such transformation using NH4I as iodide source and O2 as terminal oxidant [94]. Treatment of benzene (1.0 equiv.) with NH4I

9.3 Summary

(1.1 equiv.) in the presence of NO+BF4─ (0.1 equiv.) in CF3CO2H/(CF3CO)2O solution under O2 at room temperature for 20 h affords iodobenzene in 93% yield (Scheme 9.83). Preparative iodination of benzene in 50 mmol scale also gives 78% yield of iodobenzene. It was proposed that treatment of I− with NO+ species probably generates I+ intermediate, whose reaction with benzene through SEAr process gives iodobenzene product. +

NH4I

0.1 equiv. NO+BF4–

1.1 equiv.

1.0 equiv.

I

CF3CO2H/(CF3CO)2O, O2, rt, 20 h 93%

Scheme 9.83  Oxidative iodination of benzene with NH4I using NO+BF4−.

A greener method to prepare iodobenzene was provided by Stavber and coworkers in 2008 using KI as iodide source and air as oxidant [95]. Treatment of benzene (1.0 mmol) with KI (1.05 mmol) in the presence of NaNO2 (12 mol%) and 96% H2SO4 (1.2 mmol) in 90% aqueous CF3CO2H (6 mL) under air (balloon) at 30 °C for 10 h affords iodobenzene in 83% yield (Scheme 9.84). +

KI

12 mol% NaNO2

1.2 mmol 96% H2SO4, 90% CF3CO2H (6 mL) Air (balloon), 30 °C, 10 h 1.0 mmol 1.05 mmol

I 83%

Scheme 9.84  Aerobic oxidative iodination of benzene with KI in the presence of catalytic NaNO2.

9.3 ­Summary According to the performance of a reaction, including yield (reactivity and selectivity), catalytic efficiency, functional tolerance, substrate scope, reaction scale, etc., and the understanding of reaction mechanism such as active species, catalytic cycle, key intermediate, etc., there are four types of reactions cataloged, namely, (i) reaction not realized with attempted mechanism, (ii) reaction occurred reluctantly and harshly with low performance and rough understanding of mechanism, (iii) reaction proceeded with usable performance and supported mechanism, and (iv) reaction conducted in the state of the art for organic synthesis or industrial production, with well‐established mechanism model for guidance and prediction. Alkylation, trifluoromethylation, arylation, alkenylation, carbonylation, and formation of C─heteroatom bonds (heteroatom = N, O, F, Cl, Br, or I) via either indirect SEAr or radical process or direct C─H activation pathway are described in this chapter. Basically, these described reactions lie in between reaction types two and three, which are able to occur but not so well with working mechanism but not fully clarified. Nevertheless, some reaction modes toward ideal synthesis are

277

278

9  Oxidation of Benzene

established; for example, atmospheric aerobic oxidative alkenylation of benzene with alkene, atmospheric aerobic oxidation of benzene to produce phenol, and atmospheric aerobic oxidative iodination of benzene with iodide, though much further improvement is still needed. Besides, some novel reaction modes are established; for example, the direct arylation of benzene with aryl halides under transition‐metal‐free conditions through BHAS process, and again atmospheric aerobic oxidation of benzene to produce phenol under photocatalysis with >99/1 chemoselectivity despite the fact that phenol is far more reactive than benzene. However, basic problem of either reactivity or chemoselectivity of benzene still exists with very limited methods to cleave and oxidize phenyl sp2C─H bond, thus making many reactions not occur or occur hardly; for example, alkylation through direct cross‐coupling of benzene and alkane, trifluoromethylation, arylation through direct cross‐coupling of benzene and arene, alkynylation through direct cross‐coupling of benzene and alkyne, cyanidation, amination through direct cross‐coupling of benzene and amine, and fluorination. Therefore, new catalytic systems and new mechanisms are still urgently desired for achieving these challenging reactions. In addition, for these already established reactions of phenyl sp2C–H oxidation, their improvement to atmospheric aerobic oxidative reactions is also full of worth. NO2+ O

H N

O2N O

H2N

H2O2 or O2

HO

RCO2H

RCO2

ROH

RO

CuF2 or HF



Cl

F

Cl

9.2.2

9.1

9.2.1.1



Br

Alkyl

9.2.1.2

CF3

9.2.4.1



I Summary

CHR

FG CF3

9.2.1.3

X

9.2.1.4

H

9.2.4.2

9.2.4.3

O R O

I

R FG H2C

9.2.3

9.2.1.5

Br

Introduction

9.2.4.4

9.3

OH

FG

O R

CO or CO2

­Reference

­References [1] Folkins, H. O. Benzene; Ullmann’s Encyclopedia of Industrial Chemistry.

[2] [3] [4]

[5]

[6] [7] [ 8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 5. Production. Van Helden, R.; Verberg, G. Recueil, 1965, 84, 1263–1273. Fujiwara, Y.; Moritani, M.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166–7169. Booth, G. Nitro compounds, aromatic; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 1. Introduction. Röper, M.; Gehrer, E.; Narbeshuber, T.; Siegel, W. Acylation and alkylation; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 2. Alkylation and acylation of aromatic compounds. Mine, N.; Fujiwara, Y.; Taniguchi, H. Chem. Lett. 1986, 357–360. Yamauchi, T.; Hattori, K.; Mizutaki, S.; Tamaki, K.; Uemura, S. Bull. Chem. Soc. Jpn. 1986, 59, 3617–3620. Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.‐I. Synlett 1996, 557–559. Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.‐I. J. Org. Chem. 1997, 62, 6997–7005. Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 3913–3917. Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033–1037. Jefferies, L. R.; Cook, S. P. Org. Lett. 2014, 16, 2026–2029. Song, C. E.; Shim, W. H.; Roh, E. J.; Choi, J. H. Chem. Commun. 2000, 1695–1696. Matsumoto, T.; Taube, D. J.; Periana, R. A.; Taube, H.; Yoshida, H. J. Am. Chem. Soc. 2000, 122, 7414–7415. Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 13098–13101. Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475–4521. Chen, Q.‐Y.; Wu, S.‐W. J. Chem. Soc. Chem. Commun. 1989, 705–706. Kamigata, N.; Fukushima, T.; Yoshida, M. Chem. Lett. 1990, 649–650. Kamigata, N.; Ohtsuka, T.; Fukushima, T.; Yoshida, M.; Shimizu, T. J. Chem. Soc. Perkin Trans. I 1994, 1339–1346. Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224–228. Sladojevich, F.; McNeill, E.; Börgel, J.; Zheng, S.‐L.; Ritter, T. Angew. Chem. Int. Ed. 2015, 54, 3712–3716. Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600–8601. Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464–5467.

279

280

9  Oxidation of Benzene

[24] Seo, S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2013, 6385–6387. [25] Shi, G.; Shao, C.; Pan, S.; Yu, J.; Zhang, Y. Org. Lett. 2015, 17, 38–41. [26] (a) Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101; (b) Magano, J.; Dunetz, J. R.

Chem. Rev. 2011, 111, 2177–2250.

[27] Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, Jr., J. L.;

[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39]

[40]

[41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]

Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411–420. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–16497. Qin, C.; Lu, W. J. Org. Chem. 2008, 73, 7424–7427. Vicente, J.; Arcas, A.; Juliá‐Hernández, F.; Bautista, D. Angew. Chem. Int. Ed. 2011, 50, 6896–6899. Fujita, K.; Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004, 1926–1927. Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706–13707. Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737–16740. Sun, C.‐L.; Li, H.; Yu, D.‐G.; Yu, M.; Zhou, X.; Lu, X.‐Y.; Huang, K.; Zheng, S.‐F.; Li, B.‐J.; Shi, Z.‐J. Nat. Chem. 2010, 2, 1044–1049. Shirakawa, E.; Itoh, K.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537–15539. Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2011, 50, 5018–5022. Studer, A.; Curran, D. P. Nat. Chem. 2014, 6, 765–773. New Process for Producing Styrene Cuts Costs, Saves Energy, and Reduces Greenhouse Gas Emissions. U.S. Department of Energy. 2012, http:// www1.eere.energy.gov/office_eere/pdfs/exelus_case_study.pdf, accessed on August 24, 2016. James, D. H.; Castor, W. M. Styrene; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 7. Uses and economic aspects. Zhou, L.; Lu, W. Chem. Eur. J. 2014, 20, 634–642. Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 12, 1119–1122. Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097–2100. Matsumoto, T.; Yoshida, H. Chem. Lett. 2000, 1064–1065. Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337–338. Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476–1477. Zhang, Y.‐H.; Shi, B.‐F.; Yu, J.‐Q. J. Am. Chem. Soc. 2009, 131, 5072–5072. Babu, B. P.; Meng, X.; Bäckvall, J.‐E. Chem. Eur. J. 2013, 19, 4140–4145. Hong, P.; Cho, B.‐R.; Yamazaki, H. Chem. Lett. 1979, 339–342. Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252–7263. Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633–639. Soriano, E.; Marco‐Contelles, J. Organometallics 2006, 25, 4542–4553.

­Reference

[53] [54] [55] [56]

[57] [58] [59] [60] [61] [62] [63]

[64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74]

Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219–2222. Tagawa, T.; Amemiya, J.; Goto, S. Appl. Catal. A Gen. 2004, 257, 19–23. Shimizu, K.; Niimi, K.; Satsuma, A. Catal. Commun. 2008, 9, 980–983. Maki, T.; Takeda, K. Benzoic acid and derivatives; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 4. Production. Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc. Chem. Commun. 1980, 220–221. Fujiwara, Y.; Kawata, I.; Sugimoto, H.; Taniguchi, H. J. Organomet. Chem. 1983, 256, C35–C36. Taniguchi, Y.; Yamaoka, Y.; Nakata, K.; Takaki, K.; Fujiwara, Y. Chem. Lett. 1995, 345–346. Sugimoto, H.; Kawata, I.; Taniguchi, H.; Fujiwara, Y. J. Organomet. Chem. 1984, 266, C44–C46. Suga, T.; Mizuno, H.; Takaya, J.; Iwasawa, N. Chem. Commun. 2014, 50, 14360–14363. Waller, F. J.; Barrett, A. G. M.; Braddock, D. C.; Ramprasad, D. Chem. Commun. 1997, 613–614. (a) Kahl, T.; Schröder, K.‐W.; Lawrence, F. R.; Marshall, W. J.; Höke, H.; Jäckh, R. Aniline; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 7. Economic aspects; (b) Vogt, P. F.; Gerulis, J. J. Amines, aromatic; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 3. Production. Díaz‐Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc. 2003, 125, 12078–12079. Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011, 133, 16382–16385. Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.; DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960–19965. Walling, C.; Johnson, R. A. J. Am. Chem. Soc. 1975, 97, 363–367. Olah, G. A.; Ohnishi, R. J. Org. Chem. 1978, 43, 865–867. Niwa, S.; Eswaramoorthy, M.; Nair, J.; Raj, A.; Itoh, N.; Shoji, H.; Namba, T.; Mizukami, F. Science, 2002, 295, 105–107. Morimoto, Y.; Bunno, S.; Fujieda, N.; Sugimoto, H.; Itoh, S. J. Am. Chem. Soc. 2015, 137, 5867. Jintoku, T.; Taniguchi, H.; Fujiwara, Y. Chem. Lett. 1987, 1865–1868. Jintoku, T.; Takai, K.; Fujiwara, Y.; Fuchita, Y.; Hiraki, K. Bull. Chem. Soc. Jpn. 1990, 63, 438–441. Passoni, L. C.; Cruz, A. T.; Buffon, R.; Schuchardt, U. J. Mol. Catal. A 1997, 120, 117–123. Ohkubo, K.; Kobayashi, T.; Fukuzumi, S. Angew. Chem. Int. Ed. 2011, 50, 8652–8655.

281

282

9  Oxidation of Benzene

[75] (a) Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Am. Chem. Soc. 2013, 135,

[76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86]

[87] [88] [89] [90]

[91] [92] [93] [94] [95]

5368–5371; (b) Ohkubo, K.; Hirose, K.; Fukuzumi, S. Chem. Eur. J. 2015, 21, 2855–2861. Davidson, J. M.; Triggs, C. J. Chem. Soc. A 1968, 1331–1334. Henry, P. M. J. Org. Chem. 1971, 36, 1886–1890. (a) Eberson, L.; Jönsson, L. J. Chem. Soc. Chem. Commun. 1974, 885–886; (b) Eberson, L.; Jönsson, L. Acta Chem. Scand. B 1976, 30, 361–364. Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996, 108, 35–40. Stock, L. M.; Tse, K.; Vorvick, L. J.; Walstrum, S. A. J. Org. Chem. 1981, 46, 1757–1759. Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem. Int. Ed. 2011, 50, 9409–9412. Gary, J. B.; Cook, A. K.; Sanford, M. S. ACS Catal. 2013, 3, 700–703. Zultanski, S. L.; Stahl, S. S. J. Organomet. Chem. 2015, 793, 263–268. Ohkubo, K.; Kobayashi, T.; Fukuzumi, S. Opt. Express 2012, 20, A360–A365. (a) Grushin, V. US Patent 7,202,388; 2007; (b) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160–171. Siegemund, G.; Schwertfeger, W.; Feiring, A.; Smart, B.; Behr, F.; Vogel, H.; McKusick, B.; Kirsch, P. Fluorine compounds, organic; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 11. Ring‐fluorinated aromatic, heterocyclic, and polycyclic compounds. Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García‐Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–1664. Subramanian, M. A.; Manzer, L. E. Science 2002, 297, 1665. Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Phys. Chem. A 2013, 117, 10719–10725. Beck, U.; Löser, E. Chlorinated benzenes and other nucleus‐chlorinated aromatic hydrocarbons; Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley‐VCH Verlag GmbH & Co. KGaA. 2012, Section 1. Introduction. (a) Ledwith, A.; Russell, P. J. J. Chem. Soc. Chem. Commun. 1974, 291–292; (b) Ledwith, A.; Russell, P. J. J. Chem. Soc. Perkin II 1975, 1503–1508. Gu, L.; Lu, T.; Zhang, M.; Tou, L.; Zhang, Y. Adv. Synth. Catal. 2013, 355, 1077–1082. Kumar, L.; Mahajan, T.; Agarwal, D. D. Ind. Eng. Chem. Res. 2012, 51, 11593–11597. Radner, F. J. Org. Chem. 1988, 53, 3548–3553. Stavber, G.; Iskra, J.; Zupan, M.; Stavber, S. Adv. Synth. Catal. 2008, 350, 2921–2929.

283

10 Oxidation of Aryl sp2C─H Bond on Substituted Benzene 10.1 ­Introduction Aryl sp2C─H bonds are the sp2C─H bonds on aromatic rings. However, when a substituted group is attached to the aromatic ring, it will increase or decrease the electrophilic ability of the ring according to the substituted group, an electron‐donating, or an electron‐withdrawing group. Meanwhile, three types of aryl sp2C─H bonds are normally generated for a monosubstituted benzene, namely, ortho‐, meta‐, and para‐aryl sp2C─H bond. The reactivity and selectivity of all aryl sp2C─H bonds are influenced by the substituted groups dramatically. For example, in the SEAr process for the monosubstituted benzenes, it is well known that an electron‐rich one with electron‐donating group such as ─OH, ─OR, ─NH2, ─NHR, or ─NRR′ is more reactive than benzene with ortho‐, para‐regioselectivity. In contrast, an electron‐deficient substituted benzene with electron‐withdrawing group such as ─NO2, ─CF3, ─CN, ─COR, ─CO2R, or ─CO2H is less reactive than benzene with meta‐regioselectivity. When the substituted group is halogen (F, Cl, Br, I), the SEAr process is not good but shows ortho‐, para‐regioselectivity. Thus, methodologies for phenyl sp2C─H bonds are usually available for ­electron‐rich aryl sp2C─H bonds, and there are additional methodologies only suitable for electron‐rich aryl sp2C─H bonds. Moreover, harsher conditions or special reaction strategies and novel catalytic systems are highly required for oxidation of electron‐deficient aryl sp2C─H bonds. The distinct concern in the oxidation of aryl sp2C─H bonds is the regioselectivity. Transition metal‐catalyzed electrophilic activation and oxidation of aryl sp2C─H bonds via electrophilic C─H activation normally gives the similar regioselectivity in the SEAr process. It is desired to know how to cleave and oxidize one specific aryl sp2C─H bond to get the target product only when various types of aryl sp2C─H bonds exist during the reaction.

Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

284

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

10.2 ­Formation of C─C Bond 10.2.1 Alkylation

Currently, the main method to construct aryl–alkyl bonds is the Friedel–Crafts alkylation in the presence of stoichiometric amount of Lewis acid such as AlCl3 using either alkyl halides or alkenes as the alkylating reagents. As mentioned in Chapter  9, use of catalytic amount of Lewis acid or reusable catalyst after aqueous work‐up of the reaction is highly desired, which avoids stoichiometric consumption and disposal of Lewis acid (metal halide). Besides, use of more environmentally benign alkyl alcohol instead of alkyl halide is also preferred, if deactivation of Lewis acids by either alkyl alcohol or H2O generated in situ during alkylation is overcome. In addition, using not only activated alcohols such as benzyl alcohol but also normal alkyl alcohols as substrates is also highly desired. In this context, alkylation of arene to form aryl–alkyl bond is described later, and the emphasis is on the regioselectivity of aryl C─H bond oxidation. In the work of rare earth Lewis acid LnCl3 as reusable catalyst for alkylation of arenes with benzyl halides reported by Fujiwara and coworkers in 1986 [1], electron‐rich toluene is also available as well as benzene in this reaction. For example, treatment of benzyl chloride (1.34 mmol) with toluene (2 mL) in the presence of catalytic DyCl3 at 75  °C for 1 h affords mixtures of tolylphenylmethanes in 64% yield based on benzyl chloride, and the TON is 6. The ortho‐/ meta‐/ para‐ regioselectivity­of toluene is 31.2/6.4/62.4 with the para‐position of the highest reactivity, which indicates that an SEAr process is probably involved (Scheme 10.1). Me + 2 mL

CH2Cl

Cat. DyCl3 75 °C, 1 h

1.34 mmol

Me 64%, TON = 6 o/m/p = 31.2/6.4/62.4

Scheme 10.1  Reusable LnCl3 catalyst for the Friedel–Crafts alkylation.

Also in 1986, in the research of SeCl4‐ or TeCl4‐mediated conversion of alkyl alcohol into alkyl halides, Uemura and coworkers observed that 1‐phenylethanol (30 mmol) reacted with toluene (30 mL) in the presence of catalytic TeCl4 (10 mol%) at 25 °C for 3 h to afford mixtures of benzylation products in 93% yield with 11/89 ortho‐/para‐regioselectivity [2] (Scheme  10.2). When more sterically hindered tert‐butyl alcohol is used as substrate, the alkylation occurs exclusively on para‐position of toluene with 1/99 ortho‐/para‐regioselectivity. Catalytic alkylation of arenes with benzyl alcohols was further developed by Fukuzawa and coworkers in 1997 using Sc(OTf )3 as efficient Lewis acid [3].

10.2  Formation of C─C Bond Me

Me Me

OH

+ 30 mL

10 mol% TeCl4 25 °C, 3 h

Me

30 mmol

93% o/p = 11/89

Scheme 10.2  TeCl4‐catalyzed alkylation of toluene with benzyl alcohols.

Electron‐rich arenes including toluene, anisole, etc. are available for this reaction. For example, treatment of benzyl alcohol (1.0 mmol) with toluene (5.0 mL) catalyzed by Sc(OTf )3 (0.1 mmol) at 115–120  °C for 4 h affords quantitative yield of the diphenylmethane based on benzyl alcohol, and the ortho‐/meta‐/ para‐regioselectivity of toluene is 48/7/45. When more reactive anisole is the substrate, the reaction is carried out with anisole in slight excess (5.0 equiv.) using CH3NO2 (5 mL) as solvent at 115–120 °C for only 1 h gives quantitative yield of benzylation products with 59/1/40 ortho‐/meta‐/para‐regioselectivity of anisole (Scheme 10.3). CH2OH

Me +

115–120 °C, 4 h 1.0 mmol

5.0 mL

OMe + 5.0 mmol

10 mol% Sc(OTf)3

CH2OH 1.0 mmol

Me Quantitative o/m/p = 48/7/45

10 mol% Sc(OTf)3 CH3NO2 (5.0 mL) 115–120 °C, 1 h

MeO Quantitative o/m/p = 59/1/40

Scheme 10.3  Sc(OTf )3‐catalyzed alkylation of arenes with benzyl alcohol.

More economic and environmentally benign FeCl3 [4] or Bi(OTf )3 [5] was found as effective catalyst in benzylation of arenes with various benzyl alcohols or acetates. In 2005, Beller and coworkers demonstrated that treatment of 1‐phenylethyl acetate (0.5 mmol) with toluene (5.0 mL) or anisole (5.0 mL) in the presence of FeCl3 (10 mol%) at 50 °C for 20 h afforded the corresponding benzylation products in >99% yield, respectively [4]. In the example of toluene, all three types of aryl C─H bonds react, with ortho‐/meta‐/para‐regioselectivity of 13/3/84. As for anisole, only ortho‐ and para‐aryl C─H bonds react in the ratio of 16/84 (Scheme 10.4). In 2006, Rueping et al. disclosed that benzyl alcohols such as 1‐phenylethanol reacted with electron‐rich arenes including toluene, anisole, etc. to afford benzylation products [5]. Treatment of 1‐phenylethanol

285

286

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene Me Me Me 5.0 mL

> 99% o/m/p = 13/3/84 or

Me

or

OAc

+

10 mol% FeCl3 50 °C, 20 h

Me

0.5 mmol

OMe

MeO > 99% o/p = 16/84

5.0 mL

Scheme 10.4  FeCl3‐catalyzed alkylation of arene with benzyl acetates.

(1.0 mmol) with toluene in slightly excess (3.0 mmol) in the presence of 0.5 mol% of Bi(OTf )3 at 100  °C for 4 h affords product mixtures in 72% yield. Also all three types of tolyl C─H bonds react with ortho‐/meta‐/para‐regioselectivity of 3/1/5, which is similar with the FeCl3‐catalyzed examples reported by Beller et al. When anisole is the substrate, the reaction temperature is lowered to 55 °C, and the yield is also high (95%) with only ortho‐ and para‐aryl C─H bonds reacting and the regioselectivity being 1/4 (ortho/para) (Scheme 10.5). Me Me

OH

+ 3.0 mmol

Me 0.5 mol% Bi(OTf)3 100 °C, 4 h

Me

1.0 mmol

72% o/m/p = 3/1/5

Me OMe + 3.0 mmol

Me OH

0.5 mol% Bi(OTf)3 CH2Cl2 (3mL),55 °C,1h

MeO

1.0 mmol

95% o/p = 1/4

Scheme 10.5  Bi(OTf )3‐catalyzed alkylation of arene with benzyl alcohols.

In the previous examples, only activated alkyl alcohols such as benzylic alcohols or acetates were used as reactants. Expansion of the substrate scope to normal alkyl alcohols was highly desired. In 2014, Cook and Jefferies found that FeCl3–AgSbF6 combination was an effective catalytic system in alkylation of

10.2  Formation of C─C Bond

benzene as well as electron‐rich arenes with unactivated secondary alcohols such as cyclohexanol [6]. Treatment of cyclohexanol (0.8 mmol) with toluene (15 equiv.) in the presence of 15 mol% of FeCl3 and 45% AgSbF6 at 80 °C for 24 h affords mixtures of cyclohexyltoluene in 76% yield with regioselectivity of 2/1/3 (ortho/meta/para). Phenol also reacts with cyclohexanol in the same conditions and affords mixtures of ortho‐ and para‐cyclohexylphenol in 63% yield with the ratio of 1/1 (Scheme 10.6). Me Me 15 equiv. OH or

+ OH

0.8 mmol

76% o/m/p = 2/1/3 or

15 mol% FeCl3 45 mol% AgSbF6 DCE (8 mL), 80 °C, 24 h HO

15 equiv.

63% o/p = 1/1

Scheme 10.6  FeCl3/AgSbF6‐catalyzed alkylation of arene with alkyl alcohol.

In the previously described examples of alkylation with monoelectron‐ donating group-substituted arenes such as toluene, anisole, or phenol, mixtures of alkylated products in ortho-/para- or ortho‐/meta‐/para‐positions were usually obtained. It is still challenging for synthesis of specified monosubstituted alkylation product. On the other hand, in addition to alkyl halides and alcohols, alkenes are also available partners for Friedel–Crafts alkylation reaction. Rare earth metal complexes such as Sc(OTf )3 immobilized in ionic liquids were demonstrated; the efficient and reusable catalysts in the alkylation of benzene with either benzyl halides or benzyl alcohols and electron‐rich arenes such as phenol or anisole are also available for this reaction as reported by Song, Choi, et al. in 2000 [7]. For example, treatment of either phenol (2.0 mL) or anisole (2.0 mL) with cyclohexene (1.0 mmol) in the presence of [emim][SbF6] (1.0 mL) immobilized Sc(OTf )3 catalyst (0.2 mmol) at 20 °C for 12 h affords mixtures of ortho‐ and para‐cyclohexylarenes in 93 or 85% yield, respectively. The ortho‐/para‐regioselectivities are ca. 2.5/1 for phenol and ca. 1.8/1 for anisole (Scheme 10.7). Friedel–Crafts alkylation reactions are usually applied for benzene and electron‐rich arenes. Electron‐poor arenes normally do not react due to the low reactivity of alkyl cation. Besides, it is usually almost impossible for Friedel– Crafts alkylation to afford linear alkylbenzene product because rearrangement

287

288

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

OH

HO

2.0 mL or

20 mol% Sc(OTf)3

+ OMe

93% o/p = ca. 2.5/1 or

1.0 mmol

[emin] [SbF6] (1.0 mL) 20 °C, 12 h

MeO 85% o/p = ca. 1.8/1

2.0 mL

Scheme 10.7  Immobilized Sc(OTf )3‐catalyzed addition of alkene to arene.

of alkyl cation to the more stable secondary or tertiary alkyl cation dominates. In 2014, Hartwig and coworkers reported that strongly electron‐deficient arenes such as 1,3‐bis(trifluoromethyl)benzene reacted with 1‐octene to produce linear alkyl arene as major products in nickel catalysis [8]. For example, treatment of 1,3‐bis(trifluoromethyl)benzene (1.5  mmol) with 1‐octene (0.5 mmol) in the presence of Ni(IPr)2 (20 mol%) and t‐BuONa (0.25 mmol) in THF (0.5 mL) at 100 °C for 5 h affords mixtures of alkylation products in 65% yield. Only the most reactive meta‐aryl C─H bond reacted, and high linear/ branched selectivity of 97/3 is obtained. Very interestingly, when internal octene such as E‐2‐octene, E‐3‐octene, or E‐4‐octene is used as substrate, also linear alkylation product is afforded as major product with ca. 9/1 linear/branched selectivity in all three cases. Besides, reaction of 1,3-bis(trifluoromethyl)benzene with internal E‐4‐octene gives linear alkylation product in ca. 9/1 ratio as major product as well (Scheme 10.8). Combined experimental and computational CF3 Me

+

0.25 mmol NaOtBu F3C THF (0.5 mL) 100 °C, 5 h

F3C 1.5 mmol

0.5 mmol

CF3

Me +

F3C 0.15 mmol

Me

CF3

20 mol% Ni(IPr)2

Me 65%, L/B = 97/3

Me or or

Me 0.5 mmol

Me Me

CF3

20 mol% Ni(IPr)2 THF (0.15 mL) 100 °C, 24 h

F3C

76%, L/B = 91/9 or 61%, L/B = 90/10 or 59%, L/B = 92/8 Me

Scheme 10.8  Linear alkylation of electron‐deficient arene with alkene L/B=ratio of linear to branched product.

10.2  Formation of C─C Bond

studies reveal the reversible formation of alkyl–Ni–Ph intermediate followed by rate‐determining reductive elimination to afford linear alkylbenzene mechanism, in which lower barrier for formation of linear alkylbenzene from reductive elimination leads to the high linear selectivity. In the Friedel–Crafts alkylation, basic functional groups attached to arenes (such as aniline) are usually not available due to the strong interaction between basic functional groups and Lewis acids. One example of alkylation of basic aniline was demonstrated by Bertrand and coworkers in 2014 wherein treatment of N,N‐dimethylaniline (1.5 mmol) with 2‐phenylpropene (0.5 mmol) in the presence of 5 mol% electrophilic carbene pyrNHC- supported gold(I) chloride complex in benzene at 135 °C for 24 h produces the alkylation product in 97% yield [9]. The regioselectivity is excellent and only para‐position of aniline is alkylated (Scheme 10.9). Me Et2N 1.5 mmol

+

5 mol% [pyrNHC·AuCl + KB(C6F5)4] Benzene, 135 °C, 24 h

0.5 mmol

Et2N Me 97%

Me

Scheme 10.9  Alkylation of aniline derivative with alkene.

Stereoselectivity in alkylation of arenes is concerned when the forming ­ enzyl carbon of aryl–alkyl bond is attached with two different functional b groups. Construction of chiral aryl–alkyl structure by stereoselective alkylation of arene to obtain specified chiral product is of great importance and is quite challenging. In 2015, Zhu and coworkers reported enantioselective alkylation of aniline derivatives with α‐aryl‐α‐diazoacetate through carbene C─H bond insertion catalyzed by rhodium complex ligated by chiral spiro phosphoric acid [10]. For example, treatment of 1‐phenylpyrrolidine (0.2 mmol) with methyl  2‐diazo‐2‐phenylacetate (0.4 mmol) in the presence of 1 mol% rhodium complex and 2 mol% chiral spiro ligand in CHCl3 (3 mL) at 45 °C for 0.5 h affords the corresponding methyl 2‐phenyl‐2‐(4‐(pyrrolidin‐1‐yl)phenyl)acetate as the sole product in 79% yield with 97% ee value. Various functional group-substituted 1‐phenylpyrrolidine derivatives are available for this enantioselective alkylation, and normally >90% ee values are obtained. The reaction performed in gram scale affords the chiral α‐diaryl­ acetates in 98% ee value after recrystallization, and the obtained chiral α‐ diarylacetates products are easily further transformed with retention of the chirality. In the proposed mechanism, Rh carbene generated from methyl 2‐diazo‐2‐phenylacetate and rhodium complex in situ reacts with electron‐ rich aromatic ring of aniline to form rhodium zwitterion followed by dissociation of rhodium complex to fulfill the catalytic cycle and to give metal‐free

289

290

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

zwitterion key intermediate. This intermediate undergoes 1,2‐proton shift mediated by chiral spiro phosphoric acid (SPA) via a proton shuttle model, in which the chiral induction occurs. After this process, chiral α‐diarylacetate is afforded with high enantioselectivity, and the chiral spiro phosphoric acid is regenerated (Scheme 10.10). N2 +

N 0.2 mmol

CO2Me

CO2Me

1 mol% Rh2L4 2 mol% (R)-SPAs

*

CHCl3 (3 mL), 45 °C, 0.5 h

N

0.4 mmol

79%, 97% ee N2

CO2Me Rh2L4

H N

(R)-SPAs Mes MeO

CO2Me

O

MeO2C Rh2L4

O O H P O O H

H

Rh2L4

N

Mes

CO2Me

N

CO2Me * N

N

Scheme 10.10  Enantioselective alkylation of aniline by carbene insertion.

10.2.2 Trifluoromethylation

Current formation of aryl–trifluoromethyl bond is achieved using either ­radical reagents such as CF3I; CF3SO2Cl; CF3SO2Na; nucleophilic reagents, for example, CF3H; FSO2CF2CO2Et; TMSCF3; or electrophilic reagents including 5‐(trifluoromethyl)dibenzothiophenium salts, 3,3‐dimethyl‐1‐(trifluoromethyl)‐1,2‐benzodioxole (Togni reagent) etc., and the actual reaction pathway for trifluoromethylation of arenes stays close to the trifluoromethylating ­reagents and reaction conditions applied as described in Chapter 9. In the tri­ fluoromethylation of arenes, traditional radical trifluoromethylating reagent CF3I is a gas at atmospheric pressure (−23 °C bp) and thus is difficult to handle

10.2  Formation of C─C Bond

in the laboratory. Kamigata and coworkers [11] used easy‐to‐treat liquid tri­ fluoromethylating reagent CF3SO2Cl (32  °C bp) in 1990. In addition to benzene, ­electron‐rich arenes such as toluene or anisole are also available for this reaction. Treatment of toluene (5.0 mL) with CF3SO2Cl (2.0 mmol) using 1 mol% Ru(PPh)3Cl2 at 120 °C for 18 h to afforded mixtures of trifluoromethylated toluene in 36% yield. The ortho‐/meta‐/para‐regioselectivity for toluene is 32/36/32. Reaction of anisole in the same conditions affords mixtures of trifluoromethylated anisole in 58% yield with ortho‐/meta‐/para‐regioselectivity of 53/25/22 (Scheme  10.11). The observed regioselectivity consistent with the proposed radical mechanism in which trifluoromethyl radical generated in situ adds to arene homolytically to afford the trifluoromethylation products. Me

CF3 Me

5.0 mL or OMe

+ CF3SO2Cl 2.0 mmol

1 mol% RuCl2(PPh3)3 120 °C, 18 h

36% o/m/p = 32/36/32 or CF3 MeO 58% o/m/p = 53/25/22

5.0 mL

Scheme 10.11  Homolytic trifluoromethylation of arene.

This redox radical aryl C─H trifluoromethylation strategy was further developed by MacMillan in 2011 using photocatalysis [12]. Electron‐rich arenes, such as anisole and N‐Boc aniline, are also available for this reaction. Treatment of anisole (0.5 mmol, 1-equiv.) or N‐Boc aniline (0.5 mmol, 1 equiv.) with CF3SO2Cl (2.0 equiv.) in the presence of 1 mol% Ir(Fppy)3 photocatalyst, CF3

OMe

MeO

0.5 mmol or NHBoc

+

CF3SO2Cl 1.0 mmol

84% o/p = 2/1 or

1 mol% Ir(Fppy)3 3 equiv. K2HPO4 MeCN-d3 (4 mL) 26 W light, rt, 24 h

CF3

BocHN

0.5 mmol

Scheme 10.12  Ir‐catalyzed homolytic trifluoromethylation of arene.

80% o/p = 3/1

291

292

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

K2HPO4 (3.0 equiv.), in CH3CN (4 mL) at room temperature for 24 h affords mixtures of trifluoromethylation products in 84 or 80% yield. The regioselectivity is 2/1 (ortho/para) for anisole or 3/1 (ortho/para) for aniline derivative (Scheme  10.12). The fact that ortho‐trifluoromethylation occurs to give the major product indicates an SET process is probably involved. On the other hand, adduct of CF3I with tetramethylguanidine (TMG) was found as an effective liquid trifluoromethylating reagent by Ritter and coworkers in 2015 [13]. For example, treatment of mesitylene (0.25 mmol, 1 equiv.) with TMG·CF3I (0.5 mmol) in the presence of Cu(OAc)2·H2O (0.5 mmol) and K2S2O8 (1.0 mmol) in HOAc (2 mL) at 90 °C for 24 h affords the corresponding benzotrifluoride in 75% yield (Scheme 10.13). Me

Me +

Me

TMG·CF3I

Me

0.25 mmol

0.5 mmol Cu(OAc)2∙H2O

CF3

1.0 mmol K2S2O8 HOAc (2 mL), 90 °C, 24 h

Me

0.5 mmol

Me 75%

Scheme 10.13  Trifluoromethylation of arene with TMG·CF3I.

Trifluoromethyltrimethylsilane (TMSCF3, Ruppert’s reagent) is another kind of common effective trifluoromethylating reagent. In 2011, Sanford and coworkers reported silver‐promoted trifluoromethylation of aryl C─H bonds using TMSCF3 as trifluoromethyl source [14]. Electron‐rich arenes such as toluene (20 equiv.) or anisole (20 equiv.) are converted into the corresponding trifluoromethylarenes in 81 or 87% yield at 85 °C for 24 h in the presence of TMSCF3 (0.081 mmol, 1 equiv.), AgOTf (4.0 equiv.), and KF (4.0 equiv.). The ortho‐/meta‐ /para‐regioselectivity is 1.4/1/2.7 for toluene with para‐trifluoromethylation CF3 Me

Me

20 equiv. or

+ OMe

20 equiv.

TMSCF3 0.081 mmol

4.0 equiv. AgOTf 4.0 equiv. KF DCE (0.2 mL) 85 °C, 24 h, dark

81% o/m/p = 1.4/1/2.7 or

MeO

CF3

87% o/m/p = 2.7/1/1.2

Scheme 10.14  Ag‐mediated trifluoromethylation of arene with TMSCF3.

10.2  Formation of C─C Bond

giving the major product, while for anisole the ortho‐/meta‐/para‐regioselectivity is 2.7/1/1.2 with ortho‐trifluoromethylation giving the major product (Scheme 10.14). This silver‐mediated aryl C─H bond trifluoromethylation reaction was improved to silver catalysis using PhI(OAc)2 as oxidant and DMSO as crucial solvent, as reported by Greaney and coworkers in 2013 [15]. Electron‐rich arenes such as 1,4‐dimethoxybenzene or N,N‐dimethylaniline are available for this reaction. Treatment of 1,4‐dimethoxybenzene (0.3 mmol, 1 equiv.) or N,N‐ dimethylaniline (0.3 mmol, 1 equiv.) with TMSCF3 (2.0 equiv.) in the presence of AgF (25 mol%) and PhI(OAc)2 (2.0 equiv.) in DMSO (1 mL) at room temperature for 20 h affords the corresponding trifluoromethylarenes in 55 or 75% yield. For monosubstituted arene N,N‐dimethylaniline, the regioselectivity is 2/1 ortho/para (Scheme 10.15). CF3 MeO

OMe 0.3 mmol or NMe2

+

MeO

TMSCF3 2.0 equiv.

OMe 55%

25 mol% AgF 2.0 equiv. PhI(OAc)2 DMSO (1 mL), rt, 20 h

or CF 3 Me2N

0.3 mmol

75% o/p = 2/1

Scheme 10.15  Ag‐catalyzed trifluoromethylation of arene with TMSCF3.

More commercially available and economical trifluoroacetic acid (TFA) was applied as the effective trifluoromethylation reagent in silver catalysis reported by Zhang and coworkers in 2015 [16]. Not only benzene or electron‐rich arenes such as tert‐butylbenzene but also a range of electron‐deficient arenes, such as benzonitrile and ethyl benzoate, are available in this reaction. For example, treatment of benzonitrile (0.25 mmol, 1 equiv.) or ethyl benzoate (0.25 mmol, 1 equiv.) with TFA (6.1 equiv.) in the presence of Ag2CO3 (40 mol%), K2S2O8 (2.0 equiv.), Na2CO3 (2.5 equiv.), and H2SO4 (0.2 equiv.) in CH2Cl2 (0.7 mL) at 120 °C for 10 h affords the corresponding trifluoromethylarenes in 88 or 74% yield, respectively. In these reactions, all three positions of  arene substrate react with TFA to afford mixtures of trifluoromethylation products. Besides, further trifluoromethylation occurs in both cases to give bis(trifluoromethyl)arene. The proportions of ortho‐, meta‐, and para‐ monosubstituted trifluoromethylarene and bis(trifluoromethyl)arene is 28/11/29/20 for benzonitrile or 35/11/19/9 for ethyl benzoate. Electron‐rich tert‐butylbenzene was trifluoromethylated in 81% yield with ortho‐/meta‐/ para‐regioselectivity of 46/29/6 (Scheme 10.16).

293

294

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene CF3

CN NC 0.25 mmol or

40 mol% Ag2CO3

CO2Et

+

CF3CO2H 6.1 equiv.

0.25 mmol or tBu

0.25 mmol

2.0 equiv. K2S2O8 2.5 equiv. Na2CO3 0.2 equiv. H2SO4 DCM (0.7 mL), 120 °C, 10 h

88% o/m/p/di = 28/11/29/20 or EtO 2C

CF3

74% o/m/p/di = 35/11/19/9 or tBu

CF3

81% o/m/p = 46/29/6

Scheme 10.16  Ag‐catalyzed trifluoromethylation of arene with CF3CO2H.

Currently, the strategy applied for synthesis of trifluoromethylarene products directly using aryl C─H bond as precursor is mainly reliant on homolytic trifluoromethylation of arenes. In homolytic aryl C─H bond trifluoromethylation, the reactivity is usually high, and trifluoromethylation products are obtained in high yields for either benzene, electron‐rich arene, or even electron‐deficient arene. However, the main limitations for this kind of homolytic trifluoromethylation are the problem of regioselectivity for trifluoromethylating at one specific position to afford the desired product alone, as well as the problem of chemoselectivity for avoiding further trifluoromethylation of the formed trifluoromethyl product to afford bis(trifluoromethyl)arene as side product without controlling the arene substrate in large excess. 10.2.3 Arylation

In the formation of aryl–aryl bond, direct use of simple arenes instead of aryl halides or aryl metal reagents to synthesize biaryls is of high demand especially for pharmaceutical manufacturers. One strategy to fulfill such transformation is through direct arylation, coupling of one arene with one prefunctionalized arene, such as aryl iodide or bromide, as described in Chapter 9. In addition to benzene, electron‐rich arenes are usually available for direct arylation. In 2006, Fagnou and Lafrance reported direct arylation of arenes with aryl bromides to afford biaryls [17]. Anisole or fluorobenzene reacted with 4‐bromotoluene to afford the corresponding biaryls conducted in the mechanistic studies competing

10.2  Formation of C─C Bond

with benzene. Treatment of benzene (53 equiv., 3.0 mL) and anisole (53 equiv., 3.0 mL) with 4‐bromotoluene (0.64 mmol, 1 equiv.) in the presence of Pd(OAc)2 (3 mol%), DavePhos (3 mol%), PivOH (0.3 equiv.), and K2CO3 (2.5 equiv.) in DMA (7 mL) at 120 °C for 12 h affords mixtures of arylation products in 95% conversion. The ratio of anisole to benzene in arylation is 1/2 wherein electron‐rich anisole is of lower reactivity than benzene. The regioselectivity is 22/53/25 (ortho/meta/para) for anisole, and the least reactive meta‐position in SEAr process of anisole is reacts to afford the major product. Competing experiment of fluorobenzene with benzene is conducted in the same conditions. The mixtures of arylation products are obtained in 100% conversion, and the ratio of fluorobenzene to benzene in arylation is 11/1, and again electron‐poor fluorobenzene, which is less reactive than benzene in SEAr process, owns the  higher reactivity. The ortho‐/meta‐/para‐regioselectivity is 22/3/1 for fluorobenzene, with ortho‐position of fluorobenzene to giving the major product (Scheme 10.17). The chemo‐ or regio-selectivity exhibited in the previous competing reactions is incompatible with the SEAr process. Therefore, it was proposed that a proton transfer pathway was probably involved in this direct arylation reaction. Me 3.0 mL 53 equiv.

+

Br

OMe

Me 0.64 mmol 1 equiv.

3.0 mL 53 equiv.

3 mol% Pd(OAc)2 3 mol% DavePhos 2.5 equiv. K2CO3 0.3 equiv. tBuCO2H DMA (7 mL), 120 °C, 12 h 95% conversion

3.0 mL 53 equiv.

MeO

Me 32% conversion o/m/p = 22/53/25

F

F 3.0 mL 53 equiv.

63% conversion

+

Br

Me 0.64 mmol 1 equiv.

3 mol% Pd(OAc)2 3 mol% DavePhos 2.5 equiv. K2CO3 0.3 equiv. tBuCO2H DMA (7 mL), 120 °C, 12 h 100% conversion

Me 92% conversion o/m/p = 22/3/1 Me 8% conversion

Scheme 10.17  Pd(0)/Pd(II)‐catalyzed arylation of arene with aryl bromides.

On the other hand, a Pd(II)/Pd(IV) catalytic cycle was established for cross‐ coupling benzene with aryl iodide in 2008 by Lu and Qin to avoid using phosphine ligands in the previous example [18]. For example, treatment of a­ nisole

295

296

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

(1.0 mmol) with 4‐iodonitrobenzene (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%), AgOCOCF3 (1.2 equiv.), and CF3CH2OH (1.0 mmol) at 120 °C for 30 h affords the corresponding mixtures of biaryls in 56% yield. As for tert‐butylbenzene, also 56% yield of mixtures of arylation products are obtained by treatment of tert‐butylbenzene (5.0 mmol) with 4‐iodonitrobenzene (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%), AgOCOCF3 (1.2 equiv.), and CF3CH2OH (4.0 mmol) at 150 °C for 15 h. The regioselectivity for anisole is 1/1.1 at ortho‐ to para‐position. As for tert‐butylbenzene, arylation occurs at meta‐ and para‐positions with ratio of 1/1.2 (Scheme 10.18).

OMe

+ I

NO2 0.2 mmol

1.0 mmol

tBu

+ I

NO2

5.0 mmol

0.2 mmol

5 mol% Pd(OAc)2 0.24 mmol CF3CO2Ag

MeO

NO2

1.0 mmol CF3CH2OH 120 °C, 30 h

5 mol% Pd(OAc)2 0.24 mmol CF3CO2Ag

56% o/p = 1/1.1

tBu

NO2

4.0 mmol CF3CH2OH 140 °C, 15 h

56% m/p = 1/1.2

Scheme 10.18  Pd(II)/Pd(IV)‐catalyzed arylation of arene with aryl iodides.

The previous examples of direct arylation of benzene with aryl halides are based on the direct cleavage of aryl C─H bond through Pd(II)-involved aryl C─H activation. Alternatively, such transformations are also available through indirect cleavage of aryl C─H bond by homolytic aromatic substitution process. In the homolytic aromatic substitution of benzene reported by Fujita and Me Me 16% o/m/p = 58/27/15

40 equiv or

+ OMe

40 equiv

I 0.5 mmol

5 mol% [Cp*IrHCl]2 1.65 mmol KOtBu 80 °C, 30 h

or MeO 55% o/m/p = 72/16/12

Scheme 10.19  Ir‐catalyzed homolytic arylation of arene with aryl iodides.

10.2  Formation of C─C Bond

coworkers in 2004, electron‐rich toluene or anisole is also available for this reaction [19]. Treatment of toluene (20 mmol) or anisole (20 mmol) with phenyl iodide (0.5 mmol) in the presence of [Cp*IrHCl]2 (5 mol%) and t‐BuOK (3.3 equiv.) at 80 °C for 30 h affords the corresponding mixtures of biaryl products in 16 or 55% yield. All three positions of either toluene or anisole are arylated. The ortho‐/meta‐/para‐regioselectivity is 58/27/15 for toluene or 72/16/12 for anisole (Scheme 10.19). The ortho‐arylation dominant regioselectivity is featured by the radical aromatic substitution mechanism. In 2010, the homolytic aromatic substitution reactions of arenes with aryl iodide or aryl bromide were further developed by using catalytic amount of bidentate nitrogen ligand and stoichiometric amount of base at three independent research groups, which are Kwong and Lei [20], Shi and coworkers [21] and Shirakawa and Hayashi [22]. Either electron‐rich or electron‐poor arenes are available in the last two reports. For example, in the work of Shi and coworkers treatment of anisole (2.0 mL), toluene (2.0 mL), or trifluoromethylbenzene (2.0 mL) with 4‐iodoanisole (0.2 mmol) in the presence of 1,10‐phenanthroline (Phen, 20 mol%) and t‐BuOK (2.0 equiv.) at 100 °C for 24 h gives 70, 58, or 70% yield of mixtures of biaryl products [21]. Ortho‐arylation is the major product in the case of anisole and toluene with ortho‐/meta‐/para‐regioselectivity of 4.8/1.6/1 for anisole or 1/0.4/0.35 for toluene. In the example of trifluoromethylbenzene, meta‐arylation becomes the major product with ortho‐/meta‐/para‐regioselectivity of 1.7/4.7/1 (Scheme 10.20). As in the work of Shirakawa, Hayashi, et al. [22], arylation of anisole (27 mmol) with phenyl iodide (0.225 mmol) under 4,7‐ diphenyl‐1,10‐phenanthroline (Ph‐phen, 10 mol%) and t‐BuONa (2.0 equiv.) at 178 °C for 6 h produces biaryl mixtures in 51% yield with ortho‐/meta‐/para‐ regioselectivity of 59/26/15. Benzonitrile is also arylated in similar conditions MeO

OMe 2.0 mL or Me 2.0 mL

+ I

OMe 0.2 mmol

20 mol% Phen

70% o/m/p = 4.8/1.6/1 or Me

2.0 equiv. KOtBu 100 °C, 24 h

2.0 mL

OMe

58% o/m/p = 1/0.4/0.35 or

or CF3

OMe

F3C

OMe 70% o/m/p = 1.7/4.7/1

Scheme 10.20  Base‐promoted homolytic arylation of arene with aryl iodide.

297

298

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

OMe + I 27 mmol

Me 0.225 mmol

CN + I 27 mmol

Me 0.225 mmol

MeO

10 mol% Ph-phen 2.0 equiv. NaOtBu 178 °C, 6 h

10 mol% Ph-phen

Me 51% o/m/p = 59/26/15

NC

3.0 equiv. NaOtBu 182 °C, 6 h

Me

73% o/m/p = 58/17/25

Scheme 10.21  Base‐promoted homolytic arylation of arene with aryl iodide.

except when increasing the amount of t‐BuONa to 3.0 equiv. and raising the temperature to 182 °C to afford mixtures of biaryl products in 73% yield with ortho‐/meta‐/para‐regioselectivity of 58/17/25 (Scheme 10.21). Except for trifluoromethylbenzene, direct arylation occurs on ortho‐position of arene to afford the major biaryl product. 10.2.4 Alkenylation

The Fujiwara–Moritani reaction, oxidative cross‐coupling of arenes with ­alkenes, is an ideal way for synthesis of styrene derivatives. In the early work of the Fujiwara–Moritani reaction reported in 1969, it was found that either ­electron‐rich or electron‐poor arenes were available for this reaction [23]. For example, treatment of anisole (230 mL) with styrene (24.5 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5.50 g, 1.0 equiv.) in HOAc (55 mL) at 110 °C for 8 h affords trans‐4‐methoxystilbene in 61% yield. Reaction of toluene (340 mL) MeO

OMe

1.0 equiv. Pd(OAc)2

+ 230 mL

HOAc (55 mL), 110 °C, 8 h 24.5 mmol

61% Me

Me

1.0 equiv. Pd(OAc)2

+ Me 340 mL

32 mmol

NO2

55% 1.0 equiv. Pd(OAc)2

+ 235 mL

HOAc (80 mL), 110 °C, 8 h

HOAc (55 mL), 110 °C, 8 h

O2N

24.5 mmol

Scheme 10.22  Pd(II)‐mediated cross‐coupling of arene with alkene.

60%

Me

10.2  Formation of C─C Bond

with 4‐methylstyrene (32 mmol) in the presence of Pd(OAc)2 (7.21 g, 1.0 equiv.) in HOAc (80 mL) at 110  °C for 8 h gives trans‐4,4′‐dimethylstilbene in 55% yield. In both cases, only para‐position of anisole or toluene is coupled with alkenes. In addition, electron‐deficient nitrobenzene (235 mL) also reacted with styrene (24.5 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5.52 g, 1.0 equiv.) in HOAc (55 mL) at 110 °C for 8 h to afford trans‐3‐nitrostilbene in 60% yield. In this case, only meta‐position of nitrobenzene is coupled with styrene (Scheme 10.22). The initial Fujiwara–Moritani reaction owns some limitations including arene substrate in large excess (often as solvent), low catalytic efficiency, and harsh oxidizing conditions, etc. and is not ready for synthetic applications. Owing to the hardness for this kind of reaction involving dual cleavage of C─H bonds, it took decades for Fujiwara et al. and other groups to improve this reaction. In the last report on Fujiwara–Moritani reaction in 1999, Fujiwara and coworkers provided a highly mild and efficient cross‐coupling of benzene with alkene to produce styrene under palladium catalysis [24]. Electron‐rich arenes such as toluene or anisole are also available although the reaction is not as efficient as that with benzene. For example, treatment of toluene (15 mmol) with ethyl acrylate (3.0 mmol) in the presence of Pd(OAc)2 (0.09 mmol, 3 mol%), benzoquinone (BQ, 0.3 mmol), tBuOOH (3.9 mmol), HOAc (3 mL), and Ac2O (1 mL) at 90 °C for 12 h affords mixtures of alkenylation products in 24% yield. All three positions of toluene reacted and para‐alkenylation is the major product (1/1/3, ortho/meta/para). When anisole is the substrate, the reaction is performed under similar conditions except CF3CO2H (0.2 mL) is added. Also all three positions of anisole are alkenylated in 48% total yield with para‐position of anisole as the major product (1/1/6, ortho/meta/para) (Scheme 10.23). Me

CO2Et

+ 15 mmol OMe

15 mmol

3.0 mmol

+

CO2Et 3.0 mmol

3 mol% Pd(OAc)2, 10 mol% BQ 3.9 mmol tBuOOH, Ac2O (1 mL) HOAc (3 mL), 90 °C, 12 h

3 mol% Pd(OAc)2, 10 mol% BQ 3.9 mmol tBuOOH, Ac2O (1 mL) HOAc (3 mL), CF3CO2H (0.2 mL) 90 °C, 12 h

CO2Et

Me

24% o/m/p = 1/1/3

MeO

CO2Et

48% o/m/p = 1/1/6

Scheme 10.23  Pd(II)‐catalyzed cross‐coupling of arene with alkene.

Though the oxidant t‐BuOOH applied in the previous example is economical, use of low pressured or atmospheric O2 or air as oxidant is always the pursuit of an ideal oxidation of C─H bonds. In 2003, Ishii and coworkers

299

300

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

reported the use of atmospheric O2 (1 atm) as terminal oxidant by using heteropoly acid (HPA) as cocatalyst in the cross‐coupling of arenes and alkenes [25]. In addition to benzene, either toluene or chlorobenzene is also available for this reaction. For example, treatment of toluene (30 mmol) with ethyl acrylate (1.5 mmol) in the presence of Pd(OAc)2 (0.1 mmol), H7PMo8V4O40 (43 mg, ca. 0.02 mmol), acacH (0.1 mmol), NaOAc (0.08 mmol), and O2 (1 atm) in CH3CH2CO2H (5 mL) at 90 °C for 2 h affords mixtures of alkenylation products in 69% yield. All three positions of toluene reacted, and the ortho‐/ meta‐/ para‐regioselectivity is 14/42/44. Reaction of chlorobenzene is conducted in similar conditions for 6 h to give mixtures of alkenylation products in 68% yield. All three positions of chlorobenzene reacted as well, and the ortho‐/ meta‐/para‐regioselectivity is 27/40/33 (Scheme 10.24). Me + 30 mmol

Cl

CO2Et

0.1 mmol Pd(OAc)2, 0.02 mmol H7PMo8V4O40 0.1 mmol acacH, 0.08 mmol NaOAc O2 (1 atm), EtCO2H (5 mL), 90 °C, 2 h

1.5 mmol

+

30 mmol

CO2Et

0.1 mmol acacH, 0.08 mmol NaOAc O2 (1 atm), EtCO2H (5 mL), 90 °C, 3 h

CO2Et 69% o/m/p = 14/42/44

0.1 mmol Pd(OAc)2, 0.02 mmol H7PMo8V4O40

1.5 mmol

Me

Cl

CO2Et 68% o/m/p = 27/40/33

Scheme 10.24  The Fujiwara–Moritani cross‐coupling using atmospheric O2 as oxidant (i).

Use of atmospheric O2 as oxidant in palladium‐catalyzed cross‐coupling of arene with alkene is also available by using combination of iron phthalocyanine ([Fe(Pc)]) and 1,4-benzoquinone (BQ) as the effective cocatalysts reported by Bäckvall and coworkers [26] in 2013. Treatment of toluene (10 mmol) with n-butyl acrylate (1.0 mmol) in the presence of 5 mol% Pd(OAc)2, 2 mol% Me CO2nBu 10 mmol

OMe + 5.0 mmol

1.0 mmol

CO2nBu

5 mol% Pd(OAc)2 2 mol% [Fe(Pc)], 20 mol% BQ O2 (1 atm), HOAc (1 mL), 90 °C, 24 h

2.5 mol% Pd(OAc)2

Me

MeO 2 mol% [Fe(Pc)], 20 mol% BQ 1.0 mmol O2 (1 atm), HOAc (0.5 mL), 90 °C, 24 h

CO2nBu 58% o/m/p = 1/1/2.5 CO2nBu 64% o/m/p = 4/1/7

Scheme 10.25  The Fujiwara–Moritani cross‐coupling using atmospheric O2 as oxidant (ii).

10.2  Formation of C─C Bond

[Fe(Pc)], 20 mol% BQ, and O2 (1 atm) in acetic acid (1 mL) at 90  °C for 24 h affords mixtures of alkenylation products in 58% yield with ortho‐/meta‐/para‐ regioselectivity of 1/1/2.5 with para‐­alkenylation as the major product. Anisole reacted in similar conditions with less of both palladium catalyst and arene substrate to afford mixtures of styrene derivatives in 64% yield. The ortho‐ /meta‐/para‐regioselectivity is 4/1/7 and para‐alkenylation is major product as well (Scheme 10.25). Another concern in the Fujiwara–Moritani reaction is to expand the scope of arene substrates to electron‐deficient arenes, which are of lower reactivity in either SEAr process or C─H bond activation. Although nitrobenzene was coupled with styrene effectively in the presence of stoichiometric amount of Pd(OAc)2 in the early work of the Fujiwara–Moritani reaction, catalytic cross‐coupling of ­electron‐deficient arenes with alkenes has not been established until recently. In 2009, Yu and coworkers reported that catalytic cross‐coupling of electron‐ deficient­arenes including nitrobenzene, trifluoromethylbenzene, ethyl benzoate, acetophenone, and even very electron‐deficient 1,3‐bis(trifluoromethyl)benzene with alkenes was achieved by applying a bulky 2,6‐dialkyl‐substituted pyridine ligand [2,6‐bis(2‐ethylhexyl)pyridine] as the effective ligand [27]. For example, treatment of 1,3‐bis(trifluoromethyl)benzene (2.0 mL) with methyl acrylate (0.6 mmol) in the presence of Pd(OAc)2 (10 mol%), 2,6‐bis(2‐ethylhexyl)pyridine (20 mol%), Ac2O (1.5 equiv.), and O2 (1 atm) at 90 °C for 38 h affords methyl (E)‐3‐ [3,5‐bis(trifluoromethyl)phenyl]acrylate in 62% yield (Scheme  10.26). Various other typical electron‐deficient arenes such as nitrobenzene, trifluoromethylbenzene, or ethyl benzoate are coupled with different alkenes in similar conditions to give the corresponding alkenylation products in high yields with meta‐alkenylation of electron‐deficient arenes as the major products. CF3 + F3C 2.0 mL

CO2Me 0.6 mmol

1.0–1.5 equiv. Ac2O, O2 (1 atm), 90 °C, 38 h

F3C

62%

CO2Me

O

Ph H2N

CF3

10 mol% Pd (OAc)2 20 mol% 2,6-bis(2-ethylhexyl)pyridine

CO2Me

F3C

73% (16 h) after hydrogenation 70% (56 h) m/p = 78/22 m/p = 84/16

P OEt OEt

EtO2C

CO2Et 70% (2 h) m/p = 80/20

Scheme 10.26  Pd(II)‐catalyzed cross‐coupling of electron‐deficient arenes with alkenes using atmospheric O2.

Electron‐deficient trifluoromethylbenzene or ethyl benzoate was also treated with alkenes to afford alkenylation products as reported by Sanford and

301

302

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

coworkers­in 2012 using 3,5‐dichloropyridine as effective ligand [28]. Treatment of ­trifluoromethylbenzene (5.4 mL) with ethyl acrylate (1.5 mmol) in the ­presence of Pd(OAc)2 (5 mol%), 3,5‐dichloropyridine (5 mol%), and tert‐butyl ­peroxybenzoate (1.0 equiv.) in HOAc (7 mL) at 100 °C for 6 h affords mixtures of alkenylation products in 32% yield with ortho‐/meta‐/para‐regioselectivity of 1/15.8/4.2. Ethyl benzoate reacted under similar conditions to give the corresponding mixtures of alkenylation products in 42% yield with ortho‐/meta‐/ para‐regioselectivity of 1/5.6/1.5 (Scheme 10.27). CF3

5.4 mL

+

CO2Et

5 mol% Pd(OAc)2 5 mol% 3,5-dichloropyridine 1.0 equiv. PhCO3tBu HOAc (7 mL), 100 °C, 6 h

CO2Et F3C 32% o/m/p = 1/15.8/4.2

1.5 mmol CO2Et EtO2C 42% o/m/p = 1/5.6/1.5

Scheme 10.27  Pd(II)‐catalyzed cross‐coupling of electron‐deficient arenes with alkene.

Bromobenzene was also coupled with alkenes directly in rhodium catalysis as reported by Glorius and coworkers in 2011 [29]. Treatment of bromobenzene (5.0 mL) with styrene (1.0 mmol) in the presence of [RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 (2.2 equiv.), and PivOH (1.1 equiv.) at 140 °C for 21 h affords mixtures of alkenylation products in 66% yield with meta‐/para‐ regioselectivity of 2/1 [29a]. Besides, vinylic amides are coupled with bromobenzene [29b]. For example, treatment of bromobenzene (5.0 mL) with vinylic amide (1.0 mmol) in the presence of [RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 (2.2 equiv.), PivOH (1.1 equiv.), and CsOPiv (0.2 equiv.) at 140  °C for 21 h affords mixtures of alkenylation products in 65% yield with meta‐/para‐regioselectivity of 3/1 (Scheme 10.28). On the other hand, in addition to cross‐coupling of benzene with alkene, a phenyl–alkenyl bond is also formed through addition of alkyne to benzene. In 1979, Hong and coworkers reported addition of internal alkyne to arene in rhodium catalysis [30]. In addition to benzene, monosubstituted arenes such as anisole, toluene, and fluorobenzene also react with diarylacetylenes. Treatment of anisole, toluene, or fluorobenzene (30 mL) with diphenylacetylene (1 g) in the presence of Rh4(CO)12 (0.04 g) and CO (25 kg/cm2) at 220 °C for 7 h affords the corresponding alkenylation products in 42, 24, and 49% yield, respectively. In all cases, all three positions of monosubstituted arenes reacted. Anisole or fluorobenzene

10.2  Formation of C─C Bond

Br

+

5.0 mL

Br

2.5 mol% [RhCp*Cl2]2 10 mol% AgSbF6

1.0 mmol

+

2.2 equiv. Cu(OAc)2 1.1 equiv. PivOH, 140 °C, 21 h

CON(iPr)2 Me 1.0 mmol

5.0 mL

Br 66% m/p = 2/1

2.5 mol% [RhCp*Cl2]2 10 mol% AgSbF6

CON(iPr)2

20 mol% CsOPiv 2.2 equiv. Cu(OAc)2 1.1 equiv. PivOH, 140 °C, 21 h

Br

Me 65% m/p = 3/1

Scheme 10.28  Rh‐catalyzed cross‐coupling of bromobenzene with alkenes.

gives ortho‐alkenylation as major products with ortho‐/meta‐/para‐regioselectivity of 64/26/10 or 70/22/8. Toluene affords meta‐alkenylation as major product with ortho‐/meta‐/para‐regioselectivity of 6/65/29 (Scheme 10.29). Me + 30 mL

Ph

Ph

0.05 mmol Rh4(CO)12

Me Ph

CO (25 kg/cm2), 220 °C, 7 h

Ph 24% o/m/p = 6/65/29

5.6 mmol MeO

F Ph

Ph 42% o/m/p = 64/26/10

Ph Ph 49% o/m/p = 70/22/8

Scheme 10.29  Rh‐catalyzed addition of internal alkyne to arenes.

In 2000, Fujiwara and coworkers gave examples of platinum‐ or palladium‐ catalyzed addition of internal alkyne to arene under mild conditions [31]. Reaction of electron‐rich arenes such as pentamethylbenzene exhibits high efficiency. For example, treatment of pentamethylbenzene (10 mmol) with ethyl propiolate (5.0 mmol) in the presence of Pd(OAc)2 (1 mol%) in mixtures of CF3CO2H (4 mL) and CH2Cl2 (1 mL) at room temperature for 3 h gives the cis‐alkenylation product in 85% yield. Platinum catalyst generated from PtCl2 with two equivalents of AgOAc is also available for this reaction to afford the cis‐alkenylation product in high yield. The stereoselectivity for cis‐alkenylation product is quite unique and is different from the configuration in cross‐coupling of arene with alkene, in which trans‐alkenylated product is usually afforded. When a monosubstituted electron‐rich arene such as anisole is used as

303

304

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

s­ ubstrate, further reaction of alkenylation product with anisole occurs to afford diarylation as the major product. For example, treatment of anisole (10 mmol) with ethyl propiolate (5.0 mmol) in the presence of Pd(OAc)2 (1 mol%) in mixtures of CF3CO2H (4 mL) and CH2Cl2 (1 mL) at room temperature for 12 h gives the alkenylation product ethyl 3‐(2‐methoxyphenyl)acrylate in 10% yield (trans/cis = 4/1) and ethyl 3,3‐bis(4‐methoxyphenyl)propanoate in 38% yield (Scheme 10.30). Me

Me

Me +

Me Me Me 10 mmol Me

1 mol% Pd(OAc)2

Me

CF3CO2H (4 mL), CH2Cl2 (1 mL), rt, 3 h

85% Me

+

CO2Et

Me

10 mmol

Me CO2Et

Me

5.0 mmol

Me

Me Me

CO2Et

Me

5 mol% PtCl2, 10 mol% AgOAc

Me

Me

CF3CO2H (4 mL), CH2Cl2 (1 mL), rt, 24 h

Me CO2Et Me 92%

5.0 mmol MeO

OMe + 10 mmol

CO2Et 5.0 mmol

1 mol% Pd(OAc)2 CF3CO2H (4 mL) MeO CH2Cl2 (1 mL), rt, 12 h

+

COEt 10% trans/cis = 4/12 MeO

CO2Et 38%

Scheme 10.30  Pd(II) or Pt(II)‐catalyzed addition of alkyne to arene.

More environmentally benign and economic FeCl3 was found as effective catalyst reported by Lu and coworkers in 2007 [32]. For example, treatment of electron‐rich mesitylene (3.0 mmol) with phenylacetylene (1.0 mmol) in the p ­ resence of FeCl3 (10 mol %) in CH3NO2 (0.5 mL) at room temperature for 5 h gives the alkenylation product in 86% yield. CH3NO2 is screened as the ­crucial solvent to enhance the reactivity of FeCl 3. Electron‐rich alkyne 4‐methoxylphenylacetylene performs well in this reaction, giving the alkenylation product in quantitative yield. Reaction of electron‐poor 4‐chlorophenylacetylene with mesitylene is less efficient, affording the corresponding p ­ roduct in 77% yield (Scheme 10.31). These observations are in accord with the proposed mechanism that a­ ddition of FeCl3 to alkyne forms alkenyl ­cation, which attacks arene through an SEAr process to give the alkenylation product.

10.2  Formation of C─C Bond Me

Me R

Me + Me 3.0 mmol

10 mol% FeCl3 CH3NO2 (0.5 mL), rt, 5 h

R

Me

Me

R : OMe, H, or Cl Yield: > 99%, 86%, or 77% (6 h)

1.0 mmol

Scheme 10.31  Fe(III)‐catalyzed addition of alkyne to arene.

10.2.5  Acylation and Carboxylation

Phenyl carbonyl compounds include phenyl ketones, benzaldehyde, benzoic acid, and its derivatives. Current preparation of phenyl ketone derivatives or benzaldehyde is mainly through the Friedel–Crafts acylation, which is the reaction of aromatic compounds with acyl halides or formyl halides generated in situ from CO in the presence of stoichiometric amount of Lewis acid traditionally. Using more environmentally benign acyl anhydride or even acid directly instead of acyl halide as the acylating reagent is highly desired. Besides, searching for environmentally benign and reusable catalyst, mainly solid acid including zeolite, modified clay, solid superacid, HPA, Nafion‐H, etc. to avoid stoichiometric or overstoichiometric use of corrosive Lewis acid most commonly AlCl3, is also highly concerned. In 1992, Izumi and coworkers reported HPA‐catalyzed acylation of arenes with acyl anhydrides [33]. For example, treatment of anisole (100 mmol) with either Ac2O (5.0 mmol) or (PhCO)2O (5.0 mmol) in the presence of Cs2.5H0.5PW12O40 (0.01 mmol) under reflux for 2 h affords the aryl ketone products in 89 or 85% yield, respectively (Scheme 10.32). Ac MeO

Ac2O 5.0 mmol

OMe + 100 mmol

or (PhCO)2O 5.0 mmol

89% or

0.01 mmol Cs2.5H0.5PW12O40

COPh

Reflux, 2 h MeO 85%

Scheme 10.32  HPA‐catalyzed acylation of anisole with acyl anhydrides.

In addition to HPA, some other catalytic systems applied to for electron‐rich arenes only were also developed. In 1992, Mukaiyama, Suzuki, Han, and Kobayashi reported SbCl5‐catalyzed LiClO4‐promoted carboxylation of electron‐rich arenes with carboxylic anhydrides [34]. For example, anisole (5.0 mmol) was treated with acetic anhydride (10 mmol) or (C5H11CO)2O

305

306

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

(10 mmol) in the presence of SbCl5 (0.2 mmol) and LiClO4 (5.0 mmol) under reflux for 30 min to afford the corresponding acylation product in 89 or 92% yield, respectively, and only para‐position of anisole is reactive to give the sole product exclusively (Scheme 10.33). The amount of LiClO4 influenced the performance of reaction much, and it was proposed that SbCl5 reacted with LiClO4 to form SbCl4ClO4, which transformed (RCO)2O to RCOClO4, which further reacted with arenes to produce acylation product and HClO4 to regenerating the catalyst.

OMe

+

10 mmol or (C5H11CO)2O

5.0 mmol

10 mmol

Ac

MeO

Ac2O

89% or

0.2 mmol SbCl5 5.0 mmol LiClO4 CH2Cl2 (2 mL) 0° C, 1 h; reflux, 30 min

MeO

COC5H11 92%

Scheme 10.33  SbCl5‐catalyzed acylation of anisole with acyl anhydrides.

In 1993, Kawada and coworkers reported lanthanide trifluoromethanesulfonate‐catalyzed acylation of electron‐rich arenes. Anisole (5.0 mmol) was treated with acetic anhydride (10 mmol) with various lanthanide triflates such as Yb(OTf )3 (0.2 mmol) in CH3NO2 (5 mL) at 50 °C for 18 h to afford the acylation product in quantitative yield [35]. The lanthanide catalyst is of reactivity after three recyclings. Moreover, basic aromatic compound dimethylaminobenzene is tolerated under reaction conditions and is acylated in 76% yield (Scheme 10.34).

OMe 5.0 mmol or NMe2 5.0 mmol

Ac

MeO

+

Ac2O 10 mmol

99% or

0.2 mmol Yb(OTf)3 CH3NO2(5 mL), 50 °C, 18 h Me2N

Ac 76%

Scheme 10.34  Yb(OTf )3‐catalyzed acetylation of arenes with acetic anhydride.

Carboxylic acids are usually of lower reactivity than carboxylic anhydrides as well as acyl halides. One example of acylation of arenes with carboxylic acid was

10.2  Formation of C─C Bond

reported in 2008 by Shimizu and coworkers using polyvalent metal salts of HPA as the effective catalyst [36]. For example, treatment of anisole (110 mmol) or toluene (110 mmol) with nC11H23CO2H (1.0 mmol) or C9H19CO2H (1.0 mmol) gave acylation product in 97 or 94% yield, respectively, with ortho‐/meta‐/para‐ regioselectivity of 2/0/98 for anisole or 10/4/86 for toluene (Scheme  10.35). Compared with benzene, the reaction performance of electron‐rich anisole or toluene is much more efficient. O OMe

+

110 mmol

nC11H23CO2H

0.3 mol% FePW12O40 130–160 °C, reflux, 1 h

1.0 mmol

nC11H23

MeO

97% o/p = 2/98

O Me

nC9H19

94% (72 h) o/m/p = 10/4/86

Scheme 10.35  HPA‐catalyzed acylation of arenes with carboxylic acids.

In 2015, Le and coworkers gave another example of acylation of electron‐rich arenes using Er(OTf )3 as the effective catalyst with various benzoic acids [37]. Treatment of anisole (5.0 mmol) with benzoic acid (1.0 mmol) with 10 mol% Er(OTf )3 under microwave irradiation at 220 °C for 30 min affords the para‐ acylation as the sole product in 72% yield. Toluene is also benzoylated with benzoic acid in 80% yield with ortho‐/meta‐/para‐regioselectivity of 22/4/74 (Scheme 10.36). O

O

OMe

+

OH

0.1 mmol Er(OTf)3 mw, 220 °C, 30 min MeO

1.0 mmol

5.0 mmol

O

Me +

1.0 mmol

OH 2.0 mmol

72% O

0.1 mmol Er(OTf)3 mw, 180 °C, 20 min

Me 80% o/m/p = 22/4/74

Scheme 10.36  Er(OTf )3‐catalyzed acylation of arenes with carboxylic acids.

307

308

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

As for benzoic acid, current industrial production is mainly reliant on oxidation of toluene with O2. Alternatively, benzoic acid is synthesized through carboxylation of benzene through CO insertion. In 1980, Fujiwara et al. reported palladium‐promoted carboxylation of arenes with pressured CO to afford ­various benzoic acids [38]. Anisole (20 mL), toluene (20 mL), or chlorobenzene (20 mL) reacted with CO (15 atm) to form the corresponding carboxylic acid in 48, 33, or 14% yield based on Pd(OAc)2 with ortho‐/meta‐/para‐regioselectivity of 5/0/43, 12/3/18, or 4/2/8, respectively (Scheme 10.37). More electron‐ rich anisole gives the better performance in this reaction compared with toluene or chlorobenzene. Me + 20 mL

1.0 mmol Pd(OAc)2

CO

100 °C, 20 h

CO2H Me 33% o/m/p = 12/3/18

15 atm

CO2H MeO 48% o/p=5/43

CO2H Cl 14% o/m/p=4/2/8

Scheme 10.37  Pd(II)‐mediated carboxylation of arenes with CO.

Catalytic carboxylation reaction using t‐BuOOH as oxidant using atmosphere pressure of CO was established at the same group in 1983 [39]. Treatment of anisole (12 mL) with CO (1 atm) in the presence of catalytic Pd(OAc)2 (0.1 mmol), allyl chloride, and t‐BuOOH as terminal oxidant in HOAc (3 mL) at 75 °C for 2 h affords mixtures of anisic acids in TON of 2 with ortho‐/meta‐/ para‐regioselectivity of 126/8/123 (Scheme 10.38). OMe

12 mL

+

CO 1 atm

0.1 mmol Pd(OAc)2 0.05–1.0 mmol allyl chloride 35–50 mmol tBuOOH HOAc (3 mL), 75 °C, 2 h

CO2H MeO TON = 2 o/m/p = 126/8/123

Scheme 10.38  Pd(II)‐catalyzed carboxylation of arenes with CO.

In 1995, Fujiwara and coworkers provided a highly efficient and mild method for carboxylation of arenes with atmosphere CO [40]. Treatment of anisole (56 mmol), toluene (56 mmol), or chlorobenzene (56 mmol) with CO (1 atm,

10.2  Formation of C─C Bond Me + 56 mmol

CO 1 atm

0.1 mmol Pd(OAc)2 5.0 mmol K2S2O8 CF3CO2H (5 mL), rt, 120 h

CO2H Me TON = 8 o/m/p = 26/6/67 CO2H

CO2H Cl

MeO TON = 12 o/p = 33/67

TON = 17 o/m/p = 19/27/54

Scheme 10.39  Pd(II)‐catalyzed carboxylation of arenes with CO at room temperature.

balloon) in the presence of Pd(OAc)2 (0.1 mmol) and K2S2O8 (5.0 mmol) in CF3CO2H (5 mL) at room temperature for 120 h affords the corresponding aromatic carboxylic acids in TON of 12, 8, 17. The regioselectivity is 33/67 (ortho/para) for anisole, 26/6/67 (ortho/meta/para) for toluene, and 19/27/54 (ortho/meta/para) for chlorobenzene (Scheme  10.39). The reaction is more efficient and under milder conditions at room temperature due to the use of TFA, which reacts with Pd(OAc)2 to form the more electrophilic cationic Pd (OCOCF3)+ catalyst to cleave the aryl C─H bonds. Carbon dioxide (CO2) is also an available carbonyl source in carboxylation of benzene. In 1984, Fujiwara and coworkers reported palladium‐catalyzed ­carboxylation of arenes with atmosphere pressure of CO2 [41]. Treatment of anisole (16 mL) or chlorobenzene (16 mL) with CO2 (1 atm) in the presence of Pd(OAc)2 (0.2 mmol) and t‐BuOOH (8.0 mmol) in HOAc (4 mL) at 70 °C for 3 days afforded the corresponding benzoic acid in 125 or 40% yield based on Pd(OAc)2 (Scheme 10.40). OMe

16 mL

+ CO2 1 atm

0.2 mmol Pd(OAc)2 8.0 mmol tBuOOH HOAc (4 mL), 70 °C, 3 d

CO2H MeO 125% CO2H

Cl 40%

Scheme 10.40  Pd(II)‐catalyzed carboxylation of arenes with CO2.

The catalytic efficiency was largely improved in rhodium catalysis by Iwasawa and coworkers in 2014 [42]. Various electron‐rich arenes including anisole and toluene are converted into the corresponding benzoic acids. Treatment of a­ nisole

309

310

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

(2.0 mL) or toluene (2.0 mL) with CO2 (1 atm) in the presence of 0.005 mmol rhodium complex and 1.0 mmol AlMe1.5(OEt)1.5 in DMA (0.1 mL) at 145 °C or 120 °C for 6 h affords the mixtures of anisic acids or toluic acids in TON of 15 or 18 with ortho‐/meta‐/para‐regioselectivity of 23/54/23 or 17/57/26, respectively. Basic N,N‐dimethylbenzene is converted into the corresponding carboxylic acid in TON of 9 with meta‐/para‐regioselectivity of 56/44. Furthermore, ­electron‐deficient arenes such as fluorobenzene, trifluoromethylbenzene, or even 1,3‐bis(trifluoromethyl)benzene are available for this reaction to afford the corresponding aromatic carboxylic acids. The TON for carboxylation of fluorobenzene is 39, and the ortho‐/meta‐/para‐regioselectivity is 59/29/12 with the ortho‐carboxylation as the major product. For carboxylation of ­trifluoromethylbenzene or 1,3‐bis(trifluoromethyl)benzene, the TON is 44 or 48, respectively, and the regioselectivity for trifluoromethylbenzene is 77/23 (meta/para), and only meta‐aryl C─H bond of bis(trifluoromethyl)benzene reacted (Scheme 10.41). +

R 2.0 mL

MeO

CO2 1 atm CO2H

145 °C, TON = 15 o/m/p = 23/54/23

F

CO2H

0.005 mmol Rh complex 1.0 mmol AlMe1.5(OEt)1.5 DMA (0.1 mL), T, 6 h

Me

CO2H

120 °C, TON = 18 o/m/p = 17/57/26

F3C

CO2H

R

CO2H

Me2N

145 °C, TON = 9 m/p = 56/44 CF3

CO2H F3C

85 °C, TON = 39 o/m/p=59/29/12

120 °C, TON = 44 m/p=77/23

CO2H

145 °C, TON = 48

Scheme 10.41  Rh‐catalyzed carboxylation of arenes with CO2.

10.2.6 Alkynylation

Aryl–alkynyl bonds are basic structure linkages and are important building units in photoelectric materials. Current synthesis of phenylacetylene derivatives are mainly reliant on the Sonogashira coupling, the cross‐coupling of aryl halides with terminal alkynes in palladium and copper catalysis. Alternatively, direct cross‐coupling of aryl C─H bonds with alkynes is an ideal method to produce aryl–alkynyl linkage. In 2001, Fuchita and coworkers reported formation of

10.2  Formation of C─C Bond

aryl–alkynyl bond from arenes and terminal alkynes in a tandem process promoted by a gold(III) complex [43]. Treatment of anhydrous gold(III) chloride dimer [AuCl3]2 (0.15 mmol) with various arenes (6.0 mmol) including benzene, toluene, anisole, chlorobenzene, etc. in hexane at 20 or 0 °C for 30 min, followed by addition of 2,6‐lutidine (0.30 mmol) in Et2O at room temperature for 1 h, gives stable arylgold(III) complexes [AuArCl2(lut)]. Reaction of these arylgold(III) complexes (0.103 mmol) with phenylacetylene (0.217 mmol) in THF at 50 °C for 5 h affords the corresponding diarylacetylene in 82 or 94% yield, respectively (Scheme 10.42). It is worth noting that neither alkene nor internal alkyne is reactive with this arylgold(III) complex, which is sharply different from the aryl‐Pd(II) complexes, which is willing to react with styrene or internal alkyne to afford the styrene derivatives as shown in the Pd(II)‐catalyzed cross‐coupling of arene with alkene or addition of alkyne to arene. Cl Cl Au N 6.0 mmol or Me

Me 20 °C, 30% or Me

(1) 0.15 mmol [AlCl3]2, hexane, 20 or 0 °C, 30 min (2) 0.30 mmol 2,6-lutidine, Et2O, rt, 1 h

Me

Me 6.0 mmol

Me

Cl

Au

Cl N

Me

Me 0 °C, 39%

Cl

Au

Cl N

Me

Me 0.103 mmol or Me Me

Cl

Au

Cl N

Me 0.103 mmol

+ Me

82% or Me

THF, 50 °C, 5 h 0.217 mmol Me

94%

Scheme 10.42  Au‐mediated cross‐coupling of arenes and alkynes.

This gold‐promoted tandem reaction of arene with alkyne to produce arylacetylene was improved to gold catalytic cross‐coupling of arene with alkyne in one step as reported by Nevado and de Haro in 2010 [44]. For example, treatment of electron‐rich 1,3,5‐trimethoxybenzene (2.0 equiv.) with either methyl

311

312

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

propiolate (1 equiv.) or phenylacetylene (1 equiv.) in the presence of 5 mol% Ph3PAuCl, PhI(OAc)2 (1.5 equiv.) as oxidant and NaHCO3 (1 equiv.) in DCE at 90  °C for 12 h affords the corresponding diarylacetylene in 85 or 25% yield, respectively (Scheme  10.43). Two possible reaction mechanisms were proposed. In one situation, Au(I) complex reacted with terminal alkyne to form alkynyl–Au(I) complex, which is oxidized by PhI(OAc)2 to give alkynyl–Au(III) complex. This alkynyl–Au(III) complex cleaves aryl C─H bond to form alkynyl–Au(III)–aryl key intermediate, followed by reductive elimination of alkynyl and aryl group to afford diarylacetylene product and Au(I) complex to fulfill the catalytic cycle. In the other situation, the alkynyl–Au(I) complex, which is formed from Au(I) complex with terminal alkyne, reacts with PhI(OAc)2 to give alkynyl–I intermediate complexed with Au(I) complex. Gold‐mediated addition of arenes to alkynyl–I intermediate followed by β‐ elimination produces diarylacetylene and Au(I) to fulfill the catalytic cycle. OMe + MeO

OMe 2.0 equiv.

CO2Me 1 equiv (0.5 M)

5 mol% Ph3PAuCl 1.5 equiv. PhI(OAc)2 1 equiv. NaHCO3 DCE, 90 °C, 12 h

OMe CO2Me

MeO

OMe

OMe 85%

MeO OMe 25%

Scheme 10.43  Au‐catalyzed cross‐coupling of arene and alkynes.

10.2.7 Cyanidation

Aryl–cyanide bond is the structure core of benzonitriles. Benzonitriles are of substantial interest in pharmaceuticals and versatile intermediates in organic synthesis. Current construction of aryl–cyanide bond is mainly from either diazoarenes through Sandmeyer reaction or aryl halides via Rosenmund–von Braun reaction or transition metal‐catalyzed reactions. Synthesis of benzonitriles using arenes as raw materials directly instead of diazoarenes or aryl halides is an ideal method to form aryl–cyanide bond. One example was shown by Chen and coworkers in 2011; electron‐rich arenes were successfully converted into the corresponding aryl cyanides with CuCN in iron catalysis [45]. For example, treatment of 1,3,5‐trimethoxybenzene (0.2 mmol) with CuCN (0.25 mmol) in the presence of 30 mol% FeI2 and PhI(OAc)2 as oxidant (0.6 equiv.) in DMF (2 mL) at 130  °C for 8 h affords 2,4,6‐trimethoxybenzonitrile in 83% yield (Scheme 10.44).

10.3 ­Formation of C─N Bond OMe

OMe + MeO

30 mol% FeI2

CuCN

0.6 equiv. PhI(OAc)2 DMF (2 mL), 130 °C, 8 h

OMe 0.25 mmol

0.2 mmol

MeO

CN

83%

OMe

Scheme 10.44  FeI2‐catalyzed cyanation of arene with CuCN.

Another example was shown in 2012 by Ohe and coworkers using BrCN as cyanide source in gallium catalysis [46]. For example, treatment of 1,3‐dimethoxybenzene (0.40 mmol) with BrCN (0.48 mmol) in the presence of 10 mol% GaCl3 in DCE (1.6 mL) at 120 °C for 1 h gives mixtures of 2,4‐dimethoxybenzonitrile and 2,6‐dimethoxybenzonitrile in 82% yield with ratio of 95/5 (Scheme 10.45). OMe + MeO 0.40 mmol

BrCN

OMe

OMe

10 mol% GaCl3 DCE (1.6 mL), 120 °C, 1 h

MeO

0.48 mmol

CN

+

82% (95/5)

CN OMe

Scheme 10.45  GaCl3‐catalyzed cyanation of arene with BrCN.

10.3 ­Formation of C─N Bond Aryl–nitrogen bond constitutes the basic structure of aryl–NO2 and aryl–NH2 species. In the preparation of nitroarenes, using more environmentally benign nitronium ion reagents instead of a combination of concentrated mixture acids of HNO3 and H2SO4 to generate nitronium ion (NO2+) in situ to construct aryl– NO2 structure is highly demanded. One example was shown by Waller, Barrett, and coworkers in 1997 wherein nitration of aromatic compounds with HNO3 was achieved in lanthanide catalysis [47]. In addition to benzene, monosubstituted arenes such as toluene or bromobenzene are also available for this reaction. Me

3.0 mmol

+

HNO3 (69%)

10 mol% Yb(OTf)3 DCE (5 mL), reflux, 12 h

3.0 mmol Br

NO2

Me

NO2

95% o/m/p = 52/7/41

92% o/m/p = 44/trace/56

Scheme 10.46  Yb(OTf )3‐catalyzed nitration of arenes with HNO3.

313

314

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

Treatment of toluene (3.0 mmol) or bromobenzene (3.0 mmol) with 69% HNO3 (3.0 mmol, 1 equiv.) in the presence of 10 mol% Yb(III) triflate in DCE (5 mL) under reflux for 12 h affords the corresponding mixtures of nitroarene in 95 or 92% yield, respectively. The ortho‐/meta‐/para‐regioselectivity for toluene is 52/7/41 and for bromobenzene is 44/trace/56 (Scheme 10.46). In the synthesis of aniline, direct amination of aryl C─H bonds instead of transformation of prefunctionalized arenes such as nitrobenzene through either catalytic or hydrogen transfer hydrogenation or aryl halides via either Ullmann or Buchwald–Hartwig amination to aniline derivatives is of considerable interest. In 2011, two groups, namely, Cho and Chang [48] and DeBoef [49], independently reported synthesis of aniline derivatives by imidation of aryl C─H bonds with phthalimide under transition‐metal‐free conditions. In the work of Cho, Chang, and coworkers for example, monosubstituted arenes such as ­toluene, chlorobenzene, or phenyl acetate are transformed to the corresponding aniline derivatives [48]. Treatment of toluene (1.5 mL), chlorobenzene (1.5 mL), or phenyl acetate (1.5 mL) with phthalimide (0.5 mmol) in the presence of PhI(OAc)2 (5.0 equiv.) at 140 °C for 4 h affords the aniline derivative in 99, 80, or 99% yield. In either cases, all three types of aryl C─H bonds are aminated with  ortho‐/meta‐/para‐regioselectivity of 1.7/1/1.1, 1.4/1.1/1, or 1.2/1/1.1 (Scheme 10.47). O Cl +

1.5 mL

5.0 equiv. PhI(OAc)2

HN

140 °C, 4 h

NPhth Cl 80% o/m/p = 1.4/1.1/1

O 0.5 mmol NPhth

NPhth

Me

AcO

99% o/m/p = 1.7/1/1.1

99% o/m/p = 1.2/1/1.1

Scheme 10.47  Imidation of arenes with phthalimide.

In the example of DeBoef and coworkers 1,4‐disubstituted arenes, for e­xample, such as p‐xylene (4.0 mL), 1,4‐difluorobenzene (4.0 mL), or 1,4‐ bis(trifluoromethyl)benzene (4.0 mL), are treated with phthalimide (0.68 mmol) in the presence of PhI(OAc)2 (1.7 mmol) under microwave irradiation at 145 °C for 3 h to afford the corresponding monoimidated product in 90, 53, or 24% yield [49]. Besides, monosubstituted toluene is available in the same conditions, imidated in 70% yield with ortho‐/meta‐/para‐regioselectivity of 10/6/5 (Scheme 10.48).

10.3 ­Formation of C─N Bond O Me

+

1.7 mmol PhI(OAc)2

HN

145 °C, mw, 3 h

NPhth Me

O 0.68 mmol

4.0 mL

70% o/m/p = 10/6/5

NPhth F

Me

53%

90%

CF3

F

Me

NPhth F3C

NPhth 24%

Scheme 10.48  Imidation of arenes with phthalimide HNPhth.

Synthesis of aniline derivatives by amination of aryl C─H bonds with hetero­ aromatic amines was achieved by Antonchick, Chupakhin, and coworkers in 2015 [50]. The reaction is either stoichiometric or catalytic by PhI(OAc)2. In the PhI(OAc)2‐mediated amination reaction, treatment of electron‐rich mesitylene (2.5 mmol) with 3‐aminopyridine (0.25 mmol) in the presence of PhI(OAc)2 (0.275 mmol) in hexafluoroisopropanol (HFIP) (0.25 M) at room temperature for 3 h affords the corresponding aminated product in 94% yield. Toluene is available under the similar conditions, giving mixtures of amination products in 28% yield with ortho‐/para‐regioselectivity of 1/1.2. Moreover, catalytic amination of electron‐rich arenes such as anisole (2.5 mmol) was established with 2,4‐dichloro‐3‐aminopyridine (0.25 mmol) in the presence of 25 mol% PhI

Me

Me NH2 +

Me

Me 2.5 mmol

0.275 mmol PhI(OAc)2 HFIP (0.25 M), rt, 2–6 h

N 0.25 mmol

Me

H N Me

N

94%

H N Me N 28% o/p = 1/1.2

OMe

Cl NH2

+ N

2.5 mmol

Cl

H N

25 mol% PhI 5 equiv AcOOH HFIP (0.25 M), rt, 12–16 h

0.25 mmol

Scheme 10.49  Amination of arenes with heteroaromatic amines.

MeO

Cl 58%

Cl

N

315

316

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

and peracetic acid (AcOOH, 5 equiv.) as oxidant in HFIP (0.25 M) at room temperature to give the 4‐methoxyaniline derivative in 58% yield (Scheme 10.49). Amination of aryl C─H bonds with heteroaromatic amines was also achieved by Nicewicz and coworkers in 2015 under photocatalysis [51]. For example, treatment of electron‐rich anisole (1.0 equiv.) with pyrazole (1.25–2.0 equiv.) in the presence of 5 mol% acridinium tetrafluoroborate, TEMPO (20 mol%), and O2, in DCE under 455 nm LEDs, at 33 °C affords mixtures of aminated products in 88% yield with ortho‐/para‐regioselectivity of 1/8.8 (Scheme 10.50). OMe 1.0 equiv.

+

HN

5 mol% [acridinium][BF4] N

1.25–2.0 equiv.

20 mol% TEMPO 455 nm LEDs DCE, O2, 33 °C, 20 –72 h

MeO

N N 88% o/p = 1/8.8

Scheme 10.50  Amination of arenes with heteroaromatic amines.

10.4 ­Formation of C─O Bond Phenol derivatives are important industrial intermediates of high demand, and the ideal synthesis of phenol derivatives is through direct oxidation of arenes. One challenge in such transformation to prepare phenol derivatives is the reaction chemoselectivity since the products (phenol derivatives) are usually far more reactive than the raw materials of arenes. One strategy to increase chemoselectivity of phenol derivatives in oxidation of arenes by Fenton’s reagent (Fe2+–H2O2) was addition of extra Fe3+ or Cu2+ into the reaction system as observed by Walling and Johnson in 1975 [52]. For example, toluene is converted into cresols in 6% yield along with benzyl alcohol in 11% yield with additional Fe3+. The regioselectivity for toluene is 54/3/43 for ortho‐/meta‐/para‐position. Another strategy to raise the chemoselectivity of phenol derivatives is to conduct the reaction in superacidic solutions; thus the forming phenol derivatives are completely protonated and thus are deactivated for further oxidation as disclosed by Olah and Ohnishi in 1978 [53]. For example, treatment of toluene (13 mmol) or chlorobenzene (13 mmol) with H2O2 (15 mmol) in the presence of FSO3H‐SbF5(1/1)‐SO2ClF solution (4–2 mL) at −78  °C afforded the corresponding phenol derivatives in 67 or 53% yield, respectively. In either case, all three types of aryl C─H bonds reacted, with ortho‐/meta‐/para‐ regioselectivity of 71/6/23 for toluene or 28/7/65 for chlorobenzene (Scheme 10.51). In addition, nickel catalysis was applied in the oxidation of benzene to phenol reported by Itoh and coworkers in 2015 [54]. For example, treatment of benzene (5.0 mmol) with H2O2 (30%; 25 mmol) in the presence of [Ni(tepa)]2+ (0.5 µmol) and Et3N (5.0 µmol) in CH3CN (5.0 mL) at 60 °C for 24 h affords mixtures of

10.4  Formation of C─O Bond OH

Me

13 mmol or

Me

+

H2O2 15 mmol

Cl

67% o/m/p = 71/6/23 or OH Cl

FSO3H-SbF5(1/1)-SO2ClF(4–2 mL) –78 °C

53% o/m/p = 28/7/65

13 mmol

Scheme 10.51  Oxidation of arenes with H2O2 to phenols by superacid.

cresols in TON of 96 with 90% chemoselectivity for cresols and with ortho‐ /meta‐/para‐regioselectivity of 57/18/25 (Scheme 10.52). Me +

H2O2 30% 25 mmol

5.0 mmol

0.5 μmol [Ni(tepa)]2+ 5.0 μmol Et3N MeCN (5.0 mL), 60 °C, 24 h

OH Me TON = 96 o/m/p = 57/18/25

Scheme 10.52  Ni‐catalyzed oxidation of arenes with H2O2 to phenols.

Direct oxidation of arene with atmospheric O2 as terminal oxidant is the dream reaction to afford phenol derivatives. In addition to palladium catalysis reported by Jintoku, Fujiwara, et al. [55] and Schuchardt and coworkers [56], in phenol synthesis, photocatalysis has also been developed in recent years to give phenol derivatives in high chemoselectivity by Fukuzumi and coworkers. For example, 3‐cyano‐1‐methylquinolinium ion (QuCN+) was found as an efficient photocatalyst for selective oxidation of arene with O2 and H2O to produce phenol derivative in 2011 [57]. Treatment of chlorobenzene (30 mM) in the presence of QuCN+ClO4− (2.0 mM) in O2‐saturated MeCN solution containing H2O (3.0 M) under photoirradiation at 20 °C by cooling with water for 0.5 h affords mixtures of chlorophenol in 30% yield with 97% chemoselectivity. Both ortho‐ and para‐positions of chlorobenzene reacted and the ratio is 11/88 (Scheme 10.53). Cl + 30 mM

O2

2.0 mM QuCN+ ClO4– O2-saturated MeCN, H2O (3.0 M) hv, 20 °C, 0.5 h, 31% convn

OH Cl 30% o/p = 11/88

Scheme 10.53  QuCN+‐catalyzed hydroxylation of chlorobenzene with O2.

317

318

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

In 2013, 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone (DDQ) was found as a superior photocatalyst for synthesis of phenol derivatives from arenes at the same group [58]. In addition to benzene, aryl halides including fluorobenzene, chlorobenzene, and iodobenzene are transformed to the corresponding phenol derivatives catalytically. Treatment of fluorobenzene (30 mM), chlorobenzene (30 mM), or iodobenzene (30 mM) with H2O (0.5 M) in the presence of DDQ (9.0 mM) and t-butyl nitrite (TBN) (1.5 mM) in O2‐saturated CH3CN (0.6 mL) under irradiation at room temperature for 30 h affords the phenol product in 30, 34, or 14% yield, respectively. In all cases, only ortho‐ and para‐aryl C─H bonds of aryl halides are reactive, and the ortho‐/para‐regioselectivity is 1/4.2, 1/4.5, or 1/4.0 with para‐halophenol as the major product (Scheme 10.54). F +

OH

9.0 mM DDQ, 1.5 mM tbutyl nitrite

O2

O2-saturated MeCN (0.6 mL) H2O (0.5 M), hv, rt, 30 h

30 mM

F

OH

+

30% (o/p = 1/4.2)

OH

14%

OH Br

Cl 34% (o/p =1/4.5)

14% (o/p = 1/4.0)

Scheme 10.54  DDQ‐catalyzed hydroxylation of arenes with O2.

This DDQ photocatalytic synthesis of derivatives from arenes was further improved by Ohkubo and coworkers in 2015 [59]. The reaction efficiency was  largely increased in the case of chlorobenzene, for example, by further optimization of the reactions. Treatment of chlorobenzene (3.0 mL) as solvent +

R

0.30 mM DDQ, 3.0 mM tbutyl nitrite

O2

H2O (50 mM), hv, time

OH R

3.0 mL OH tBu

OH

7 h, 92% o/p = 17/83

6 h, 25% o/p = 4/96 OH NC 30 h, 87% o/m/p = 44/18/38

OH F 3C

Cl

52 h, 8% o/m/p = 37/59/4

OH O2N 30 h, 10% o/m/p = 45/40/10

Scheme 10.55  DDQ‐catalyzed hydroxylation of arenes with O2.

10.4  Formation of C─O Bond

with H2O (50 mM) in the presence of DDQ (0.30 mM) and TBN (3.0 mM) under irradiation for 7 h affords the mixtures of chlorophenol in 92% yield with ortho‐/para‐regioselectivity of 17/83. For electron‐deficient arenes, benzonitrile or nitrobenzene reacts in similar conditions to give ortho‐phenol derivative as major product, while trifluoromethylbenzene affords meta‐trifluoromethylphenol as major product. Reaction of tert‐butylbenzene is mainly on its para‐position (Scheme 10.55). On the other hand, direct acetoxylation of aryl C─H bond is another ideal way to afford phenol derivatives. One example of catalytic acetoxylation of arene with HOAc was established by Henry in 1971 [60]. For example, reaction of toluene (32 mmol) with HOAc (25 mL) in the presence of Pd(OAc)2 (0.5 mmol), K2Cr2O7 (15 mmol), and CH3SO3H (9.3 mmol) at 90  °C for 16 h affords 1.0 mmol of tolyl acetate, and the yield is 3% based on toluene with TON of 2. All three types of aryl C─H bonds are acetoxylated and the ortho‐ /meta‐/para‐regioselectivity is 19/62/19. When Hg(OAc)2 (3.0 mmol) is used instead of CH3SO3H, the yield is increased to 6%, and the TON is raised to 4, with ortho‐/meta‐/para‐regioselectivity of 12/39/49 (Scheme 10.56). Me + 32 mmol

HOAc 25 mL

Me + 32 mmol

HOAc 25 mL

0.5 mmol Pd(OAc)2 15 mmol K2Cr2O7 9.3 mmol CH3SO3H, 90 °C, 16 h

0.5 mmol Pd(OAc)2 15 mmol K2Cr2O7 3.0 mmol Hg(OAc)2, 90 °C, 16 h

OAc Me 1.0 mmol, TON = 2 o/m/p = 19/62/19 OAc Me 1.95 mmol, TON = 4 o/m/p = 12/39/49

Scheme 10.56  Pd(II)‐catalyzed acetoxylation of arene with HOAc.

In 1974, Eberson and Jönsson reported palladium‐catalyzed acetoxylation of arenes by nonmetal oxidant K2S2O8 [61]. Benzene is acetoxylated to afford phenyl acetate in TON of 7. For monosubstituted arenes, anisole, toluene, or chlorobenzene is converted into the corresponding aryl acetate in TON of 2, 1, or 3.5 by treatment of arene (10 mmol) with HOAc (50 mL) in the presence of Pd(OAc)2 (1.0 mmol), 2,2′‐bipyridine (0.5 or 1.0 mmol), and K2S2O8 (10 or 20 mmol) at 110  °C for 4 h [61a]. The acetoxylation mainly occurs on meta‐ position of monosubstituted arene, and the ortho‐/meta‐/para‐regioselectivity is 3/61/36, 3/60/37 or 5/51/44 for anisole, toluene, or chlorobenzene, respectively (Scheme 10.57). The catalytic efficiency was further improved by them in 1976 [61b]. Treatment of anisole (0.25 mol), toluene (0.25 mol), or chlorobenzene (0.25 mol)

319

320

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene Me +

0.5 or 1.0 mmol 2,2′-bipyridine 10 or 20 mmol K2S2O8, 110 °C, 4 h

50 mL

10 mmol

OAc

1.0 mmol Pd(OAc)2

HOAc

Me TON = 1 o/m/p = 3/60/37 OAc

OAc Cl

MeO TON = 2 o/m/p = 3/61/36

TON = 3.5 o/m/p = 5/51/44

Scheme 10.57  Pd(II)‐catalyzed acetoxylation of arenes using K2S2O8 (I).

with HOAc (1000 mL) in the presence of Pd(OAc)2 (0.01 mmol), 2,2′‐bipyridine (0.005 mol), and K2S2O8 (0.30 mol) under reflux for 4 h gives the corresponding aryl acetate in TON of 6, 6, or 9. Again, meta‐aryl acetate product is still the major product with ortho‐/meta‐/para‐regioselectivity of 2/58/40 for anisole, 6/59/36 for toluene, or 7/51/42 for chlorobenzene. Other haloarenes such as bromobenzene and fluorobenzene are also available for this reaction to also afford meta‐aryl acetate as major product. Furthermore, electron‐deficient arenes such as benzotrifluoride, acetophenone, or methyl benzoate are also acetoxylated under the same conditions with TON of 1, 4, or 5, respectively, to afford meta‐aryl acetates as major products (Scheme 10.58). R + 0.25 mol

0.01 mol Pd(OAc)2

HOAc

0.005 mol 2,2′-bipyridine 0.30 mol K2S2O8, reflux, 4 h

1000 mL OAc

TON = 6 o/m/p = 2/58/40

TON = 4 o/m/p = 20/42/38

OAc Br

Cl

TON = 6 o/m/p = 6/59/36

OAc F

OAc

OAc Me

MeO

OAc R

TON = 9 o/m/p = 7/51/42

OAc F3C TON = 1 o/m/p = trace/73/27

TON = 8 o/m/p = 8/55/37

OAc MeOC

OAc MeO2C

TON = 4 o/m/p = 1/77/22

Scheme 10.58  Pd(II)‐catalyzed acetoxylation of arenes using K2S2O8 (II).

TON = 5 o/m/p = 4/62/34

10.4  Formation of C─O Bond

In 1996, Crabtree and Yoneyama found that PhI(OAc)2 was a very efficient oxidant in Pd(II)‐catalyzed acetoxylation of arenes [62]. In addition to benzene, monosubstituted arenes such as anisole, toluene, or chlorobenzene are also available for this reaction. Treatment of anisole (18.4  mmol), toluene (18.8 mmol), or chlorobenzene (19.7 mmol) with HOAc (2.0 mL) in the presence of Pd(OAc)2 (22.3 µmol) and PhI(OAc)2 (4.47 mmol) at 100  °C for 20 h affords the corresponding aryl acetates in 40, 39, or 14% yield based on PhI(OAc)2, and the TON is 80, 80, or 27, respectively. Ortho‐ and para‐acetoxylation are the major products with ortho‐/meta‐/para‐regioselectivity of 44/5/51 for anisole, 43/26/31 for toluene, or 41/29/30 for chlorobenzene (Scheme 10.59). Me + 18.8 mmol

HOAc 2.0 mL

22.3 μmol Pd(OAc)2 4.47 mmol PhI(OAc)2 100 °C, 20 h

TON = 80 o/m/p = 44/5/51

TON = 80 o/m/p = 43/26/31 OAc

OAc MeO

OAc Me

Cl TON = 27 o/m/p = 41/29/30

Scheme 10.59  Pd(II)‐catalyzed acetoxylation of arenes using PhI(OAc)2.

The catalytic efficiency of aryl C─H oxygenation to produce aryl acetate was dramatically improved when pyridine was applied in this reaction as reported by Sanford and coworkers in 2011 [63]. In addition to benzene, haloarenes such as c­ hlorobenzene or bromobenzene are acetoxylated in 62 or 70% yield based on oxidant with TON of 35 or 31 by treatment of haloarene (11.2 mmol) with HOAc (0.5 mL) in the presence of Pd(OAc)2 (2 mol%), pyridine (1.8 mol%), PhI(OAc)2 (1.0 equiv.), and Ac2O (0.1 mL) at 100 °C. Finely tuning the ratio of Pd(OAc)2 to pyridine to 1/0.9 is crucial to the success of this reaction. 1,2‐ Dichlorobenzene is acetoxylated in 59% yield based on PhI(OAc)2 with TON of 29. Furthermore, electron‐deficient arenes such as ethyl benzoate, benzotrifluoride, or even 1,3‐bis(trifluoromethyl)benzene are available for this reaction. meta‐acetoxylated electron‐deficient arenes are afforded as major products for ethyl benzoate and benzotrifluoride and as sole product for 1,3‐ bis(trifluoromethyl)benzene (Scheme 10.60).

321

322

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

R

+

11.2 mmol

2 mol% Pd(OAc)2 1.8 mol% pyridine

HOAc

OAc R

1.0 equiv. PhI(OAc)2 Ac2O (0.1 mL), 100 °C

0.5 mL

OAc

OAc Br

a

Cl

Cl

70% o/m/p = 23/46/31

62% o/m/p = 29/40/31

Cl

59% a/b = 29/71 CF3

OAc

OAc

a

F3C

EtO2C

F3C 47% o/m/p = 1/78/21

68% o/m/p = 11/71/18

OAc b

b OAc 23% a/b≤1/99

Scheme 10.60  Pd(II)/pyridine‐catalyzed acetoxylation of arenes.

10.5 ­Formation of C─S Bond Aryl sulfides are important building blocks in organic synthesis. In one recent example reported by Cossy and coworkers in 2015, sulfenylation of electron‐ rich arenes was achieved at room temperature using N‐(alkylthio)succinimides or N‐(arylthio)succinimides as sulfur source promoted by CF3CO2H [64]. For example, treatment of anisole (1.0 equiv.) with N‐(phenylthio)succinimide (1.0 equiv.) in the presence of CF3CO2H (15 equiv.) in CH2Cl2 (0.5 M) at room temperature for 6 h affords 4‐phenylthioanisole in 76% yield (Scheme 10.61). It is proposed that protonation of TFA to N‐thiosuccinimide generates electrophilic intermediate in situ, which attacks arene in an SEAr‐type process to afford the sulfenylation product.

O OMe 1.0 equiv.

+

N SPh

15 equiv. CF3CO2H CH2Cl2(0.5 M), rt, 6 h

MeO

O 1.0 equiv.

Scheme 10.61  Sulfenylation of arenes with N‐(alkylthio)succinimides.

SPh

76%

10.6  Formation of C─Halogen Bond

10.6 ­Formation of C─Halogen Bond 10.6.1 Fluorination

Current preparation of aryl fluoride compounds is mainly through the Balz– Schiemann reaction, which is a two‐step process that aromatic amines are transformed to aromatic diazonium fluoroborates followed by thermolysis to give fluoroarenes. In addition, aryl halides or triflate are used to synthesize aryl fluorides, but the reactions are not easy. It is even more difficult to prepare aryl fluoride through direct fluorination of aryl C─H bond under mild conditions due to difficulty for both the cleavage of the inert aryl C─H bond and introduction of the fluorine atom exhibited previously. Thus, few examples are found for aryl C─H fluorination. One example was shown by Fukuzumi and coworkers in 2013 that fluorination of aryl C─H bonds was achieved by photocatalysis [65]. In addition to benzene, haloarenes such as chlorobenzene or bromobenzene were tested for fluorination. Treatment of chlorobenzene (20 mM) or bromobenzene (20 mM) with tetraethylammonium fluoride tetrahydrogen fluoride salt (TEAF·4HF, 50 mM) in the presence of photocatalyst (QuCN+ClO4−, (2 mM) in oxygen‐saturated MeCN under irradiation for 50 min affords fluorinated products in 7 or 6% yield. Only para‐position of either chlorobenzene or bromobenzene is fluorinated though the yield is low (Scheme 10.62).

20 mM or Br

F

Cl

Cl + TEAF·4HF

7% or

2 mM QuCN+ClO4– O2-saturated CD3CN (0.6 mL), hv, rt, 50 min

50 mM

20 mM

Br

F 6%

Scheme 10.62  QuCN+‐catalyzed fluorination of arenes.

In addition to the fluorination methods applying for both benzene and arenes, some other fluorination methods have been developed in recent years applying for phenol or aniline derivatives only [66]. One recent example was demonstrated by Miyamoto and coworkers in 2011 wherein treatment of 3‐ phenylpropyl methyl ether (1 equiv.) with PhI(OH)BF4 (3.0 equiv.) in the presence of BF3·Et2O (3.0 equiv.) at 40–45  °C for 6 h affords the corresponding para‐ fluorinated arene in 61% yield (Scheme 10.63). It was proposed that addition of iodine(III) species to the para‐position of 3‐phenylpropyl methyl ether followed by the subsequent internal cyclization of methoxy group to the ipso‐position produces spiro‐1,4‐cyclohexadiene. This spiro‐1,4‐cyclohexadiene is then

323

324

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

transformed to the target fluorinated product through loss of BF3 to form C─F bond and rearomatization with loss of proton.

OMe

OH + Ph

I · 18C6

BF4 3.0 equiv.

1 equiv.

F

3.0 equiv. BF3·Et2O 40–45 °C, 6 h

MeO 61%

Scheme 10.63  Fluorination of 3‐phenylpropyl methyl ether.

Another example of para‐fluorination of arene was shown by Meng, Li, and coworkers in 2013, applying aniline derivatives as substrates [67]. For example, treatment of N‐pivaloylaniline (0.5 mmol) with HF·pyridine (3.0 mmol) in the presence of PhI(OPiv)2 (0.75 mmol) in CH2Cl2 (5 mL) at room temperature for 12 h affords 4‐fluoro‐N‐pivaloylaniline in 85% yield (Scheme 10.64). It was proposed that addition of PhI(OPiv)2 to the aniline followed by loss of phenyl iodide generated a nitrenium intermediate, which was trapped by HF·pyridine to give the para‐fluorination product.

NHPiv

0.5 mmol

+ HF·pyridine

F

0.75 mmol PhI(OPiv)2 CH2Cl2 (5 mL), rt, 12 h

3.0 mmol

PivHN 85%

Scheme 10.64  Fluorination of N‐pivaloylaniline.

10.6.2 Chlorination

It is of high interest in the demand of green chemistry that formation of aryl– chlorine bond through chlorination of aryl C─H bond using chloride anion as chlorine source under oxidative conditions avoids involvement of hazardous chlorine gas and stoichiometric disposal of hydrogen chloride. One example was given by Ledwith and Russel in 1974 wherein formation of aryl– chlorine bond was achieved by chlorination of arene with Cl− using Na2S2O8 as terminal oxidant [68a]. In addition to benzene, toluene is also available for this reaction, and chlorination selectively occurs on aryl C─H bonds rather than benzyl C─H bond. Treatment of toluene (0.22 M) in the presence of CuCl2·2H2O (0.48 M), Na2S2O8 (0.05 M), and HCl (0.2 M) in mixtures of MeCN/H2O (1/4, v/v) affords mixtures of chlorotoluenes in 85% yield (Scheme 10.65).

10.6  Formation of C─Halogen Bond Me + 0.22 M

CuCl2·2H2O

Cl

0.05 M Na2S2O8 0.2 M HCl, MeCN/H2O (1/4, v/v)

Me

0.48 M

85%

Scheme 10.65  Oxidative chlorination of arene with CuCl2 using Na2S2O8.

A full report was disclosed in 1975 by them [68b]. For monosubstituted arenes, anisole, toluene, or chlorobenzene are all available for this reaction. Treatment of anisole (0.15 M), toluene (0.15 M), or anisole (0.15 M) with LiCl (0.3 M) in the presence of CuCl2·2H2O (0.02 M), Na2S2O8 (0.05 M), and HCl (0.2 M) in mixtures of MeCN/H2O (1/4, v/v) at 80  °C for 3 h affords mixtures of the corresponding chloroarenes in 86, 80, or 18% yield. The regioselectivity is 25/75 with ortho/(meta + para) for anisole, 58/4/38 with ortho/meta/para for toluene or 40/5/55 with ortho/meta/para for chlorobenzene (Scheme 10.66). Me + 0.15 M

LiCl

0.02 M CuCl2 • 2H2O, 0.05 M Na2S2O8 0.2 M HCl, MeCN/H2O (1/4, v/v), 80 °C, 3 h

0.3 M

Cl Me 80% o/m/p = 58/4/38 Cl

Cl MeO 86% o/m+p = 25/75

Cl 18% o/m/p = 40/5/55

Scheme 10.66  Oxidative chlorination of arenes with LiCl using Na2S2O8.

This kind of reaction without transition metals was further developed by Zhang and coworkers in 2013 [69]. Besides benzene, various other arenes such as  haloarenes are chlorinated in high yields. Treatment of fluorobenzene (0.25 mmol) with K2S2O8 (1.0 mmol) in 1.0 mL of MeCN/saturated NaCl solution (1/1, v/v) at 100  °C for 1.5 h affords solo 4‐chloro‐1‐fluorobenzene in quantitative yield. Chlorobenzene is chlorinated under similar conditions to give mixtures of dichlorobenzene quantitatively with ortho‐/para‐regioselectivity of 1/2. When bromobenzene is the substrate, also quantitative yield of dichlorobenzene with ortho‐/para‐regioselectivity of 1/2 is afforded. Reaction of iodobenzene affords just chlorobenzene in quantitative yield under similar conditions (Scheme 10.67). In addition, some aerobic aryl C─H chlorination reactions applying for electron‐rich arenes with atmospheric O2 as terminal oxidant under milder conditions have been developed in recent years. For example, an atmospheric aerobic chlorination of phenol was reported by Gusevskaya and Menini in 2006 [70].

325

326

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene F

1.0 mmol K2S2O8

+ NaCl

MeCN/saturated NaCl (1.0 mL,1/1, v/v) 100 °C, 1.5 h

0.25 mmol

F

Cl

Quantitative

Cl 0.25 mmol 1.0 mmol K2S2O8 or + NaCl MeCN/saturated NaCl (1.0 mL, 1/1, v/v) Br 100 °C, 2 h

Cl Cl Quantitative o/p=1/2

0.25 mmol I

+ NaCl

0.25 mmol

1.0 mmol K2S2O8

Cl MeCN/saturated NaCl (1.0 mL,1/1, v/v) 100 °C, 1 h Quantitative

Scheme 10.67  Oxidative chlorination of arenes with NaCl using K2S2O8.

Treatment of phenol with LiCl (0.8 M) in the presence of CuCl2 (0.05 M) and O2 (1 atm) in HOAc at 80 °C for 24 h affords 4‐chlorophenol as sole product in 90% yield (Scheme 10.68). +

OH

LiCl 0.8 M

0.05 M CuCl2 HOAc, O2 (1 atm), 80 °C, 24 h

HO

Cl 90%

Scheme 10.68  Oxidative chlorination of phenol with LiCl using O2 (1 atm).

In 2009, Stahl and coworkers reported chlorination of electron‐rich arenes such as 1,3‐dimethoxybenzene or 1,3,5‐trimethoxybenzene. In the example of 1,3‐dimethoxybenzene, mono‐ or di-chlorination is selectively afforded by adjusting the amount of CuCl2 complex [71]. Treatment of 1,3‐dimethoxybenzene (0.3 mmol) with LiCl (1.8 mmol) in the presence of CuCl2 (25 mol%) and O2 (1 atm) in HOAc (1 mL) at 100 °C for 40 h affords 4‐chloro‐1,3‐dimethoxybenzene in 77% yield. Selective dichlorination of 1,3‐dimethoxybenzene is achieved when 200 mol% CuCl2 is applied in the reaction system to give 4,6‐ dichloro‐1,3‐dimethoxybenzene in 88% yield (Scheme 10.69).

MeO

HOAc (1 mL), O2 (1 atm), 100 °C, 40 h MeO OMe 1.8 mmol 0.3 mmol

+ LiCl MeO

Cl

25 mol% CuCl2

+ LiCl

OMe

0.3 mmol

200 mol% CuCl2

77%

Cl

Cl

HOAc (1 mL), O2 (1 atm), 110 °C, 24 h MeO

1.8 mmol

Scheme 10.69  Oxidative chlorination of arene with LiCl using O2 (1 atm).

OMe

OMe 88%

10.6  Formation of C─Halogen Bond

Chlorination of electron‐rich arenes using atmospheric air as terminal oxidant was reported by Laali and coworkers in 2013 [72]. For example, treatment of anisole (1.0 mmol) with 37% HCl (1.8 mmol) in the presence of [BMIM] [SO3H][(NO3)0.5(Cl)0.5] (3.0 mmol) and air (balloon) at 80  °C for 4 h affords mixtures of chloroanisole in quantitative conversion with ortho‐/para‐regioselectivity of 1/2.5 (Scheme 10.70). OMe +

HCl 37%

Cl

3.0 mmol [BMIM][SO3H][(NO3)0.5(Cl)0.5]

MeO

Air (balloon), 80 °C, 4 h

100% o/p = 1/2.5

1.8 mmol

1.0 mmol

Scheme 10.70  Oxidative chlorination of arene with HCl using air (1 atm).

10.6.3 Bromination

It is highly demanded that formation of aryl–bromine bond through aryl C─H bromination using bromide anion as brominating reagent under oxidative conditions avoids using hazardous Br2 and disposing of stoichiometric HBr as side product. For electron‐rich arenes, effective atmospheric aerobic bromination was established. For example, Liu, Liang, and coworkers reported that treatment of anisole (10 mmol) or toluene (10 mmol) with 42% HBr (11.3 mmol) in the presence of NaNO2 (0.3 mmol) and O2 (1 atm) at 25 °C for 1 h affords the corresponding bromination product in 91 or 76% yield [73]. Anisole is brominated at para‐position exclusively, but both ortho‐ and para‐position of toluene are brominated with ratio of 33/67 (Scheme 10.71). OMe

10 mmol

+

HBr 42%

Br

0.3 mmol NaNO2 O2 (1 atm), 25 °C, 1 h

11.3 mmol

MeO Br

91%

Me 76% o/p = 33/67

Scheme 10.71  Oxidative bromination of arenes with HBr using O2 (1 atm).

In 2009, Stahl and coworkers reported bromination of electron‐rich arenes such as 1,3‐dimethoxybenzene or 1,3,5‐trimethoxybenzene with LiBr as bromine source using 1 atm pressure of O2 as terminal oxidant [71]. For 1,3‐ dimethoxybenzene, selective mono‐ or di-bromination is achieved by ­applying 1.0 or 2.0 equiv. of LiBr, giving 4‐bromo‐1,3‐dimethoxybenzene or  4,6‐dibromo‐1,3‐methoxybenzene in 84 or 100% yield, respectively (Scheme 10.72).

327

328

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

+ MeO

OMe 0.3 mmol

Br

0.075 mmol CuBr2

LiBr 0.3 mmol

HOAc (1 mL), O2 (1 atm), 60 °C, 24 h Br MeO

MeO

84%

OMe

Br OMe

100% (LiBr = 0.6 mmol)

Scheme 10.72  Oxidative bromination of arene with LiBr using O2 (1 atm).

Bromination of electron‐rich arenes using atmospheric air as terminal ­ xidant was established by Laali and coworkers in 2013 [72]. For example, o treatment of anisole (1.0 mmol) with 48% HBr (1.8 mmol) in the presence of ionic liquid [BMIM][SO3H][(NO3)0.5(Br)0.5] (3.0 mmol) and air (balloon) at 30 °C for 1 h affords mixtures of bromoanisole in 90% conversion with ortho‐/ para‐regioselectivity of 1/2 (Scheme 10.73). OMe + 1.0 mmol

HBr 48%

3.0 mmol [BMIM][SO3H][(NO3)0.5(Br)0.5] Air (balloon), 30 °C, 1 h

1.8 mmol

Br MeO 90% o/p = 1/2

Scheme 10.73  Oxidative bromination of arene with HBr using air (1 atm).

Bromination of electron‐deficient arenes is usually conducted under harsher conditions applying more electrophilic brominating reagents. One example of bromination of electron‐deficient arenes was disclosed by Dolbier Jr. and co­workers in 1999, applying reported NBS/H2SO4/CF3CO2H brominating system. Bromination of monoelectron‐withdrawing group-attached arene such as nitrobenzene, benzotrifluoride, benzoic acid, benzaldehyde, or even dielectron‐withdrawing group-attached arene such as 1,3‐bis(trifluoromethyl)benzene is conducted at room temperature [74]. Bromination of 1,3‐dinitrobenzene is achieved when the temperature is raised to 45 °C. Besides, monobromination occurs selectively on the meta‐position of electron‐deficient arene. For example, treatment of nitrobenzene (100 mmol) with NBS (150 mmol) in the presence of mixture acids (98% H2SO4/CF3CO2H, v/v = 0.1, 50 mL) at 25 °C for 24 h affords meta‐bromonitrobenzene in 88% yield (Scheme 10.74). In 2012, Kumar and coworkers reported bromination of electron‐deficient arenes using sodium bromide as brominating reagent with sodium periodate as terminal oxidant in acidic aqueous solution [75]. Strongly electron‐deficient arenes such as 1,3‐dinitrobenzene are brominated in 88% yield at meta‐position. Besides, other electron‐deficient arenes, such as nitrobenzene and

10.6  Formation of C─Halogen Bond

+

EWG 100 mmol

NBS

98% H2SO4/CF3CO2H (50 mL)

Br EWG

150 mmol CF 3

F 3C

NO 2

Br

O2N

F3C

Br

Br

H2SO4/CF3CO2H

H2SO4/CF3CO2H

H2SO4/CF3CO2H

(v/v = 0.4) 25 °C, 51 h, 84%

(v/v = 0.4) 45 °C, 48 h, 45%

(v/v = 0.3) 25 °C, 48 h, 81%

Br

O2N

HO2C

Br

OHC

Br

H2SO4/CF3CO2H (v/v = 0.1)

H2SO4/CF3CO2H (v/v = 0.2)

H2SO4/CF3CO2H (v/v = 0.2)

25 °C, 24 h, 88%

25 °C, 44 h, 78%

25 °C, 42 h, 84%

Scheme 10.74  Bromination of electron‐deficient arenes with NBS.

­ enzoic acid, are also brominated exclusively at meta‐position. For example, b treatment of nitrobenzene (10 mmol) with NaBr (10 mmol) in the presence of NaIO4 (5.0 mmol) in the mixtures of H2SO4 (4 mL) and H2O (5 mL) at 50 °C for 4 h affords 3‐bromonitrobenzene in 83% yield. Chlorobenzene is brominated under similar conditions to give para‐bromination product in 90% yield (Scheme 10.75). EWG 10 mmol

+

Br

5.0 mmol NaIO4

NaBr

H2SO4 (4 mL), H2O (5 mL), 50 °C, time

EWG

10 mmol NO 2

NO2

Br

O2N 4 h, 88%

OHC

OHC

Br

Br

O2N 4 h, 88%

3.5 h, 81%

Br Br

O2N 4 h, 83%

Br

HO2C 3 h, 93%

Scheme 10.75  Bromination of electron‐deficient arenes with NaBr.

Cl 3 h, 90%

329

330

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

10.6.4 Iodination

Iodination of arenes using iodide anion as iodine source under atmospheric O2 is an ideal reaction to prepare aryl iodides. One such example was reported in 1988 by Radner using NH4I as iodide source and O2 as terminal oxidant [76]. Haloarenes including fluorobenzene, chlorobenzene, bromobenzene, and iodobenzene are all available in this reaction as well as electron‐rich arenes such as anisole. For example, treatment of anisole (1.1 equiv.) with NH4I (1.0 equiv.) in the presence of NO+BF4− (0.1 equiv.) in CF3CO2H/ (CF3CO)2O/CH2Cl2 solution under O2 at 40  °C for 2 h affords mixtures of iodomethoxybenzene in 100% yield with ortho‐/para‐regioselectivity of 5/95. Iodination of haloarene also gives para‐iodoarene product as major product (Scheme 10.76).

R

+

1.0 equiv.

NH4I 1.5 equiv.

I F

I

+ 1.1 equiv.

NH4I

93% I

Br 82% o/p = 9/91

OMe

R

CF3CO2H/(CF3CO)2O O2, 40 °C, 20 h

Cl

86% o/p = 3/97

I

0.2 equiv. NO+BF4–

I I

87% o/p = 10/90

92% o/p = 10/90

0.1 equiv. NO+BF4– CF3CO2H/(CF3CO)2O

1.0 equiv. CH2Cl2 (10 vol%), O2, 40 °C, 2 h

I MeO 100% o/p = 5/95

Scheme 10.76  Oxidative iodination of arenes with NH4I using O2.

Moreover, using atmospheric air as terminal oxidant was established later. Based on the work of Samant and coworkers that iodination of electron‐rich arenes is conducted with molecular iodine using silica‐supported stoichiometric bismuth(III) nitrate pentahydrate as oxidant at room temperature as reported in 2003 [77], Lu and coworkers disclosed in 2006 that an electron‐ rich arene such as anisole was iodinated in 90% yield using atmospheric air as terminal oxidant at room temperature [78]. Treatment of anisole (1.0 mmol) with I2 (0.5 mmol) in the presence of 2.5 mol% Bi(NO3)3/BiCl3 in MeCN (1 mL) under air (1 atm) at room temperature for 6 h affords 4‐iodoanisole exclusively in 90% yield (Scheme 10.77).

10.7 ­Summary OMe + 1.0 mmol

2.5 mol% Bi(NO3)3/BiCl3

I2

MeCN (1 mL), air (1 atm), rt, 6 h

I

MeO 90%

0.5 mmol

Scheme 10.77  Oxidative iodination of arenes with I2 using air (1 atm)(i).

Similar transformation was reported by Iskra and coworkers in 2008 using sodium nitrite as catalytic species [79]. For example, treatment of anisole (1.0 mmol) with I2 (0.5 mmol) in the presence of NaNO2 (0.05 mmol) and 50% H2SO4 on SiO2 (0.1 mmol) in MeCN (2 mL) under air (1 atm) at room temperature for 12 h gives 4‐iodoanisole exclusively in 100% yield (Scheme 10.78). It is proposed that NO2 generated in situ from NaNO2 oxidizes I2 followed by ­iodination of arenes to afford the iodination product. OMe + 1.0 mmol

0.05 mmol NaNO2

I2

0.1 mmol 50% H2SO4/SiO2 (3.62 mmol H2SO4/g) MeCN (2 mL), air(1 atm), 22 °C, 12 h 0.5 mmol

I

MeO 100%

Scheme 10.78  Oxidative iodination of arenes with I2 using air (1 atm)(ii).

Sodium nitrite (NaNO2) catalytic aerobic iodination of electron‐rich arenes using air (1 atm) as terminal oxidant was further developed using KI as iodinating reagent provided by Stavber and coworkers in 2008 [80]. For example, treatment of electron‐rich 1,3‐dimethoxybenzene (1.0 mmol) with KI (1.05 mmol) in the presence of NaNO2 (12 mol%) and 96% H2SO4 (0.75 mmol) in MeCN (6 mL) under air (balloon) at 30  °C for 10 h affords 4‐iodo‐1,3‐dimethoxybenzene in 94% yield (Scheme 10.79). OMe MeO 1.0 mmol

OMe

+

KI

12 mol% NaNO2

0.75 mmol 96% H2SO4, MeCN (6 mL) air (balloon), 30 °C, 10 h 1.05 mmol

I

MeO 94%

Scheme 10.79  Oxidative iodination of arenes with KI using air (1 atm).

10.7 ­Summary In this chapter, it is described that alkylation, trifluoromethylation, arylation, alkenylation, carbonylation, alkynylation, cyanidation, and formation of aryl– heteroatom bonds (heteroatom = N, O, S, F, Cl, Br, or I) via either indirect SEAr

331

332

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

or radical process or direct C─H activation pathway. Basically, these described reactions lie in between reaction types two and three, which are able to occur but not so well with working mechanism but not fully clarified as mentioned in Chapter 9. One major concern is the reactivity of electron‐deficient arenes, benzene attached to electron‐withdrawing group(s). Oxidation of electron‐deficient arenes is largely unexplored especially using normal oxidative partners under mild conditions. Nickel‐catalyzed linear alkylation of 1,3‐bis(trifluoromethyl)benzene with either terminal or internal alkynes and 2,6‐dialkylpyridine‐ ligated palladium‐catalyzed cross‐coupling of various electron‐deficient arenes including 1,3‐bis(trifluoromethyl)benzene, nitrobenzene, trifluoromethylbenzene, ethyl benzoate, etc. with alkenes are the rare examples of oxidation of aryl C─H bonds of electron‐deficient arenes. Another major concern is the regioselectivity of monosubstituted benzenes. Examples of obtaining monooxidized product at specific position are also very limited, mainly confined to para‐position of electron‐rich arene or meta‐position of electron‐poor arene with weak oxidizing reagent. Reverse of the regioselectivity such as affording meta‐oxidized product of electron‐rich arenes such as aniline is not accessible. In addition, control of the stereoselectivity when the forming oxidized product owns a chiral center is even rarer, exhibited by the enantioselective alkylation of aniline derivatives by carbene insertion catalyzed by rhodium complex ligated by chiral spiro phosphoric acid. Besides, some oxidation reactions not applied for benzene but only suitable for electron‐rich arenes were developed; for example, gold‐catalyzed cross‐coupling of 1,3,5‐trimethoxybenzene with terminal alkynes. However, these novel oxidative reactions are at a very early stage generally, and much further improvement is still needed for both reactivity and selectivity. Besides, new catalytic systems and new mechanisms are still urgently desired for achieving alkylation through direct cross‐coupling of arene with alkane, trifluoromethylation, arylation through cross‐coupling of two different arenes, alkynylation through cross‐coupling of arene and alkyne, cyanidation, amination through cross‐coupling of arene with amine, and fluorination. In addition, for these already established reactions of aryl C─H oxidation, their improvement to atmospheric aerobic oxidative reactions is also full of worth.

References NO2+ Phthalimide or amine

H2N

H2O2 or O2

HO

RCO2H ROH

10.3

O2N

10.1 10.2.1

Introduction Alkyl

10.4

RCO2

10.2.2

RO

CF3

R

FG

H2C

CHR

FG

CF3

FG 10.2.3

O N SR

X

10.5

RS

10.2.4

O HF

Cl–

F

Cl

H

10.6.1

10.6.2

10.2.5

O FG

R O

Br–

Br

10.6.3

OH

O R

CO or CO2

10.2.6 I–

I

10.6.4

Summary

10.7

10.2.7

N

CN–

References [1] Mine, N.; Fujiwara, Y.; Taniguchi, H. Chem. Lett. 1986, 357–360. [2] Yamauchi, T.; Hattori, K.; Mizutaki, S.; Tamaki, K.; Uemura, S. Bull. Chem.

Soc. Jpn. 1986, 59, 3617–3620.

[3] (a) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.‐I. Synlett 1996,

557–559; (b) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.‐I. J. Org. Chem. 1997, 62, 6997–7005. [4] Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 3913–3917. [ 5] Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033–1037. [ 6] Jefferies, L. R.; Cook, S. P. Org. Lett. 2014, 16, 2026–2029.

333

334

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

[7] Song, C. E.; Shim, W. H.; Roh, E. J.; Choi, J. H. Chem. Commun. 2000,

1695–1696.

[8] Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F.

J. Am. Chem. Soc. 2014, 136, 13098–13101.

[9] Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G. J. Am. Chem. Soc. 2014, 136,

13594–13597.

[10] Xu, B.; Li, M.‐L.; Zuo, X.‐D.; Zhu, S.‐F.; Zhou, Q.‐L. J. Am. Chem. Soc. 2015,

137, 8700–8703.

[11] (a) Kamigata, N.; Fukushima, T.; Yoshida, M. Chem. Lett. 1990, 649–650;

[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]

[30] [31]

[32] [33]

(b) Kamigata, N.; Ohtsuka, T.; Fukushima, T.; Yoshida, M.; Shimizu, T. J. Chem. Soc. Perkin Trans. I 1994, 1339–1346. Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224–228. Sladojevich, F.; McNeill, E.; Börgel, J.; Zheng, S.‐L.; Ritter, T. Angew. Chem. Int. Ed. 2015, 54, 3712–3716. Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464–5467. Seo, S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2013, 6385–6387. Shi, G.; Shao, C.; Pan, S.; Yu, J.; Zhang, Y. Org. Lett. 2015, 17, 38–41. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–16497. Qin, C.; Lu, W. J. Org. Chem. 2008, 73, 7424–7427. Fujita, K.; Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004, 1926–1927. Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737–16740. Sun, C.‐L.; Li, H.; Yu, D.‐G.; Yu, M.; Zhou, X.; Lu, X.‐Y.; Huang, K.; Zheng, S.‐F.; Li, B.‐J.; Shi, Z.‐J. Nat. Chem. 2010, 2, 1044–1049. Shirakawa, E.; Itoh, K.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537–15539. Fujiwara, Y.; Moritani, M.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166–7169. Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097–2100. Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476–1477. Babu, B. P.; Meng, X.; Bäkvall, J.‐E. Chem. Eur. J. 2013, 19, 4140–4145. Zhang, Y.‐H.; Shi, B.‐F.; Yu, J.‐Q. J. Am. Chem. Soc. 2009, 131, 5072–5074. Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760–1763. (a) Patureau, F. W.; Nimphius, C.; Glorius, F. Org. Lett. 2011, 13, 6346–6349; (b) Wencel‐Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Chem. Asian J. 2012, 7, 1208–1212. Hong, P.; Cho, B.‐R.; Yamazaki, H. Chem. Lett. 1979, 339–342. (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995; (b) Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252–7263. Li, R.; Wang, S. R.; Lu, W. Org. Lett. 2007, 9, 2219–2222. Izumi, Y.; Ogawa, M.; Nohara, W.; Urabe, K. Chem. Lett. 1992, 1987–1990.

References

[ 34] Mukaiyama, T.; Suzuki, K.; Han, J. S.; Kobayashi, S. Chem. Lett. 1992, 435–438. [35] Kawada, A.; Mitamura, S.; Kobayashi, S. J. Chem. Soc. Chem. Commun. 1993,

1157–1158.

[36] Shimizu, K.; Niimi, K.; Satsuma, A. Catal. Commun. 2008, 9, 980–983. [37] Tran, P. H.; Hansen, P. E.; Nguyen, H. T.; Le, T. N. Tetrahedron Lett. 2015, 56,

612–618.

[38] Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc. Chem. Commun.

1980, 220–221.

[39] Fujiwara, Y.; Kawata, I.; Sugimoto, H.; Taniguchi, H. J. Organomet. Chem.

1983, 256, C35–C36.

[40] Taniguchi, Y.; Yamaoka, Y.; Nakata, K.; Takaki, K.; Fujiwara, Y. Chem. Lett.

1995, 345–346.

[41] Sugimoto, H.; Kawata, I.; Taniguchi, H.; Fujiwara, Y. J. Organomet. Chem.

1984, 266, C44–C46.

[42] Suga, T.; Mizuno, H.; Takaya, J.; Iwasawa, N. Chem. Commun. 2014, 50,

14360–14363.

[43] Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem. Soc. Dalton Trans. 2001,

2330–2334.

[44] de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512–1513. [45] Zhang, G.; Lv, G.; Pan, C.; Cheng, J.; Chen, F. Synlett 2011, 20, 2991–2994. [46] Okamoto, K.; Watanabe, M.; Murai, M.; Hatano, R.; Ohe, K. Chem. Commun.

2012, 48, 3127–3129.

[47] Waller, F. J.; Barrett, A. G. M.; Braddock, D. C.; Ramprasad, D. Chem.

Commun. 1997, 613–614.

[48] Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S.; J. Am. Chem. Soc. 2011, 133,

16382–16385.

[49] Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.; DeBoef, B.

J. Am. Chem. Soc. 2011, 133, 19960–19965.

[50] Manna, S.; Serebrennikova, P. O.; Utepova, I. A.; Antonchick, A. P.;

Chupakhin, O. N. Org. Lett. 2015, 17, 4588–4591.

[51] Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A. Science 2015, 349,

1326–1330.

[52] Walling, C.; Johnson, R. A. J. Am. Chem. Soc. 1975, 97, 363–367. [53] Olah, G. A.; Ohnishi, R. J. Org. Chem. 1978, 43, 865–867. [54] Morimoto, Y.; Bunno, S.; Fujieda, N.; Sugimoto, H.; Itoh, S. J. Am. Chem. Soc.

2015, 137, 5867–5870.

[55] (a) Jintoku, T.; Taniguchi, H.; Fujiwara, Y. Chem. Lett. 1987, 1865–1868;

(b) Jintoku, T.; Takai, K.; Fujiwara, Y.; Fuchita, Y.; Hiraki, K. Bull. Chem. Soc. Jpn. 1990, 63, 438–441. [56] Passoni, L. C.; Cruz, A. T.; Buffon, R.; Schuchardt, U. J. Mol. Catal. A 1997, 120, 117–123. [ 57] Ohkubo, K.; Kobayashi, T.; Fukuzumi, S. Angew. Chem. Int. Ed. 2011, 50, 8652–8655.

335

336

10  Oxidation of Aryl sp2C─H Bond on Substituted Benzene

[58] Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Am. Chem. Soc. 2013, 135,

5368–5371.

[59] Ohkubo, K.; Hirose, K.; Fukuzumi, S. Chem. Eur. J. 2015, 21, 2855–2861. [60] Henry, P. M. J. Org. Chem. 1971, 36, 1886–1890. [61] (a) Eberson, L.; Jösson, L. J. Chem. Soc. Chem. Commun. 1974, 885–886;

(b) Eberson, L.; Jösson, L. Acta Chem. Scand. B 1976, 30, 361–364.

[ 62] Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996, 108, 35–40. [63] Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem. Int. Ed.

2011, 50, 9409–9412.

[64] Hostier, T.; Ferey, V.; Ricci, G.; Pardo, D. G.; Cossy, J. Org. Lett. 2015, 17,

3898–3901.

[65] Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Phys. Chem. A 2013, 117,

10719–10725.

[66] Saito, M.; Miyamoto, K.; Ochiai, M. Chem. Commun. 2011, 47, 3410–3412. [67] Tian, T.; Zhong, W.‐H.; Meng, S.; Meng, X.‐B.; Li, Z.‐J. J. Org. Chem. 2013,

78, 728–732.

[68] (a) Ledwith, A.; Russell, P. J. J. Chem. Soc. Chem. Commun. 1974, 291–292;

(b) Ledwith, A.; Russell, P. J. J. Chem. Soc. Perkin Trans. II 1975, 1503–1508.

[69] Gu, L.; Lu, T.; Zhang, M.; Tou, L.; Zhang, Y. Adv. Synth. Catal. 2013, 355, [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80]

1077–1082. Menini, L.; Gusevskaya, E. V. Chem. Commun. 2006, 42, 209–211. Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 45, 6460–6462. Prebil, R.; Laali, K. K.; Stavber, S. Org. Lett. 2013, 15, 2108–2111. Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 348, 862–866. Duan, J.; Zhang, L. H.; Dolbier Jr., W. R. Synlett 1999, 8, 1245–1246. Kumar, L.; Mahajan, T.; Agarwal, D. D. Ind. Eng. Chem. Res. 2012, 51, 11593–11597. Radner, F. J. Org. Chem. 1988, 53, 3548–3553. Alexander, V. M.; Khadilkar, B. M.; Samant, S. D. Synlett 2003, 12, 1895–1897. Wan, S.; Wang, S. R.; Lu, W. J. Org. Chem. 2006, 71, 4349–4352. Iskra, J.; Stavber, S.; Zupan, M. Tetrahedron Lett. 2008, 49, 893–895. Stavber, G.; Iskra, J.; Zupan, M.; Stavber, S. Adv. Synth. Catal. 2008, 350, 2921–2929.

337

11 Oxidation of Aryl sp2C─H Bond Assisted by Directing Group 11.1 ­Introduction Directing groups can catch the reactive species such as catalysts or reagents to direct them to cleave or react with the target bonds, as mentioned in Chapter 4. Herein, the directing groups are the substituted functional groups attached on benzene rings, which usually coordinate with transition metals and assist them to cleave and oxidize aryl sp2C─H bonds in their vicinity, normally at ortho‐ or even meta‐positions. Since various functional groups either with strong coordinating ability such as aniline, benzoic acid, phenol, etc. or with weak coordinating ability such as benzyl alcohol, benzoic ester, etc. serve as directing groups, the substrate scope is very large. Applying this strategy of directing‐group‐assisted transition‐metal‐catalyzed aryl C─H oxidation, much novel transformation is achieved, which is often orthogonal to the oxidation of normal arenes.

11.2 ­Formation of C─C Bond 11.2.1 Alkylation

The classical method in current organic synthesis for formation of aryl–alkyl bond is the Friedel–Crafts alkylation, which is the Lewis acid such as AlCl3‐ mediated electrophilic substitution of arenes by alkyl halides, normally tertiary or secondary alkyl halides. Friedel–Crafts alkylation is usually applied for electron‐rich arenes, giving mixtures of ortho‐ and para‐alkylation as major products. Alternatively, alkylation of arenes to make them ortho‐ or even meta‐alkylated as sole or major product has been established in recent decades through transition‐metal‐catalyzed C─H reactions assisted by directing groups. In 1984, Tremont and Rahman reported alkylation of aryl C─H bond in the ­presence of amide as directing group to afford ortho-alkylated products. [1] Monoor di-ortho-alkylation is selectively achieved by varying the solvent system. Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

338

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

When acetanilide is treated with stoichiometric Pd(OAc)2 (1.5 equiv.) followed by quenching with MeCN (27 equiv.) before addition of methyl iodide (10–15 equiv.) at 60 °C, quantitative yield of mono-ortho-methylation product is afforded. When acetanilide (5.9 mmol) is treated with excess Pd(OAc)2 (18 mmol) and methyl iodide (31.7 mmol) in HOAc (7.0 g) at 100 °C, quantitative di-ortho-alkylation product is afforded. Catalytic ortho-alkylation of acetanilide was also established using palladium(II) salts. Treatment of acetanilide (4.0 equiv.) with MeI (10 equiv.) in the presence of Pd(OAc)2 (1 equiv.) at 100 °C for 2.5 hours affords mono-ortho-alkylation product in TON of 1.5. Performing the above reaction in the presence of palladium trifluoroacetate and trifluoroacetic acid instead of Pd(OAc)2 and HOAc gives TON of 1.8 in five minutes. Furthermore, when excess AgOAc is applied in the reaction system, the TON is up to 10 in ten minutes. In the proposed mechanism, metalation of acetanilide at ortho-aryl C─H bond by Pd(II) salt forms aryl‒Pd(II) complex. Oxidative addition of this aryl‒Pd(II) complex to methyl iodide gives aryl‒Pd(IV)‒alkyl key intermediate. Reductive elimination of aryl and alkyl group affords aryl‒ alkyl bond and Pd(II) iodide, which is treated with AgOAc to regenerate Pd(OAc)2 fulfilling the catalytic cycle (Scheme 11.1). Ortho‐alkylation of a benzyl amine was achieved in 2011 as reported by Chen and Zhao using picolinamide (PA) as directing group in palladium catalysis [2]. Treatment of PA‐benzyl amine substrate (0.2 mmol, 1 equiv.) with n‐propyl iodide (3.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), K2CO3 (2.0 equiv.), NaOTf (3.0 equiv.), and O2 in t‐AmylOH at 125 °C for 36 h affords ortho‐alkylation product in 95% yield (Scheme 11.2). Moreover, meta‐alkylation of monosubstituted arenes was reported by Yu and coworkers in 2015, using norbornene as a transient mediator and a ­2‐alkoxypyridine containing two fused rings as effective ligand [3]. Treatment of phenylacetic acid‐derived N‐2,3,5,6‐tetrafluoro‐4‐trifluoromethylphenyl amide substrate (0.1 mmol, 1 equiv.) with either methyl iodide (3.0 equiv.) or ethyl iodoacetate (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), ligand (20 mol%), norbornene (1.5 equiv.), and AgOAc (3.0 equiv.) in DCE (1.5 mL) at 95 °C for 16 h affords the corresponding alkylation product in 90 or 84% yield, respectively. In the proposed mechanism, metalation of phenylacetic acid‐ derived amide at ortho‐aryl C─H bond by Pd(II) salt gives aryl–Pd(II) bond, which is inserted by norbornene to form arylalkyl‐Pd(II) intermediate followed by metalation of meta‐aryl C─H bond to afford meta‐aryl–Pd(II)–alkyl–aryl intermediate. Oxidative addition of this meta‐aryl‐Pd(II)–alkyl–aryl intermediate to alkyl iodide gives aryl‐Pd(IV)–alkyl key intermediate, followed by reductive elimination of aryl and alkyl groups to afford meta‐aryl–alkyl bond and β‐elimination to release norbornene and to give meta‐alkyl ortho‐aryl‐Pd(II) intermediate. Protonation of this meta‐alkyl–ortho‐aryl‐Pd(II) intermediate affords the meta‐alkylation product and Pd(II) species followed by ligand exchange with AgOAc to fulfill the catalytic cycle. The key to the success of this

11.2 ­Formation of C─C Bond NHAc

+

H3C I

NHAc

(1) Pd(OAc)2 (1.5 equiv.), 3 h (2) CH3I (10–15 equiv.) CH3CN (27 equiv.), 60 °C, 8 h

CH3 100% CH3

NHAc

+

5.9 mmol

18 mmol Pd(OAc)2

H3C I

NHAc

HOAc (7.0 g), 100 °C, 18 h CH3 100%

31.7 mmol

NHAc + 4.0 equiv.

NHAc

1 equiv. Pd(OAc)2

H3C I

HOAc, 100 °C, 2.5 h

CH3 TON = 1.5

10 equiv.

NHAc +

4.0 equiv.

H3C I

NHAc

1equiv. Pd(OCOCF3)2 CF3CO2H, 100 °C, 5 min

CH3

10 equiv.

TON = 1.8

NHAc +

H3C I

Excess

NHAc

Cat. Pd(OAc)2 AgOAc CF3CO2H, 100 °C, 10 min

CH3 TON = 10

NHAc AgI

AgOAc

AcO PdII Ligand exchange

C H activation

HOAc NHAc

I PdII

NHAc Me

PdII Reductive elimination

Oxidative addition

Me I

NHAc I IV

Pd Me

Scheme 11.1  Pd(II)/Pd(IV)‐catalyzed ortho‐alkylation of aniline with CH3I.

339

340

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group CH3

O nPr

+

N H

I

N

0.2 mmol

3.0 equiv.

CH3

5 mol% Pd(OAc)2

O N H

2.0 equiv. K2CO3, 3.0 equiv. NaOTf tAmylOH, O , 125 °C, 36 h 2

N

nPr

> 95%

Scheme 11.2  Pd‐catalyzed ortho‐alkylation of a benzylamine with alkyl iodide.

meta‐alkylation reaction is to control the chemoselectivity by addition of screened pyridine‐based ligand to avoid formation of ortho‐alkylation, addition of norbornene to ortho‐ and meta‐aryl C─H bonds, and di‐alkylation at both ortho‐ and meta‐positions (Scheme 11.3). Me O 10 mol Pd(OAc)2 Me Me Me O

I Me F F

HN F

CF3 I

0.1 mmol

F

CF3

90% or

3.0 equiv. AgOAc DCE (1.5 mL), 95 °C, 16 h

F

F

F

N O 20 mol% ligand

3.0 equiv. or +

F

HN

Me O

CO2Et

F F

HN

3.0 equiv.

1.5 equiv. norbornene

EtO2C

F 84%

CF3 F

O CONHArF

II

NHArF

Pd L

Alkyl Protonation, ligand exchange

Ag, H

Orthometalation

CONHArF

CONHArF

+

PdIIL

OA, RE, β-elimination

Alkyl

H

Insertion, metametalation

PdIIL

CONHArF I

Alkyl LPdII

Scheme 11.3  Pd‐catalyzed meta‐alkylation of a phenylacetamide with alkyl iodide enabled by norbornene and ligand.

11.2 ­Formation of C─C Bond

This meta‐alkylation of phenylacetamide reaction was further optimized using a modified norbornene as reported by Yu and coworkers in 2015 [4]. For example, treatment of phenylacetic acid‐derived N‐2,3,5,6‐tetrafluoro‐4‐­ trifluoromethylphenyl amide (0.1  mmol, 1  equiv.) with n‐butyl iodide (2.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), a pyridine‐derived ligand (10 mol%), modified norbornene (3.0 equiv.), and AgOAc (3.0 equiv.) in DCE (1.5 mL) at 75 °C for 16 h affords the corresponding alkylation product in 85% yield (Scheme 11.4). 10 mol Pd(OAc)2 Me tBu

Me O

F F +

HN F

nBu

I

CF3 2.5 equiv.

Me O

Me O N 10 mol% ligand 3.0 equiv. AgOAc DCE (1.5 mL), 75 °C, 16 h

F F

HN nBu

F 0.1 mmol

F 85%

CF3 F

MeO2C 3.0 equiv. modified norbornene

Scheme 11.4  Pd‐catalyzed meta‐alkylation of a phenylacetamide with alkyl iodide enabled by modified norbornene and ligand.

Alkyl bromides are also available for the alkylation. In 2009, Ackermann and coworkers reported ortho‐alkylation of aryl C─H bond with alkyl bromide using pyridine as effective directing group [5]. For example, treatment of 2‐phenylpyridine (1.0 mmol, 1 equiv.) with n‐hexyl bromide (3.0 equiv.) in the presence of ruthenium catalyst (2.5 mol%), MesCO2H (30 mol%) as ligand, and K2CO3 (2.0 equiv.) in NMP (N-methyl-2-pyrrolidone, 4 mL) at 80 °C for 20 h affords the corresponding ortho‐alkylation product in 68% yield. In addition to pyridine, pyrazole or ketimine derivatives are also found as the effective directing groups, cross‐coupling ortho‐aryl C─H bonds with either primary or secondary alkyl bromides (Scheme 11.5).

N

1.0 mmol

+

Br

nHex

3.0 equiv.

2.5 mol% [{RuCl2(p-cymene)}2] 30 mol% 1-AdCO2H

N

2.0 equiv. K2CO3 NMP (4 mL), 80 °C, 20 h

nHex

68%

Scheme 11.5  Ru‐catalyzed ortho‐alkylation of 2‐pyridylbenzene with alkyl bromide.

341

342

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Meta‐alkylation of 2‐phenylpyridine with alkyl bromides was established in 2013 by Ackermann and Hofmann [6]. For example, treatment of 2‐phenylpyridine (0.5 mmol, 1 equiv.) with 2‐octayl bromide (3.0 equiv.), a secondary alkyl bromide, in the presence of ruthenium catalyst (2.5  mol%), MesCO2H (30 mol%) as ligand, and K2CO3 (2.0 equiv.) in 1,4‐dioxane (2 mL) at 100 °C for 20 h affords the corresponding meta‐alkylation product in 60% yield. It was proposed that ruthenium catalyst coordinated with pyridine and cleaved ortho‐aryl C─H bond of 2‐pyridylbenzene to form aryl–ruthenium complex, in which meta‐C─H bond of 2‐pyridylbenzene was activated and reacted with secondary alkyl bromide in SEAr process to afford the meta‐alkylation product (Scheme 11.6).

N 0.5 mmol

+

Br Me

nHex

3.0 equiv.

2.5 mol% [{RuCl2(p-cymene)}2] 30 mol% MesCO2H 2.0 equiv. K2CO3 1,4-dioxane (2 mL), 100 °C, 20 h

nHex

N

Me 60%

Scheme 11.6  Ru‐catalyzed meta‐alkylation of 2‐pyridylbenzene with alkyl bromide.

Alkyl chlorides are available for the alkylation as well. In 2003, Buchwald and Hennessy reported an intramolecular alkylation of ortho‐aryl C─H bond of α‐chloroacetanilides to prepare substituted oxindoles [7]. For example, treatment of N‐methyl‐α‐chloroacetanilides (1.0 mmol, 1 equiv.) in the presence of Pd(OAc)2 (1 mol%), di‐tert‐butylbiphenyl phosphine ligand (0.5 mol%), and EtN3 (1.5 equiv.) in toluene (1 mL) at 80 °C for 2.5 h affords the corresponding oxindole product in 93% yield. In the proposed mechanism, oxidative addition of Pd(0) species to alkyl–Cl bond forms alkyl‐Pd(II) intermediate, which is a metalation of ortho‐aryl C─H bond to give alkyl‐Pd(II)‐aryl intermediate. After reductive elimination of alkyl and aryl group, it affords oxindole product and Pd(0) to fulfill the catalytic cycle (Scheme 11.7). Intermolecular alkylation of ortho‐aryl C─H bond of benzoic acid with alkyl chloride was disclosed by Yu and coworkers in 2009 [8]. For example, treatment of 3‐methylbenzoic acid (0.5 mmol, 1 equiv.) with 1,2‐dichloroethane (2.0 mL) in the presence of Pd(OAc)2 (10 mol%) and K2HPO4 (3.0 equiv.) at 115  °C for 36 h affords the corresponding lactone product in 81% yield (Scheme 11.8). Possibility of benzoic acid reacting with alkyl chloride to form benzoic ester first followed by intramolecular ortho‐alkylation to afford lactone is ruled out by the observation that intramolecular ortho‐alkylation does not occur using benzoic ester as substrate prepared from benzoic acid and alkyl chloride or bromide. Furthermore, isolated ortho‐aryl‐Pd(II) complex reacts with CH2Br2 to afford the desired product, which also supports the intermolecular mechanism.

11.2 ­Formation of C─C Bond 1 mol% Pd(OAc)2 0.5 mol% 2-(di-tert-butylphosphino)biphenyl

Me N

O

Me N

1.5 equiv. Et3N, toluene (1 mL), 80 °C, 2.5 h

Cl 1.0 mmol

O

93% Me

Me N

N

O

Pd0

O

Cl Oxidative addition

Reductive elimination

Me N

Me

O

N

PdII C H activation

O

PdII

Scheme 11.7  Pd‐catalyzed intramolecular ortho‐alkylation of anilines with alkyl chloride. O Me

Cl OH + 0.5 mmol

Cl 2.0 mL

10 mol% Pd(OAc)2

O Me

O

3.0 equiv. K2HPO4, 115 °C, 36 h 81%

Scheme 11.8  Pd‐catalyzed intermolecular ortho‐alkylation of a benzoic acid with alkyl chloride.

Epoxides are also available as the alkylating reagents in the alkylation. In 2004, He and Shi reported an intramolecular alkylation of ortho‐aryl C─H bond of alkoxybenzene [9]. For example, treatment of 2‐(phenoxymethyl)oxirane (0.5 mmol, 1 equiv.) in the presence of AuCl3 (2.5 mol%) and AgOTf (7.5 mol%) in DCE (3 mL) at 83 °C for 4 h affords cyclization product 3‐chromanol in 65% yield. This cyclization of epoxide substrate is stereospecific with the inversion of configuration of benzyl carbon attached on oxirane exemplified by the reaction of (2S,3S)‐2‐(2‐(naphthalen‐2‐yl)ethyl)‐3‐phenyloxirane to afford (3S,4S)‐4‐phenyl‐1,2,3,4‐tetrahydrophenanthren‐3‐ol (Scheme 11.9). An intermolecular alkylation of ortho‐aryl C─H bond of 2‐pyridylbenzene was reported by Kanai and coworkers in 2015 [10]. For example, treatment of  2‐phenylpyridine (0.2  mmol, 1  equiv.) with 2‐(phenoxymethyl)oxirane (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) in mixtures of HFIP (0.8 mL)

343

344

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group O

2.5 mol% AuCl3, 7.5 mol% AgOTf

O

DCE (3 mL), 83 °C, 4 h

O 0.5 mmol

OH 65%

2.5 mol% AuCl3, 7.5 mol% AgOTf

O

OH

DCE (3 mL), 50 °C, 3 h

0.5 mmol

82%

Scheme 11.9  Pd‐catalyzed intramolecular ortho‐alkylation of arenes with epoxides.

and HOAc (0.2 mL) at room temperature for 24 h affords the corresponding ring opening product in quantitative yield. This intermolecular alkylation of ortho‐aryl C─H bond with epoxide is also stereospecific, exhibited by the reaction of 2‐phenylpyridine with either enantiomerically pure (S)‐2‑(methoxymethyl)oxirane or (R)‐2‐(methoxymethyl)oxirane to give the corresponding enantiomerically pure alkylation product with stereoretention (Scheme 11.10).

N 0.2 mmol

+

O OPh 0.4 mmol

10 mol% Pd(OAc)2 HFIP (0.8 mL), HOAc (0.2 mL) 25 °C, 24 h

N

HO > 99%

OPh

N O OMe

N 0.2 mmol

(S), > 99% ee 0.4 mmol + or O OMe (R), > 99% ee 0.4 mmol

10 mol% Pd(OAc)2 HFIP (0.8 mL), HOAc (0.2 mL) 25 °C, 24 h

OMe HO 79%, (S), > 99% ee or N OMe HO 88%, (R), > 99% ee

Scheme 11.10  Pd‐catalyzed intermolecular ortho‐alkylation of 2‐pyridylbenzene with epoxides.

11.2 ­Formation of C─C Bond

Using this intermolecular alkylation of ortho‐aryl C─H bond strategy, one‐ step synthesis of 3,4‐dihydroisocoumarins was achieved by reaction of benzoic acid with epoxide as reported by Yu and coworkers in 2015 [11]. For example, treatment of 3‐methylbenzoic acid (0.1 mmol, 1 equiv.) with 2‐((benzyloxy)methyl)oxirane (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), amino acid derivative Ac‐t‐Leu‐OH (2 mol%), and KOAc (1.0 equiv.) in HFIP (0.25 mL) at 75  °C for 24 h affords the corresponding 3,4‐dihydroisocoumarin product in quantitative yield (Scheme 11.11). O Me

OH + 0.1 mmol

O OBn

1 mol% Pd(OAc)2 2 mol% Ac-t-Leu-OH

O Me

O

1.0 equiv. KOAc HFIP (0.25 mL), 75 °C, 24 h

2.0 equiv.

OBn 99%

Scheme 11.11  Pd‐catalyzed intermolecular ortho‐alkylation of a benzoic acid with epoxides.

Imines are available as the alkylating reagents in the alkylations as well. In 2011, Bergman, Ellman, and coworkers reported rhodium‐catalyzed alkylation of ortho‐aryl C─H bond of 2‐pyridylbenzene with imines [12]. For example, treatment of 2‐phenylpyridine (0.05 mmol, 1 equiv.) with N‐bocbenzaldimine (1.0 equiv.) in the presence of rhodium catalyst (10 mol%) and AgSbF6 (40 mol%) in CH2Cl2 (2.5 mL) at 75 °C for 20 h affords the alkylation product in 87% yield (Scheme 11.12).

N

0.05 mmol

+

NBoc H

Ph

1.0 equiv.

10 mol% [Cp*RhCl2]2 40 mol% AgSbF6 CH2Cl2 (2. 5 mL), 75 °C, 20 h

N NBoc Ph 87%

Scheme 11.12  Rh‐catalyzed ortho‐alkylation of 2‐pyridylbenzene with imines.

Almost at the same time, Shi and coworkers [13] also reported rhodium‐ catalyzed alkylation of ortho‐aryl C─H bonds of 2‐pyridylbenzene with imines. For example, treatment of 2‐phenylpyridine (0.25 mmol, 1 equiv.) with N‑tosylbenzaldimine (2.0 equiv.) in the presence of rhodium catalyst (5 mol%) in t‐BuOH (1 mL) at 90 °C for 10 h affords the alkylation product in 84% yield (Scheme 11.13). Methylboroxine and alkylboronic acids are also used as alkylating reagents in the alkylations. In 2006, Yu and coworkers reported palladium‐catalyzed pyridine‐directed alkylation of ortho‐aryl C─H bonds with alkylboronic acids

345

346

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

N

NTs

+ H

0.25 mmol

5 mol% [Cp*Rh(MeCN)3][SbF6]2

N NTs

tBuOH (1 mL), 90 °C, 10 h

Ph

Ph 84%

0.50 mmol

Scheme 11.13  Rh‐catalyzed ortho‐alkylation of 2‐pyridylbenzene with imines.

to afford alkylation product [14]. For example, treatment of 2‐phenylpyridine (0.2 mmol, 1 equiv.) with 2,4,6‐trimethyl‐1,3,5,2,4,6‐trioxatriborinane (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Cu(OAc)2 (1.0 equiv.), and benzoquinone (1.0 equiv.) in CH2Cl2 (1 mL) at 100  °C for 24 h affords the alkylation product in 72% yield. Since alkylation of aryl C─H bond is an oxidative ­reaction and alkylboronic acid is not an oxidant, additional oxidant such as Cu(OAc)2 and BQ in this case is required in this type of transformation (Scheme 11.14). Me N

+ Me

0.2 mmol

O B

B O

O B

10 mol% Pd(OAc)2 Me

2.0 equiv.

1.0 equiv. Cu(OAc)2, 1.0 equiv. BQ CH2Cl2 (1 mL), 100 °C, 24 h

N Me 72%

Scheme 11.14  Pd‐catalyzed ortho‐alkylation of 2‐pyridylbenzene with methylboroxine.

In the previous examples of directing‐group‐assisted transition‐metal‐ catalyzed alkylation of aryl C─H bonds, high‐valent transition metals such as Pd(OAc)2 are normally applied to cleave aryl C─H bonds through electrophilic activation. Alternatively, cleavage of aryl C─H bonds by low‐valent transition metals through oxidative addition is also available. In 1993, Murai and coworkers reported ruthenium‐catalyzed alkylation of ortho‐aryl C─H bonds of aromatic ketones with alkenes [15]. Selective mono‐ or di‐alkylation of ortho‐aryl C─H bonds is achieved by controlling the amount of alkene and the reaction time. For example, treatment of acetophenone (2.0 mmol, 1 equiv.) with triethoxy(vinyl)silane (1.0 equiv.) in the presence of ruthenium catalyst (2 mol%) in toluene (3 mL) at 135 °C for 0.2 h affords the corresponding mono‐alkylation product in 75% yield. By increasing the loading of alkene to 3.0 equiv. and prolonging the reaction time to 90 h, 94% yield of di‐alkylation product is obtained. In the proposed mechanism, Ru(0) complex coordinates with ketone group and cleaves ortho‐aryl C─H bond by oxidative addition to form aryl–Ru(II)–H intermediate. Insertion of alkene into Ru(II)–H bond rather than aryl–Ru(II)

11.2 ­Formation of C─C Bond

bond gives aryl–Ru(II)–alkyl species. Reductive elimination of aryl and alkyl group affords corresponding alkylation product and Ru(0) to fulfill the catalytic cycle (Scheme 11.15). O Me Si(OEt)3

Si(OEt)3 75% (0.2 h)

1.0 equiv.

O Me

+

or

2 mol% RuH2(CO)(PPh3)3

Si(OEt)3 or

Toluene (3 mL), 135 °C

O

Si(OEt)3

2.0 mmol

Me

3.0 equiv.

Si(OEt)3 94% (90 h) O

O

Me

Ru0

Me

Si(OEt)3 Reductive elimination

Oxidative addition O

O

Me

Me RuII

RuII Insertion

H

Si(OEt)3 Si(OEt)3

Scheme 11.15  Ru‐catalyzed ortho‐alkylation of acetophenone with alkene via oxidative addition.

This ketone‐directing ruthenium‐catalyzed ortho‐aryl C─H alkylation reaction was further improved to perform at room temperature as reported by Kakiuchi, Murai, and coworkers in 2010, using a highly active ruthenium species generated by RuH2(CO)(PPh3)3 and trimethyl(vinyl)silane in benzene at 90  °C [16]. Applying this ruthenium complex (2 mol%), quantitative yield of either mono‐ or di‐ortho‐alkylation product is afforded at room temperature by treatment of aromatic ketone (1.0 mmol, 1 equiv.) with trimethyl(vinyl)silane (2.0 or 6.0 equiv.) in toluene (1 mL) for 48 or120 h (Scheme 11.16).

347

348

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group Me

Me

O Me +

1.0 mmol

SiMe3 2.0 equiv.

O

2 mol% Ru complex

Me

Toluene (0.5 mL), rt, 48 h OC H

SiMe3

PPh3 PPh3 Ru

99%

PPh3 SiMe3

O Me +

1.0 mmol

SiMe3

6.0 equiv.

2 mol% Ru complex Toluene (1 mL), rt, 120 h PPh3 OC PPh3 Ru H PPh3

O Me SiMe3 96%

Scheme 11.16  Ru‐catalyzed ortho‐alkylation of acetophenones with alkene via oxidative addition at room temperature.

11.2.2 Trifluoromethylation

Trifluoromethylation of aryl C─H bond without the assistance of a directing group usually affords mixtures of ortho‐, meta‐, and para‐trifluoromethylated products, as described in Chapter 10. However, with the assistance of a directing group, ortho‐trifluoromethylation as sole product is obtained. In 2010, Yu and coworkers reported trifluoromethylation of ortho‐aryl C─H bond using pyridine as directing group in palladium catalysis [17]. Electrophilic trifluoromethylating reagent 5‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate acts as both the oxidant and the trifluoromethyl source effectively. For example, treatment of 2‐phenylpyridine (0.2 mmol, 1 equiv.) with 5‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Cu(OAc)2 (1.0 equiv.), and CF3CO2H (10 equiv.) in DCE (1 mL) at 110 °C for 48 h affords the mono‐ortho‐trifluoromethylation product 2‐(2‐pyridyl)trifluoromethylbenzene in 86% yield. In the proposed mechanism, Pd(II) catalyst coordinates with pyridine and cleaves ortho‐aryl C─H bond of 2‐pyridylbenzene to form aryl‐Pd(II) complex. Oxidation of this aryl‐ Pd(II) complex by CF3+ reagent gives key aryl‐Pd(IV)–CF3. Reductive elimination of aryl and CF3 group affords the trifluoromethylation product and Pd(II) species to fulfill the catalytic cycle (Scheme 11.17). The substrate scope was expanded to benzamide derivatives in 2012 at the same group. N‐2,3,5,6‐Tetrafluoro‐4‐trifluoromethylphenyl amide serves as the

11.2 ­Formation of C─C Bond

10 mol% Pd(OAc)2

+

N

S BF4 CF3

0.2 mmol

N

1.0 equiv. Cu(OAc)2 10 equiv. CF3CO2H 1,2-DCE (1 mL), 110 °C, 48 h

1.5 equiv.

PdII

CF3 86%

N

N Reductive elimination

CF3

C H activation

N PdII

N PdIV

Oxidation

CF3 S BF4 CF3

Scheme 11.17  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of 2‐pyridylbenzene with CF3+ reagent.

effective directing group, and N‐methylformamide is applied as the critical ligand [18]. For example, treatment of benzamide derivative (0.1 mmol, 1 equiv.) with 5‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.0 equiv.), CF3CO2H (10 equiv.), and N‐methylformamide (15 equiv.) in DCE (3 mL) at 130 °C for 24 h affords the mono‐ortho‐trifluoromethylation product in 79% yield (Scheme 11.18). F O

F

CF3 +

N H

10 mol%Pd(OAc)2 2.0 equiv. Cu(OAc)2

F F

0.1 mmol

S BF4 CF3 1.5 equiv.

10 equiv. CF3CO2H 15 equiv. N-methylformamide 1,2-DCE (3 mL), 130 °C, 24 h

F O

F

N H F CF3 79%

CF3 F

Scheme 11.18  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of benzamide with CF3+ reagent.

349

350

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Trifluoromethylation of aniline derivatives at ortho‐aryl C─H bond was achieved by Shi and coworkers in 2013 [19]. For example, treatment of N‐acylaniline (0.1 mmol, 1 equiv.) with 5‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.2 equiv.), and PivOH (5.0 equiv.) in DCE (1 mL) at 110 °C for 24 h affords the mono‐ortho‐trifluoromethylation product in 69% yield (Scheme 11.19). H N

Me O

0.1 mmol

+

10 mol% Pd(OAc)2 2.2 equiv. Cu(OAc)2 S BF4 CF3 1.5 equiv.

H N

5.0 equiv. PivOH 1,2-DCE (1 mL), 110 °C, 24 h

Me

O CF3 69%

Scheme 11.19  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of aniline with CF3+ reagent.

Benzyl amine derivatives were also available for ortho‐trifluoromethylation as reported by Yu and coworkers in 2013 [20]. Treatment of ortho‐methylbenzylamine (0.1 mmol) with 5‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate (1.5 + 1.5 equiv.) in palladium catalysis followed by protection with Boc group affords N‐protected ortho‐trifluoromethylation product in 79% yield, for example (Scheme 11.20). (1)10 mol% Pd(OAc)2,15 mol% Ag2O 2.0 equiv. Cu(OAc)2, 5.0 equiv. CF3CO2H H2O (0.1 mL), 1,2-DCE (1 mL), 130 °C, 6 h

Me NH2 +

S BF4 CF3

0.1mmol

1.5 + 1.5 equiv.

(2) 15 mol% Ag2O, 2.0 equiv. Cu(OAc)2 130 °C, 6 h (3) 3.0 equiv. Boc2O, H2O (1 mL), 1,4-dioxane (1 mL) 5.0 mmol NaOH, rt, 12 h

Me NHBoc CF3 79%

Scheme 11.20  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of benzylamine with CF3+ reagent.

In the previous examples, electrophilic trifluoromethylating reagent 5‐(tri­ fluoromethyl)dibenzothiophenium tetrafluoroborate is usually applied, which is expensive. A more economical nucleophilic trifluoromethylating reagent such as TMSCF3 was deployed in trifluoromethylation of benzamide derivatives as disclosed in 2014 by Dai, Yu, and coworkers using stoichiometric copper salts [21]. Benzamide derivative prepared from benzoic acid and 2‐(2‐oxazolyl)aniline serves as the effective directing group. For example, treatment of benzamide derivative (0.1 mmol) with TMSCF3 (5.0 equiv.) in the presence of Cu(OAc)2 (1.0 equiv.), Ag2CO3 (1.5 equiv.), NMO (N-methylmorpholine N-oxide, 2.0 equiv.), and KF (4.0 equiv.) in DMSO (1 mL) at 100 °C for 30 min affords the mono‐ortho‐trifluoromethylation product in 79% yield. It was proposed that Cu(II) coordinated and cleaved ortho‐aryl C─H bond of benzamide derivative

11.2 ­Formation of C─C Bond

to form aryl‐Cu(II) intermediate followed by disproportionation with Cu(OAc)2 to form aryl‐Cu(III)–OAc intermediate. Transmetalation of this aryl‐Cu(III)– OAc intermediate with TMSCF3 gives aryl‐Cu(III)–CF3 key intermediate. Reductive elimination of aryl and CF3 groups from Cu(III) center affords the target trifluoromethylation product (Scheme 11.21). O N H

+ N

O

0.1 mmol

TMSCF3

1.0 equiv. Cu(OAc)2 1.5 equiv. Ag2CO3

2.0 equiv. NMO, 4.0 equiv. KF 5.0 equiv. DMSO (1.0 mL), 100 °C, 30 min

O N H CF3 N

O

79%

Scheme 11.21  Cu‐mediated ortho‐trifluoromethylation of a benzamide with CF3− reagent.

11.2.3 Arylation

Direct arylation of aryl C─H bond with prefunctionalized arenes such as PhI(OAc)2, phenyl iodide, etc. is an alternative method to construct the basic aryl–aryl core, which is normally prepared by transition‐metal‐catalyzed cross‐coupling such as the Suzuki–Miyaura reaction using aryl halides and aryl boronic acid as substrates, a powerful tool for formation of aryl–aryl bonds in current organic synthesis. However, direct arylation of aryl C─H bonds without the assistance of a direct group usually affords mixtures of ortho‐, meta‐, and para‐regioisomers. On the other hand, with the assistance of a directing group, ortho‐ and even meta‐arylation as sole product is now accessible. In 2005, Sanford and coworkers reported direct arylation of aryl C─H bond using pyridine or amide as the effective directing group under palladium catalysis [22]. The key to the success of this reaction is using high‐valent iodine [Ph2I] [BF4] for phenylation or [Mes–I–Ar] [BF4] for arylation acting as both the oxidant and the aryl source. For example, treatment of 2‐(o‐tolyl)pyridine (1.18 mmol, 1 equiv.) with [Ph2I][BF4] (1.15 equiv.) in the presence of Pd(OAc)2 (5 mol%) in HOAc (10 mL) at 100 °C for 12 h affords the mono‐ortho‐phenylation product in 88% yield. In the proposed mechanism, Pd(II) catalyst coordinates and cleaves ortho‐aryl C─H bond of 2‐pyridylbenzene to form aryl‐Pd(II) complex. Oxidation of this aryl‐Pd(II) complex by reagent [Ph2I][BF4] gives aryl‐Pd(IV)–Ph key intermediate. Reductive elimination of aryl and Ph groups affords aryl–Ph bond and Pd(II) species to fulfill the catalytic cycle. Stoichiometric reaction of 2‐pyridylbenzene with Pd(OAc)2 to form aryl‐Pd(II) dimer followed by treatment of [Ph2I][BF4] to afford the desired ortho‐arylation product confirms the proposed mechanism (Scheme 11.22). Phenol ester is proved to be the effective directing group for ortho‐arylation in palladium catalysis with I+ reagent as disclosed by Fu, Liu, and coworkers in

351

352

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group Me +

N

[Ph2I]BF4

Me

5 mol% Pd(OAc)2

N

HOAc (10 mL), 100 °C, 12 h Ph

1.18 mmol 1 equiv.

1.15 equiv.

88%

PdII

N

N Reductive elimination

Ph

C H activation

N PdII

N PdIV Ph

Oxidation [Ph2I]BF4

Scheme 11.22  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of 2‐pyridylbenzene with [Ph2I][BF4].

2010 [23]. For example, treatment of m‐tolyl pivalate (0.25 mmol, 1 equiv.) with [Ph2I][OTf ] (1.2 equiv.) in the presence of Pd(OAc)2 (10 mol%), HOTf (10 mol%), and Ac2O (0.5 equiv.) in DCE (1 mL) at room temperature for 3 h affords the mono‐ortho‐phenylation product in 94% yield (Scheme  11.23). The reaction mechanism was proposed to involve Pd(II)/Pd(IV) catalytic cycle and was confirmed by stoichiometric reaction of phenol ester with Pd(OAc)2 to form aryl‐ Pd(II) complex determined by X‐ray characterization, followed by oxidation with [Ph2I][OTf ] to afford the desired product. Me

Me O O 0.25 mmol

Me

Me 10 mol%Pd(OAc)2 Me + [Ph2I]OTf 10 mol%HOTf,0.5equiv. Ac2O 1.2 equiv. 1,2-DCE (1 mL), 25 °C, 3 h

Me O

Me Me

O Ph 94%

Scheme 11.23  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of phenol derivative with [Ph2I][OTf ].

Direct arylation of aryl C─H bond of aniline derivatives at meta‐position with [Ph2I][OTf ] reagent in copper catalysis was reported by Gaunt and Phipps in 2009 [24]. For example, treatment of N‐(o‐tolyl)pivalamide (0.5 mmol,

11.2 ­Formation of C─C Bond

1 equiv.) with [Ph2I][OTf ] (2.0 equiv.) in the presence of Cu(OAc)2 (10 mol%) in DCE (2.5 mL) at 70 °C for 20 h affords the mono‐meta‐phenylation product in 79% yield (Scheme 11.24). Me

Me H Me N

Me

Me + [Ph2I]OTf 2.0 equiv.

O 0.5 mmol

10 mol% Cu(OAc)2

H Me N

Me Me

O

1,2-DCE (2.5 mL), 70 °C, 20 h Ph

79%

Scheme 11.24  Copper‐catalyzed meta‐arylation of aniline derivative with [Ph2I][OTf ].

This copper‐catalyzed meta‐arylation strategy was applied for phenylacetamide derivatives at the same group in 2011 [25]. For example, treatment of N‐methoxy‐N‐methyl‐2‐(o‐tolyl)acetamide (1.0 mmol, 1 equiv.) with [Ph2I][OTf ] (2.0 equiv.) in the presence of Cu(OTf )2 (5 mol%) in DCE (10 mL) at 70  °C for 48 h affords the mono‐meta‐phenylation product in 84% yield (Scheme 11.25). Me

Me

OMe N

O 1.0 mmol

Me

+ [Ph2I]OTf 2.0 equiv.

OMe N

5 mol% Cu(OTf)2

Me

O

1,2-DCE(10mL), 70 °C, 48 h Ph

84%

Scheme 11.25  Copper‐catalyzed meta‐arylation of phenylacetamides with [Ph2I][OTf ].

Direct arylation of aryl C─H bond with I+ reagent such as [Ph2I][BF4] or [Ph2I][OTf ] is effective, but the I+ reagent needs an additional step to prepare, and the direct arylation reaction disposes one aryl iodide for obtaining one arylation product. Thus, direct use of aryl iodide instead of I+ reagent as arylating partner offers a greener transformation. In 2005, Daugulis and Zaitsev observed ortho‐arylation of aryl C─H bond with I+ reagent [Ph2I][PF6] using amide as the effective directing group to afford di‐ortho‐arylation product in HOAc. Furthermore, aryl iodides were found as promising arylation reagents as well compared with I+ reagent [Ph2I][PF6] in the ortho‐arylation of aryl C─H bond of N‐phenylpivalamide derivatives, upon using stoichiometric silver salts to scavenge the iodides [26]. For example, treatment of N‐phenylpivalamide (1.0 mmol, 1 equiv.) with phenyl iodide (2.2 equiv.) in the presence of Pd(OAc)2 (1.5 mol%) and AgOAc (2.0 equiv.) in CF3CO2H (2 mL) at 120 °C for 3 h affords the di‐ortho‐phenylation product in 91% yield. The catalytic efficiency is up to 1000 TONs by further enlarging the ratio of substrate to catalyst and prolonging the reaction time (Scheme 11.26).

353

354

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group H Me N

Ph

Me Me

+

[Ph2I]PF6

O

Me

H Me N

HOAc Ph 79%

Me

Ph

Me +

Me

I

1.5 mol% Pd(OAc)2

Ph

2.0 equiv. AgOAc CF3CO2H (2 mL), 120 °C, 3 h

O 2.2 equiv.

1.0 mmol

H Me N

5 mol% Pd(OAc)2

H Me N

Me Me

O

Me Me

O

Ph 91% Me

H Me N

Me Me

+

I

Me

O 3.0 mmol

0.2 mol% Pd(OAc)2 NHPiv

2.0 equiv. AgOAc CF3CO2H (2 mL), 90 °C, 3 d

5.0 equiv. Me > 99% TON = 1000

Scheme 11.26  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of aniline derivatives with aryl iodides.

2‐Pyridylbenzene derivatives were also available in the arylations reported by Daugulis and Shabashov in 2005 [27]. For example, treatment of 2‐phenylpyridine (1.0 mmol, 1 equiv.) with 4‐tolyl iodide (5.0 equiv.) in the presence of Pd(OAc)2 (3 mol%) and AgOAc (2.1 equiv.) in HOAc (5 mL) at 130 °C for 165 h affords the di‐ortho‐arylation product in 80% yield (Scheme 11.27). Me

N 1.0 mmol

+

I

Me

3 mol% Pd(OAc)2 2.1 equiv. AgOAc HOAc (5 mL), 130 °C, 165 h

N

5.0 equiv. 80%

Me

Scheme 11.27  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of 2‐pyridylbenzene with aryl iodides.

Mono‐ortho‐arylation of aryl C─H bond with aryl iodide was available using benzamide derivatives as substrates as reported by Daugulis and Shabashov in 2006 [28]. For example, treatment of N‐isopropyl‐4‐methylbenzamide (0.7 mmol) with 1‐(4‐iodophenyl)ethan‐1‐one (2.3 equiv.) in the presence of Pd(OAc)2 (5 mol%) and AgOAc (1.8 equiv.) in mixtures of HOAc and CF3CO2H (0.5 mL; 4/1 = v/v)

11.2 ­Formation of C─C Bond

at 130  °C for 3.5 h affords the mono‐ortho‐arylation product in 53% yield. Further arylation of this mono‐ortho‐arylation product with 1‐iodo‐3,5‐ bis(trifluoromethyl)benzene under similar conditions using CF3CO2H as sole solvent adds another aryl group at the other ortho‐position, accomplishing the synthesis of 2,6‐di‐different‐aryl‐substituted product (Scheme 11.28). Me Me

O N H

Me

O

Me + I

0.7 mmol

Me 2.3 equiv.

5 mol% Pd(OAc)2 NHiPr 53% O

O CF3

N H

CF3

Me

0.5 mmol

O

5 mol% Pd(OAc)2

+ I

Me

O

Me

O

1.8 equiv. AgOAc HOAc/CF3CO2H (4/1, 0.5 mL) 130 °C, 3.5 h Me Me

Me

O

1.5 equiv. AgOAc CF3CO2H (0.35 mL) 130 °C, 3 h

NHiPr CF3

Me

2.3 equiv.

64% CF3

Scheme 11.28  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of benzamides with aryl iodides.

This palladium‐catalyzed ortho‐arylation of aryl C─H bond with aryl iodide was expanded to benzylamine derivatives as substrates in 2006 by Daugulis and Lazareva [29]. Treatment of 4‐bromobenzylamine (1.01 mmol, 1 equiv.) with phenyl iodide (10 equiv.) in the presence of Pd(OAc)2 (5 mol%) and AgOAc (2.4 equiv.) in CF3CO2H (0.37 mL) at 130 °C for 2.5 h, followed by addition of trifluoroacetic anhydride, affords the N‐protected di‐ortho‐phenylation product in 68% yield (Scheme 11.29).

NH2

+

(1) 5 mol% Pd(OAc)2 2.4 equiv. AgOAc CF3CO2H (0.37 mL) 130 °C, 2.5 h

I

1.01 mmol

NHCOCF3

(2)(CF3CO)2O (1 mL)

Br 10 equiv.

Br 68%

Scheme 11.29  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of benzylamines with aryl iodides.

355

356

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Eventually, carboxylic acid as effective directing group was found in the ortho‐arylation of benzoic acid with aryl iodide by Daugulis and coworkers in 2007 [30]. Either electron‐poor or electron‐rich aryl iodide is available in this reaction. For example, treatment of 3‐methylbenzoic acid (1.0 mmol) with 3,5‐ bis(trifluoromethyl)phenyl iodide (3.0  equiv.) in the presence of Pd(OAc)2 (5 mol%) and AgOAc (1.3 equiv.) in HOAc (200 μL) at 120 °C for 4.5 h affords the mono‐ortho‐arylation product in 59% yield. Treatment of 3,4‐dimethylbenzoic acid with 3,5‐dimethylphenyl iodide under similar conditions gives the mono‐ ortho‐arylation product in 54% yield. The previous examples of palladium‐catalyzed direct ortho‐arylation of aryl C─H bonds were probably involving a Pd(II)/ Pd(IV) catalysis. Pd(II) catalyst coordinates with the directing group and cleaves the ortho‐aryl C─H bond to form aryl‐Pd(II) complex. Oxidative addition of this aryl‐Pd(II) complex to aryl iodide gives aryl‐Pd(IV)‐aryl key intermediate. Reductive elimination of two aryl groups affords the corresponding biaryl and Pd(II) iodide followed by transmetalation with silver salts or inorganic bases to regenerate the Pd(II) catalyst, fulfilling the catalytic cycle (Scheme 11.30). Alternatively, such direct arylation is also accomplished through a Pd(0)/ Pd(II) catalysis [30]. Treatment of benzoic acid (0.5 mmol, 1 equiv.) with phenyl chloride (5.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), trialkylphosphine ligand n‐BuAd2P (10 mol%), and Cs2CO3 (2.2 equiv.) in DMF (2.5 mL) at 145 °C for 24 h affords the di‐ortho‐arylation product in 71% yield. Either electron‐ rich 4‐tolyl chloride or electron‐poor 4‐trifluoromethylphenyl chloride was available for 3‐fluorobenzoic acid to produce the corresponding di‐ortho‐ arylation product. Electron‐poor 4‐trifluoromethylbenzoic acid is also reacted with 4‐trifluoromethylphenyl chloride to give the di‐ortho‐arylation product. In the proposed mechanism, oxidative addition of Pd(0) species generated in situ from Pd(OAc)2 to aryl–chlorine bond forms aryl‐Pd(II)–Cl complex. Transmetalation of this aryl‐Pd(II)–Cl complex with PhCO2Cs generated from benzoic acid and Cs2CO3 in situ gives aryl‐Pd(II)–O2CPh, followed by ortho‐ palladation to generate aryl‐Pd(II)‐aryl key species. Reductive elimination of two aryl groups from Pd(II) center affords the target biaryl product and Pd(0) species to fulfill the catalytic cycle (Scheme 11.31). Benzonitrile derivatives were also found available in the ortho‐arylation as reported by Sun and coworkers in 2011 [31]. Treatment of benzonitrile (1.0 mmol, 1 equiv.) with either electron‐rich 3‐tolyl iodide (2.0 equiv.), electron‐ neutral phenyl iodide (2.0 equiv.), or electron‐poor 3‐nitrophenyl iodide (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) and Ag2O (1.0 equiv.) in CF3CO2H (2 mL) at 110  °C for 9 h affords the corresponding mono‐ortho‐arylation product. However, synthesis of important drug intermediate for angiotensin‐ II‐receptor blockers 4′‐methylbiphenyl-2‐nitrile was not reported in this direct ortho‐arylation (Scheme 11.32). In addition to direct ortho‐arylation of aryl C─H bonds assisted by directing groups to prepare biaryls exemplified previously, meta‐arylation of aryl C─H

11.2 ­Formation of C─C Bond

Me

+

OH

CF3 3.0 equiv.

CF3

1.3 equiv. AgOAc HOAc (200 µL) 120 °C, 4.5 h

59% Me

Me

O OH

Me

5 mol% Pd(OAc)2

+ I Me 3.0 equiv.

1.0 mmol

CO2H

5 mol% Pd(OAc)2

I

1.0 mmol

Me

Me

CF3

O

CF3 CO2H Me

Me

1.3 equiv. AgOAc HOAc (200 µL) 110 °C, 5 h

54%

Me

CO2H AgI

II

AcO Pd

C H activation

Ligand exchange

AgOAc

HOAc CO2H

I

PdII

PdII Reductive elimination

CO2H

Oxidative addition CO2H I

I

IV

Pd

Scheme 11.30  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of benzoic acid with aryl iodides.

bonds was also available in recent years. In 2014, Larrosa and coworkers reported meta‐arylation of phenol derivatives [32]. The key to the success of this meta‐arylation is using CO2 as a traceless directing group. In the stoichiometric reaction, treatment of 2‐hydroxybenzoic acid (1.0 equiv.) with 3,5‐ dimethylphenyl iodide (3.0 equiv.) in the presence of iridium catalyst (2 mol%), Ag2CO3 (0.5 equiv.), and K2CO3 (0.5 equiv.) in HOAc (1.0 M) at 150 °C for 16 h affords 3‐(3,5‐dimethylphenyl)phenol product in 92% yield with loss of CO2 through decarboxylation of the benzoic acid. Since carboxylation of phenol at ortho‐position with CO2 to give salicylic acid through SEAr process is well established, using CO2 as a traceless directing group through carboxylation of phenol before direct arylation and decarboxylation after the arylation gives meta‐arylation product of phenol. For example, treatment of phenol (3.0 equiv.)

357

358

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

5 mol% Pd(OAc)2 10 mol% nBuAd2P

O +

OH

Cl

0.5 mmol

CO2H

2.2 equiv. Cs2CO3 3A MS, DMF (2.5 mL) 145 °C, 24 h

5.0 equiv.

71% CF3

CF3

Me

F

F

CO2H

CO2H

CO2H F3C

68%

91%

Me

HO2C

CF3

0

Cl

Pd Reductive elimination PdII

Oxidative addition

CO2H

PdII

C H activation

Ligand exchange

PdII

CF3

75%

Cl PhCO2

Cl O

O

Scheme 11.31  Pd(0)/Pd(II)‐catalyzed ortho‐arylation of benzoic acids with aryl chlorides.

C

1.0 mmol

R

N +

I 2.0 equiv.

CN 10 mol% Pd(OAc)2 1.0 equiv. Ag2O CF3CO2H (2 mL) 110 °C, 9 h

R

R: Me, H, or NO2 Yield: 51, 70, or 93%

Scheme 11.32  Pd(II)/Pd(IV)‐catalyzed ortho‐arylation of benzonitrile with aryl iodides.

11.2 ­Formation of C─C Bond

with either electron‐rich 4‐iodoansole (0.167 mmol) or electron‐poor 4‐nitrophenyl iodide (0.167 mmol) in the presence of KOH (3.0 equiv.) in toluene first, then carboxylation with CO2, and then followed by direct arylation under iridium catalysis affords the corresponding mono‐meta‐arylation product (Scheme 11.33). OH Me

OH O OH + 1.0 equiv.

I Me 3.0 equiv

2 mol% PEPPSI-IPr 0.5 equiv. Ag2CO3

Me

0.5 equiv. K2CO3 HOAc (1.0 M), 150 °C, 16 h Ar N

92% Cl

PdII

Cl

Me

Cl

Ar = 2,6-diisopropylphenyl Ar PEPPSI-IPr complex N

OH

I OH

0.167 mmol or

+ I 3.0 equiv.

OMe

NO2 0.167 mmol

(1) Phenol, KOH (3.0 equiv.) PhMe (1.0 mL), 50 °C, 10 min (2) CO2 (25 atm), 190 °C, 2 h (3) PEPPSI-IPr (2 mol%) Ag2CO3 (0.5 equiv.) HOAc (400 μL), 150 °C, 16 h

63% or

OMe

OH

54%

NO2

Scheme 11.33  Pd(II)/Pd(IV)‐catalyzed meta‐arylation of phenol with aryl iodides via carboxylation and decarboxylation.

Meta‐arylation of aryl C─H bonds was also achieved using norbornene as a transient mediator combined with a finely screened pyridine‐derived ligand as reported by Yu and coworkers in 2015 [3]. For example, treatment of phenyl­ acetic acid‐derived N‐2,3,5,6‐tetrafluoro‐4‐trifluoromethylphenyl amide substrate (0.1 mmol) with either methyl 2‐iodobenzoate (3.0 equiv.) or 3,5‐bis(trifluoromethyl)phenyl iodide (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), pyridine‐derived ligand (20 mol%), norbornene (1.5 equiv.), and AgOAc (3.0 equiv.) in t‐BuOMe (1 mL) at 95 °C for 12 h affords the corresponding arylation product in moderate yield, respectively (Scheme  11.34). The reaction mechanism is similar to the meta‐alkylation of phenylacetic acid‐derived N‐2,3,5,6‐tetrafluoro‐4‐trifluoromethylphenyl amide described previously.

359

360

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group Me O 10 mol% Pd(OAc)2 MeO2C

Me MeO2C

I

Me O

F F

HN F

+

CF3

CF3 F

F

F

CF3 F

O N 20 mol% ligand

3.0 equiv. or

F

HN

64% or

3.0 equiv. AgOAc (1 mL), 95 °C, 12 h

Me

tBuOMe

O

I

F F

HN

0.1mmol

CF3 1.5 equiv. norbornene

6.0 equiv.

F F C 3

CF3 F

CF3

76%, AgOPiv used instead of AgOAc

Scheme 11.34  Pd(II)/Pd(IV)‐catalyzed meta‐arylation of a benzamide with aryl iodides enabled by norbornene and ligand.

This meta‐arylation of aryl C─H bonds was further optimized applying a modified norbornene as transient mediator by Yu and coworkers in 2015 [4]. Treatment of 2‐methylphenylacetic acid‐derived N‐2,3,5,6‐tetrafluoro‐4‐ trifluoromethylphenyl amide substrate (0.1 mmol, 1 equiv.) with electron‐rich 4‐iodotoluene (3.0 equiv.), electron‐neutral phenyl iodide (3.0 equiv.), or electron‐poor 4‐trifluoromethylphenyl iodide (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), pyridine‐derived ligand (20 mol%), modified norbornene (3.0 equiv.), and AgOAc (3.0 equiv.) in benzotrifluoride as solvent (1.5 mL) at 90 °C for 24 h affords the corresponding meta‐arylation product in high yield, respectively (Scheme 11.35). 10 mol% Pd(OAc)2 Me

Me

tBu

Me O

F

HN F F 0.1 mmol

O N O 20 mol% ligand

F + I

R

CF3

Me

3.0 equiv. AgOAc PhCF3 (1.5 mL), 90 °C, 24 h

3.0 equiv. MeO2C 3.0 equiv. modified norbornene

F F

HN F

CF3 F

R R: Me, H, or CF3 Yield: 87, 73, or 84%

Scheme 11.35  Pd(II)/Pd(IV)‐catalyzed meta‐arylation of a benzamide with aryl iodides enabled by modified norbornene and ligand.

11.2 ­Formation of C─C Bond

Meta‐arylation of aryl C─H bonds using norbornene as a transient mediator was also reported by Dong and coworkers in 2015, while applying benzylamines as substrates in combination of AsPh3 as effective ligand and mixtures of various acetates [33]. For example, treatment of dimethyl benzylamine (0.1 mmol) with methyl 2‐iodobenzoate (4.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), AsPh3 ligand (20  mol%), norbornene (2.0  equiv.), and AgOAc (4.5 equiv.) as well as CsOAc (3.0 equiv.), LiOAc·2H2O (1.0 equiv.), Cu(OAc)2·H2O (0.5 equiv.), and HOAc (15 equiv.) in PhCl (1.5 mL) at 100 °C for 36 h affords the di‐meta‐arylation product in 70% yield. Applying either electron‐rich 3,N,N-tri‐ methylbenzylamine or electron‐poor 3,N,N-dimethyl-trifluoromethylbenzylamine with methyl 2‐iodobenzoate in similar conditions with less AgOAc (2.5 equiv.) gives the corresponding mono‐meta‐arylation product, respectively (Scheme 11.36). CO2Me MeO2C NMe2 0.1 mmol

+

10 mol Pd(OAc)2, 20 mol% AsPh3 2.0 equiv. norbornene, 4.5 equiv. AgOAc

I 4.0 equiv.

NMe2

3.0 equiv. CsOAc,1.0 equiv. LiOAc•2H2O 0.5 equiv. Cu(OAc)2•H2O, 15 equiv. HOAc PhCl (1.5 mL), 100 °C, 36 h

CO2Me

70%

R

NMe2 +

0.1 mmol

MeO2C

10 mol Pd(OAc)2, 20 mol% AsPh3 2.0 equiv. norbornene, 2.5 equiv. AgOAc

R

NMe2

CO2Me 3.0 equiv. CsOAc,1.0 equiv. LiOAc•2H2O 0.5 equiv. Cu(OAc)2•H2O, 15 equiv. HOAc PhCl (1.5 mL), 100 °C, 24 h 2.0 equiv. R: Me or CF3 I

Yield: 73 or 55% (130 °C)

Scheme 11.36  Pd‐catalyzed meta‐arylation of benzylamines with aryl iodides enabled by norbornene and ligand.

Aryl bromides were also available in the arylation of aryl C─H bonds. In 1999, Miura and coworkers reported palladium‐catalyzed multiple arylation of aromatic ketones [34]. Treatment of α‐phenyl‐substituted acetophenone (1.0 mmol, 1 equiv.) with 3‐trifluoromethylphenyl bromide (4.0 equiv.) in the presence of Pd(PPh3)4 (0.5 mol%) and Cs2CO3 (3.0–5.0 equiv.) in o‐xylene (5 mL) at 160 °C for 44 h affords the tri‐arylation product (mono‐α‐position of carbonyl group and di‐ortho‐position of arene) in 68% yield. When α,α‐ diphenyl‐substituted acetophenone is the substrate, arylation occurs solely at ortho‐aryl C─H bonds, giving di‐ortho‐arylation product in 43% yield. In the proposed mechanism, oxidative addition of Pd(0) catalyst to aryl bromide forms aryl‐Pd(II)–Br complex. Transmetalation of this aryl‐Pd(II)–Br complex with enolate generated from ketone and inorganic base Cs 2CO 3 gives

361

362

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

aryl‐Pd(II)–enolate intermediate. Metalation of ortho‐aryl C─H bond by this aryl‐Pd(II)–enolate intermediate gives key aryl‐Pd(II)–aryl intermediate. Reductive elimination of two aryl groups affords biaryl product and Pd(0) species to fulfill the catalytic cycle (Scheme 11.37). CF3 O

CF3 +

Br

Ph 1.0 mmol

O

0.5 mol% Pd(PPh3)4 3.0–5.0 equiv. Cs2CO3 o-xylene (5 mL), 160 °C, 44 h

4.0 equiv.

CF3 Ph CF3 68%

O Ph

+

Ph 1.0 mmol

O

0.5 mol% Pd(PPh3)4 Br

3.0–5.0 equiv. Cs2CO3 o-xylene (5 mL), 160 °C, 44 h

4.0 equiv.

Ph Ph

43% Ph O

Reductive elimination Ph O

Br

Pd0

Ph

Oxidative addition PdII

Ph

PdII

Br OCs

C H activation

PdII

O

Ph

Ligand exchange

Ph

Ph Br

Ph

Scheme 11.37  Pd‐catalyzed ortho‐arylation of acetophenones with aryl bromides.

Nitrobenzene was used as substrate in palladium‐catalyzed ortho‐arylation of aryl C─H bonds with aryl bromides as reported by Fagnou and coworkers in 2008 [35]. Treatment of nitrobenzene (10 equiv.) with either electron‐rich 3‐bromoanisole (1 equiv.), electron‐neutral phenyl bromide (1 equiv.), or electron‐poor

11.2 ­Formation of C─C Bond

4‐trifluoromethylphenyl bromide (1 equiv.) in the presence of Pd(OAc)2 (5  mol%), trialkylphosphine ligand t‐Bu2PMe·HBF4 (15  mol%), PivOH (0.3 equiv.), and K2CO3 (1.3 equiv.) in mesitylene at 125 °C for 16 h affords the corresponding mono‐ortho‐arylation product, respectively. This is a rare example of functionalization of nitrobenzene through palladium‐catalyzed C─H activation due to the inertness of electron‐deficient arenes (Scheme 11.38). NO2

R +

Br

5 mol% Pd(OAc)2 0.3 equiv. PivOH 1.3 equiv. K2CO3

1 equiv.

10 equiv.

NO2

15 mol% tBu2PMe·HBF4

mesitylene (1.3 M) 125 °C, 16 h

R R: 3-OMe, H, or 4-CF3 Yield: 77, 62, or 60%

Scheme 11.38  Pd‐catalyzed ortho‐arylation of nitrobenzene with aryl bromides.

This ortho‐arylation of aryl C─H bonds was applied for efficient preparation of key intermediate in the synthesis of angiotensin‐II‐receptor blockers reported by Ackermann in 2015 [36]. Treatment of 1‐(2‐methoxybenzyl)‐5‐ phenyl‐1H‐tetrazole which is easily deprotected with 4‐bromobenzyl acetate in the presence of ruthenium catalyst, MesCO2H as additive, and K2CO3 in toluene at 120 °C for 18 h affords the desired mono‐ortho‐arylation product in up to 75% yield, and the yield is 66% when the loading of ruthenium catalyst is ­lowered to 1 mol% (Scheme 11.39). OMe

OMe

Cat. [RuCl2(p-cymene)]2 N N N

N

+

OAc Br

N N

Cat. MesCO2H

N

K2CO3, toluene

N

120 °C, 18 h OAc 75%, 5 mol% [Ru] 72%, 2.5 mol% [Ru] 66%, 1 mol% [Ru]

Scheme 11.39  Pd‐catalyzed ortho‐arylation of arene with aryl bromide.

The ortho‐arylation of aryl C─H bonds is applied for aryl chlorides as substrates as well. In 2005, Ackermann reported ortho‐arylation of aryl C─H bonds with aryl chlorides using pyridine or imine as directing group in ruthenium catalysis [37]. For example, treatment of 2‐phenylpyridine (1.0 mmol, 1 equiv.) with either electron‐rich 4‐chloroanisole (2.2 equiv.), electron‐neutral phenyl chloride (2.2 equiv.), or electron‐poor 4‐bromobenzonitrile (2.2 equiv.) in the presence of Ru catalyst (2.5 mol%), phosphine ligand (10 mol%), and

363

364

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

K2CO3 (3.0 equiv.) in NMP (2 mL) at 120 °C for 24 h affords the corresponding di‐ortho‐arylation product in high yield, respectively. N‐Arylimines are also arylated with either electron‐rich 4‐chloroanisole or electron‐poor 4‐chloroacetophenone under similar conditions for arylation of 2‐phenylpyridine, followed by hydrolysis in HCl aq. and Et2O to give the corresponding mono‐ ortho‐arylated aromatic ketone (Scheme 11.40). R

2.5 mol% [RuCl2(p-cymene)]2 10 mol% (1-Ad)2PHO

R

+ Cl

N

2.2 equiv.

1.0 mmol

N

3.0 equiv. K2CO3 NMP (2 mL), 120 °C, 24 h R R: OMe, H, or CN Yield: 87, 95, or 81% (8 h) O Me

Cl

MeO N

1.0 mmol

2.2 equiv. or

+ Me

OMe

Cl

O

Me 1.2–2.2 equiv.

(1) 2.5 mol% [RuCl2(p-cymene)]2 10 mol% (1-Ad)2PHO 2.0–3.0 equiv. K2CO3 NMP (2 mL), 120 °C, 16–24 h (2) HCl (aq, 1 M, 100 mL) Et2O (100 mL), rt, 3 h

74% or

OMe

O Me O 79%

Me

Scheme 11.40  Ru‐catalyzed ortho‐arylation of 2‐pyridylbenzene or N‐arylimine with aryl chlorides.

Arylboronic acids are also effective coupling partners in the ortho‐arylation of aryl C─H bonds. In 2003, Kakiuchi and coworkers [38] reported ortho‐ arylation of aromatic ketones with aryl boronates in ruthenium catalysis. For example, treatment of α,α,α‐trimethylacetophenone (2.0 equiv.) with either electron‐rich 4‐N,N‐dimethylaminophenyl boronate (1.0 mmol, 1 equiv.) or electron‐ poor 4‐trifluoromethylphenyl boronate (1.0 mmol, 1 equiv.) in the presence of Ru catalyst (2 mol%) in toluene (1 mL) under reflux for 1 h affords the corresponding mono‐ortho‐arylation product in high yield. In the proposed mechanism, coordination of Ru(0) catalyst with ketone group followed by oxidative addition of Ru(0) species to ortho aryl C─H bond of acetophenone forms arylRu(II)–H intermediate. Oxidation of this transition‐metal–hydride species by

11.2 ­Formation of C─C Bond

another molecule of acetophenone gives aryl-Ru(II)-OCH(CH3)Ph intermediate. Transmetalation of this aryl‐Ru(II)–OCH(CH3)Ph intermediate with aryl boronate affords aryl‐Ru(II)‐aryl key intermediate. Reductive elimination of two aryl groups from Ru(II) center affords the ortho‐arylation product and Ru(0) species to fulfill the catalytic cycle. The ketone group of acetophenone serves as oxidant in this oxidative coupling of aryl C─H bonds with aryl boronates (Scheme 11.41). O Me O B O 1.0 mmol or O B O 1.0 mmol

Me Me

O Me Me

Me

+ Me Me

2.0 equiv.

Me

Me

NMe2

NMe2

86% or O

2 mol% RuH2(CO)(PPh3)3 Toluene (1 mL), reflux, 1 h

Me

CF3 Me

Me

86%

CF3

Me O

Me Ru0 Reductive elimination

Me

O Oxidative addition Me

O

Me

O

Me

O

Me Me Me Me

O

B

O

O RuII

O

Me H

Oxidation

Ligand exchange

B O

O RuII

RuII

O

Me

Scheme 11.41  Ru‐catalyzed ortho‐arylation of acetophenones with arylboronic acids.

Aniline derivatives were also available in the ortho‐arylation of aryl C─H bonds with aryl boronic acids using silver and copper salts as oxidant as reported by Shi and coworkers in 2007 [39]. For example, treatment of 1‐(3,4‐dihydroquinolin‐1(2H)‐yl)ethan‐1‐one (0.2 mmol, 1 equiv.) or 1‐(indolin‐1‐yl)ethan‐1‐ one (0.2 mmol, 1 equiv.) with phenylboronic acid (2.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), Ag2O (1.0 equiv.), and Cu(OTf )2 (1.0 equiv.) in toluene

365

366

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

(4 mL) at 120 °C for 24 h affords the corresponding ortho‐arylation product in high yield, respectively (Scheme 11.42).

N Ac N Ac 0.2 mmol or N Ac 0.2 mmol

+

(HO)2B 2.0 equiv.

5 mol% Pd(OAc)2 1.0 equiv. Ag2O 1.0 equiv. Cu(OTf)2 Toluene (4 mL), 120 °C, 24 h

85% or

N Ac

84%

Scheme 11.42  Pd‐catalyzed ortho‐arylation of aniline derivatives with arylboronic acids.

Phenylacetic acids were available in the ortho‐arylation of aryl C─H bonds with aryl boronates as reported by Yu and coworkers in 2011 [40]. Protected amino acid accelerates the reaction dramatically. When Ag2CO3 serves as oxidant, either electron‐rich or electron‐poor phenylacetic acid and either electron‐rich, electron‐neutral, or electron‐poor phenyl boronates are available for coupling partners. For example, treatment of either 2‐methylphenylacetic acid (0.5 mmol, 1 equiv.) or 2‐trifluoromethylphenylacetic acid (0.5 mmol, 1 equiv.) with electron‐neutral phenyl–BF3K (3.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), protected amino acid Ac‐lle‐OH (10 mol%), BQ (5 mol%), Ag2CO3 (2.0 equiv.), and KHCO3 (2.0 equiv.) in t‐AmylOH (2.5 mL) at 110 °C for 2 h affords the corresponding ortho‐arylation product in quantitative yield, respectively, while without the addition of protected amino acid, the yield is much lower. Either electron‐rich 4‐tolyl–BF3K or electron‐poor 4‐trifluoromethylphenyl–F3K couples with 2‐methylphenylacetic acid under similar conditions to give quantitative yield of the corresponding ortho‐arylation product as well, and the yields are also much lowered in the absence of protected amino acids. Moreover, O2 serves as effective terminal oxidant. Direct ortho‐arylation of 2‐methylphenylacetic acid with phenyl–BF3K using atmospheric O2 instead of Ag2CO3 gives 65% yield of ortho‐arylation product, and 96% yield is obtained when 5 atm of O2 is used (Scheme 11.43). In addition to ortho‐arylation, meta‐arylation of aryl C─H bonds assisted by directing groups in palladium catalysis was reported by Yu and coworkers in 2013 [41]. Either phenylpropanoic acids or phenols derived with a nitrile‐ containing U‐shaped template serve as the effective meta‐directing group.

11.2 ­Formation of C─C Bond Me CO2H

Me CO2H 0.5 mmol or CF3

+

KF3B

CO2H

> 99% No aminoacid, 17% or CF3

5 mol% Pd(OAc)2 10 mol% Ac-lle-OH, 5mol% BQ

3.0 equiv.

2.0 equiv. Ag2CO3, 2.0 equiv. KHCO3 tAmylOH

(2.5 mL), 110 °C, 2h

CO2H

0.5 mmol > 99% No aminoacid, 44% Me CO2H

KF3B

Me

Me

3.0 equiv. or

CO2H + KF B 0.5 mmol

5 mol% Pd(OAc)2 10 mol% Ac-lle-OH, 20mol% BQ CF3

3

2.0 equiv. Ag2CO3, 2.0 equiv. KHCO3 tAmylOH

Me > 99% No aminoacid, 19% or Me

(2.5 mL), 110 °C, 2h

CO2H

3.0 equiv. CF3 > 99% No aminoacid, 46%

CF3 CO2H + 0.5 mmol

KF3B 3.0 equiv.

5 mol% Pd(OAc)2 10 mol% Ac-lle-OH, 5mol% BQ

CF3 CO2H

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH

(2.5 mL), 110 °C, 2 h 65% (96% with 5 atm of O2) No aminoacid, 12%

Scheme 11.43  Pd‐catalyzed ortho‐arylation of phenylacetic acids with arylboronic acids.

For example, treatment of either phenylpropanoic acid derivative (0.1 mmol, 1 equiv.) or phenol derivative (0.1 mmol, 1 equiv.) with aryl pinacol boronic esters (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), protected amino acid Ac‐Gly‐OH (20 mol%), Ag2CO3 (2.0 equiv.), CsF (2.0 equiv.), and TBAPF6 (tetrabutylammonium hexafluorophosphate, 3.0 equiv.) in HFIP (1 mL) at 70  °C for 24 h affords the corresponding meta‐arylation product, respectively. For 2‐methylphenylpropanoic acid derivatives, either e­lectron‐rich

367

368

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

4‑tolyl boronate or electron‐poor 4‐trifluoromethylphenyl ­boronate is available to give the corresponding meta‐arylation product (Scheme 11.44). OMe Me

OMe Me

O N

O

NC

CN

N NC

CN OMe 10 mol% Pd(OAc)2

0.1 mmol or

OMe

+ MeO2C

Bpin

O O

3.0 equiv.

N

NC

CN

20 mol% Ac-Gly-OH 2.0 equiv. Ag2CO3 2.0 equiv. CsF 3 equiv. TBAPF6 HFIP (1 mL), 70 °C, 24 h

CO2Me 85% or O O

N

NC

CN

0.1 mmol

CO2Me

64% OMe

OMe Me

Me

O N

0.1 mmol

N

10 mol% Pd(OAc)2

NC

CN

OMe

+

R

Bpin

3.0 equiv.

NC

20 mol% Ac-Gly-OH 2.0 equiv. Ag2CO3 2.0 equiv. CsF 3 equiv. TBAPF6 HFIP (1 mL), 70 °C, 24 h

O

CN

OMe R

R: Me or CF3 Yield: 72 or 60%

Scheme 11.44  Pd‐catalyzed meta‐arylation of phenylpropanoic acid derivatives or phenol derivatives with arylboronic acids.

More difficult substrate indoline derivatives due to steric effects were available in the meta‐arylation with aryl boronates as reported by Yu and coworkers in 2014 while using finely modified nitrile‐containing U‐shaped template with a key sulfonamide structure linking indoline with template [42]. For example, moderate yields of meta‐arylation products of indoline derivatives are obtained by treatment of indoline derivatives containing U‐shaped template (0.1 mmol, 1 equiv.) with either electron‐neutral phenyl boronate (4.0 equiv.) or electron‐ poor 3‐trifluoromethylphenyl boronate (4.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), protected amino acid Ac‐Gly‐OH (20 mol%), Ag2CO3 (2.5 equiv.), CsF (2.5 equiv.), and TBAPF6 (3.0 equiv.) in HFIP (1 mL) at 100  °C for 36 h (Scheme 11.45).

11.2 ­Formation of C─C Bond Me

Me R

N H S O + O

N tBu

Bpin

tBu

MeO 0.1 mmol

4.0 equiv.

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH

2.5 equiv. Ag2CO3 2.5 equiv. CsF 3.0 equiv. TBAPF6 HFIP (1 mL), 100 °C, 36 h

R CN tBu

N H S O O

tBu

MeO R : H or CF3 Yield: 51 or 60%

Scheme 11.45  Pd‐catalyzed meta‐arylation of an indoline derivative with arylboronic acids.

11.2.4 Alkenylation

Catalytic cross‐coupling of aryl C─H bonds with alkenyl C─H as bonds disclosed by Fujiwara and Moritani half a century ago is an ideal method to form aryl– alkenyl bonds. In the assistance of directing groups, an example was reported by Miura and coworkers in 1998 [43]. Sulfonamide of 2‐aminobiphenyl derivative and carboxylic acid of benzoic acid serve as the effective directing groups, and atmospheric air acts as the promising terminal oxidant. For example, treatment of N‐(4‐chlorobenzenesulfonamido)‐2‐aminobiphenyl (1.0 mmol, 1 equiv.) with ethyl acrylate (3.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), Cu(OAc)2·H2O (5 mol%) as cocatalyst, NaOAc (10 mol%), and air (1 atm) as terminal oxidant in DMF (5 mL) at 100 °C for 9 h affords the ortho‐alkenylated and cyclization product in 92% yield with TON of 18. Benzoic acid is also available, coupling with n‐butyl acrylate under similar conditions to ortho‐alkenylation and cyclization lactone products. In the proposed mechanism, Pd(II) catalyst coordinates with carboxylic acid of benzoic acid and cleaves ortho‐aryl C─H bond to form aryl‐Pd(II) intermediate, which is inserted by alkene to give arylCH2CH2Pd(II) species. β‐Elimination followed by reduction of hydride releases ortho‐alkenylated product, proton, and Pd(0) species. Intramolecular cyclization of carboxylic acid and alkene affords lactone product. Oxidation of Pd(0) species in the presence of Cu(OAc)2 and O2 of air regenerates Pd(II) catalyst to fulfill the catalytic cycle (Scheme 11.46). N‐Acylanilines were available in the ortho‐alkenylation with alkene performed at room temperature as reported by de Vries, van Leeuwen and coworkers in 2002 [44]. For example, treatment of either N‐acyl‐4‐methylaniline (3.0 mmol, 1 equiv.), N‐acylaniline (3.0 mmol, 1 equiv.), or N‐acyl‐4‐trifluoromethylaniline (3.0 mmol, 1 equiv.) with n‐butyl acrylate (1.0 equiv.) in the presence of Pd(OAc)2 (2 mol%), BQ (1.0 equiv.) as oxidant and TsOH (0.5 equiv.) in mixtures of HOAc (4.5 mL) and toluene (2.25 mL) at 20 °C overnight affords the corresponding ortho‐alkenylation product, respectively, with electron‐poor

369

370

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Cl HN

+

CO2Et

S

O O 1.0 mmol

3.0 equiv.

O OH +

1.0 mmol

CO2nBu

3.0 equiv.

5 mol% Pd(OAc)2 5 mol% Cu(OAc)2•H2O 10 mol% NaOAc Air (1 atm) 4A MS (400 mg) DMF (5 mL), 100 °C, 9 h

Cl N O

EtO2C

S

O

92%

O

5 mol% Pd(OAc)2 5 mol% Cu(OAc)2•H2O

O

10 mol% NaOAc N2-air (500 mL, 5/1) 4A MS (400 mg) DMF (5 mL), 120 °C, 7 h

CO2nBu 50%

PdII Cu(OAc)2 O2

OH C H activation

Oxidation

O H+ PdII

Pd(0)

OH Reductive β-H elimination nBu

H+

CO2

H nBu

CO2

O O

O

OH

HO

O

H

O

Insertion PdII H

CO2nBu

CO2nBu

Scheme 11.46  Pd‐catalyzed ortho‐alkenylation of 2‐aminobiphenyl derivative or benzoic acid with alkenes.

aniline derivative giving lower yield. In either case, intramolecular cyclization to form lactam does not occur (Scheme 11.47). H N R

O 3.0 mmol

2 mol% Pd(OAc)2 Me

+

CO2nBu 1.0 equiv.

NHAc

1.0 equiv. BQ, 0.5 equiv. TsOH HOAc (4.5 mL), toluene (2.25 mL) 20 °C, overnight

CO2nBu

R

R: Me, H, or CF3 Yield: 85, 72 or 29%

Scheme 11.47  Pd‐catalyzed ortho‐alkenylation of aniline derivatives with alkenes.

Benzylamines were available for ortho‐alkenylation with alkene as reported by Shi and coworkers in 2007 [45]. Reaction of either N,N‐dimethyl‐4‐methylbenzylamine (0.5 mmol, 1 equiv.), N,N‐dimethylbenzylamine (0.5 mmol, 1 equiv.), or N,N‐dimethyl‐4‐trifluoromethylbenzylamine (0.5 mmol, 1 equiv.) with n‐butyl

11.2 ­Formation of C─C Bond

acrylate (2.0  equiv.) in the presence of Pd(OAc)2 (5  mol%), Cu(OAc)2 (1.0 equiv.) as oxidant, and air in mixtures of CF3CH2OH and HOAc (2.5 mL; 4/1 = v/v) at 85 °C for 48 h affords the corresponding ortho‐alkenylation product in high yield, respectively. Intramolecular cyclization does not occur, and electron‐ poor benzylamine also gives good yield as well as electron‐rich benzylamine (Scheme 11.48). NMe2 R 0.5 mmol

+

CO2nBu 2.0 equiv.

5 mol% PdCl2 1.0 equiv. Cu(OAc)2 CF3CH2OH/HOAc (4/1, 2.5 mL) Air, 85 °C, 48 h

NMe2 R

CO2nBu

R: Me, H, or CF3 Yield: 70, 86, or 74%

Scheme 11.48  Pd‐catalyzed ortho‐alkenylation of benzylamine derivatives with alkenes.

In 2010, Yu and co-workers reported ligand enabled ortho-vinylation of aryl C─H bonds using carboxylic acid of phenylacetic acid or phenylpropanoic acid as directing group [46]. Using protected amino acid as ligand is critical to the  success of this reaction. Atmospheric O2 serves as the efficient terminal oxidant. Electron-deficient phenylacetic acid derivatives are also available for this ortho-alkenylation. Treatment of 2-trifluoromethylphenylacetic acid (0.2 mmol) with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), protected amino acid Boc-Val-OH (10 mol%), BQ (5 mol%), KHCO3 (2.0 equiv.), and O2 (1 atm) as terminal oxidant in tAmylOH (2 mL) at 85 °C for 48 hours affords the corresponding ortho-alkenylation product in 90% yield. Only 12% yield of product is obtained without the addition of Boc-Val-OH. Besides, intramolecular cyclization of carboxylic acid and alkene does not occur. Reaction of 2-nitrophenylacetic acid with ethyl acrylate under similar conditions gives ortho-alkenylation decarboxylation product in moderate yield. No reaction occurs in the absence of protected amino acid. Ortho-alkenylation of phenylpropanoic acid is also available, giving ortho-alkenylation product in the assistance of protected amino acid. When two different ortho-aryl C─H bonds are available for alkenylation, >20/1 regioselectivity is achieved by using the finely screened protected amino acid. Also by applying appropriate protected amino acid, di-ortho-alkenylated product is prepared in quantitative yield (Scheme 11.49). This ortho‐alkenylation of aryl C─H bond of phenylacetic acid was further developed and reported in 2010 by the same group [47]. Unsymmetrical multi‐ ortho‐alkenylation product, for example, a four‐substituted aromatic carboxylic acid, is prepared by stepwise aryl C─H alkenylation with different alkene strategy. Reaction of phenylacetic acid (10 mmol, 1 equiv.) with t‐butyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), BQ (5 mol%), KHCO3 (2.0 equiv.), and O2 (1 atm) as terminal oxidant in t‐AmylOH (25 mL) at 90 °C for 48 h affords the corresponding ortho‐alkenylation product in 75% yield with the scale of 2 g. Treatment of this ortho‐alkenylated phenylacetic acid (7.5 mmol)

371

372

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group 5 mol% Pd(OAc)2 10 mol% Boc-Val-OH, 5 mol% BQ

CF3 CO2H +

CO2Et

O2(1 atm), 2.0 equiv. KHCO3 tAmylOH (2 mL), 85 °C, 48 h

2.0 equiv.

CO2H CO2Et 90% No Boc-Val-OH, 12%

0.2 mmol 10 mol% Pd(OAc)2 20 mol% Boc-Val-OH, 10 mol% BQ

NO2 CO2H +

CF3

CO2Et

NO2 Me

O2(1 atm), 2.0 equiv. KHCO3 tAmylOH (2 mL), 85 °C, 48 h

2.0 equiv.

CO2Et 50% No Boc-Val-OH, 0%

0.2 mmol Me CO2H +

CO2Et 2.0 equiv.

5 mol% Pd(OAc)2 10 mol% Boc-Val-OH, 5 mol% BQ

Me CO2H

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH (2 mL), 85 °C, 48 h

CO2Et 60% No Boc-Val-OH, 8%

0.2 mmol

Me

*

CO2H +

OMe 0.2 mmol

CO2H + MeO 0.2 mmol

7 mol% Pd(OAc)2 Me 14 mol% Formyl-lle-OH, 7 mol% BQ CO2Et O2 (1 atm), 2.0 equiv. KHCO3 2.0 equiv. tAmylOH (2 mL), 85 °C, 48 h

* CO2H

CO2Et OMe 75% (20/1) No Formyl-lle-OH, 68% (1.4/1)

CO2Et 2.0 equiv.

CO2Et

2 mol% Pd(OAc)2 4 mol% Boc-lle-OH, 2 mol% BQ O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH (2 mL), 85 °C, 48 h

CO2H MeO

CO2Et >99% di No Boc-lle-OH, 10% mono

Scheme 11.49  Pd‐catalyzed ortho‐alkenylation of phenylacetic acids with alkenes.

with benzyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), protected amino acid Ac‐Val‐OH (10 mol%), KHCO3 (2.0 equiv.), and O2 (1 atm) as terminal oxidant in t‐AmylOH (25 mL) at 90 °C for 6 h affords the corresponding ortho‐alkenylation product in 95% yield with the scale of 3 g. Esterification of carboxylic acid with methyl iodide followed by hydrogenation with atmospheric H2 under Pd/C (5 mol%, 10 wt%) affords the benzoic acid derivative with a new ortho‐aryl C─H bond available in the vicinity of carboxylic acid. Alkenylation of this benzoic acid derivative affords the final four‐substituted aromatic carboxylic acid (Scheme 11.50). The substrate scope of this ortho‐alkenylation of aryl C─H bond with alkenes was further expanded to mandelic acid and α‐phenylglycine in 2015 by Yu and coworkers [48]. Reaction of (R)‐(pivaloyloxy)phenylacetic acid (0.1 mmol, 1 equiv.) with t‐butyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2

11.2 ­Formation of C─C Bond

CO2H

tBu

+

CO2

10 mmol

2.0 equiv.

CO2tBu +

CO2Bn

CO2H

2.0 equiv.

5 mol% Pd(OAc)2 5 mol% BQ

CO2H

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH

CO2tBu 75%, 1.97 g

(25 mL), 90°C, 48 h

5 mol% Pd(OAc)2 10 mol% Ac-Val-OH

CO2tBu

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH

CO2H

(25 mL), 90 °C, 6 h

7.5 mmol

CO2Bn 95%, 3.01 g

CO2tBu

2.0 equiv. MeI 2.0 equiv. K2CO3

CO2tBu

Acetone (50 mL) 55 °C, 12 h CO2Bn 93%

H2 (1 atm) 5 mol% Pd/C (10 wt%)

CO2tBu

MeOH (40 mL) 6h 91% CO2Bn

CO2Me

CO2H

CO2Me CO2H CO2tBu

tBu

CO2

+ CO2Me CO2H 0.2 mmol

CO2Bn 2.0 equiv.

10 mol% Pd(OAc)2 10 mol% Boc-Val-OH

CO2Me

O2 (1 atm), 2.0 equiv. KHCO3

CO2H

t

AmylOH (1mL), 90 °C, 12 h CO2Bn

35%

Scheme 11.50  Pd‐catalyzed ortho‐alkenylation of phenylacetic acids with alkenes.

(5 mol%), protected amino acid Ac‐Tle‐OH (N-Acyl-tert-Leucine, 5 mol%), KHCO3 (2.0 equiv.), and air (1 atm) as terminal oxidant in t‐AmylOH (0.5 mL) at 80 °C for 3 h affords the corresponding mono‐ortho‐alkenylation product in 72% yield with 98% ee value. Di‐ortho‐alkenylated product is obtained in 85% yield by applying atmospheric O2 as oxidant instead of air and prolonging the reaction time to 6 h. Treatment of α‐phenylglycine under similar conditions gives mono‐ortho‐alkenylation product in 88% yield with 99% ee value (Scheme 11.51). In addition to amine derivatives and carboxylic acids, some other functional groups normally regarded as owning weak coordinating ability with transition metals were found available in recent years for ortho‐alkenylation of aryl C─H bonds with alkenes. In 2010, Yu and coworkers reported ortho‐alkenylation of phenylethanol derivatives with alkene in palladium catalysis promoted by finely tuned protected amino acids [49]. For example, treatment of 2‐methyl‐1‐(o‐tolyl)propan‐2‐ol (0.2  mmol, 1  equiv.) with ethyl acrylate (1.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), protected amino acid

373

374

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group OPiv CO2H +

CO2tBu

5 mol% Pd(OAc)2 5 mol% Ac-Tle-OH

OPiv CO2H +

0.1 mmol

CO2tBu

CO2H + 0.1 mmol

tBu

CO2

CO2tBu 72%, 98% ee

5 mol% Pd(OAc)2 5 mol% Ac-Leu-OH

CO2tBu OPiv

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH (0.5 mL), 90 °C, 6 h

2.0 equiv.

NHBoc

CO2H

Air (1 atm), 2.0 equiv. KHCO3 tAmylOH (0.5 mL), 80 °C, 3 h

2.0 equiv.

0.1 mmol

OPiv

CO2H CO2tBu 85%

5 mol% Pd(OAc)2 15 mol% Ac-Leu-OH

NHBoc CO2H

O2 (1 atm), 2.0 equiv. KHCO3 tAmylOH (0.5 mL), 80 °C, 3 h

2.0 equiv.

CO2tBu 88%, 99% ee

Scheme 11.51  Pd‐catalyzed ortho‐alkenylation of protected mandelic acid or α‐phenylglycine with alkenes.

(+)‐menthyl(O2C)‐Leu‐OH (20 mol%), Li2CO3 (1.0 equiv.), and AgOAc (4.0 equiv.) as oxidant in p ­ erfluorobenzene (1.5 mL) at 80 °C for 48 h affords the corresponding ortho‐alkenylation and cyclization product in 88% yield (Scheme 11.52). Me

Me Me OH

0.2 mmol

+

CO2Et 1.0 equiv.

10 mol% Pd(OAc)2 20 mol% (+)-menthyl(O2C)-Leu-OH 4.0 equiv. AgOAc, 1.0 equiv. Li2CO3 C6F6 (1.5 mL), 80 °C, 48 h

Me

Me Me O CO2Et 88%

Scheme 11.52  Pd‐catalyzed ortho‐alkenylation of phenylethanol derivatives with alkenes.

Benzoic esters were available for ortho‐alkenylation of aryl C─H bonds with alkenes in rhodium catalysis, as reported by Chang and coworkers in 2011 [50]. For example, treatment of ethyl 2‐methylbenzoate (0.2 mmol, 1 equiv.) with ethyl acrylate (2.0 equiv.) in the presence of [Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), and Cu(OAc)2 (0.2 equiv.) in DCE (0.7 mL) at 110 °C for 12 h affords the corresponding ortho‐alkenylation product in 80% yield (Scheme 11.53). Ruthenium was also found as effective catalyst for ortho‐alkenylation of benzoic esters with alkene as disclosed by Jeganmohan and coworkers [51] and Ackermann and coworkers [52] independently in 2012. In the work of Jeganmohan and coworkers reaction of methyl benzoate (1.0 mmol, 1 equiv.)

11.2 ­Formation of C─C Bond Me

Me

OEt +

O 0.2 mmol

CO2Et 2.0 equiv.

OEt

2.5 mol% [Cp*RhCl2]2 10 mol% AgSbF6 0.2 equiv. Cu(OAc)2 1,2-DCE (0.7 mL), 110 °C, 12 h

O 80%

CO2Et

Scheme 11.53  Rh‐catalyzed ortho‐alkenylation of benzoic ester with alkenes.

with ethyl acrylate (3.0 equiv.) in the p ­ resence of [RuCl2(p‐cymene)]2 (3 mol%), AgSbF6 (20 mol%), and Cu(OAc)2 (0.3 equiv.) in DCE (4 mL) at 100 °C for 12 h affords the corresponding ortho‐alkenylation product in 75% yield [51] (Scheme  11.54). In the example of Ackermann and coworkers, treatment of methyl 4‐methoxybenzoate (0.5 mmol, 1 equiv.) with ethyl acrylate (2.0 equiv.) in the presence of [RuCl2(p‐cymene)2]2 (5 mol%), AgSbF6 (40 mol%), and Cu(OAc)2 (2.0 equiv.) in DCE (2 mL) at 100 °C for 16 h affords the corresponding ortho‐alkenylation product in 62% yield [52] (Scheme 11.55). OMe

OMe CO2Et

O 1.0 mmol

3.0 equiv.

3 mol% [RuCl2(p-cymene)]2 20 mol% AgSbF6 0.3 equiv. Cu(OAc)2 1,2-DCE (4 mL), 100 °C, 12 h

O 75%

CO2Et

Scheme 11.54  Ru‐catalyzed ortho‐alkenylation of benzoic ester with alkenes. OMe

OMe O + MeO 0.5 mmol

CO2Et 2.0 equiv.

5 mol% [RuCl2(p-cymene)]2 40 mol% AgSbF6 MeO 2.0 equiv. Cu(OAc)2 1,2-DCE (2 mL), 100 °C, 16 h

O CO2Et 62%

Scheme 11.55  Ru‐catalyzed ortho‐alkenylation of benzoic ester with alkenes.

In 2012, alkene was applied as directing group for cross‐coupling of ortho‐ aryl C─H bond with alkene as disclosed by Cheng and Gandeepan using atmospheric O2 as terminal oxidant at room temperature [53]. Reaction of (E)‐ prop‐1‐ene‐1,3‐diyldibenzene (0.5  mmol, 1  equiv.) with n‐butyl acrylate (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), CF3CO2H (8.0 equiv.), and O2 (1 atm) as oxidant in CH2Cl2 (3 mL) at 25 °C for 36 h affords the corresponding ortho‐alkenylation product in 81% yield (Scheme 11.56). Ortho‐alkenylation of phenylethanol ether with alkene was reported by Yu and coworkers in 2013 [54], enabled by protected amino acid. For example, reaction of 1‐(2‐methoxypropyl)‐2‐methylbenzene (0.2  mmol) with ethyl acrylate (1.25 equiv.) in the presence of Pd(OAc)2 (10 mol%), protected amino acid Ac‐Gly‐OH (20 mol%), and Ag2CO3 (4.0 equiv.) as oxidant in hexafluoroisopropyl alcohol (2 mL) at 90 °C for 24 h affords the corresponding ortho‐ alkenylation product in 76% yield (Scheme 11.57).

375

376

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group CO2nBu + 0.5 mmol

CO2nBu 3.0 equiv.

10 mol% Pd(OAc)2 8.0 equiv. CF3CO2H O2 (1 atm) CH2Cl2 (3 mL), 25 °C, 36 h

81%

Scheme 11.56  Ru‐catalyzed ortho‐alkenylation of aryl C─H bond using alkene as directing group.

Stereoselective alkenylation of ortho‐aryl C─H bonds with alkene to synthesize enantiomer‐excess product was achieved by asymmetric alkenylation of Me Me Me

CO2Et

OMe 0.2 mmol

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 4.0 equiv. Ag2CO3 HFIP (2 mL), 90 °C, 24 h

1.25 equiv.

Me OMe 76%

CO2Et

Scheme 11.57  Pd‐catalyzed ortho‐alkenylation of phenylethanol ether with alkenes.

diphenylacetic acid derivatives as reported by Yu and coworkers in 2010 [55]. For example, the reaction of sodium 2,2‐diphenylpropanoate (0.5 mmol, 1 equiv.) with styrene in the presence of Pd(OAc)2 (5 mol%), protected amino acid Boc‐Ile‐OH (10 mol%) which is chiral and serves as ligand, BQ (5 mol%), and KHCO3 (0.5 equiv.) in t‐AmylOH (3 mL) at 90  °C for 48 h affords the c­ orresponding ortho‐alkenylation product in 73% yield with 97% ee value (Scheme 11.58).

CO2Na Me 0.5 mmol

+

5 mol% Pd(OAc)2 0.1 equiv. Boc-Ile-OH•0.5 H2O

CO2Na

5 mol% BQ, 0.5 equiv. KHCO3 tAmylOH(3mL), 90 °C, 48 h

Me 73%, 97% ee

Scheme 11.58  Stereoselective Pd‐catalyzed ortho‐alkenylation of diphenylacetic acid derivative with alkenes.

In addition to the ortho‐alkenylation of aryl C─H bonds with alkenes exemplified previously, alkenylation of meta‐aryl C─H bonds was also established in recent years. In 2012, Yu and coworkers reported meta‐alkenylation of aryl C─H bonds of phenylpropanoic acid derivatives and benzyl alcohol derivatives in palladium catalysis enabled by applying a nitrile‐containing template as

11.2 ­Formation of C─C Bond

meta‐directing group [56]. For benzyl alcohol derivatives, either electron‐rich, electron‐neutral, or electron‐deficient substrates are available for meta‐­ alkenylation. Treatment of O‐nitrile‐containing template-substituted benzyl alcohols (0.1 mmol, 1 equiv.) with ethyl acrylate (1.5 equiv.) in the presence of Pd(OPiv)2 (10 mol%), AgOPiv (3.0 equiv.) as oxidant in DCE (1 mL) at 90 °C for 42 h affords the corresponding mono‐meta‐alkenylation product, respectively, with at least >10/1 regioselectivity of meta‐position versus other positions. For phenylpropanoic acid derivatives, treatment of either electron‐neutral or electron‐poor substrate condensation with nitrile‐containing template under similar conditions with additional protected amino acid affords mono‐ meta‐alkenylation product, respectively. The regioselectivity of meta‐position versus other positions is also at least >10/1. Using this nitrile‐containing template-promoted meta‐alkenylation of aryl C─H bonds with alkene, some novel structures, which are not accessible normally, are prepared in one step by treating easily prepared substrate such as 2,6‐dimethyl phenylpropanoic amide or 2‐biphenylcarboxamide for examples with alkenes under optimal conditions (Scheme 11.59). tBu Me

Me

N

O N

iBu iBu

CO2Et

iBu iBu

Mono: 86%, m/others = 94/6 or

0.1 mmol or

tBu

tBu tBu

tBu

+

O

tBu

CO2Et 1.5 equiv.

iBu N iBu 0.1 mmol or

F3C

O

tBu

tBu

tBu

tBu

O

10 mol% Pd(OPiv)2 3.0 equiv. AgOPiv 1,2-DCE (1 mL), 90 °C, 42 h

CO2Et Mono: 55%, m/others = 93/7 Di: 31%, (m,m′)/others = 88/12 or tBu

O N 0.1 mmol

iBu iBu

iBu iBu

N

F3C

tBu

O N

iBu iBu

CO2Et Mono: 54%, m/others = 98/2 2.0 equiv. olefin, 100 °C, 48 h

Scheme 11.59  Pd‐catalyzed meta‐alkenylation of phenylpropanoic acid derivatives or benzyl alcohol derivatives with alkenes.

377

378

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group O N

O

NC

CN

N NC

CN

0.1 mmol or O F C 3

CO2Et Mono: 37%, m/others = 95/5 Di: 42%, (m,m′)/others = 88/12 10 mol% Pd(OAc)2 CO2Et or 20 mol% Ac-Gly-OH O 2.0 equiv. 3.0 equiv. AgOPiv F3C N HFIP (0.6 mL), 90 °C, 24 h NC CN

+

N NC

CN

0.1 mmol

CO2Et Mono: 82%, m/others = 95/5 Me

Me

O

O NC Me

N NC Me

CN

0.1 mmol + or

CN

CO2Et 2.0 equiv.

10 mol% Pd(OAc)2

20 mol% Ac-Gly-OH 3.0 equiv. AgOPiv HFIP (0.6 mL), 90 °C, 24 h

N CN

CO2Et Mono: 49%, m/others = 91/9 Di: 22%, (m,m′)/others = 88/12 or CN

N O NC 0.1 mmol

O NC CO2Et Mono: 45%, m/others = 95/5 Di: 48%, (m,m′)/others = 95/5

Scheme 11.59  (Continued)

This meta‐alkenylation of aryl C─H bonds with alkenes enabled by a nitrile‐containing template was further applied for phenol derivatives as reported by Yu and coworkers in 2013 [57]. For example, treatment of O‐ nitrile‐containing template-substituted 3‐methylphenol (0.1  mmol) with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH as ligand (20 mol%), and AgOAc (3.0 equiv.) as oxidant in HFIP (1 mL) at 90 °C for 24 h affords the corresponding mono‐meta‐alkenylation product, with >15/1 regioselectivity of meta‐position versus other positions. Electron‐ deficient phenol derivative gives similar meta‐regioselectivity with lowered yield. Thus, switch of ortho‐ or meta‐regioselectivity for alkenylation of phenol derivatives is achieved without or with the addition of nitrile‐containing template in the presence of protected amino acid. Without the nitrile‐containing

11.2 ­Formation of C─C Bond O Me

O

or

CO2Et Mono: 91%, m/others = 94/6 10 mol% Pd(OAc)2 or CO2Et O 20 mol% Ac-Gly-OH 2.0 equiv. O 3.0 equiv. AgOAc F3C N HFIP (1 mL), 90 °C, 24 h NC CN

+ O

O

N

NC

CN CO2Et Mono: 52%, m/others = 96/4

0.1 mmol

CO2H

+

0.1 mmol

O NC

CO2Et

O

5 mol% Pd(OAc)2

10 mol% Boc-Val-OH 2.0 equiv. 2.0 equiv. KHCO3, O2 (1 atm) tAmylOH (1 mL), 90 °C, 24 h

O N

0.1 mmol

CN

CN

0.1 mmol

O

N

NC

N

NC

F3C

O

Me

O

CN

+

CO2Et 2.0 equiv.

CO2Et Mono: 91% o/others = 100/0

O

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 3.0 equiv. AgOAc HFIP (1 mL), 90 °C, 24 h

CO2H

NC

O N CN

CO2Et Mono: 60%, m/others = 95/5 Di: 31%, (m,m′)/others = 96/4

Scheme 11.60  Pd‐catalyzed ortho‐ or meta‐alkenylation of phenol derivatives with alkenes.

template, phenol derivative is alkenylated exclusively at ortho‐position with alkene in 91% yield. However, >95/5 regioselectivity of meta‐position versus other positions is obtained by adding the nitrile‐containing template on phenol (Scheme 11.60). Such meta‐alkenylation of aryl C─H bonds with alkenes was applied for benzyl alcohol derivatives using silicon‐ether‐linked nitrile‐containing template as reported by Tan and coworkers in 2013 [58]. For example, treatment of O‐silicon‐ether‐linked nitrile‐containing template-substituted benzyl alcohol (0.1 mmol, 1 equiv.) with ethyl acrylate (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH as ligand (20 mol%), AgOAc (3.0 equiv.) as oxidant, and HFIP (5.0 equiv.) in DCE (1 mL) at 90 °C for 24 h followed by hydrolysis in TBAF‐THF solution affords the corresponding mono‐meta‐alkenylation phenol as a major product with 95/5 meta‐regioselectivity (Scheme 11.61).

379

380

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group (1) 10 mol% Pd(OAc)2 iPr

N

O

iPr

Si

sBu

0.1 mmol

+ sBu

CO2Et 1.5 equiv.

20 mol% Ac-Gly-OH 3.0 equiv. AgOAc, 5.0 equiv. HFIP 1,2-DCE (1mL), 90 °C, 24 h (2) 1.0 MT BAF (0.2 mL) THF (3 mL), rt, 1 h

OH

CO2Et Mono: 51%, m/others = 95/5 Di: 28%, (m,m′)/others = 92/8

Scheme 11.61  Pd‐catalyzed meta‐alkenylation of benzyl alcohol derivatives with alkenes.

More ortho‐ and para‐oriented aniline derivatives were developed for meta‐ alkenylation by applying this nitrile‐containing template modification strategy reported by Yu and coworkers in 2014 [59]. Using tetrahydroquinoline derivatives for screening the optimal conditions, a dramatic influence of incorporation with monofluorine atom on nitrile‐containing template is found critical for achieving the high meta‐regioselectivity for aryl C─H alkenylation with alkene. Besides, protected amino acid Ac‐Gly‐OH is also crucial for high meta‐ regioselectivity. Thus, treatment of tetrahydroquinoline derivative (0.1 mmol, 1 equiv.) added on monofluorine‐incorporated nitrile‐containing template with ethyl acrylate (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐ OH as critical ligand (20 mol%), and AgOAc (3.0 equiv.) as oxidant in HFIP (1 mL) at 90 °C for 24 h followed by hydrolysis in HCl‐EtOH solution affords the corresponding mono‐meta‐alkenylation tetrahydroquinoline in 85% yield with meta‐regioselectivity of 92/8. For aniline derivatives, either electron‐donating methyl group-or electron‐withdrawing trifluoromethyl group-attached substrate is available to give the mono‐meta‐alkenylation product with up to >99/1 regioselectivity (Scheme 11.62). Challenge for meta‐alkenylation of indoline derivatives with more steric difficulty as well as high ortho‐ and para‐orientation was overcome by Yu and coworkers in 2014 [42]. The previously successful monofluorine‐incorporated nitrile‐containing template is not appropriate for indoline derivatives, giving meta‐alkenylation as minor product. However, by finely tuning the nitrile‐ containing template with two bulky tert‐butyl groups as well as applying sulfonamide as linking bridge, >20/1 meta‐regioselectivity is achieved with 78% yield to afford the mono‐meta‐alkenylation product. Protected amino acid is also crucial to the success of this meta‐alkenylation. Control experiment with N‐phenyl sulfonamido indoline clearly exhibits the effectiveness for this sterically hindered sulfonamide‐bridging nitrile‐containing template. With optimal conditions on hand, either electron‐rich or electron‐poor templatesubstituted indoline derivatives (0.1 mmol, 1 equiv.) are available for mono‐meta‐ alkenylation­with alkene (2.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH as critical ligand (20 mol%), and AgOAc (3.0 equiv.) as oxidant in HFIP (1 mL) at 55 °C for 24 h with >20/1 regioselectivity (Scheme 11.63).

11.2 ­Formation of C─C Bond

N Me

N N H

O

Me

O

EtO2C

0.1 mmol or

N

H

N O

H

+

CO2Et

1.5 equiv.

O

(1) 10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 3.0 equiv. AgOAc HFIP (1mL), 90 °C, 24 h (2) 36 wt% HCl/EtOH (1/5,v/v) 90 °C, 2–4 h

F

N H EtO 2C 45%, m/o = 84/16 No Ac-Gly-OH, 26%, m/o = 11/89 or

0.1 mmol or

N

92%, m/o = 9/91 No Ac-Gly-OH, 7%, m/o = 0/100 or

N N H

O

H O

EtO2C 85%, m/o = 92/8 No Ac-Gly-OH, 74%, m/o = 20/80

0.1 mmol

Me

Me

N

H

N

Me N EtO2C

O

F

H O

83%, m/others = 99/1

0.1 mmol or

+

CO2Et

1.5 equiv.

CF3

H

Me O

F

O

N

N

N

O

0.1 mmol

or

20 mol% Ac-Gly-OH 3.0 equiv. AgOAc HFIP (1mL), 90 °C, 24 h

CF3

Me N O

F

10 mol% Pd(OAc)2

EtO2C

H

N

Me O

F O

80%, m/others = 94/6

Scheme 11.62  Pd‐catalyzed meta‐alkenylation of aniline derivatives with alkenes.

381

N

F

N

H

O

EtO2C

H

O

N S O + O

Me Me MeO

N O O

20%, m/(o + p) = 1/1.6 No Ac-Gly-OH, trace or

0.1 mmol or

N

F

N

CO2Et 2.5 equiv.

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH

EtO2C

N O S O

NC

3.0 equiv. AgOAc HFIP (1 mL), 55 °C, 24 h

Me Me MeO 81%, m/(o + p) = 13/4.2 No Ac-Gly-OH, 29%, m/(o + p) = 3.5/11 or

0.1 mmol or p N m o tBu

N S O O

EtO2C

N S O O

NC tBu

tBu

tBu

MeO

MeO 78%, m/(o + p) = ≥20/1 No Ac-Gly-OH, 32%, m/o = 1/1.5

0.1 mmol

N O S O

+

CO2Et 2.5 equiv.

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH

N S O O

EtO2C

3.0 equiv. AgOAc HFIP (1 mL), 55 °C, 24 h

21%, m/others = 1/4.2 No Ac-Gly-OH, 11%, m/o = 1/6.5

0.1 mmol Me

Me

p N m o tBu

N O S O

EtO2C

tBu

tBu

+

tBu

MeO 0.1 mmol

CO2Et 2.5 equiv.

p

tBu

N O S O

tBu

MeO 0.1 mmol or Cl

N m o

NC

N S O O

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 3.0 equiv. AgOAc HFIP (1 mL), 55 °C, 24 h

MeO

70%, m/others = ≥20/1 or Cl

EtO2C

N NC

S

tBu

O O

tBu

MeO 67%, m/others = ≥20/1

Scheme 11.63  Pd‐catalyzed meta‐alkenylation of indoline derivatives with alkenes.

11.2 ­Formation of C─C Bond

Meta‐alkenylation of acetic acid derivatives was reported by Maiti and coworkers in 2014, also by applying a nitrile‐containing template [60]. Treatment of phenylacetic acid derivative (0.2 mmol, 1 equiv.) added on nitrile‐containing template with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH (20 mol%), and Ag2CO3 (2.0 equiv.) in HFIP (1 mL) at 90 °C for 24 h affords hexafluoroisopropyl mono‐meta‐alkenylated phenylacetate in 73% yield with meta‐regioselectivity of 11/1 (Scheme 11.64). CO2Et

N +

O

CO2Et 2.0 equiv.

O 0.2 mmol

CF3

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 2.0 equiv. Ag2CO3 HFIP (1 mL), 90 °C, 24 h

O

CF3

O 73%, m/others = 11/1

Scheme 11.64  Pd‐catalyzed meta‐alkenylation of phenylacetic acid derivatives with alkenes.

Benzyl sulfonic acid derivatives were available for meta‐alkenylation with alkene as reported in 2015 by Maiti and coworkers using a nitrile‐containing template [61]. Selective mono‐ or di‐meta‐alkenylation is achieved by controlling the amount of alkene, Pd(II) catalyst with protected amino acid, and silver(I) oxidant. Reaction of benzyl sulfonic acid derivative (0.1 mmol, 1 equiv.) added on nitrile‐containing template with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (2 mol%), Ac‐Gly‐OH (4 mol%), and Ag2CO3 (2.5 equiv.) in HFIP (0.7 mL) at 80 °C for 24 h affords mono‐meta‐alkenylated product in 68% yield with meta‐regioselectivity of >20/1. Treatment of the same substrate with ethyl acrylate (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐ OH (20 mol%), and Ag2CO3 (3.0 equiv.) under otherwise similar conditions gives di‐meta‐alkenylated product in 86% yield with meta‐regioselectivity of >20/1. Using this meta‐alkenylation method, the illustrated meta‐di‐different‐ alkenylation butenone product is obtained in 87% yield with >20/1 meta‐regioselectivity by reaction of meta‐alkenyl benzyl sulfonic acid derivative with alkene under optimal c­ onditions (Scheme 11.65). Meta‐alkenylation of phenylacetic acid derivatives was also achieved by Yu and Deng [62] in 2015 by transforming phenylacetic acid into nitrile‐ containing phenylacetamide derivative. Treatment of either electron‐rich, electron‐neutral, or electron‐poor nitrile‐containing phenylacetamide derivative (0.1 mmol, 1 equiv.) with ethyl acrylate (5.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), formyl‐Gly‐OH (20 mol%), KH2PO4 (0.5 equiv.), and AgOAc (3.0 equiv.) as oxidant in HFIP (1 mL) at 90  °C for 24 h affords the ­corresponding mono‐meta‐alkenylation product as sole or major product with >10/1 regioselectivity (Scheme 11.66).

383

CO2Et

N

NC +

O S O O

CO2Et 2.0 equiv.

2 mol% Pd(OAc)2 4 mol% Ac-Gly-OH 2.5 equiv. Ag2CO3 HFIP (0.7 mL), 80 °C, 24 h

0.1 mmol

O O S O 68%, m/others = ≥20/1 CO2Et

N

NC +

O S O

O

CO 2Et 3.0 equiv.

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 3.0 equiv. Ag2CO3 HFIP (0.7 mL), 80 °C, 24 h

0.1 mmol COMe

O O S O EtO2C

86%, m/others = ≥20/1 COMe

N

NC +

O O S O

CO2Et 3.0 equiv.

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH 3.0 equiv. Ag2CO3 HFIP (0.7 mL), 80 °C, 24 h

0.1 mmol

O S O O EtO2C

87%, m/others = ≥20/1

Scheme 11.65  Pd‐catalyzed meta‐alkenylation of benzyl sulfonic acid derivatives with alkenes.

NC Me

N

NC Me

O NC

N O N 0.1 mmol or

CO2Et 73%, m/others = 92/8 or

NC

+

N

CO2Et 5.0 equiv.

O N 0.1 mmol or

NC

10 mol% Pd(OAc)2 20 mol% formyl-Gly-OH

N O NC

3.0 equiv. AgOAc 0.5 equiv. KH2PO4 HFIP (1 mL), 90 °C, 24 h

CO2Et Mono: 53%, m/others = 93/7 Di: 22%, (m,m′)/others = 93/7 or

NC F3C

N O N 0.1 mmol

NC F3C

N O NC

CO2Et 52%, m/others = 95/5

Scheme 11.66  Pd‐catalyzed meta‐alkenylation of phenylacetic acid derivatives with alkenes.

11.2 ­Formation of C─C Bond

The substrate scope of this meta‐alkenylation of aryl C─H bonds with alkene was expanded to phenylethylamine derivatives by Li and coworkers in 2015 [63]. Treatment of either electron‐rich, electron‐neutral, or electron‐poor nitrile‐containing phenylethylamine derivative (0.2 mmol, 1 equiv.) with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH (20 mol%), and AgOAc (3.0 equiv.) as oxidant in mixtures of DCE (1 mL) and HFIP (1 mL) at 80 °C affords the corresponding mono‐meta‐alkenylated phenyl­ ethylamine derivative as sole product (Scheme 11.67). Me Me Me Me

O

N

N

O

NC

NC

0.2 mmol or Me O

N

+

NC

0.2 mmol or Me F3C

N NC

0.2 mmol

O

CO2Et

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH

CO2Et DMF (5.0 equiv.) added, 32 h 76% or Me O N NC

3.0 equiv. AgOAc 2.0 equiv DCE (1 mL), HFIP (1 mL), 80 °C CO2Et 32 h, mono: 45%, di: 37% or Me F3C O N NC

CO2Et DCE (0 mL), HFIP (2 mL) 90 °C, 48 h, 78%

Scheme 11.67  Pd‐catalyzed meta‐alkenylation of phenylethylamine derivatives with alkenes.

Benzyl acetate derivatives were also available for meta‐alkenylation as reported by Yu and coworkers [64] in 2015. Treatment of either electron‐rich, electron‐neutral, or electron‐poor nitrile‐containing benzyl acetate derivative (0.2 mmol) with ethyl acrylate (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Gly‐OH (20 mol%), and AgOAc (3.0 equiv.) as oxidant in HFIP (2 mL) at 80 °C for 18 h affords the corresponding mono‐meta‐alkenylated b ­ enzyl acetate derivative as sole or major product with regioselectivity of >20/1 (Scheme 11.68). In addition to meta‐alkenylation of aryl C─H bonds with alkenes, this strategy was also applied for para‐alkenylation of aryl C─H bonds with alkenes. In 2015, Maiti and coworkers reported para‐alkenylation of aryl C─H bonds with alkenes applying benzyl silicon‐ether derivatives as substrates [65]. Treatment

385

386

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group Me

Me

O

O

CO2Et 62%; m/others = ≥20/1 or Me

0.2 mmol or Me O F

O

+

N

O

10 mol% Pd(OAc)2 20 mol% Ac-Gly-OH

F

O

CO2Et 3.0 equiv. AgOAc 3.0 equiv. HFIP (2 mL), 80 °C, 18 h

N

CO2Et Mono: 46%, di: 28%; m/others = ≥20/1 or Me

0.2 mmol or Me

O

O

N

F

O

F

O F 3C

N

MeO

N

MeO

F

O

F

O

F3C

N CO2Et

0.2 mmol

70%; m/others = ≥20/1

Scheme 11.68  Pd‐catalyzed meta‐alkenylation of benzyl acetate derivatives with alkenes.

of either electron‐rich, electron‐neutral, or electron‐poor nitrile‐containing benzyl silicon ether derivative (0.2 mmol, 1 equiv.) with ethyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ac‐Phe‐OH (20 mol%), and AgOAc (3.0 equiv.) as oxidant in HFIP (2 mL) at 90 °C for 36 h affords the corresponding para‐alkenylated benzyl silicon ether derivatives as major product with regioselectivity of 7/1, 8/1, or 6/1, respectively (Scheme 11.69). On the other hand, formation of aryl–alkenyl bond is also accessible by addition of alkyne to arene with the assistance of directing groups in transition‐metal catalysis. In 1995, Murai and coworkers reported ruthenium‐catalyzed ortho‐­ alkenylation of aromatic ketones with alkynes [66]. For example, treatment of 3,4‐ dihydronaphthalen‐1(2H)‐one (2.0  mmol, 1  equiv.) with an internal alkyne (2.0 equiv.) in the presence of Ru(H)2(CO)(PPh3)3 (6 mol%) in toluene (3 mL) at 135 °C for 3 h affords the ortho‐alkenylation product in 83% yield. In the proposed mechanism, Ru(0) species coordinates with ketone group and cleaves ortho‐aryl C─H bond to form aryl-Ru(II)–H species. Oxidation of Ru(II)–H bond in this aryl-Ru(II)–H species by internal alkyne gives aryl‐Ru(II)‐alkenyl key intermediate.

11.2 ­Formation of C─C Bond

iPr

Si

iPr

iPr

iPr

Si

O

Me

NC

N

CO2Et 73%; p/others=7/1 or

0.2 mmol or Si

iPr

iPr

iPr

iPr

O

Me

Si

O +

CO2Et 2.0 equiv.

N

10 mol% Pd(OAc)2 20 mol% Ac-Phe-OH 3.0 equiv. AgOAc HFIP (2 mL), 90 °C, 36 h

O

NC CO2Et

0.2 mmol or iPr

Si

iPr

O

F3C

N

71%; p/others = 8/1 or iPr iPr Si O F3C

NC CO2Et

0.2 mmol

55%; p/others = 6/1

Scheme 11.69  Pd‐catalyzed para‐alkenylation of benzyl silicon ether derivatives with alkenes.

Reductive elimination of aryl and alkenyl group affords the ortho‐alkenylation product and Ru(0) species to fulfill the catalytic cycle (Scheme 11.70). Alternatively, ortho‐alkenylation of aryl C─H bonds assisted by a directing group with the addition of alkyne was achieved through insertion of alkyne to aryl–metal bond instead of metal–hydride bond described previously, as reported by Kitamura and coworkers in their synthesis of alkoxycoumarins [67]. For example, treatment of 3‐methoxyphenol (1.0 mmol, 1 equiv.) with an internal alkyne (2.0 equiv.) in the presence of Pd(OAc)2 (2.5 mol%) in CF3CO2H (1 mL) at room temperature for 20 h affords the ortho‐alkenylation and cyclization product 3‐methoxycoumarin derivative in 85% yield. In the proposed mechanism, Pd(II) catalyst coordinates and cleaves ortho‐aryl C─H bond to form

387

388

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

O

+

Me

2.0 mmol

6 mol% Ru(H)2(CO)(PPh3)3

TMS

O

Toluene (3 mL), 135 °C, 3 h

TMS Me 83%

2.0 equiv.

O

Ru0

O

TMS Me

Reductive elimination

Oxidative addition

O O

Me

RuII

RuII

H

Insertion

Me TMS

Me

TMS

Scheme 11.70  Ru‐catalyzed ortho‐addition of alkyne to aromatic ketones.

aryl‐Pd(II) intermediate, which is inserted by alkyne to give aryl‐Pd(II)‐alkenyl key intermediate. Protonation of this aryl‐Pd(II)‐alkenyl intermediate affords the ortho‐alkenylation product and Pd(II) species to fulfill the catalytic cycle. The sequence of transesterification of phenol with ethyl phenylpropiolate versus ortho‐aryl C─H palladation was not described in this report (Scheme 11.71). Applying this strategy, some important heteroarenes were synthesized through commercial or readily available substrates. Indole derivatives were synthesized by ortho‐alkenylation of aniline derivatives with internal alkynes using atmospheric O2 as oxidant as reported by Jiao and coworkers in 2009 [68]. For example, treatment of aniline (1.2 equiv.) with an internal alkyne (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (10 mol%) and O2 (1 atm) as oxidant in mixtures of DMA and PivOH (1.25 mL; 4/1 = v/v) at 120 °C for 12 h affords the ortho‐alkenylation and cyclization product indole derivative in 85% yield (Scheme 11.72). Isoquinoline derivatives were synthesized by ortho‐alkenylation of aryl aldimines with internal alkynes in rhodium catalysis as reported by Fagnou and Guimond in 2009 [69]. For example, treatment of (E)‐N‐tert‐butyl‐1‐phenylmethanimine (1.2 equiv.) with an internal alkyne (0.3 mmol) in the presence of

11.2 ­Formation of C─C Bond

OH

MeO

+ Ph

1.0 mmol

MeO

O

85%

Protonation

Ph

Electrophilic metalation

MeO

OH CO2Et

MeO

O

OH

MeO

PdII

Ph

O

CF3CO2H (1 mL), rt, 20 h

2.0 equiv.

O

MeO

CO2Et

2.5 mol% Pd(OAc)2

OH PdII

PdII Insertion

Ph

Ph

CO2Et

Scheme 11.71  Pd‐catalyzed ortho‐addition of alkyne to phenol derivatives.

NH2

+ MeO2C

1.2 equiv.

CO2Me 0.2 mmol

10 mol% Pd(OAc)2 DMA/PivOH (4/1 = v/v, 1.25 mL) O2(1 atm), 120 °C, 12 h

H N

CO2Me

CO2Me 85%

Scheme 11.72  Pd‐catalyzed ortho‐addition of alkyne to anilines.

Me

Me

N

Me

1.2 equiv.

+

nPr

nPr

0.3 mmol

N

2.5 mol% [Cp*Rh(MeCN)3][SbF6]2 2.1 equiv. Cu(OAc)2•H2O DCE, 83 °C (reflux), 16 h

nPr nPr

80%

Scheme 11.73  Pd‐catalyzed ortho‐addition of alkyne to aryl aldimines.

rhodium catalyst (2.5 mol%) and Cu(OAc)2·H2O (2.1 equiv.) as oxidant in DCE at 83  °C under reflux for 16 h affords the ortho‐alkenylation and cyclization product isoquinoline derivative in 80% yield (Scheme 11.73). Such synthesis of isoquinoline derivatives was improved to avoid consuming stoichiometric copper salts as oxidant and to be conducted at room

389

390

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

temperature by using hydrazones instead of aldimines as substrates as reported by Huang and coworkers in 2014 [70]. For example, treatment of (E)‐1‐(1‐phenylethyl)‐2‐(1‐phenylethylidene)hydrazine (0.3 mmol, 1 equiv.) with diphenylacetylene (0.5 mmol) in the presence of rhodium catalyst (2 mol%), benzoic acid (25 mol%), and air in MeOH (4 mL) at room temperature for 24 h affords the corresponding ortho‐alkenylation and cyclization product isoquinoline derivative in 75% yield (Scheme 11.74). Me

Me H N N

+ Ph

Ph

Me 0.3 mmol

2 mol% [Cp*Rh(H2O)3][OTf]2 25 mol% PhCO2H MeOH (4 mL), air, 25 °C, 24 h

0.5 mmol

2

N Ph Ph 75%

Scheme 11.74  Pd‐catalyzed ortho‐addition of alkyne to hydrazone.

11.2.5  Carbonylation and Carboxylation

Formation of aryl–carbonyl bonds constitutes aromatic ketone, benzoic acid, and other important basic skeletons in organic chemistry. Directing‐group‐ assisted transition‐metal‐catalyzed ortho‐carbonylation of aryl C─H bonds with carbon monoxide offers a convenient route to such structures. In 2002, Chatani and coworkers reported ruthenium‐catalyzed ortho‐carbonylation of N‐pyridineindoline derivatives in the presence of CO and olefin to give the corresponding aromatic ketones [71]. For example, treatment of 1‐(4‐methylpyridin‐2‐yl)indoline (1.0 mmol, 1 equiv.) with CO (10 atm) and ethylene (5 atm) in the presence of Ru3(CO)12 catalyst (5 mol%) in DMA (3 mL) at 160 °C for 20 h affords the corresponding ortho‐carbonylation product in 65% yield. In the proposed mechanism, Ru(0) catalyst coordinates with pyridine group and cleaves ortho‐aryl C─H bond of indoline to form aryl-Ru(II)–H species. Insertion of ethylene to Ru(II)–H bond of this aryl-Ru(II)–H species produces aryl‐Ru(II)‐alkyl species, which is then inserted by CO to give aryl‐Ru(II)– carbonylalkyl species. Reductive elimination of aryl and carbonylalkyl group affords the target product aromatic ketone and Ru(0) species to fulfill the catalytic cycle (Scheme 11.75). Applying this ortho‐carbonylation method, transformation of N‐arylpyrazoles to the corresponding aromatic ketones was conducted in 2003 at the same group [72]. For example, treatment of 1‐phenyl‐1H‐pyrazole (2.0 mmol) with CO (20 atm) and ethylene (7 atm) in the presence of Ru3(CO)12 catalyst (2.5 mol%) in DMA (6 mL) at 160 °C for 20 h affords the corresponding ortho‐ carbonylation product in 94% yield (Scheme 11.76). Ortho‐carbonylation of aryl C─H bonds was also achieved by the coupling of arenes with toluene derivatives in oxidizing conditions [73]. For example,

11.2 ­Formation of C─C Bond Me

Me N

+ CO + H2C

N

10 atm

1.0 mmol

CH2

N

5 mol% Ru3(CO)12

N Me

DMA (3 mL), 160 °C, 20 h

O 65%

5 atm

Me Me

N Ru0

N Me

N N

Reductive elimination

O

Oxidative addition

Me N

N RuII H Insertion Me

N

RuII

Insertion

O Me

Me N H2C CH2

N N RuII H2C CH

CO

3

Scheme 11.75  Ru‐catalyzed ortho‐carbonylation of indoline derivatives with CO and ethylene.

N N

2.0 mmol

+

CO

20 atm

+ H2C

CH2

7 atm

2.5 mol% Ru3(CO)12

N

DMA (6 mL), 160 °C, 20 h

N Me

O 94%

Scheme 11.76  Ru‐catalyzed ortho‐carbonylation of N‐arylpyrazoles with CO and ethylene.

Sun and Yin reported in 2012 that treatment of N‐acylaniline derivatives (0.5 mmol, 1 equiv.) with toluene derivatives (2.0 equiv.) in the presence of Pd(OAc)2 (5 mol%) and tert-butyl hydroperoxide (TBHP) (4.0 equiv.) as oxidant in DMSO (1 mL) at 100 °C for 20 h affords the corresponding diphenyl ketone derivatives (Scheme 11.77). Directing‐group‐assisted transition‐metal‐catalyzed ortho‐insertion of CO strategy was also applied for synthesis of benzoic acid derivatives. In 2008, Yu and Giri reported ortho‐carboxylation of benzoic acids or phenylacetic acids with atmospheric CO to synthesize 1,2‐ or 1,3‐dicarboxylic acids by

391

392

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group NHAc H N

Me

Me

+

4.0 equiv. TBHP DMSO (1 mL), 100 °C, 20 h

O 0.5 mmol

O

5 mol% Pd(OAc)2

2.0 equiv.

81%

Scheme 11.77  Pd‐catalyzed ortho‐carbonylation of aniline derivative with toluene and TBHP.

palladium‐catalyzed insertion of CO to ortho‐aryl C─H bonds using carboxylic acid as directing group [74]. For example, treatment of 3‐methoxybenzoic acid (0.2 mmol, 1 equiv.) with CO (1 atm) in the presence of Pd(OAc)2 (10 mol%), Ag2CO3 (2.0 equiv.), and NaOAc (2.0 equiv.) in 1,4‐dioxane (2 mL) at 130 °C for 18 h affords the corresponding 1,2‐dicarboxylic acid product in 80% yield (Scheme 11.78). MeO

CO2H +

CO 1 atm

0.2 mmol

10 mol% Pd(OAc)2

MeO

2.0 equiv. Ag2CO3, 2.0 equiv. NaOAc 1,4-dioxane (2 mL), 130 °C, 18 h

CO2H CO2H 80%

Scheme 11.78  Pd‐catalyzed ortho‐carboxylation of benzoic acids with CO.

A more economical cobalt catalyst was applied for ortho‐carboxylation of aryl C─H bonds using 8‐aminoquinoline directing group as reported by Daugulis and Grigorjeva in 2014 [75]. Reaction of N‐(quinolin‐8‐yl)benzamide (0.5 mmol, 1 equiv.) with CO (1 atm) in the presence of Co(acac)2 (20 mol%), NaOPiv (2.0 equiv.), and Mn(OAc)3 (1.0 equiv.) in CF3CH2OH (5 mL) at room temperature for 16 h affords the ortho‐carboxylation and cyclization product phthalimide in 81% yield (Scheme 11.79). O

O N H 0.5 mmol

+ N

CO 1 atm

20 mol% Co(acac)2 2.0 equiv. NaOPiv 1.0 equiv. Mn(OAc)3 • 2H2O CF3CH2OH (5 mL), air, rt, 16 h

N O N 81%

Scheme 11.79  Pd‐catalyzed ortho‐carboxylation of benzamide derivative with CO.

In addition to CO, CO2 was also available for ortho‐carboxylation of aryl C─H bonds as reported in 2011 by Iwasawa and coworkers [76]. For example, treatment of 2‐phenylpyridine (0.3 mmol, 1 equiv.) with CO2 (1 atm) in the presence of rhodium catalyst [Rh(coe)2Cl]2 (chlorobis(cyclooctene)rhodium(I) dimer, (5 mol%), trialkylphosphine ligand (12 mol%), Me3Al (2.0 equiv.), and

11.2 ­Formation of C─C Bond

MeOH (2.0 equiv.) in DMA (3 mL) at 70 °C for 8 h followed by esterification affords the corresponding methyl 2‐(pyridin‐2‐yl)benzoate product in 73% yield. In the proposed mechanism, Rh(I)–Me species generated from Ru(I)–Cl catalyst and Me3Al in situ coordinates with pyridine group and cleaves ortho‐ aryl C─H bond through oxidative addition followed by reductive elimination to form aryl–Rh(I) species and to release CH4. Insertion of CO2 to this aryl– Rh(I) species gives arylCO2–Rh(I) species. Transmetalation of this arylCO2– Rh(I) species with Me3Al followed by esterification affords the target carboxylic ester product and Rh(I)–Me species to fulfill the catalytic cycle (Scheme 11.80).

N

0.3 mmol

+ CO2

(1) 5 mol% [Rh(coe)2Cl]2 12 mol% PCy3, CO2 (1 atm) 2.0 equiv. Me3Al, 2.0 equiv. MeOH DMA (3 mL), 70 °C, 8 h

N

(2) TMSCHN2 (2.0 M in Et2O, 1m L) Et2O-MeOH (7.5 mL; 4/1 = v/v), 0 °C, 1 h

1 atm

CO2Me 73%

RhI Cl N CO2Me

Me3Al

N

Oxidative addition Transmetalation and reductive elimination

Me3Al

N

RhI Me

CO2AlMe2

CH4

N RhI

N CO2RhI

Insertion

CO2

Scheme 11.80  Rh‐catalyzed ortho‐carboxylation of 2‐pyridylbenzene with CO2.

11.2.6 Alkynylation

Formation of aryl–alkynyl bond via ortho‐alkynylation of aryl C─H bonds with either prefunctionalized alkyne such as alkynyl chloride, bromide, etc. or alkyne directly was developed in recent years. In 2002, Yamaguchi and coworkers

393

394

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

reported ortho‐alkynylation of phenols with alkynyl chloride in gallium catalysis [77]. For example, treatment of phenol with (chloroethynyl)triethylsilane in the presence of GaCl3 (10 mol%), pyridine‐derived ligand, and butyllithium (30 mol%) in chlorobenzene at 160 °C for 3 h affords the corresponding ortho‐ alkynylation product in 80% yield. PhO–GaCl2 generated from phenol and GaCl3 in situ is inserted by alkynyl chloride followed by β‐elimination to afford the target product and GaCl3 to fulfill the catalytic cycle (Scheme 11.81).

OH

+

Cl

SiEt3

10 mol% GaCl3 10 mol% 2, 6-di(tert-butyl)4-methylpyridine

OH

30 mol% butyllithium PhCl, 160 °C, 3 h

SiEt3 80%

OH

OH GaCl3 SiEt3 β-Elimination

HCl

OH

OGaCl2

Cl Cl2Ga

SiEt3

Insertion

Cl

SiEt3

Scheme 11.81  GaCl3‐catalyzed ortho‐alkynylation of phenol with alkynyl chlorides.

Alkynyl bromides were available for ortho‐alkynylation of aryl C─H bonds as reported in 2009 by Tobisu and coworkers [78]. For example, treatment of N‐ acyl‐N‐methylaniline (0.5 mmol, 1 equiv.) with alkynyl bromide (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), AgOTf (1.0 equiv.), and K2CO3 (1.0 equiv.) in toluene (1 mL) at 70 °C for 15 h affords the corresponding ortho‐alkynylation product in 70% yield. It is proposed that Pd(II) catalyst coordinates with amide group of aniline derivative and cleaves ortho‐aryl C─H bond to form aryl‐Pd(II) intermediate, which is inserted by alkynyl bromide followed by β‐elimination and ligand exchange to release the target product and Pd(II) catalyst to fulfill the catalytic cycle (Scheme 11.82).

11.2 ­Formation of C─C Bond Me

Me Me

N

+

Br

0.5 mmol

O

1.0 equiv. AgOTf 1.0 equiv. K2CO3 Toluene (1 mL), 70 °C, 15 h

O 1.5 equiv.

Me

N

10 mol% Pd(OAc)2

TIPS

70%

TIPS

Me Me

N AgBr

Ligand exchange

AgX

O

PdIIX2 Metalation

HX Me N

LnPdIIBrX

Me

N

X

β-Elimination

Me

Ac

PdII Insertion Me N

O TIPS

Br

TIPS

Ac Br PdIIX

TIPS

Scheme 11.82  Pd‐catalyzed ortho‐alkynylation of aniline derivatives with alkynyl bromides.

The substrate scope was expanded to benzamide derivatives using 8‐aminoquinoline as directing group as reported in 2012 at the same group, using ­inorganic base CsOAc instead of silver salts to scavenge the bromides [79]. For  example, treatment of 2‐methyl‐N‐(quinolin‐8‐yl)benzamide (0.3 mmol, 1 equiv.) with alkynyl bromide (1.2 equiv.) in the presence of Pd(OAc)2 (5 mol%) and CsOAc (1.0 equiv.) in toluene (0.6 mL) at 110 °C for 15 h affords the corresponding ortho‐alkynylation product in 86% yield (Scheme 11.83). Me O

Me O N H

+ Br

TIPS

1.0 equiv. CsOAc Toluene (0.6 mL), 110 °C,15 h

N

0.3 mmol

5 mol% Pd(OAc)2

1.2 equiv.

N H

N

TIPS 86%

Scheme 11.83  Pd‐catalyzed ortho‐alkynylation of benzamide derivatives with alkynyl bromides.

Moreover, direct use of alkyne as coupling partner was available in the directing‐group‐assisted ortho‐alkynylation reaction. In 2012, Chang and coworkers

395

396

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

reported ortho‐alkynylation of aryl C─H bonds with alkyne using pyridine as directing group [80]. Treatment of N-methyl-N‐(2‐pyridyl)aniline (0.2 mmol, 1 equiv.) with ethynyltriisopropylsilane (1.3 equiv.) in the presence of Pd(acac)2 (10 mol%), TsOH/H2O (10 mol%), and BQ (2.0 equiv.) as oxidant in benzene (1 mL) at 80  °C for 12 h affords the corresponding mono‐ortho‐alkynylation product in 68% yield. In the proposed mechanism, Pd(II) catalyst coordinates with pyridine group and cleaves the ortho‐aryl C─H bond to form aryl‐Pd(II) complex. Transmetalation of this aryl‐Pd(II) complex with alkyne gives aryl‐ Pd(II)‐alkynyl key intermediate. Reductive elimination of aryl and alkynyl group affords the ortho‐alkynylation product and Pd(0) species, which is oxidized by BQ to regenerate the Pd(II) species, fulfilling the catalytic cycle. Transmetalation of alkyne followed by reductive elimination instead of insertion of alkynyl halides followed by β‐elimination introduces alkynyl group to the ortho‐aryl C─H bond (Scheme 11.84).

N

+

TIPS

N 0.2 mmol

Me

10 mol% Pd(acac)2 10 mol% TsOH/H2O

Me

N N

2.0 equiv. BQ Benzene (1 mL), 80 °C, 12 h

0.13 mmol*2 over 4 h

TIPS 68%

Me N N PdIIX2 Oxidation

Metalation

HX Me N

Pd0

Ln Me

Reductive Transmetalation elimination

N N

N PdII X H

TIPS

Me TIPS

N

HX

N PdII

TIPS

Scheme 11.84  Pd‐catalyzed ortho‐alkynylation of aniline derivatives with alkyne.

11.2 ­Formation of C─C Bond

More economical copper slats were applied for promoting ortho‐alkynylation of aryl C─H bond of benzamide with alkyne using 8‐aminoquinoline as directing group as reported by You and coworkers in 2014 [81]. Treatment of  N‐(quinolin‐8‐yl)benzamide (0.25 mmol, 1 equiv.) with phenylacetylene (2.5 equiv.) in the presence of stoichiometric Cu(OAc)2 (3.0 equiv.) in t‐ AmylOH (2 mL) at 120  °C for 24 h affords the corresponding mono‐ortho‐ alkynylation product in 91% yield (Scheme 11.85). O O

3.0 equiv. Cu(OAc)2

+

N H

N

tAmylOH

(2 mL) 120 °C, 24 h

N

0.25 mmol

N H

2.5 equiv.

91%

Scheme 11.85  Cu‐mediated ortho‐alkynylation of benzamide derivatives with alkyne using 8‐aminoquinoline as directing group.

Almost at the same time, Yu and coworkers [82] also reported copper‐mediated ortho‐alkynylation of aryl C─H bond of benzamide with alkyne by applying 2‐phenyloxazoline as directing group. Treatment of N‐(2‐(4,5‐dihydrooxazol‐2‐yl)-phenyl)benzamide (0.1  mmol, 1  equiv.) with phenylacetylene (3.0 equiv.) in the presence of stoichiometric Cu(OAc)2 (1.0 equiv.), NaOAc (1.0 equiv.), and air in DMSO (5 mL) at 60 °C for 12 h affords the corresponding mono‐ortho‐alkynylation product in 52% yield (Scheme 11.86). O

O N H

1.0 equiv. Cu(OAc)2

+ N

0.1 mmol

N H

1.0 equiv. NaOAc DMSO (5 mL) Air, 60 °C, 12 h

O 3.0 equiv.

oxa

52%

Scheme 11.86  Cu‐mediated ortho‐alkynylation of benzamide derivatives with alkyne using 2‐phenyloxazoline as directing group.

Ortho‐alkynylation of aryl C─H bond of benzamide derivatives with alkyne catalyzed by nickel complex was reported by Shi and coworkers in 2015 [83]. Treatment of N‐(2‐(pyridin‐2‐yl)propan‐2‐yl)benzamide (1.5  equiv.) with ethynyltriisopropylsilane (0.1 mmol, 1 equiv.) in the presence of NiI2 (10 mol%), NaI (1.0 equiv.), and O2 (1 atm) in tBuCN (0.5 mL) at 140 °C for 12 h affords the corresponding mono‐ortho‐alkynylation product in 91% yield. Atmospheric O2 is applied as the terminal oxidant, and PIP (2‐pyridinyl isopropyl) group acts as the effective directing group (Scheme 11.87).

397

398

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group O Me N H

OMe

Me +

10 mol% NiI2

TIPS

N

1.0 equiv. NaI, O2 (1 atm) (0.5 mL), 140 °C, 12 h

tBuCN

1.5 equiv.

0.1 mmol

Me

N H

N

TIPS 91%

Scheme 11.87  Ni‐catalyzed ortho‐alkynylation of benzamide derivatives with alkyne.

Ortho‐alkynylation of aryl C─H bond of benzamide derivatives with alkyne catalyzed by cobalt complex was also achieved by Niu, Song, and coworkers in 2015 [84]. Treatment of 2‐benzamidopyridine 1‐oxide (0.15 mmol, 1 equiv.) with phenylacetylene (1.2 equiv.) in the presence of CoC2O4·4H2O (5 mol%), Na2C2O4 (1.0 equiv.), and AgOAc (2.0 equiv.) in DMSO (1 mL) at 100 °C for 12 h affords the corresponding mono‐ortho‐alkynylation product in 85% yield (Scheme 11.88).

O

O N H

N

+

O 1.2 equiv.

0.15 mmol

5 mol% CoC2O4·4H2O

N

1.0 equiv. Na2C2O4 2.0 equiv. AgOAc DMSO (1 mL), 100 °C, 12 h

85%

O N

Scheme 11.88  Cocatalyzed ortho‐alkynylation of benzamide derivatives with alkyne.

Ortho‐alkynylation of aryl C─H bond of benzamide derivatives with alkyne catalyzed by cobalt complex was achieved by Zhang and coworkers as well in 2015 [85]. Treatment of N‐(quinolin‐8‐yl)benzamide (0.2 mmol, 1 equiv.) with phenylacetylene (2.0 equiv.) in the presence of Co(OAc)2·4H2O (20 mol%), Ag2CO3 (4.0 equiv.), and TBAI (tetrabutylammonium iodide 3.0 equiv.) in benzotrifluoride (1 mL) at 120 °C for 3 h affords the corresponding cyclized mono‐ ortho‐alkynylation product in 78% yield (Scheme 11.89). O

O N H

+ N

0.2 mmol

2.0 equiv.

20 mol% Co(OAc)2 • 4H2O

N

4.0 equiv. Ag2CO3 3.0 equiv. TBAI PhCF3 (1 mL), 120 °C, 3 h

78%

N

Scheme 11.89  Co-catalyzed ortho‐alkynylation of benzamide derivatives with alkyne.

11.2 ­Formation of C─C Bond

11.2.7 Cyanidation

Transition‐metal‐catalyzed functionalization of ortho‐aryl C─H assisted by a directing group also offers a convenient method to introduce a cyanide group into ortho‐aryl C─H bond in one step. In 2006, Yu and coworkers reported ortho‐cyanidation of 2‐phenylpyridine with either TMSCN or even CH3NO2 as cyanating reagent promoted by copper salt by applying pyridine as directing group [86]. When TMSCN is applied as cyanating source, treatment of 2‐phenylpyridine (0.3 mmol, 1 equiv.) with TMSCN (2.0 equiv.) in the presence of Cu(OAc)2 (1.0 equiv.) in MeCN (1 mL) at 130 °C for 24 h affords mono‐ortho‐cyanidation product in 42% yield. Surprisingly, treatment of 2‐phenylpyridine in CH3NO2 as solvent without the addition of TMSCN affords the desired mono‐ortho‐ cyanidation product in 67% yield under similar conditions (Scheme 11.90).

N

+

TMSCN

1.0 equiv. Cu(OAc)2

N

MeCN (1 mL), 130 °C, 24 h

CN 0.3 mmol

N

2.0 equiv.

42%

1.0 equiv. Cu(OAc)2

N

MeNO2 (1 mL), 130 °C, 24 h

CN 0.3 mmol

67%

Scheme 11.90  Cu‐mediated ortho‐cyanidation of 2‐pyridylbenzene with TMSCN or MeNO2.

Copper‐catalyzed ortho‐cyanidation of 2‐phenylpyridine was achieved by Shen in 2013, applying CH3CN as cyanidation reagent using atmospheric O2 as oxidant [87]. For example, treatment of 2‐phenylpyridine (0.4 mmol) with MeCN (1.5 mL) in the presence of Cu(OAc)2 (30 mol%), TMEDA (30 mol%), (Me3Si)2 (1.0 equiv.), H2O (1.0 equiv.), and O2 (1 atm) at 150 °C for 39 h affords mono‐ and di‐ortho‐cyanidation product in 57 and 33% yield, respectively. It is proposed that transmetalation of Cu(II) species with MeCN in the presence of (Me3Si)2 forms Cu(II)CN species, which coordinates with pyridine group and disproportionates with Cu(II) species to give Cu(III)─CN species, followed by cleaving of ortho‐aryl C─H bond to produce key aryl–Cu(III)─CN species. Reductive elimination of aryl and CN group affords the target ortho‐cyanidation product and Cu(I), which is oxidized by O2 to regenerate Cu(II) species, fulfilling the catalytic cycle (Scheme 11.91).

399

400

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

N

+ MeCN

0.4 mmol

1.5 mL

30 mol% Cu(OAc)2 30 mol% TMEDA

Oxidation

+

CN 57%

N CN 33%

MeCN, (Me3Si)2

Transmetalation CuIICN

CuI Reductive elimination

Disproportionation metalation

N +

N CN

N

1.0 equiv. (Me3Si)2 1.0 equiv. H2O, O2 (1 atm) 150 °C, 39 h CuIIX2

O2, HX

CN

N

HX

CuIIX2

CuIII CN

Scheme 11.91  Cu‐catalyzed ortho‐cyanidation of 2‐pyridylbenzene with MeCN.

11.3 ­Formation of C─N Bond Direct cross‐coupling of aryl C─H bond and N─H bond assisted by directing groups in transition‐metal catalysis provides an ideal way for regioselective formation of aryl–nitrogen bond. In 2005, Buchwald and coworkers reported intramolecular amination of ortho‐C─H bond of N‐acyl‐2‐biphenylamines to synthesize carbazole derivatives using atmospheric O2 as terminal oxidant [88]. For example, treatment of N‐acyl‐2‐biphenylamine (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%), Cu(OAc)2 (1.0 equiv.), and O2 (1 atm) in toluene (2 mL) at 120 °C for 12 h affords the desired N‐acylcarbazole in 94% yield. The reaction mechanism is proposed involving a Pd(II)/Pd(0) catalytic cycle. Pd(II) catalyst coordinates with amide group and cleaves the ortho‐aryl C─H bond to form aryl‐Pd(II) complex. Deprotonation of amine group with acetate releases HOAc and produces key aryl‐Pd(II)–amino intermediate. Reductive elimination of aryl and amino group from Pd(II) center at 120  °C affords the ortho‐amination product carbazole and Pd(0) species, which is oxidized by Cu(OAc)2 and O2 to regenerate the Pd(II) catalyst, fulfilling the catalytic cycle (Scheme 11.92). Alternatively, synthesis of carbazole derivatives by directing‐group‐assisted palladium‐catalyzed intramolecular ortho‐amination of 2‐biphenylamine derivatives was also accessible through a Pd(II)/Pd(IV) catalytic cycle reported

11.3 ­Formation of C─N Bond

5 mol% Pd(OAc)2 Me

HN O 0.2 mmol

N

1.0 equiv.Cu(OAc)2 3A MS (40 mg), O2 (1 atm) Toluene (2 mL), 120 °C, 12 h

O 94%

Me

HN PdIIX

O

2

Oxidation Cu(OAc)2, O2

Coordination metalation

LnPd0 Reductive elimination

Me

HX

HN Me PdII O X Deprotonation

N Me

O

Me

N

II

HX

Pd

O

Scheme 11.92  Pd(0)/Pd(II)‐catalyzed intramolecular ortho‐amination of 2‐aminobiphenyl derivative.

5 mol%Pd(OAc)2 HN 0.19 mmol

0.23 mmol PhI(OAc)2 Toluene (3.8 mL), rt, 1 h

N

95%

Scheme 11.93  Pd(II)/Pd(IV)‐catalyzed intramolecular ortho‐amination of 2‐aminobiphenyl derivative.

by Gaunt and coworkers in 2008, using N‐benzyl‐2‐aminophenyls as substrates [89]. For example, treatment of N‐benzyl‐2‐biphenylamine (0.19 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%) and PhI(OAc)2 (0.23 mmol) in toluene (3.8 mL) at room temperature for 1 h affords the corresponding N‐benzylcarbazole product in 95% yield (Scheme  11.93). In the proposed mechanism, Pd(II) catalyst coordinates with amide group and cleaves the ortho‐aryl

401

402

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

C─H bond to form aryl‐Pd(II) intermediate. Deprotonation of amine group with acetate gives HOAc and produces aryl‐Pd(II)–amino intermediate. Oxidation of this aryl‐Pd(II)–amino intermediate by PhI(OAc)2 produces key aryl‐Pd(IV)–amino intermediate. Reductive elimination of aryl and amino group from Pd(IV) center at room temperature affords the desired ortho‐ amination carbazole product and Pd(II) to fulfill the catalytic cycle. Through the novel Pd(II)/Pd(IV) catalysis utilizing the high electrophilic character of Pd(IV) species, aryl–nitrogen bond is formed by reductive elimination of aryl and amino group at room temperature instead of 120 °C in Pd(II)/Pd(0) catalysis, at the expense of using PhI(OAc)2 as critical oxidant displacing the ideal oxidant atmospheric O2. Applying this strategy, some other nitrogen‐containing heterocycles are ­prepared successfully. In 2008, Yu and Wasa reported the synthesis of γ‐ and δ‐lactams through Pd(II)‐catalyzed ortho‐amination of phenylacetamide derivatives [90]. For example, treatment of N‐methoxy‐2‐methyl‐2‐phenylpropanamide (0.5 mmol, 1 equiv.) in the presence of Pd(OAc)2 (10 mol%), CuCl2 (1.5 equiv.), and AgOAc (2.0 equiv.) in DCE (10 mL) at 100 °C for 6 h affords the desired γ‐lactam in 94% yield (Scheme 11.94). Me

Me HN

0.5 mmol

Me O OMe

10 mol% Pd(OAc)2 1.5 equiv. CuCl2, 2.0 equiv. AgOAc DCE (10 mL), N2, 100 °C, 6 h

Me O

N OMe 94%

Scheme 11.94  Pd‐catalyzed intramolecular ortho‐amination of phenylacetamide derivative.

Indoline derivatives were also prepared in 2009 at the same group applying phenylethylamine derivatives as substrates, using either single‐electron or two‐ electron oxidant Ce(SO4)2 or F+ reagent, respectively [91]. For example, reaction of 1,1,1‐trifluoro‐N‐phenethylmethanesulfonamide (0.2 mmol, 1 equiv.) in the presence of Pd(OAc)2 (15 mol%), Ce(SO4)2 (3.0 equiv.), and DMF (6.0 equiv.) in CH2Cl2 (2 mL) at 100 °C for 36 h affords the desired N‐protected indoline in 68% yield. Treatment of 1,1,1‐trifluoro‐N‐phenethylmethanesulfonamide with F+ reagent N-fluoro-2,4,6-trimethylpyridinium triflate salt (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) produces the target product in 75% yield under similar conditions (Scheme 11.95). In either case, it is proposed that a high‐valent palladium species is probably involved in the reaction pathway. Indole derivatives were prepared by similar strategy as reported by Hartwig and Tan in 2010, while using N‐acetyloxime as both the directing group and the oxidant [92]. For example, treatment of (E)‐1,1‐diphenylpropan‐2‐ one O‐acetyl oxime ester (0.1 mmol) in the presence of Pd(dba)2 (1 mol%) and Cs2CO3 (1.0 equiv) in toluene (10 mL) at 150  °C for 24 h affords the

11.3 ­Formation of C─N Bond 15 mol% Pd(OAc)2 NHTf 0.2 mmol

N Tf

3.0 equiv. Ce(SO4)2 6.0 equiv. DMF CH2Cl2 (2 mL), 100 °C, 36 h

68%

10 mol% Pd(OAc)2 2.0 equiv. F+ oxidant 1.25 equiv. DMF DCM (2 mL), 120 °C, 72 h

NHTf 0.2 mmol

N Tf

Me OTf N F

Me

Me F+ oxidant

75%

Scheme 11.95  Pd‐catalyzed intramolecular ortho‐amination of phenylethylamine derivative.

1 mol% Pd(dba)2 Me N

OAc

1.0 equiv. Cs2CO3 Toluene (10 mL), 150 °C, 24 h

0.1 mmol

Me N H 69%

Scheme 11.96  Pd‐catalyzed intramolecular ortho‐amination of aryl C─H bond using oxime as directing group.

ortho‐amination indole derivative in 69% yield (Scheme 11.96). A Pd(0)/Pd(II) catalytic cycle is proposed, in which oxidative addition of Pd(0) to N─O bond forms N–Pd(II)–OAc species followed by cleavage of ortho‐aryl C─H bond to give N–Pd(II)‐aryl intermediate with loss of HOAc. Reductive elimination of nitrogen and aryl group affords the target product and Pd(0) to fulfill the catalytic cycle. Intermolecular ortho‐amination of aryl C─H bonds assisted by directing groups is also established. In 2006, Yu and coworkers gave one example of intermolecular ortho‐amination of 2‐pyridylbenzene (0.3 mmol, 1 equiv.) with TsNH2 (2.0 equiv.) mediated by Cu(OAc)2 (1.0 equiv.) in MeCN (1 mL) at 130 °C for 24 h to afford the target product in 74% yield [86] (Scheme 11.97).

N

+

TsNH2

1.0 equiv. Cu(OAc)2

N

MeCN (1 mL), 130 °C, 24 h

NHTs 0.3 mmol

2.0 equiv.

74%

Scheme 11.97  Pd‐catalyzed intermolecular ortho‐amination of 2‐pyridylbenzene with TsNH2.

403

404

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Also in 2006, Yu and coworkers reported intermolecular ortho‐amidation of aryl C─H bonds with amides applying pyridine or O‐methyl oxime as directing group [93]. For example, treatment of 2‐phenylpyridine (0.3 mmol, 1 equiv.) or (E)‐benzaldehyde O‐methyl oxime (0.3 mmol, 1 equiv.) with propionamide (1.2 equiv.) in the presence of Pd(OAc)2 (5 mol%) and K2S2O8 (5.0 equiv.) in DCE (2 mL) at 80 °C affords the corresponding ortho‐amidation product in 77 or 82% yield, respectively (Scheme 11.98). It is proposed that aryl C─H bond is cleaved by Pd(II) catalyst and aryl–nitrogen bond is formed by insertion of nitrene generated from amide.

N

+

1.2 equiv.

0.3 mmol

N

0.3 mmol

EtCONH2

OMe +

EtCONH2 1.2 equiv.

5 mol% Pd(OAc)2 5.0 equiv. K2S2O8 2.0 equiv. MgO DCE (2 mL), 80 °C, 14–20 h

N NHCOEt 77%

5 mol% Pd(OAc)2 5.0 equiv. K2S2O8 DCE (2 mL), 80 °C, 14–20 h

N

OMe

NHCOEt 82%

Scheme 11.98  Pd‐catalyzed intermolecular ortho‐amination of 2‐pyridylbenzene or O‐ methyl oxime with amides.

Intermolecular ortho‐aryl C─H amidation of aromatic ketones was established by Liu and coworkers in 2011 [94]. For example, treatment of tert‐butyl phenyl ketone (0.25 mmol, 1 equiv.) with benzenesulfonamide (2.0 equiv.) in the presence of Pd(OTf )2·2H2O (10 mol%) and F+ oxidant N-fluoro-2,4,6trimethylpyridinium triflate (2.0 equiv.) in DCE (1 mL) at 80 °C for 8 h affords the corresponding ortho‐sulfonamidation product in 78% yield (Scheme 11.99). A Pd(II)/Pd(IV) catalytic cycle is proposed for the transformation. Pd(II) ­catalyst coordinates with ketone group and cleaves the ortho‐aryl C─H bond to from aryl‐Pd(II) intermediate. Transmetalation of this aryl‐Pd(II) intermediate with benzenesulfonamide gives aryl‐Pd(II)–nitrogen species, which is oxidized by F+ oxidant to produce aryl‐Pd(IV)–nitrogen key intermediate. Reductive elimination of aryl and nitrogen group forms the target ortho‐sulfonamidation product and Pd(II) species to fulfill the catalytic cycle. This proposed mechanism is solidly confirmed by stoichiometric reaction of aromatic ketone and sulfonamide step by step to produce the target ortho‐sulfonamidation product, in which major intermediates are isolated and fully characterized by X‐ray diffraction. Reaction of 1‐adamantanyl 3,4‐dimethylphenyl ketone with Pd(OAc)2 and HOTf at 40 °C in DCE produces ortho‐aryl‐Pd(II)–OTf dimer in 98% yield, which shows that ortho‐aryl C─H bond is cleaved

11.3 ­Formation of C─N Bond Me Me

Me

Me O

O +

S O NH2

F+ oxidant Me

0.25 mmol

2.0 equiv.

OTf Me

Me

O

10 mol% Pd(OTf)2 2H2O 2.0 equiv. DCE (1 mL), 80 °C, 8 h

Me

O

NH S O 78%

N F Me

Scheme 11.99  Pd‐catalyzed intermolecular ortho‐amination of aromatic ketones with benzenesulfonamide.

by Pd(II) species. Following treatment of ortho‐aryl‐Pd(II)–OTf dimer with 4‐chlorobenzenesulfonamide in DCE at room temperature, trans­metalation product ortho‐aryl‐Pd(II)–NH 2SO2Ar complex was obtained in 87% yield. Treating this ortho‐aryl‐Pd(II)–NH2SO2Ar complex by F+ oxidant in DCE at 60 °C releases target ortho‐sulfonamidation product in 82% yield. Isotopic experiment using phenyl phenyl‐d5 ketone under optimal conditions gives a KIE value of 4.9, which indicates that cleavage of the ortho‐aryl C─H bond is the rate‐determining step. Intermolecular ortho‐amination of benzamides was reported by Yu and co­workers in 2011, applying 4‐(trifluoromethyl)perfluoroaniline as effective directing group [95]. For example, reaction of 4‐(tert‐butyl)‐N‐(2,3,5,6‐tetrafluoro‐4‐ (trifluoromethyl)phenyl)benzamide with morpholine (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%), dibenzoyl peroxide (1.5 equiv.), AgOAc (2.0 equiv.), and CsF (2.0 equiv.) in DCE (1 mL) at 130  °C for 18 h affords the corresponding ortho‐amination product in 64% yield. Alternatively, N-benzoyloxymorphine ­prepared from morpholine in advance also serves as the effective amination reagent, giving ortho‐amination product of benzamide derivative in 65% yield (Scheme  11.100). A Pd(II)/Pd(IV) reaction mechanism is proposed. Pd(II) ­catalyst coordinates with amide group and cleaves ortho‐aryl C─H bond with the aid of CsF form aryl‐Pd(II) intermediate. Oxidation of this aryl‐Pd(II) intermediate with amino–OBz bond produces aryl‐Pd(IV)–amino key intermediate. Reductive elimination of aryl and amino group afforded the desired aniline derivative and Pd(II) species to fulfill the catalytic cycle. Applying this strategy, ortho‐amination of a benzylamine derivative was achieved by Yu and coworkers in 2015 [96]. Treatment of N‐benzyl‐1,1,1‐trimmol) with N‐benzoyloxymorphine fluoromethanesulfonamide (0.1  (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), 2,4,6‐trimethoxypyridine (20 mol%) as critical ligand, AgOAc (2.0 equiv.), K3PO4 (1.0 equiv.), and Na2CO3 (2.0 equiv.) in perfluorobenzene (1 mL) at 130 °C for 24 h affords the corresponding ortho‐amination product in 82% yield (Scheme 11.101).

405

406

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group F

F O Me Me

F

CF3

N H

F+ O F

10 mol% Pd(OAc)2 1.5 equiv. (PhCOO)2

NH

2.0 equiv. AgOAc Me 2.0 equiv. CsF Me DCE, 130 °C,18 h Me

1.5 equiv.

Me

O

F

CF3

N H

F F

N O 64%

F

F O

F

CF3

N H

F

+ F

O

N OBz

2.0 equiv.

10 mol% Pd(OAc)2 1.0 equiv. AgOAc 2.0 equiv. CsF DCE (1mL), 130 °C, 18 h

0.2 mmol

O

F

CF3

N H

F F

N O 65%

Scheme 11.100  Pd‐catalyzed intermolecular ortho‐amination of benzamide derivatives with N‐benzoyloxymorphine.

NHTf

0.1 mmol

+

O

N OBz 2.0 equiv.

10 mol% Pd(OAc)2 20 mol% 2,4,6-trimethoxypyridine 2.0 equiv. AgOAc 1.0 equiv. K3PO4, 2.0 equiv. Na2CO3 C6F6 (1 mL), 4 AMS (40 mg), 130 °C, 24 h

NHTf N O 82%

Scheme 11.101  Pd‐catalyzed intermolecular ortho‐amination of benzylamine derivative with N‐benzoyloxymorphine.

11.4 ­Formation of C─O Bond Transition‐metal‐catalyzed functionalization of ortho‐aryl C─H bonds assisted by directing groups was applied for formation of aryl–oxygen bond in the early time of this century. In 2004, Sanford and coworkers reported ortho‐acetoxylation aryl C─H bonds using pyridine as effective directing group [97]. Treatment of benzo[h]quinoline (0.89 mmol, 1 equiv.) with PhI(OAc)2 (2.0 equiv.) in the presence of Pd(OAc)2 (2 mol%) in MeCN (7.5 mL) at 75 °C for 12 h affords the corresponding ortho‐aryl acetate in 86% yield. Selective mono‐ or di‐ortho‐ acetoxylation of aryl C─H bond(s) of 2‐pyridylbenzene is achieved by controlling the ratio of 2‐phenylpyridine substrate to PhI(OAc)2 oxidant under otherwise similar conditions, with the yield of 52 or 83%. In the proposed mechanism, Pd(II) catalyst coordinates with pyridine directing group and cleaves ortho‐aryl C─H bond to form aryl‐Pd(II) intermediate. Oxidation of this aryl‐Pd(II) intermediate by PhI(OAc)2 gives key aryl‐Pd(IV)–OAc

11.4 ­Formation of C─O Bond

N

+

2 mol% Pd(OAc)2

PhI(OAc)2

N

MeCN (7.5 mL), 75 °C, 12 h

OAc 0.89 mmol

N

2.0 equiv.

+

86%

5 mol% Pd(OAc)2

PhI(OAc)2

N

MeCN (8 mL), 100 °C, 12 h

OAc 1.29 mmol

1.80 mmol

52% OAc

N

+

0.039 mmol Pd(OAc)2

PhI(OAc)2

N

MeCN (4 mL), 100 °C, 12 h

OAc 0.64 mmol

1.61 mmol

83%

PdII

N

N Reductive elimination

OAc

C H activation

N PdII

N IV

Pd OAc

Oxidation PhI(OAc)2

Scheme 11.102  Pd(II)/Pd(IV)‐catalyzed ortho‐acetoxylation of benzo[h]quinoline or 2‐ pyridylbenzene with PhI(OAc)2.

intermediate. Reductive elimination of aryl and acetate group from Pd(IV) center affords the target ortho‐acetoxylation product and Pd(II) species to ­fulfill the catalytic cycle. Some key Pd(IV) complexes were synthesized and isolated with fully characterization, establishing the methodologies of ortho‐ activation and functionalization of aryl C─H bonds in the presence of directing groups via Pd(II)/Pd(IV) catalytic cycle for formation of either carbon–carbon bonds or carbon–heteroatom bonds (Scheme 11.102).

407

408

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Inexpensive, safe, and environmentally benign oxidant oxone was applied in Pd(II)‐catalyzed acetoxylation of ortho‐aryl C─H bonds using O‐methyl oxime as directing groups [98]. Reaction of (E)‐benzaldehyde O‐methyl oxime (1.34 mmol, 1 equiv.) with PhI(OAc)2 (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%) in mixtures of HOAc (5.6 mL) and Ac2O (5.6 mL) at 100 °C for 12 h affords the corresponding ortho‐acetoxylation product in 73% yield. Applying oxone as oxidant for this reaction performed in HOAc produces ortho‐ aryl  acetate in 53% yield. Increasing the reaction scale to 15 g using (E)‐3‐­ bromobenzaldehyde O‐methyl oxime as substrate gives 10 g of the desired product (Scheme 11.103).

N

OMe +

PhI(OAc)2 1.1 equiv.

1.34 mmol N

OMe +

HOAc 11.2 mL

1.34 mmol Br

N

OMe +

HOAc 493 mL

15 g, 65.7 mmol

5 mol% Pd(OAc)2

N

HOAc (5.6 mL), Ac2O (5.6 mL) 100 °C, 12 h

OAc 73%

5 mol% Pd(OAc)2 0.95 equiv. oxone 100 °C, 12 h

3 mol% Pd(OAc)2

OMe

N

OMe

OAc 53% Br

N

2.0 equiv. oxone Ac2O (55 mL), reflux, 18 h

OMe

OAc 54%,10 g

Scheme 11.103  Pd(II)/Pd(IV)‐catalyzed ortho‐acetoxylation of O‐methyl oxime with HOAc using oxone.

Another oxidant K2S2O8 was found effective in ortho‐acetoxylation of aniline derivatives as reported by Wang and coworkers in 2008 [99]. Treatment of N‐ acylaniline (1.0 mmol, 1 equiv.) with HOAc (5 mL) in the presence of Pd(OAc)2 (5 mol%) and K2S2O8 (2.0 equiv.) in DCE (5 mL) at 80  °C for 24 h affords the ­corresponding ortho‐acetoxylation product in 77% yield (Scheme 11.104). H N

Me

+

HOAc

O 1.0 mmol

5 mL

5 mol% Pd(OAc)2 2.0 equiv. K2S2O8 DCE (5 mL), 80 °C, 24 h

H N

Me

O OAc 77%

Scheme 11.104  Pd(II)/Pd(IV)‐catalyzed ortho‐acetoxylation of aniline derivative with HOAc using K2S2O8.

11.4 ­Formation of C─O Bond

In addition to ortho‐aryl acetate, ortho‐aryl ether was synthesized through similar reactions using the corresponding alcohol instead of acetic acid as reported by Sanford and coworkers [97]. Reaction of benzo[h]quinoline (0.84 mmol, 1 equiv.) with MeOH (7.5 mL) in the presence of Pd(OAc)2 (1 mol%) and PhI(OAc)2 (2.0 equiv.) at 100 °C for 22 h affords the corresponding ortho‐ methoxylation product in 95% yield (Scheme  11.105). Some other common alcohols including ethanol, isopropanol, or acidic 2,2,2‐trifluoroethanol are also available for this kind of transformation. +

N

MeOH

1 mol% Pd(OAc)2 2.0 equiv. PhI(OAc)2 100 °C, 22 h

7.5 mL

0.84 mmol

N OMe 95%

Scheme 11.105  Pd(II)/Pd(IV)‐catalyzed ortho‐alkoxylation of benzo[h]quinoline with alcohols using PhI(OAc)2.

The oxidant K2S2O8 was applied for ortho‐alkoxylation of N‐methoxybenzamide derivatives as reported by Wang and Yuan in 2010 [100]. For example, treatment of N‐methoxybenzamide (0.25 mmol, 1 equiv.) with MeOH (2 mL) in the presence of Pd(OAc)2 (5 mol%) and K2S2O8 (2.0 equiv.) in dioxane (2 mL) at 55 °C for 6.5 h affords the corresponding ortho‐methoxylation product in 73% yield (Scheme 11.106). O

O N H

OMe

0.25 mmol

+

MeOH

2 mL

5 mol% Pd(OAc)2 2.0 equiv. K2S2O8 4A MS (30 mg) Dioxane (2 mL), 55 °C, 6.5 h

N H OMe

OMe

73%

Scheme 11.106  Pd(II)/Pd(IV)‐catalyzed ortho‐alkoxylation of benzamide derivative with alcohols using K2S2O8.

When electron‐richer aniline derivatives were the substrates, ortho‐alkoxylation was conducted at room temperature using MsOH additive, as reported in 2012 by the same group [101]. For example, treatment of N‐acylaniline (0.3 mmol) with MeOH (10 equiv.) in the presence of Pd(OAc)2 (10 mol%), MsOH (20 mol%), and K2S2O8 (2.0 equiv.) in DME (2 mL) at room temperature for 24 h affords the corresponding ortho‐methoxylation product in 66% yield (Scheme 11.107). Ortho‐alkoxylation of aryl C─H bonds was applied in synthesis of dihydrobenzofuran derivatives through intramolecular ortho‐alkoxylation of phenyl­ ethanol as reported by Yu and coworkers in 2010 [102]. For example, reaction of 2‐methyl‐1‐phenylpropan‐2‐ol (0.2 mmol, 1 equiv.) in the presence of

409

410

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group H N

Me

+

MeOH

O 0.3 mmol

H N

10 mol% Pd(OAc)2

10 equiv.

20 mol% MsOH 2.0 equiv. K2S2O8 DME (2 mL), rt, 24 h

Me

O OMe 66%

Scheme 11.107  Pd(II)/Pd(IV)‐catalyzed ortho‐alkoxylation of aniline derivative with alcohols using K2S2O8.

Pd(OAc)2 (5 mol%), PhI(OAc)2 (1.5 equiv.), and Li2CO3 (1.5 equiv.) in perfluorobenzene (2 mL) at 100 °C for 36 h affords the desired dihydrobenzofuran product in 88% yield (Scheme 11.108). 5 mol% Pd(OAc)2

Me

Me

1.5 equiv. PhI(OAc)2

Me OH

1.5 equiv. Li2CO3 C6F6 (2 mL), 100 °C, 36 h

0.2 mmol

O

Me

88%

Scheme 11.108  Pd(II)/Pd(IV)‐catalyzed ortho‐alkoxylation of aniline derivative with alcohols using PhI(OAc)2.

Copper salt was used as catalyst in the etherification of ortho‐aryl C─H bonds of benzamide derivative using 8‐aminoquinoline directing group and atmospheric air as oxidant, as reported by Daugulis and Roane in 2013 [103]. For example, treatment of electron‐deficient N‐(quinolin‐8‐yl)‐3‐(trifluoromethyl)benzamide (0.1 mmol, 1 equiv.) with 4‐tert‐butylphenol (1.0 equiv.) in the presence of (CuOH)2CO3 (11 mol%), MsOH (20 mol%), K2CO3 (2.0 equiv.), and air (1 atm) in DMF at 110  °C for 12 h affords the corresponding ortho‐arylether product in 88% yield (Scheme 11.109). O F3C O F3C

N H 0.1 mmol

+ tBu

OH

N 1.0 equiv.

11 mol% (CuOH)2CO3

N H O

20 mol% MsOH 2.0 equiv. K2CO3 air (1 atm), DMF, 110 °C, 12 h

N

88% tBu

Scheme 11.109  Cu‐catalyzed ortho‐etherification of benzamide derivative with phenols in air.

Directing‐group‐assisted transition‐metal‐catalyzed ortho‐oxygenation of aryl C─H bonds was also applied in the formation of ortho‐phenol derivatives [104]. In 2012, Rao and coworkers reported preparation of ethyl 2‐hydroxybenzoate derivatives using benzoic ester as effective directing group under ruthenium catalysis with CF3CO2H as the effective hydroxylation reagent,

11.4 ­Formation of C─O Bond

which hydrolyzes automatically to hydroxy group after ortho‐trifluoroacetoxylation. For example, treatment of ethyl benzoate (0.2 mmol, 1 equiv.) with CF3CO2H (0.6 mL) in the presence of ruthenium catalyst (2.5 mol%), F+ oxidant (2.0 equiv.), and trifluoroacetic anhydride (0.4 mL) at 85 °C for 7.5 h affords the target product ethyl 2‐hydroxybenzoate in 73% yield (Scheme 11.110). OEt O

+

2.5 mol% [RuCl2(p-cymene)]2

CF3CO2H

2.0 equiv. Selectfluor (CF3CO)2O (0.4 mL), 85 °C, 7.5 h

0.6 mL

0.2 mmol

OEt O OH 73%

Scheme 11.110  Ru‐catalyzed ortho‐hydroxylation of ethyl benzoate with trifluoroacetic acid.

Ortho‐hydroxylation of aromatic ketones with CF3CO2H was reported by Rao [105] and Dong [106]. In the example of Rao and coworkers reaction of tert‐butyl phenyl ketone (0.3 mmol, 1 equiv.) with CF3CO2H (1.8 mL) in the presence of Pd(OAc)2 (5 mol%), K2S2O8 (2.0 equiv.), and trifluoroacetic anhydride (0.2 mL) at 50 °C for 4 h affords the ortho‐hydroxylated product in 84% yield [105] (Scheme 11.111). In the work of Dong and coworkers treatment of tert‐butyl phenyl ketone (0.3 mmol, 1 equiv.) with PhI(CF3CO2)2 as both the oxidant and hydroxylation reagent (2.0 equiv.) in the presence of Pd(OCOCF3)2 (5 mol%) in DCE (2 mL) at 80  °C for 2 h affords the 2‐hydroxyphenyl ketone product in 81% yield [106] (Scheme  11.112). Reaction pathway of this kind of  transformation was clarified by stoichiometric reactions described in either work. Me

Me Me O

Me +

5 mol% Pd(OAc)2

CF3CO2H

O

2.0 equiv. K2S2O8 (CF3CO)2O (0.2 mL), 50 °C, 4 h

1.8 mL

0.3 mmol

Me Me

OH 84%

Scheme 11.111  Pd‐catalyzed ortho‐hydroxylation of aromatic ketone with trifluoroacetic acid.

Me

Me Me O

+

I

Me

OCOCF3

5 mol% Pd(OCOCF3)2

OCOCF3

DCE (2 mL), 80 °C, 2 h

Me Me O OH

0.4 mmol

2.0 equiv.

81%

Scheme 11.112  Pd‐catalyzed ortho‐hydroxylation of aromatic ketone with PhI(CF3CO2)2.

411

412

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Substrate scope of this ortho‐hydroxylation was expanded to aniline derivatives as reported by Rao and coworkers in 2013 using 2,6‐difluorobenzoyl directing group [107]. Selective mono‐ or di‐ortho‐hydroxylation was achieved simply by controlling the loading of K2S2O8 oxidant (1.0 or 3.0 equiv.) in the presence of ruthenium catalyst (5 mol%), CF3CO2H (1.5 mL), and (CF3CO2)2O (0.5 mL) at 70 °C in the scale of 0.1 mmol (Scheme 11.113). Moreover, further transformation of the ortho‐hydroxylation product affords either dibenzoxazepine or benzoxazole by selective dehydrohalogenation with the fluorine atom on directing group or dehydration with the carbonyl group. H N

F + O

Cl

F CF3CO2H

F

H N

5 mol% Ru(PPh3)3Cl2 1.0 equiv. K2S2O8 (CF3CO)2O (0.5 mL), 70 °C, 13 h

0.1 mmol

O OH 78%

Cl

1.5 mL

F H N

+ O

Cl

CF3CO2H

F

0.1 mmol

OH

5 mol% Ru(PPh3)3Cl2 3.0 equiv. K2S2O8 (CF3CO)2O (0.5 mL), 70 °C, 12 h

F

F H N F

O OH 77%

Cl

1.5 mL

Scheme 11.113  Ru‐catalyzed ortho‐hydroxylation of aniline derivative with trifluoroacetic acid.

11.5 ­Formation of C─S Bond In 2006, Yu and coworkers reported two examples of copper‐mediated ortho‐ sulfenylation of 2‐pyridylbenzene with either PhSH or MeSSMe [86]. Reaction of 2‐pyridylbenzene (0.3 mmol, 1 equiv.) with PhSH (2.0 equiv.) or MeSSMe (2.0 equiv.) in the presence of Cu(OAc)2 (1 equiv.) in MeCN (1 mL) at 130 °C for 24 h affords the ortho‐sulfenylation product in 40 or 71% yield, respectively (Scheme 11.114).

N 0.3 mmol

PhSH 1.0 equiv. Cu(OAc)2 2.0 equiv. + or MeCN (1 mL), 130 °C, 24 h MeSSMe 2.0 equiv.

N SPh 40%

or

N SMe 51% (20% Di)

Scheme 11.114  Cu‐mediated ortho‐sulfenylation of 2‐pyridylbenzene with PhSH or MeSSMe.

Ortho‐sulfonation of 2‐pyridylbenzene with arenesulfonyl chlorides was reported by Dong and coworkers in 2009 [108]. Treatment of 2‐pyridylbenzene

11.5 ­Formation of C─S Bond

(0.2 mmol, 1 equiv.) with p‐toluenesulfonyl chloride (3.0 equiv.) in the presence of Pd(MeCN)2Cl2 (10 mol%) and K2CO3 (2.0 equiv.) in dioxane (1 mL) at 120 °C for 6 h affords the ortho‐sulfonation product in 73% yield (Scheme 11.115). +

N

Me

0.2 mmol

SO2Cl

10 mol% Pd(MeCN)2Cl2

N

2.0 equiv. K2CO3 dioxane (1 mL), 120 °C, 6 h

SO2Ar

3.0 equiv.

73%

Scheme 11.115  Pd‐catalyzed ortho‐sulfonation of 2‐pyridylbenzene with arenesulfonyl chlorides.

Meta‐sulfonation of 2‐pyridylbenzene with arenesulfonyl chlorides in ruthenium catalysis was achieved by Frost and coworkers in 2011 [109]. Reaction of 2‐pyridylbenzene (1.0 mmol, 1 equiv.) with benzenesulfonyl chloride (3.0 equiv.) in the presence of [Ru(p‐cymene)Cl2]2 (5 mol%) and K2CO3 (2.0 equiv.) in MeCN (3 mL) at 115  °C for 15 h affords the meta‐sulfonation product in 70% yield (Scheme 11.116). It is proposed that Ru catalyst coordinates and cleaves ortho‐ aryl C─H bond to form ortho‐aryl–Ru complex, activating the meta‐aryl C─H bond which is then sulfonated by sulfonyl chloride through an SEAr process. +

N

SO2Cl

5 mol% [Ru(p-cymene)Cl2]2

PhO2S

N

2.0 equiv. K2CO3 MeCN (3 mL), 115 °C, 15 h

3.0 equiv.

1.0 mmol

70%

Scheme 11.116  Ru‐catalyzed ortho‐sulfonation of 2‐pyridylbenzene with arenesulfonyl chlorides.

Cu‐catalyzed ortho‐pyridium fluoride salt trifluoromethylsulfenylation of benzamide derivatives with bis(trifluoromethyl) disulfide using 8‐aminoquinoline as directing group was reported by Daugulis and coworkers in 2012 [110]. For example, treatment of benzamide (0.25 mmol, 1 equiv.) with bis(trifluoromethyl) disulfide (1.0 equiv.) in the presence of Cu(OAc)2 (0.5 equiv.) in DMSO (1 mL) at 100  °C for 7 h and 40 min affords the di‐ ortho‐trifluoromethylsulfenylation product in 74% yield (Scheme 11.117). O

tBu

N H 0.25 mmol

+ F3CS–SCF3 N 1.0 equiv.

SCF3

0.5 equiv. Cu(OAc)2 DMSO (1mL) 100 °C, 7 h 40 min

tBu

O

N H N SCF3 74%

Scheme 11.117  Cu‐catalyzed ortho‐trifluoromethylsulfenylation of benzamide derivative with bis(trifluoromethyl) disulfide.

413

414

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

11.6 ­Formation of C─Halogen Bond 11.6.1 Fluorination

Soon after the establishment of ortho‐acetoxylation of aryl C─H bonds applying pyridine or oxime as an effective directing group via Pd(II)/Pd(IV) catalytic cycle, Sanford and coworkers reported the ortho‐fluorination of aryl C─H bonds using electrophilic F+ oxidant in 2006 [111]. For example, applying either electron‐rich 3‐methylpyridine or electron‐deficient 3‐trifluoromethylpyridine as directing group, ortho‐fluorination product is obtained in moderate yield by treatment of 2‐phenylpyridine derivative (1 equiv.) with N-fluoro-pyridinium tetrafluoroborate salt (2.8 equiv.) in the presence of Pd(OAc)2 (10 mol%) in mixtures of benzotrifluoride (26.2 mL) and MeCN (0.25 mL) under microwave irradiation at 150 °C. In the proposed mechanism, Pd(II) catalyst coordinates with pyridine directing group and cleaves ortho‐aryl C─H bond to form aryl‐Pd(II) intermediate. Oxidation of this aryl‐Pd(II) intermediate by F+ oxidant gives key ­aryl‐Pd(IV)–F intermediate. Reductive elimination of aryl and fluoride group from strongly electrophilic Pd(IV) center affords the target ortho‐fluorination product and Pd(II) species to fulfill the catalytic cycle (Scheme 11.118). Benzylamine derivatives were available for ortho‐fluorination of F+ oxidant through Pd(IV) species as reported by Yu and coworkers in 2009 [112]. Di‐ortho‐fluorination product is obtained in 84% yield by treatment of N‐benzyl‐ 1,1,1‐trifluoromethanesulfonamide (0.2 mmol, 1 equiv.) with N-fluoro-2,4,6trimethylpyridinium triflate salt (3.0 equiv.) in the presence of Pd(OTf )2·2H2O (10 mol%) and NMP (0.5 equiv.) in benzotrifluoride (0.5 mL) at 120 °C for 4 h. Monofluorination occurs applying either 2‐methylbenzylamine or 2‐trifluoromethylbenzylamine derivative (0.2 mmol) to afford the corresponding product in 82 or 88% yield, respectively, under similar conditions (Scheme 11.119). This ortho‐fluorination of aryl C─H bonds through Pd(II)/Pd(IV) catalytic cycle was also applied for benzamide derivatives using 4‐(trifluoromethyl)‐ perfluoroaniline as effective directing group as reported by Yu and coworkers in 2011 [113]. For example, treatment of N‐(2,3,5,6‐tetrafluoro‐4‐(trifluoromethyl) phenyl)benzamide (0.1 mmol, 1 equiv.) with N-fluoro-2,4,6-trimethylpyridinium triflate (1.5 equiv.) in the presence of Pd(OTf)2(MeCN)4 (10 mol%) and NMP (20 mol%) in MeCN (2 mL) at 120  °C for 24 h affords mono‐ortho‐fluorinated product in 84% yield (Scheme 11.120). Copper catalyst and nucleophilic AgF as fluorinating reagent were applied for ortho‐aryl C─H fluorination of benzamide derivatives using 8‐aminoquinoline directing group, as reported by Daugulis and coworkers in 2013 [114]. Selective mono‐ or di‐ortho‐fluorination was achieved by controlling the amount of copper catalyst and fluorinating reagent AgF and NMO (N-methylmorpholine N-oxide), and reaction time exemplified by treatment of

Me

Me

BF4 +

N

10 mol% Pd(OAc)2

N F

2.8 equiv.

0.58 mmol F3C +

0.59 mmol

F 52% F3C

BF4 N

N

PhCF3 (26.2 mL) MeCN (0.25 mL) mw, 150 °C, 1.5 h

10 mol% Pd(OAc)2

N F

N

PhCF3 (26.2 mL) MeCN (0.25 mL) mw, 150 °C, 2 h

2.8 equiv.

F 55%

PdII

N

N Reductive elimination

F

C H activation

N

PdII

N IV

Pd

BF4

Oxidation

N F

F

Scheme 11.118  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of 2‐pyridylbenzene with N-fluoropyridinium tetrafluoroborate.

NHTf

+ Me

0.2 mmol

R NHTf + Me 0.2 mmol

Me OTf N F Me 3.0 equiv.

Me OTf N F Me 1.5 equiv.

10 mol% Pd(OTf)2• 2H2O

F NHTf

0.5 equiv.NMP PhCF3 (0.5 mL), 120 °C, 4 h

F 84%

R 10 mol% Pd(OTf)2• 2H2O

NHTf 0.5 equiv. NMP F DCE (0.5 mL), 120 °C R: Me or CF3 Yield: 82% (0.5 h) or 88% (4 h)

Scheme 11.119  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of benzylamine derivatives with N-fluoro-2,4,6-trimethylpyridinium triflate.

416

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group F O

F

CF3 + Me

N H

F

Me OTf N F Me

F 0.1 mmol

F O

10 mol% Pd(OTf)2(MeCN)4 20 mol% NMP MeCN (2 mL), 120 °C, 24 h

F

CF3

N H

F F

F

1.5 equiv.

84%

Scheme 11.120  Pd(II)/Pd(IV)‐catalyzed ortho‐trifluoromethylation of benzamide derivatives with N-fluoro-2,4,6-trimethylpyridinium triflate.

4‐trifluoromethylbenzamide derivative (0.25  mmol, 1  equiv.) with AgF (4.0 equiv.) in the presence of CuI (15 mol%) and NMO (5.0 equiv.) in DMF (1 mL) at 80 °C for 0.5 h affords mono‐ortho‐fluorination product in 71% yield. Increasing the loading of CuI to 20mol%, AgF to 5.0 equiv., NMO to 8.0 equiv., and reaction time of 1.5h with addition of an pyridine (2.0 equiv.) produces di‐ortho‐fluorination product in 67% yield (Scheme 11.121). O

F3C

N H

+ AgF N 4.0 equiv.

0.25 mmol O

F3C

N H

+ AgF N

0.25 mmol

O

15 mol% CuI

N H F 71%

5.0 equiv. NMO DMF (1mL), 80 °C, 0.5 h F3C

20 mol% CuI 2.0 equiv. pyridine

8.0 equiv. NMO DMF (1 mL), 80 °C, 1.5 h F3C 5.0 equiv.

F

N

O N H

F 67%

N

Scheme 11.121  Cu‐catalyzed ortho‐trifluoromethylation of benzamide derivatives with AgF.

11.6.2 Chlorination

Directing‐group‐assisted ortho‐functionalization of aryl C─H bonds through Pd(II)/Pd(IV) catalytic cycle also introduces other halides more easily compared with fluorination, which is the most difficult heteroatom to reductively eliminate from Pd(IV) center due to it possessing of the highest electronegativity. In 2004, Sanford and coworkers reported ortho‐chlorination of 2‐pyridylbenzene with NCS serving as both oxidant and chlorinating reagent [97]. Treatment of benzo[h]quinoline (0.89 mmol) with NCS (1.0 mmol) in the presence of ortho‐aryl‐Pd(II) complex prepared from benzo[h]quinoline and Pd(OAc)2 (0.0079 mmol) in MeCN (7.5 mL) at 100  °C for 3 days affords the corresponding ortho‐chlorination product in 95% yield. In the proposed mechanism, Pd(II) catalyst coordinates with pyridine directing

11.6 ­Formation of C─Halogen Bond

group and cleaves ortho‐aryl C─H bond to form aryl‐Pd(II) intermediate. Oxidation of this aryl‐Pd(II) intermediate by NCS gives key aryl‐Pd(IV)–Cl intermediate. Reductive elimination of aryl and chloride group from Pd(IV) center affords the desired ortho‐chlorination product and Pd(II) species to fulfill the catalytic cycle (Scheme 11.122).

N Pd OAc O +

N

N Cl

2

0.0079 mmol

N

MeCN (7.5 mL), 100 °C, 3 days

Cl

O 1.0 mmol

0.89 mmol

95%

PdII

N

N Reductive elimination

Cl

C H activation

N PdII

N PdIV Cl

Oxidation

O N Cl O

Scheme 11.122  Pd(II)/Pd(IV)‐catalyzed ortho‐chlorination of benzo[h]quinoline with NCS.

A full article of this Pd(II)/Pd(IV)‐catalyzed ortho‐chlorination of aryl C─H bonds was reported by the same group in 2006 [115]. Details of directing‐ group‐assisted chlorination at ortho‐position or electrophilic chlorination through SEAr process at ortho- and para‐positions were described. Ortho‐chlorination occurs well when applying either pyridine, O‐methyl oxime, or amide as directing group with NCS as both oxidant and chlorine source in palladium catalysis (Scheme 11.123).

417

418

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group Me

O

Me N

5 mol% Pd(OAc)2

+

N Cl

N

HOAc, 100 °C,12 h

Cl

O 1.2 equiv.

65% O

Me N

OMe

MeO

+

N Cl

HOAc (4.6 mL), 100 °C, 12 h

O 1.1 equiv.

0.558 mmol

Me

5 mol% Pd(OAc)2

N MeO

OMe

Cl 58%

Me

H Me N Cl

Me

N

Me

O

67%

Cl

O

77%

Scheme 11.123  Pd(II)/Pd(IV)‐catalyzed ortho‐chlorination of arenes with NCS.

Ortho‐chlorination of aniline derivatives using CuCl2 as chlorinating reagent was reported by Shi and coworkers in 2006 [116]. For example, treatment of N‐acylaniline (0.5 mmol, 1 equiv.) with CuCl2 (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) and Cu(OAc)2 (2.0 equiv.) in DCE (4 mL) at 90 °C for 48 h affords the N‐acyl‐2‐chloroaniline in 80% yield (Scheme 11.124). H N

Me

+

CuCl2

O 0.5 mmol

10 mol% Pd(OAc)2

H N

2.0 equiv. Cu(OAc)2 DCE (4 mL), 90 °C, 48 h

Cl

2.0 equiv.

Me O

80%

Scheme 11.124  Pd‐catalyzed ortho‐chlorination of arenes with CuCl2.

Economical CuCl2 was found as the effective catalytic chlorinating reagent in ortho‐chlorination of 2‐pyridylbenzene using atmospheric O2 as oxidant, as reported by Yu and coworkers in 2006 [86]. For example, treatment of 2‐phenylpyridine (0.3 mmol, 1 equiv.) with CuCl2 (0.2 equiv.) in the presence of O2 (1 atm) in DCE (1 mL) at 100 °C for 24 h affords mono‐ortho‐chlorinated product in 63% yield along with 23% yield of di‐ortho‐chlorinated product. Simply by raising the reaction temperature to 130 °C, a 92% yield of di‐ortho‐chlorinated product is obtained (Scheme 11.125). Benzonitrile derivatives were ortho‐chlorinated with NCS through Pd(II)/ Pd(IV) catalytic cycle using nitrile as effective directing group, as reported by Sun and coworkers in 2013 [117]. For example, treatment of benzonitrile (0.5 mmol) with NCS (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%) and

11.6 ­Formation of C─Halogen Bond Cl N

+ CuCl2

0.3 mmol

0.2 equiv.

N

O2 (1atm) DCE (1mL), 100 °C, 24h

+

N Cl 23%

Cl 63% Cl

N

+ CuCl2

0.3 mmol

0.2 equiv.

N

O2 (1atm) DCE (1 mL), 130 °C, 24 h

Cl 92%

Scheme 11.125  CuCl2‐catalyzed ortho‐chlorination of 2‐pyridylbenzene using O2 (1 atm).

TsOH (0.5 equiv.) in DCE (2 mL) at 70 °C for 12 h affords the corresponding ortho‐chlorination product in 90% yield (Scheme 11.126). O

CN +

N Cl O 1.1 equiv.

0.5 mmol

5 mol% Pd(OAc)2

CN

0.5 equiv. TsOH DCE (2 mL), 70 °C, 12 h

Cl 90%

Scheme 11.126  Pd‐catalyzed ortho‐chlorination of benzonitrile with NCS.

11.6.3 Bromination

Formation of aryl–bromine bond by directing‐group‐assisted ortho‐aryl C─H halogenation with NXS via Pd(II)/Pd(IV) catalysis was also reported by Sanford and coworkers in 2004 [97]. Treatment of benzo[h]quinoline (0.89 mmol) with NBS (0.94 mmol) in the presence of ortho‐aryl‐Pd(II) complex prepared from benzo[h]quinoline and Pd(OAc)2 (0.0044 mmol) in MeCN (7.5 mL) at 100 °C for 1.5 days affords the corresponding ortho‐bromination product in 93% yield (Scheme 11.127).

N Pd OAc O N 0.89 mmol

+

N Br O 0.94 mmol

2

0.0044 mmol MeCN (7.5 mL), 100 °C, 1.5 days

N Br 93%

Scheme 11.127  Pd(II)/Pd(IV)‐catalyzed ortho‐bromination of benzo[h]quinoline with NBS.

419

420

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

In the full report of ortho‐halogenation of aryl C─H bonds reported by Sanford and coworkers in 2006 [115], some other substrates include 2‐phenylpyridine derivatives, O‐methyl oxime derivatives, etc. Treatment of either electron‐rich 3‐(2‐pyridyl)toluene (1.2 mmol, 1 equiv.) or electron‐poor 3‐(2‐pyridyl)benzotrifluoride with NBS (1.2 equiv. or more) in the presence of Pd(OAc)2 (5 mol%) in MeCN or HOAc at 100 to 120 °C for 12 h affords the target ortho‐bromination product, respectively. Reaction of O‐methyl oxime derivative with NBS under palladium catalysis in HOAc produces ortho‐bromoarene as well (Scheme 11.128). O F3C

+

N

N Br

5 mol% Pd(OAc)2

F3C

N

HOAc or MeCN, 100–120 °C, 12 h

Br

O 1.2–2.0 equiv.

63% Me Me

N

N Br

Br

MeO

51%

OMe

72%

Scheme 11.128  Pd(II)/Pd(IV)‐catalyzed ortho‐bromination of arenes with NBS.

Ortho‐bromination of 2‐pyridylbenzene promoted by copper salt using 1,2‐ dibromoethane as brominating reagent was reported by Yu and coworkers in 2006 [86]. Reaction of 2‐phenylpyridine (0.3 mmol, 1 equiv.) with 1,2‐dibromoethane (1 mL) in the presence of Cu(OAc)2 (1.0 equiv.) in air at 130 °C for 24 h affords mono‐ and di‐ortho‐bromination product in 65 or 20% yield, respectively (Scheme 11.129).

N 0.3 mmol

+ Br 1 mL

Br

Br

1.0 equiv. Cu(OAc)2 Air, 130 °C, 24 h

N Br 65%

+

N Br 20%

Scheme 11.129  Cu‐mediated ortho‐bromination of 2‐pyridylbenzene with 1,2‐dibromoethane.

Aniline derivatives were available for ortho‐bromination with NBS via Pd(II)/ Pd(IV) catalysis, as reported by Bedford and coworkers in 2011 [118]. For example, treatment of N‐acylaniline (0.5 mmol, 1 equiv.) with NBS (1.04 equiv.) in the presence of Pd(OAc)2 (5 mol%) and TsOH·H2O (0.5 equiv.) in toluene (2 mL) at room temperature for 1 h affords the mono‐ortho‐bromination product in 80% yield (Scheme 11.130).

11.6 ­Formation of C─Halogen Bond O

H N

Me

+

N Br

O O 1.04 equiv.

0.5 mmol

5 mol% Pd(OAc)2

H N

0.5 equiv. TsOH · H2O Toluene (2 mL), rt, 1 h

Br

Me O

80%

Scheme 11.130  Pd(II)/Pd(IV)‐catalyzed ortho‐bromination of aniline derivative with NBS.

Ortho‐bromination of benzonitrile derivatives with NBS was reported by Sun and coworkers in 2013 [117]. For example, treatment of benzonitrile (0.5 mmol, 1 equiv.) with NBS (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%) and TsOH (0.5 equiv.) in DCE (2 mL) at 70 °C for 12 h affords the corresponding ortho‐bromination product in 85% yield (Scheme 11.131). O

CN +

N Br O 1.1 equiv.

0.5 mmol

5 mol% Pd(OAc)2

CN

0.5 equiv. TsOH DCE (2 mL), 70 °C, 12 h

Br 85%

Scheme 11.131  Pd‐catalyzed ortho‐bromination of benzonitrile with NBS.

Meta‐bromination of 2‐pyridylbenzene derivatives was also achieved by Greaney and coworkers in 2015 [119]. For example, treatment of 2‐phenylpyridine (0.5 mmol, 1 equiv.) with tetrabutylammonium tribromide (3.0 equiv.) in the presence of ruthenium catalyst (5 mol%), additive MesCO2H (0.3 equiv.), and K2CO3 (2.0 equiv.) in dioxane (3 mL) at 110 °C for 20 h affords the mono‐ meta‐bromination product in 76% yield (Scheme 11.132). It is proposed that Ru catalyst coordinates with pyridine group and cleaves ortho‐aryl C─H bond to form ortho‐aryl–Ru complex, in which meta‐aryl C─H bond of 2‐pyridyl­ benzene is activated. Bromination of this activated meta‐aryl C─H bond produces meta‐bromoarene derivatives. Further transformation of these meta‐bromoarene derivatives via cross‐coupling reactions such as Suzuki– Miyaura coupling, Heck–Mizoroki coupling, etc. in one pot gives versatile meta‐arylation or alkenylation products conveniently.

N 0.5 mmol

+

nBuN

Br3

3.0 equiv.

5 mol% [Ru(p-cymene)Cl2]2

Br

0.3 equiv. MesCO2H 2.0 equiv.K2CO3 Dioxane (3 mL), 110 °C, 20 h

Scheme 11.132  Ru‐catalyzed meta‐bromination of 2‐pyridylbenzene with tetrabutylammonium tribromide.

N 76%

421

422

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

11.6.4 Iodination

Ortho‐iodination of aryl C─H bonds assisted by a directing group was also reported by Sanford and coworkers in 2006, using NIS as both the oxidant and iodinating reagent [115]. Treatment of 2‐phenylpyridine derivative with NIS (1.2 equiv.) in the presence of Pd(OAc)2 (5 mol%) in MeCN at 100 °C for 12 h affords the target ortho‐iodination product in 79% yield. O‐Methyl oxime or 3,3′-dimethylazobenzene is also available for ortho‐iodination with NIS in HOAc (Scheme 11.133). Me

O

Me N

+

5 mol% Pd(OAc)2

N I

N

MeCN, 100 °C, 12 h I 79%

O 1.2 equiv. O

Me N

OMe

+

MeO

N I

Me

5 mol% Pd(OAc)2 HOAc (4.6 mL), 100 °C, 12 h

O 1.1 equiv.

0.558 mmol

N I 46%

MeO

Me Me

N

OMe

N

I 41%

Scheme 11.133  Pd(II)/Pd(IV)‐catalyzed ortho‐iodination of arenes with NIS.

Ortho‐iodination of 2‐pyridylbenzene was achieved by applying molecular iodine (I2) as iodinating reagent promoted by copper salt as reported by Yu and coworkers in 2006 [86]. Treatment of 2‐phenylpyridine (0.3 mmol, 1 equiv.) with I2 (1.0 equiv.) in the presence of Cu(OAc)2 (1.0 equiv.) in DCE (1 mL) at 100  °C for 8 h affords mono‐ and di‐ortho‐iodination product in 61 and 10% yield, respectively (Scheme 11.134). I N

+

I2

1.0 equiv. Cu(OAc)2

N

DCE (1 mL), 100 °C, 8 h

+

I 0.3 mmol

1.0 equiv.

61%

Scheme 11.134  Cu‐mediated ortho‐iodination of 2‐pyridylbenzene with I2.

N I 10%

11.6 ­Formation of C─Halogen Bond

Benzoic acid derivatives were available for ortho‐iodination with IOAc as iodinating reagent generated from I2 and PhI(OAc)2 in situ, as reported by Yu and coworkers in 2008 [120]. Treatment of benzoic acid (0.2 mmol, 1 equiv.) with I2 (1.5 equiv.) and PhI(OAc)2 (1.5 equiv.) in the presence of Pd(OAc)2 (5 mol%) in DMF (1 mL) at 100 °C for 36 h affords the corresponding di‐ortho‐ iodination product in 85% yield. Reaction of 2‐substituted benzoic derivatives (0.2 mmol, 1 equiv.) such as 2‐methylbenzoic acid or 2‐bromobenzoic acid with I2 (1.0 equiv.) and PhI(OAc)2 (1.0 equiv.) under similar conditions for 24 h produces mono‐ortho‐iodination product in 90 or 85% yield, respectively (Scheme 11.135).

CO2H + 0.2 mmol

I2

+

PhI(OAc)2

1.5 equiv.

5 mol% Pd(OAc)2

I

DMF (1 mL), 100 °C, 36 h

1.5 equiv.

CO2H I 85% R

R CO2H

0.2 mmol

+

+

I2

PhI(OAc)2

1.0 equiv.

CO2H

5 mol% Pd(OAc)2 DMF (1 mL), 100 °C, 24 h

I R: Me or Br Yield: 90 or 85%

1.0 equiv.

Scheme 11.135  Pd‐catalyzed ortho‐iodination of benzoic acids with IOAc.

Applying this method, phenylethylamine derivatives were ortho‐iodinated as reported by the same group in 2008 [121], by IOAc generated from I2 and PhI(OAc)2 in situ. For example, reaction of 1,1,1‐trifluoro‐N‐phenethylmethanesulfonamide (0.2  mmol, 1  equiv.) with I2 (2.0  equiv.) and PhI(OAc)2 (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) and NaHCO3 (1.0 equiv.) in DMF (1 mL) at 130 °C for 72 h affords the corresponding di‐ortho‐iodination product in 56% yield (Scheme 11.136).

NHTf 0.2 mmol

+

I2

+

2.0 equiv.

PhI(OAc)2 2.0 equiv.

10 mol% Pd(OAc)2 1.0 equiv. NaHCO3 DMF (1 mL), 130 °C, 72 h

I

I 56%

NHTf

Scheme 11.136  Pd‐catalyzed ortho‐iodination of phenylethylamine derivatives with I2 and PhI(OAc)2.

423

424

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

Benzonitrile derivatives were available for ortho‐iodination with NIS as reported by Sun and coworkers in 2013 [117]. For example, treatment of benzonitrile (0.5 mmol, 1 equiv.) with NIS (1.1 equiv.) in the presence of Pd(OAc)2 (5 mol%) and TsOH (0.5 equiv.) in DCE (2 mL) at 70 °C for 12 h affords the corresponding ortho‐iodination product in 72% yield (Scheme 11.137). O CN +

0.5 mmol

N

CN

5 mol% Pd(OAc)2 I

O 1.1 equiv.

0.5 equiv. TsOH DCE (2 mL), 70 °C, 12 h

I 72%

Scheme 11.137  Pd‐catalyzed ortho‐iodination of benzonitrile with NIS.

Moreover, enantioselective ortho‐aryl C─H iodination for asymmetric synthesis of chiral diarylmethylamine derivatives was established by Yu and coworkers in 2013, applying protected amino acid as chiral auxiliary [122]. For example, treatment of symmetrical N‐(di‐o‐tolylmethyl)‐1,1,1‐trifluoromethanesulfonamide (0.2 mmol, 1 equiv.) with I2 (3.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), chiral mono‐N‐benzoyl‐protected amino acid Bz‐Leu‐OH (40 mol%), CsOAc (3.0 equiv.), Na2CO3 (3.0 equiv.), and DMSO (15 equiv.) in t‐AmylOH (2 mL) at 30 °C for 48 h affords the desymmetricalized mono‐ortho‐ iodination product a chiral diarylmethylamine derivative, in 80% yield with 98% ee value (Scheme 11.138). Me

NHTf Me +

0.2 mmol

I2

3.0 equiv.

10 mol% Pd(OAc)2, 40 mol% Bz-Leu-OH 3.0 equiv. CsOAc, 3.0 equiv. Na2CO3 15 equiv. DMSO, tAmylOH (2 mL), 30 °C, 48 h

Me

NHTf Me * I

80%, 98ee

Scheme 11.138  Pd‐catalyzed asymmetric ortho‐iodination of diarylmethylamine with I2.

11.7 ­Summary In this chapter, it is described how alkylation, trifluoromethylation, arylation, alkenylation, carbonylation, alkynylation, cyanidation, and formations of aryl C─heteroatom (heteroatom = N, O, S, F, Cl, Br, I) bond via transition‐metal‐ catalyzed oxidation of aryl C─H bonds are assisted by directing groups.

11.7 ­Summar

Although these described reactions still lie in between reaction types two and three basically, which are able to occur but not so well with working mechanism and not fully clarified as mentioned in Chapters 9 and 10, exploration and understanding of oxidation of aryl C─H bonds in the presence of directing groups are far ­better than those without directing groups through the rapid and intense development in the recent decade. The most attractive characteristics of this directing‐group‐assisted oxidation is that the regioselectivity can be controlled to afford specific ortho‐ or even meta‐regiomer product, which is usually very challenging for normal arenes without directing groups. Ortho‐directing aryl C─H oxidation has been developed so well that almost any target aryl–carbon or aryl– heteroatom bond is produced in one step applying all the old and new directing groups containing almost every functional group from common to special. Besides, meta‐directing C─H activation and oxidation have been developed very recently, applying different strategies such as applying nitrile‐containing template to deliver the Pd catalyst to the vicinity of meta‐ aryl C─H bond, using a traceless carboxylic acid as directing group by carboxylation and decarboxylation, utilizing norbornene as a transient mediator combined with appropriate ligand to fulfill the meta‐aryl C─H functionalization, and activating meta‐aryl C─H bond by ortho‐metalation followed by SE Ar process. Applying this meta‐directing C─H activation and oxidation strategy, a lot of meta‐oxidation products are afforded, which are hardly accessible conventionally, as exemplified by regioselective oxidation of meta‐aryl C─H bond of aniline derivatives, which is strong ortho‐ and para‐oriented via either SE Ar process or C─H activation. In addition, some stereoselective oxidation of aryl C─H bonds assisted by a directing group is achieved by desymmetricalization using protected amino acid as chiral auxiliary. The rapid development of this strategy on directing‐group‐assisted transition‐metal‐catalyzed C─H oxidation stems from the understanding and design of the reaction mechanism and catalytic cycle. Although ortho‐alkylation of aniline derivatives with methyl iodide via Pd(II)/Pd(IV) catalysis probably was disclosed more than 30 years ago, widely applying this Pd(II)/Pd(IV) catalysis to accomplish versatile bond formation including fluorination and trifluoromethylation of difficulty for reductive elimination was conducted gradually in the recent decade upon the isolation and characterization of the specified Pd(IV) complex. Besides, the nature of the ligand, the other side of the coin to the catalysis, such as protected chiral amino acids is also critical to fulfill some ortho‐, meta‐, or enantioselective oxidation of C─H bonds. Further improvement of these novel oxidative reactions, especially applying atmospheric O2 or air as terminal oxidant, is still highly desired for their applications in either laboratory synthesis or industrial production.

425

426

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group DG 11.3 (Sulfon)amide

11.1

H2N 11.2.1

Introduction DG Alkyl

DG PhI(OAc)2 HOAc

H2C

11.4

AcO

Alkyl RO

CF3

DG HO 11.2.3 PhSH MeSSMe ArSO2Cl CF3SSCF3

R FG

DG 11.2.2

CF3CO2–

CHR

DG

DG ROH

R FG

FG CF3

DG FG

DG RS

11.5

DG

DG

FG DG

ArSO2Cl

DG

RS

H

11.2.4 DG

F+, AgF

F

11.6.1

DG H

DG NCS, CuCl2

Cl

11.6.2

DG O 11.2.5

R

FG

O R

DG NBS

Br

DG O 11.6.3 DG

DG NIS, IOAc, I2

I

OH

CO or CO2 FG

11.2.6 11.6.4

Summary

11.7

DG 11.2.7

N

TMSCN MeCN

References [1] Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759–5760. [2] Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850–4853. [3] Wang, X.‐C.; Gong, W.; Fang, L.‐Z.; Zhu, R.‐Y.; Li, S.; Engle, K. M.; Yu, J.‐Q.

Nature 2015, 519, 334–338.

References

[4] Shen, P.‐X.; Wang, X.‐C.; Wang, P.; Zhu, R.‐Y.; Yu, J.‐Q. J. Am. Chem. Soc.

2015, 137, 11574–11577.

[5] Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem. Int. Ed. [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

[23] [24] [25] [26] [27] [28] [29] [30] [31]

2009, 48, 6045–6048. Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877–5884. Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084–12085. Zhang, Y.‐H.; Shi, B.‐F.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2009, 48, 6097–6100. Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964–5965. Wang, Z.; Kuninobu, Y.; Kanai, M. J. Am. Chem. Soc. 2015, 137, 6140–6143. Cheng, G.; Li, T.‐J.; Yu, J.‐Q. J. Am. Chem. Soc. 2015, 137, 10950–10953. Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248–1250. Li, Y.; Li, B.‐J.; Wang, W.‐H.; Huang, W.‐P.; Zhang, X.‐S.; Chen, K.; Shi, Z.‐J. Angew. Chem. Int. Ed. 2011, 50, 2115–2119. Chen, X.; Goodhue, C. E.; Yu, J.‐Q. J. Am. Chem. Soc. 2006, 128, 12634–12635. Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. Kakiuchi, F.; Kochi, T.; Mizushima, E.; Murai, S. J. Am. Chem. Soc. 2010, 132, 17741–17750. Wang, X.; Truesdale, L.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 3648–3649. Zhang, X.‐G.; Dai, H.‐X.; Wasa, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2012, 134, 11948–11951. Zhang, L.‐S.; Chen, K.; Chen, G.; Li, B.‐J.; Luo, S.; Guo, Q.‐Y.; Wei, J.‐B.; Shi, Z.‐J. Org. Lett. 2013, 15, 10–13. Miura, M.; Feng, C.‐G.; Ma, S.; Yu, J.‐Q. Org. Lett. 2013, 15, 5258–5261. Shang, M.; Sun, S.‐Z.; Wang, H.‐L.; Laforteza, B. N.; Dai, H.‐X.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2014, 53, 10439–10442. (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331; (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 112341–11241. Xiao, B.; Fu, Y.; Xu, J.; Gong, T.‐J.; Dai, J.‐J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468–469. Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597. Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 463–466. Daugulis, O.; Zaitsev, V. G. Angew. Chem. Int. Ed. 2005, 44, 4046–4048. Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657–3659. Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947–4949. Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211–5213. Chiong, H. A.; Pham, Q.‐N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879–9884. Li, W.; Xu, Z.; Sun, P.; Jiang, X.; Fang, M. Org. Lett. 2011, 13, 1286–1289.

427

428

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

[32] Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109–4112. [33] Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887–5890. [34] Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron Lett.

1999, 40, 5345–5348.

[35] Caron, L.; Campeau, L.‐C.; Fagnou, K. Org. Lett. 2008, 10, 4533–4536. [36] (a) Ackermann, L. Org. Process Res. Dev. 2015, 19, 260–269; (b) Ackermann,

L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035.

[37] Ackermann, L. Org. Lett. 2005, 7, 3123–3125. [38] (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc.

[39] [40] [41] [42]

[43] [44]

[45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55]

2003, 125, 1698–1699; (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936–5945. Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554–5558. Engle, K. M.; Thuy‐Boun, P. S.; Dang, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2011, 133, 18183–18193. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.‐Q. J. Am. Chem. Soc. 2013, 135, 18056–18059. (a) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang, R.‐Y.; Movassaghi, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2014, 136, 10807–10813; (b) Yang, G.; Butt, N.; Zhang, W. Chin. J. Catal., 2016, 37, 98–101. Miura, M.; Tsuda, T.; Satoh, T.; Pivsa‐Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211–5215. 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. J. Am. Chem. Soc. 2002, 124, 1586–1587. Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666–7673. Wang, D.‐H.; Engle, K. M.; Shi, B.‐F.; Yu, J.‐Q. Science, 2010, 327, 315–319. Engle, K. M.; Wang, D.‐H.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2010, 49, 6169–6173. Dastbaravardeh, N.; Toba, T.; Farmer, M. E.; Yu, J.‐Q. J. Am. Chem. Soc. 2015, 137, 9877–9884. Lu, Y.; Wang, D.‐H.; Engle, K. M.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 5916–5921. Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372–2375. Padala, K.; Pimparkar, S.; Madasamy, P.; Jeganmohan, M. Chem. Commun. 2012, 48, 7140–7142. Graczyk, K.; Ma, W.; Ackermann, L. Org. Lett. 2012, 14, 4110–4113. Gandeepan, P.; Cheng, C.‐H. J. Am. Chem. Soc. 2012, 134, 5738–5741. Li, G.; Leow, D.; Wan, L.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2013, 52, 1245–1247. Shi, B.‐F.; Zhang, Y.‐H.; Lam, J. K.; Wang, D.‐H.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 460–461.

References

[56] Leow, D.; Li, G.; Mei, T.‐S.; Yu, J.‐Q. Nature 2012, 486, 518–522. [57] Dai, H.‐X.; Li, G.; Zhang, X.‐G.; Stepan, A. F.; Yu, J.‐Q. J. Am. Chem. Soc.

2013, 135, 7567–7571.

[58] Lee, S.; Lee, H.; Tan, K. L. J. Am. Chem. Soc. 2013, 135, 18778–18781. [59] Tang, R.‐Y.; Li, G.; Yu, J.‐Q. Nature 2014, 507, 215–220. [60] Bera, M.; Modak, A.; Patra, T.; Maji, A.; Maiti, D. Org. Lett. 2014, 16,

5760–5763.

[61] Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D. Angew. Chem. Int. Ed. 2015, 54,

8515–8519.

[62] Deng, Y.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2015, 54, 888–891. [63] Li, S.; Ji, H.; Cai, L.; Li, G. Chem. Sci. 2015, 6, 5595–5600. [64] Chu, L.; Shang, M.; Tanaka, K.; Chen, Q.; Pissarnitski, N.; Streckfuss, E.; Yu,

J.‐Q. ACS Cent. Sci. 2015, 1, 394–399.

[65] Bag, S.; Patra, T.; Modak, A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.;

[ 66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84]

Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D. J. Am. Chem. Soc. 2015, 137, 11888–11891. Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett. 1995, 681‐682. Oyamada, J.; Jia, C.; Fujiwara, Y.; Kitamura, T. Chem. Lett. 2002, 380–381. Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572–4576. Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050–12051. Han, W.; Zhang, G.; Li, G.; Huang, H. Org. Lett. 2014, 16, 3532–3535. Chatani, N.; Yorimitsu, S.; Asaumi, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2002, 67, 7557–7560. Asaumi, T.; Chatani, N.; Matsuo, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2003, 68, 7538–7540. Yin, Z.; Sun, P. J. Org. Chem. 2012, 77, 11339–11344. Giri, R.; Yu, J.‐Q. J. Am. Chem. Soc. 2008, 130, 14082–14083. Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4688–4690. Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2011, 133, 1251–1253. Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2002, 124, 8528–8529. Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250–3252. Ano, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354–357. Kim, S. H.; Park, S. H.; Chang, S. Tetrahedron 2012, 68, 5162–5166. Dong, J.; Wang, F.; You, J. Org. Lett. 2014, 16, 2884–2887. Shang, M.; Wang, H.‐L.; Sun, S.‐Z.; Dai, H.‐X.; Yu, J.‐Q. J. Am. Chem. Soc. 2014, 136, 11590–11593. Liu, Y.‐H.; Liu, Y.‐J.; Yan, S.‐Y.; Shi, B.‐F. Chem. Commun. 2015, 51, 11650–11653. Zhang, L.‐B.; Hao, X.‐Q.; Liu, Z.‐J.; Zheng, X.‐X.; Zhang, S.‐K.; Niu, J.‐L.; Song, M.‐P. Angew. Chem. Int. Ed. 2015, 54, 10012–10015.

429

430

11  Oxidation of Aryl sp2C─H Bond Assisted by Directing Group

[85] Zhang, J.; Chen, H.; Lin, C.; Liu, Z.; Wang, C.; Zhang, Y. J. Am. Chem. Soc.

2015, 137, 12990–12996.

[86] Chen, X.; Hao, X.‐S.; Goodhue, C. E.; Yu, J.‐Q. J. Am. Chem. Soc. 2006, 128,

6790–6791.

[87] Shen, Z. Chem. Eur. J. 2013, 19, 16880–16886. [88] Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,

14560–14561.

[89] Jordan‐Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109]

[110] [111]

J. Am. Chem. Soc. 2008, 130, 16184–16186. Wasa, M.; Yu, J.‐Q. J. Am. Chem. Soc. 2008, 130, 14058–14059. Mei, T.‐S.; Wang, X.; Yu, J.‐Q. J. Am. Chem. Soc. 2009, 131, 10806–10807. Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676–3677. Thu, H.‐Y.; Yu, W.‐Y.; Che, C.‐M. J. Am. Chem. Soc. 2006, 128, 9048–9049. Xiao, B.; Gong, T.‐J.; Xu, J.; Liu, Z.‐J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466–1474. Yoo, E. J.; Ma, S.; Mei, T.‐S.; Chan, K. S. L.; Yu, J.‐Q. J. Am. Chem. Soc. 2011, 133, 7652–7655. Zhu, D.; Yang, G.; He, J.; Chu, L.; Chen, G.; Gong, W.; Chen, K.; Eastgate, M. D.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2015, 54, 2497–2500. Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301. Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141–1144. Wang, G.‐W.; Yuan, T.‐T.; Wu, X.‐L. J. Org. Chem. 2008, 73, 4717–4720. Wang, G.‐W.; Yuan, T.‐T. J. Org. Chem. 2010, 75, 476–479. Jiang, T.‐S.; Wang, G.‐W. J. Org. Chem. 2012, 77, 9504–9509. Wang, X.; Lu, Y.; Dai, H.‐X.; Yu, J.‐Q. J. Am. Chem. Soc. 2010, 132, 12203–12205. Roane, J.; Daugulis, O. Org. Lett. 2013, 15, 5842–5845. Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874–2877. Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem. Int. Ed. 2012, 51, 13070–13074. Mo, F.; Trzepkowski, L. J.; Dong, G. Angew. Chem. Int. Ed. 2012, 51, 13075–13079. Yang, X.; Shan, G.; Rao, Y. Org. Lett. 2013, 15, 2334–2337. Zhao, X.; Dimitrijević, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466–3467. Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok‐ Kohn, G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011, 133, 19298–19301. Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 18237–18240. Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135.

References

[112] Wang, X.; Mei, T.‐S.; Yu, J.‐Q. J. Am. Chem. Soc. 2009, 131, 7520–7521. [113] Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2011,

50, 9081–9084.

[114] Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135,

9342–9345.

[115] Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62,

11483–11498.

[116] Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem.

Soc. 2006, 128, 7416–7417.

[117] Du, B.; Jiang, X.; Sun, P. J. Org. Chem. 2013, 78, 2786–2791. [118] Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Angew. Chem.

Int. Ed. 2011, 50, 5524–5527.

[119] Teskey, C. J.; Lui, A. Y. W.; Greaney, M. F. Angew. Chem. Int. Ed. 2015, 54,

11677–11680.

[120] Mei, T.‐S.; Giri, R.; Maugel, N.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2008, 47,

5215–5219.

[121] Li, J.‐J.; Mei, T.‐S.; Yu, J.‐Q. Angew. Chem. Int. Ed. 2008, 47, 6452–6455. [122] Chu, L.; Wang, X.‐C.; Moore, C. E.; Rheingold, A. L.; Yu, J.‐Q. J. Am. Chem.

Soc. 2013, 135, 16344–16347.

431

433

12 Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene 12.1 ­Introduction Heteroarene is an aromatic compound having not only carbon atom but also heteroatom such as nitrogen, oxygen, etc. to construct its aromatic ring. Pyrrole, pyridine, indole, and quinoline are the most common nitrogen‐ containing heteroarenes, while furan and benzofuran are the most common oxygen‐containing heteroarenes. Characteristics of various heteroarenes differ dramatically even owning the same heteroatom. For example, indole is the electron‐rich heteroarene with high reactivity in SEAr process, but pyridine owns electron‐deficient aromatic ring with low reactivity to electrophiles. Cleavage of heteroaryl sp2C─H bonds is available by either direct or indirect way, similar in the situation of cleaving phenyl and aryl sp2C─H bonds. In the traditional SEAr process, the cleavage of heteroaryl sp2C─H bond is achieved indirectly by dearomatization of aromatic ring and subsequent rearomatiza­ tion with loss of proton on aryl sp2C─H bond. In the direct way, heteroaryl sp2C─H bond is cleaved by transition metals via electrophilic activation or by carbene species insertion. In either direct or indirect reaction pathway, electron‐ rich arene such as indole often reacts more willingly. Oxidation of heteroaryl sp2C─H bonds stays closely with the mode of cleav­ age of heteroaryl sp2C─H bonds. In the SEAr process, oxidation occurs through addition of oxidizing reagent to aromatic ring during dearomatization and rearomatization with loss of proton to give the oxidized product. In the direct way, reductive elimination or β‐elimination from heteroaryl–transition‐metal complex fulfills the oxidation of aryl sp2C─H bond. Regioselectivity in an oxidation of heteroaryl sp2C─H bond is related to the aromatic nature of the heteroarene. Oxidation of heteroaryl sp2C─H bond of indole through SEAr process usually affords the oxidation product occurring at 3‐position of indole, which is an electron‐rich position, for example. However, other modes of regioselectivity are observed according to the different oxidation pathways.

Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

434

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

Moreover, further oxidation usually occurs readily for an electron‐rich heteroarene such as pyrrole. In this chapter, the reactivity and selectivity in oxidizing heteroaryl sp2C─H bonds through modern transition‐ metal catalysis are focused with the examples of such transformations screened and chosen. In addition, oxidation of ­perfluoroaryl sp2C─H bonds is also described. Perfluoroarene is the arene con­ taining few aryl sp2C─H bonds and many aryl sp2C─F bonds. Thus, ­perfluoroaryl sp2C─H bond is usually acidic, which can be cleaved by a strong base.

12.2 ­Formation of C─C Bond 12.2.1 Alkylation

Alkylation of heteroaryl C─H bonds with either alkyl halides or alkenes p ­ rovides an alternative method for formation of heteroaryl–alkyl bonds usually through the traditional Friedel–Crafts alkylation or ortho‐deprotonation by strong bases followed by quenching with electrophiles. One challenge for such alkylation of heteroaryl C─H bonds with alkyl halides is applying nonactivated alkyl halides containing β‐hydrogen as coupling partners. In 2010, Hu and coworkers reported alkylation of heteroarenes such as benzoxazole, oxazole, thiazole, thiophene, etc. with unactivated alkyl halides under dual catalysis of nickel and copper [1]. Treatment of benzoxazole (1.3 equiv.) with n‐butyl iodide (0.5 mmol, 1 equiv.) in the presence of nickel complex (5 mol%), CuI (7.5 mol%), and inorganic base t‐BuOLi (1.4 equiv.) in dioxane (5 mL) at 140 °C for 16 h affords the correspond­ ing alkylation product in 78% yield. Moreover, more economical and stable alkyl bromide or chloride is also available in this heteroaryl C─H alkylation with addi­ tion of catalytic amount of NaI for promoting halide exchange, exemplified by the reactions of benzoxazole with octyl bromide or chloride with NaI (20 mol%) under similar conditions to produce the alkylation product in 72 or 71% yield, respectively. In the proposed mechanism, oxidative addition of Ni(0) species to alkyl–I bond forms alkyl–Ni(II)–I species. Transmetalation of this alkyl–Ni(II)–I species with benzoxazole anion generated from benzoxazole and inorganic base produces key alkyl–Ni(II)–heteroaryl intermediate. Reductive elimination of alkyl and aryl group from Ni(II) center affords the corresponding alkylation product and Ni(0) to fulfill the catalytic cycle. Through this method, versatile alkylated heteroarenes are prepared concisely (Scheme 12.1). In the same year, Hirano, Miura, and coworkers also reported alkylation of azoles with unactivated alkyl bromides or chlorides in palladium or nickel catalysis [2]. For example, treatment of benzoxazole (0.5 mmol, 1 equiv.) with n‐hexyl bromide (2.0 equiv.) in the presence of palladium complex (3.75 mol%), trialkylphosphine ligand n‐Bu3P (30  mol%), and inorganic base t‐BuOLi (3.0 equiv.) in diglyme (3 mL) at 120 °C for 4 h affords the corresponding alkylation

12.2  Formation of C─C Bond

N

nBu

+

I

O 1.3 equiv.

0.5 mmol

5 mol% nickel complex 7.5 mol% CuI

N

1.4 equiv. tBuOLi Dioxane (5 mL), 140 °C, 16 h

O

NMe2 nBu

Ni Cl NMe2

78%

Nickel complex

N

Octyl Br or +

O

Octyl Cl

1.3 equiv.

N O

5 mol% nickel complex 7.5 mol% CuI

N

20 mol% NaI, 1.4 equiv. tBuOLi Dioxane (5 mL), 140 °C, 16 h

O

72 or 71%

0.5 mmol

Ni0

nBu

nBu

Reductive elimination

N O

Octyl

I

Oxidative addition

NiII

nBu

nBu

Transmetalation

NiII I N

Li

O

Scheme 12.1  Ni‐catalyzed alkylation of heteroarenes with alkyl iodides.

product in 77% yield. Reaction of benzoxazole with octyl chloride in a prolonging reaction time (12 h) produces the target alkylation product in 63% yield under similar conditions (Scheme  12.2). These reactions are initiated by oxidative addition of Pd(0) species generated in situ to alkyl–halide bond, like in the case of nickel catalysis. In addition to alkyl halides, alkenes are also available in the alkylation of ­heteroarenes. One challenge for this kind of transformation is the regioselec­ tivity for either heteroarene or alkene. Regioselectivity for heteroarene is that alkylation of heteroarenes with alkenes through SEAr process usually occurs at electron‐rich positions and reaction of electron‐poor positions seldom occurs. Regioselectivity for alkene in alkylation is that product of branched alkylation product is usually afforded due to the stability of secondary or tertiary alkyl cation. In 2015, Nakao, Hartwig, and coworkers reported linear alkylation of

435

436

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene N

N O 0.5 mmol

Br +

nHex

or Cl

Octyl

2.0 equiv.

3.75 mol%

[{PdCl(η3-C

3H5)}2]

30 mol% nBu3P 3.0 equiv. tBuOLi Diglyme (3 mL), 120 °C

nHex

O or

77% (4h) N O

Octyl

63% (12 h)

Scheme 12.2  Pd‐catalyzed alkylation of heteroarenes with alkyl halides.

heteroarenes including indole, pyrrole, benzofuran, furan, etc. to afford anti‐Markovnikov product by applying nickel–NHC catalytic system [3]. Besides, linear alkylation of indole or benzofuran occurs at 2‐position selec­ tively. For example, treatment of N‐methylindole (0.5 mmol, 1 equiv.) with 1‐tridecene (1.5 equiv.) in the presence of nickel–NHC complex (2 mol%) neat at 100 °C for 24 h affords the corresponding linear alkylation product at 2‐position of indole. Linear alkylation of benzofuran at 2‐position is also obtained in 98% yield by treatment of benzofuran (0.25 mmol) with 1‐decene (1.2 equiv.) in the presence of Ni(cod)2 (2 mol%), NHC ligand (2 mol%), and NaOtBu (0.1 equiv.) at 50 °C for 16 h (Scheme 12.3). In addition, either pyrrole or furan is also available for l­inear alkylation at 2‐position, which is also the active position for SEAr ­process. It is proposed that reversible formation of alkyl–Ni–heteroaryl inter­ mediate and rate‐determining reductive elimination of alkyl and heteroaryl group account for the linear selectivity, which is similar with the linear alkyla­ tion of 1,3‐bis(trifluoromethyl)benzene or benzene with either terminal or internal alkenes. In addition to regioselectivity, stereoselectivity is under control in the alkyla­ tion of heteroaryl C─H bond with alkene to produce asymmetric heteroaryl– alkyl structure. In 2001, Jørgensen and coworkers reported enantioselective alkylation of indoles with activated alkenes applying chiral copper catalyst [4]. For example, treatment of indole (2.0 mmol, 1 equiv.) with enone (1.0 equiv.) in the presence of chiral Cu(II)‐bis(oxazoline) catalyst (2 mol%) in Et2O (4 mL) at −78 °C for 64 h affords the corresponding chiral 3‐alkylindole in 77% yield with 99.5% ee. Furan is also available, giving chiral 5‐alkylfuran product in quantita­ tive yield with 88% ee in the example of 2‐methylfuran (Scheme 12.4). Various indole and furan derivatives are applied for this enantioselective heteroaryl C─H alkylation. Also in 2001, MacMillan and coworker reported asymmetric alkylation of pyrroles with activated alkenes under organocatalysis [5]. For example, treat­ ment of N‐methylpyrrole (5.0 equiv.) with cinnamaldehyde (25 mmol, 1 equiv.) in the presence of iminium organocatalyst (20 mol%) in mixtures of THF

12.2  Formation of C─C Bond

+

N

2 mol% (IPr*OMe)Ni(C6H6)

C11H23

Me

Ph

0.5 mmol

Ph

1.5 equiv.

O

OMe Ph

IPr*OMe

2 mol% Ni(cod)2, 2 mol% IPrMe

C8H17

O

0.1 equiv. NaOtBu, 50 °C, 16 h Me Me Me Me Me Me

1.2 equiv.

0.25 mmol

97%

Ph Ph Ph

C11H23

Me

Ph

Ph N

MeO

+

N

100 °C, 24 h

C8H17 98%

N Me Me

Me

Me

IPrMe

Scheme 12.3  Ni‐catalyzed linear alkylation of heteroarenes with alkenes. Me

Me

O

O N

N H 2.0 mmol

+

O Ph

Cu

N

O

t

TfO OTf Bu 2 mol% chiralcatalyst tBu

Ph

CO2Me

CO2Me Et2O (4 mL), –78 °C, 64 h N H 77% yield, 99.5% ee

1.0 equiv.

Me O

Me O

N N Cu t TfO OTf Bu 10 mol% chiralcatalyst tBu

Me

O

1.33 mmol

+

O Ph

CO2Me Et2O (2 mL), 0 °C, 2 days 1.0 mmol

Me

O

CO2Me

Ph O 99% yield, 88% ee

Scheme 12.4  Cu‐catalyzed enantioselective alkylation of heteroarenes.

437

438

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

(50 mL) and H2O (7.5 mL) at −30 °C for 42 h affords the asymmetric 2‐alkylpyrrole derivative in 87% yield with 93% ee. Various pyrroles and α,β‐unsaturated alde­ hydes are available partners for this asymmetric alkylation. Enantioselective dialkylation of pyrrole is also available. Treatment of N‐methylpyrrole with excess α,β‐unsaturated aldehyde crotonaldehyde with prolonged reaction time produces enantioselective 2,5‐dialkylpyrrole product with 98% ee. Unsymmetric 2,5‐dialkylpyrrole derivative is also prepared with 99% ee by treatment of chiral 2‐alkylpyrrole with another α,β‐unsaturated aldehyde in excess under similar conditions (Scheme 12.5). O

N Me

O

+

5.0 equiv.

25 mmol

Me N Me Bn N H Me CF3CO2H 20 mol% organocatalyst

O

N Me

TH (50 mL), H2O (7.5 mL)F –30 °C, 42 h

87% yield, 93% ee O

Me N Me Bn N H Me CF3CO2H 20 mol% organocatalyst O + Me O N O (0.15 mL) THF (1.5 mL), H 2 Me –50 °C, 72 h 0.5 mmol 3.0 equiv.

O

N Me

Me Me 83% yield, 98% ee C2/meso = 90/10

O

Me N Me Bn N H Me CF3CO2H O

+ Ph N Me

Me 0.25 mmol

O

3.0 equiv.

40 mol% organocatalyst THF (1 mL), H2O(50 μL) –50 °C, 36 h

O

N Me

O

Ph Me 81% yield, 99% ee anti/syn = 90/10

Scheme 12.5  Organocatalyzed enantioselective alkylation of heteroarenes.

Copper‐ or organocatalyzed asymmetric alkylation of heteroarenes has been developed rapidly in the recent decade. However, one concern for such trans­ formations is that limiting alkylation partners are available currently, namely, activated alkenes, carbonyl compounds, and imines.

12.2  Formation of C─C Bond

12.2.2 Trifluoromethylation

Incorporation of trifluoromethyl group into (hetero)aromatic rings signifi­ cantly adjusts the molecular characteristics and thus has received intense attention. Trifluoromethylation of heteroaryl C─H bonds offers the ideal method for introduction of trifluoromethyl group into heteroarenes. In 2011, Liu and coworkers reported direct trifluoromethylation of indoles with economical nucleophilic trifluoromethylating reagent TMSCF3 at room temperature in palladium catalysis [6]. For example, treatment of N‐methyl‐3‐methylindole (0.2 mmol, 1 equiv.) with TMSCF3 (4.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), chiral bis(oxazoline) ligand (15 mol%), PhI(OAc)2 as critical oxidant (2.0 equiv.), TEMPO (0.5 equiv.), and CsF (4.0 equiv.) in MeCN (2 mL) at room temperature for 6 h affords 2‐trifluoromethylindole product in 83% yield. In the proposed mechanism, Pd(II) catalyst cleaves heteroaryl C─H bond of indole at 2‐position to form heteroaryl–Pd(II) intermediate. Oxidation and transmetalation of this heteroaryl–Pd(II) intermediate by PhI(OAc)2 and with TMSCF3 gives key heteroaryl–Pd(IV)–CF3 intermediate. Reductive elimina­ tion of heteroaryl and CF3 group affords the target 2‐trifluoromethylindole product and Pd(II) species to fulfill the catalytic cycle (Scheme 12.6). Me

+ TMSCF3 N 4.0 equiv. 2.0 equiv. PhI(OAc)2 0.5 equiv. TEMPO Me 4.0 equiv. CsF 0.2 mmol MeCN (2 mL), rt, 6 h

O N

N

Ligand

PdII CF3 Reductive elimination

PdIV CF3

N Me

C H cleavage

Me

Me N Me

N Me 83%

O CF3

Me

Me N Me

Me

10 mol% Pd(OAc)2 15 mol% ligand

Oxidation transmetalation

N Me

Pd(II)

PhI(OAc)2, TMSCF3

Scheme 12.6  Pd(II)/Pd(IV)‐catalyzed trifluoromethylation of indoles.

In addition to transition‐metal catalysis, trifluoromethylation of heteroaryl C─H bonds is also available through radical process using CF3SO2Na as

439

440

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

t­ rifluoromethylating reagent reported by Baran and coworkers in 2011 [7]. For example, treatment of indole derivative (0.25 mmol, 1 equiv.) with CF3SO2Na (3.0 equiv.) in the presence of TBHP (5.0 equiv.) in mixtures of CH2Cl2 (1 mL) and H2O (0.4 mL) at 0  °C for 18 h affords the corresponding 2‐methylindole derivative in 51% yield. Trifluoromethylation of 2‐acylpyrrole under similar conditions produces 2‐acyl‐5‐trifluoromethyl product in 57% yield. Alkaloid caffeine or its analogue theophylline of free N─H bond is trifluoromethylated at heteroaryl C─H bond efficiently (Scheme 12.7). Wide functional group com­ patibility is exhibited in this trifluoromethylation reaction. Trifluoromethylation of other heteroarenes such as pyridine usually affords mixtures of regioisomers. NHAc

MeO

+ NaSO2CF3

N H 0.25 mmol

3.0 equiv.

O CF3

N H Me 57% (24 h)

O

N

H N

N N Me 96% (17 h)

Me CF3

CF3

N H 51%

CH2Cl2 (1 mL), H2O (0.4 mL) 0 °C, 18h

Me O

NHAc

5.0 equiv. TBHP (70% aq) MeO

O

O

Me N

N

N

N

CF3

Me 80% (40 h)

Scheme 12.7  Homolytic trifluoromethylation of heteroarenes with CF3SO2Na.

Such radical trifluoromethylation of heterocycles was further developed by them in 2012, using (CF3SO2)2Zn as more promising trifluoromethylating ­reagent, which is easily prepared from CF3SO2Cl and zinc in >500 g scale [8]. For example, treatment of caffeine (0.25 mmol) with (CF3SO2)2Zn (3.0 equiv.) in the presence of TBHP (5.0 equiv.) in mixtures of CH2Cl2 (1 mL) and H2O (0.4 mL) at room temperature for 12 h affords the corresponding trifluoro­ methylcaffeine in 89% yield (Scheme 12.8). O Me O

N N

O

Me N N

Me 0.25 mmol

+ (CF3SO2)2Zn 3.0 equiv.

5.0 equiv. TBHP (70% aq)

Me

CH2Cl2 (1 mL), H2O (0.4 mL) rt, 12 h

O

Me N

N N

N

CF3

Me 89%

Scheme 12.8  Homolytic trifluoromethylation of heteroarenes with (CF3SO2)2Zn.

Radical trifluoromethylation of heteroarenes was also achieved by photo­ catalysis reported by MacMillan and coworker in 2011 [9]. A wide range of

12.2  Formation of C─C Bond

­ eteroarenes including electron‐rich pyrroles, furans, thiophenes, benzofurans, h indoles, etc. and electron‐poor pyrazine or pyridine derivatives are available in this reaction. For example, treatment of pyrrole (0.5 mmol, 1 equiv.) with CF3SO2Cl (2.0 equiv.) in the presence of photocatalyst Ru(phen)3Cl2 (1 mol%), K2HPO4 (3.0 equiv.) in MeCN (4 mL) under irradiation of visible light at room temperature for 8 h affords monotrifluoromethylation product in 88% yield. Ditrifluoromethylation is achieved simply by increasing the loading of trifluo­ romethylating reagent to 3.0 equiv. combined with prolonging reaction time to 24 h, affording 2,5‐bis(trifluoromethyl)pyrrole in 91%. As for electron‐poor heteroarenes, treatment of 2,6‐dimethylpyrazine (0.5 mmol, 1 equiv.) with CF3SO2Cl (4.0 equiv.) in the presence of photocatalyst Ir(Fppy)3 (2 mol%) and K2HPO4 (3.0 equiv.) in MeCN (4 mL) under irradiation of visible light at room temperature for 24 h affords 3,5‐dimethyl‐2‐(trifluoromethyl)pyrazine in 94% yield. 2,6‐Dimethylpyridine is trifluoromethylated in 73% yield with more CF3SO2Cl (8.0 equiv.) and longer reaction time (72 h) (Scheme 12.9).

N H 0.5 mmol

+

CF3CO2Cl

1 mol% Ru(phen)3Cl2

3.0 equiv. K2HPO4 MeCN (4 mL) 2.0 or 3.0 equiv. 26 W light, rt

CF3 or N H 88% (8 h)

N Me

N

Me

Me

0.5 mmol

4.0 equiv.

or

+

CF3CO2Cl 8.0 equiv.

Me

N

Me

0.5 mmol

CF3 N H 91% (24 h)

N

CF3

N

Me

94% (24 h)

2 mol% Ir(Fppy)3 3.0 equiv. K2HPO4 MeCN (4 mL) 26 W light, rt

F3C

or CF3 Me

N

Me

73% (72 h)

Scheme 12.9  Homolytic trifluoromethylation of heteroarenes under photocatalysis.

12.2.3 Arylation

Direct arylation of heteroaryl C─H bonds with prefunctionalized arenes pro­ vides a convenient method to form heteroaryl–aryl bonds. In 2006, Sanford and coworkers [10] reported palladium‐catalyzed arylation of indoles with [Ar2I] [BF4] as serving both arylating reagent and oxidant at room temperature. For the example of phenylation, treatment of indole (1.0 mmol, 1 equiv.) with [Ph2I] [BF4] (2.0 equiv.) in the presence of Pd(II) catalyst (5 mol%) in HOAc (10 mL) at room temperature for 15 h affords 2‐phenylindole in 81% yield. Pyrrole is also available for phenylation giving 2‐phenylpyrrole in 69% yield. Arylation is

441

442

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

also available using [Ar2I][BF4] as arylating reagent. For example, reaction of N‐methylindole with [(4‐ClC6H4)2I][BF4] under similar conditions affords 2‐(4‐chlorophenyl)indole in 90% yield (Scheme  12.10). It is proposed that Pd(II) catalyst cleaves heteroaryl C─H bond of indole at 2‐position to form heteroaryl–Pd(II) intermediate, which is oxidized by [Ar2I][BF4] to give hetero­ aryl–Pd(IV)–Ar intermediate, followed by reductive elimination of heteroaryl and aryl group to afford the 2‐arylindole product and Pd(II) species to fulfill the catalytic cycle, which is similar to the mechanism of ortho‐arylation of 2‑pyridylbenzene with PhI(OAc)2 via Pd(II)/Pd(IV) catalytic cycle reported by the same group in 2004.

N H 1.0 mmol

+

[Ph2I][BF4] 2.0 equiv.

or +

N

+

5 mol% IMesPd(OAc)2

or

HOAc (10 mL), rt, 15 h Cl

[(4-ClC6H4)2I][BF4]

Me 1.0 mmol

N H 10 equiv.

N H 81%

N Me 90%

2.0 equiv.

[Ph2I][BF4]

5 mol% IMesPd(OAc)2 HOAc (13 mL), rt, 15 h

1.4 mmol

N H 69%

PdII N H

Reductive elimination

N H

N H

C H cleavage

PdIV

N H

Ph

Pd(II)

Oxidation [Ph2I][BF4]

Scheme 12.10  Pd(II)/Pd(IV)‐catalyzed arylation of heteroarenes with [Ar2I][BF4].

Arylation of indole with diaryliodonium salts catalyzed by economical c­ opper salt was reported by Greaney and coworkers in 2015 [11]. For example, treatment of indole (0.2 mmol, 1 equiv.) with [Ph2I][OTf ] (1.1 equiv.) in the

12.2  Formation of C─C Bond

presence of Cu(OTf )2 (10 mol%) and base 2,6‐di‐tert‐butylpyridine (1.1 equiv.) in CH2Cl2 at room temperature for 24 h affords 3‐phenylindole in 81% yield. Since phenylation of one indole with [Ph2I][OTf ] gives one 3‐phenylindole and one PhI, which is also available in the Buchwald–Hartwig reaction for formation of aryl–nitrogen bond from aryl–I bond and N─H bond, a tandem diarylation of heteroaryl C─H bond and N─H bond with diaryliodonium salts is developed. Mixtures of indole (0.3 mmol, 1 equiv.) and [Ph2I][OTf ] (1.05 equiv.) are first treated by Cu(OTf )2 (20 mol%), and 2,6‐di‐tert‐butylpyridine (1.1 equiv.) in dioxane (2.5 mL) at 60 °C for 24 h, followed by addition of DMEDA (30 mol%), K3PO4 (2.0 equiv.) and reaction at 110 °C for another 16 h to produce N‐phe­ nyl‐3‐phenylindole in 63% yield. Diheteroarylation of indole is also available by using unsymmetrical diaryliodonium salts. For example, treatment of indole with phenyl(dimethyluracil)iodonium triflate under similar conditions affords N‐heteroaryl‐3‐phenylindole in 48% yield (Scheme 12.11).

N H 0.2 mmol

N H 0.3 mmol

+ [Ph2I][OTf]

10 mol% Cu(OTf)2 1.1 equiv. dtbpy CH2Cl2, rt, 24 h

1.1 equiv.

+ [Ph2I][OTf] 1.05 equiv.

N H 81%

(1) 20 mol% Cu(OTf)2, 1.1 equiv. dtbpy Dioxane (2.5 mL), 60 °C, 24 h (2) 30 mol% DMEDA, 2.0 equiv. K3PO4 110 °C, 16 h

N 63%

OTf I N H 0.3 mmol

+

O Me

N

(1) 20 mol% CuI, 1.0 equiv. dtbpy Toluene (2.5 mL), 60 °C, 24 h

N Me (2) 40 mol% DMEDA, 2.0 equiv. K3PO4 95 °C, 24 h

O 1.0 equiv.

N

O

48% Me

N

N Me O

Scheme 12.11  Cu‐catalyzed arylation of heteroarenes with [Ph2I][OTf ].

Direct use of aryl iodide instead of diaryliodonium salt in the arylation of heteroaryl C─H bonds catalyzed by copper salt was achieved by Daugulis and coworker in 2007 [12]. For example, treatment of benzoxazole (1.0 mmol, 1 equiv.) with phenyl iodide (3.0 equiv.) in the presence of copper iodide (10 mol%) and t‐BuOLi (2.0 equiv.) in DMF (1 mL) at 140 °C for 10 min affords

443

444

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

2‐phenylbenzoxazole in 93% yield (Scheme 12.12). Other heteroarenes such as benzimidazole, caffeine, etc. are available under similar conditions, giving monophenylation product, respectively. N

LiOtBu

(2.0 equiv.) DMF (1 mL), 140 °C, 10 min

O 1.0 mmol

3.0 equiv.

Me N

I

+

N 1.0 mmol O Me

N N

O

3.0 equiv. Me N N

Me 1.0 mmol

+

N

10 mol% CuI

I

+

O 93% Me N

10 mol% CuI LiOtBu (1.0 equiv.) DMF (0.5 mL), 140 °C, 30 min

I

N 89% Me

10 mol% CuI tBuOK

(2.0 equiv.) 3.0 equiv. DMF (0.5 mL), 140 °C, 10 min

O

Me N

N

N

N

O

Me

78%

Scheme 12.12  Cu‐catalyzed arylation of heteroarenes with aryl iodides.

Transition‐metal‐free arylation of heteroaryl C─H bonds with aryl iodides via BHAS process was established by Itami and coworkers in 2008 [13]. For example, treatment of electron‐deficient heteroarene pyrazine (40 equiv.) with phenyl iodide (0.5 mmol, 1 equiv.) in the presence of t‐BuOK (1.5 equiv.) sole under microwave irradiation at 50 °C for 5 min affords monophenylation product in 98% yield. Reaction of pyrazine with phenyl bromide under similar conditions for 0.5 h gives 2‐phenylpyrazine in 54% yield, while phenyl chloride or fluoride does not work for this reaction. Besides, only t‐BuOK serves as suitable strong base, whereas t‐BuONa, t‐BuOLi, KOMe, or KOH fails for this reaction. Reaction of pyridine with phenyl iodide under similar conditions N

N N

N 40 equiv. or

N 40 equiv.

+

I 0.5 mmol

98% or

1.5 equiv. tBuOK mw, 50 °C, 5 min N

63% o/m/p = 36/21/43

Scheme 12.13  Arylation of heteroarenes with aryl iodides via BHAS.

12.2  Formation of C─C Bond

affords mixtures of 2‐, 3‐, and 4‐phenylpyridine with ratio of 36/21/43 in 63% yield (Scheme  12.13). The radical process is partly supported by control experiment that addition of radical scavengers such as TEMPO, galvinoxyl, or acrylonitrile shut down the reaction completely. Regioselective arylation of pyridines at 2‐position with aryl iodides or ­bromides was reported by Charette and coworkers in 2008, applying N‐iminopyridinium ylides as substrates [14]. For example, treatment of N‐iminopyridinium ylides (1.5 equiv.) with either phenyl iodide (0.35 mmol, 1 equiv.), phenyl bromide (0.35 mmol, 1 equiv.), or even phenyl chloride (0.35 mmol, 1 equiv.) though less efficiently in the presence of Pd(OAc)2 (5 mol%), t­ rialkylphosphine ligand t‐Bu3P (15 mol%), and K2CO3 (3.0 equiv.) in toluene (1.2 mL) at 125  °C for 16–20 h affords the corresponding 2‐phenylpyridine derivative, respectively (Scheme 12.14). 5 mol% Pd(OAc)2 N N

O Ph

1.5 equiv.

+

X 0.35 mmol

15 mol% tBu3P 3.0 equiv. K2CO3 3A MS, toluene (1.2 mL) 125 °C, 16–20 h

N N

O Ph

X: I, Br, or Cl Yield: 95, 87, or 42%

Scheme 12.14  Pd‐catalyzed arylation of N‐iminopyridinium ylides with aryl halides.

Regioselective arylation of pyridines at 2‐position with aryl bromides in rho­ dium catalysis was also achieved by Bergman, Ellman, and coworkers in 2008 [15]. For example, treatment of 2‐methylpyridine (6.0 equiv.) with 3,5‐dimethylphenyl bromide (0.4 mmol, 1 equiv.) in the presence of [RhCl(CO)2]2 (5 mol%) in diox­ ane (0.25 mL) at 190  °C for 24 h affords the 2‐aryl‐6‐methylpyridine in 53% yield (Scheme 12.15). Pyridine itself does not work in this reaction. Reaction of quinoline under similar conditions affords 2‐arylquinoline product in 86% yield. Alternative regioselective arylation of pyridines at 3‐position with aryl iodides or bromides was achieved by Yu and coworkers in 2011, using combination of Pd(OAc)2 and 1,10‐phenanthroline catalytic system [16]. For ­example, treatment of pyridine (3.0 mL) with either phenyl iodide (0.5 mmol, 1 equiv.) or p ­ henyl bromide (0.5 mmol, 1 equiv.) in the presence of Pd(OAc)2 (5 mol%), 1,10‐phen­ anthroline (15 mol%), and Cs2CO3 (3.0 equiv.) at 140 °C for 48 h affords the cor­ responding 3‐phenylpyridine with excellent meta‐regioselectivity. Applying this arylation, drug molecule (±)‐preclamol is synthesized concisely in the scale of gram (Scheme 12.16). In addition to aryl iodides and bromides, aryl chlorides were also available in the arylation of heteroaryl C─H bonds. In 2007, Daugulis and coworkers

445

446

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene Me Br

+ Me

N Me 0.4 mmol

6.0 equiv.

5 mol% [RhCl(CO)2]2

Me

Me

N

Dioxane (0.25 mL) 190 °C, 24 h 53% Me Me

N

Me 86% (dioxane 1.0 mL, 175 °C, 24 h)

Scheme 12.15  Rh‐catalyzed arylation of pyridine or quinoline with aryl bromides.

5 mol% Pd(OAc)2 +

X

N 0.5 mmol

3.0 mL

15 mol% 1,10-phen 3.0 equiv. Cs2CO3 140 °C, 48 h

N X = I, 82% (m/p/o = 28/1/1) X = Br, 79% (m/p/o = 40/2/1)

5 mol% Pd(OAc)2 15 mol% 1,10-phen

+ N

Br

60 mL

OMe

OMe

3.0 equiv. Cs2CO3 140 °C, 68 h

N

10 mmol

OMe Br N

OMe N

Me

70%, 1.29 g (m/p/o = 19/1/1)

Me

OH

67% yield N for three steps

Me

(±)-Preclamol

Scheme 12.16  Pd‐catalyzed meta‐arylation of pyridine with aryl halides.

reported arylation of electron‐rich heterocycles with aryl chlorides using bulky, electron‐rich trialkylphosphine ligated palladium catalyst for oxida­ tive addition to aryl–chlorine bond [17]. For example, treatment of caffeine (1.0 mmol, 1 equiv.) with 3,5‐dimethylphenyl chloride (1.5 equiv.) in the presence of Pd(OAc)2 (5 mol%), butyl‐1‐adamantylphosphine (10 mol%),

12.2  Formation of C─C Bond

and K 3PO4 (2.0 equiv.) in NMP (4 mL) at 125 °C for 24 h affords the cor­ responding arylation product in 77% yield. Other heteroarenes such as benzoxazole, benzothiophene, etc. are also available to give arylation ­ ­product (Scheme 12.17). O Me O

N N

Me N

Me + Cl

Me

2.0 equiv. K3PO4 O Me NMP (4 mL), 125 °C, 24 h

N

Me 1.0 mmol

5 mol% Pd(OAc)2 10 mol% BuAd2P

1.5 equiv.

63%

Me N

N

N

N

Me

Me

Me 77%

N S

O

CO2Et

O 84%

Scheme 12.17  Pd‐catalyzed arylation of heteroarenes with aryl chlorides.

Arylation of indoles, pyrroles, and furans with aryl chlorides was reported in 2011 by the same group [18]. Reaction of N‐methylindole (1.0 mmol, 1 equiv.) with phenyl chloride (5.0 equiv.) in the presence of Pd(OAc)2 (5 mol%), butyl‐1‐adamantylphosphine (10 mol%), and K3PO4 (2.0 equiv.) in NMP (4 mL) at 125  °C for 24 h affords N‐methyl‐2‐phenylindole in 77% yield along with 7% of N‐methyl‐3‐phenylindole and 8% of N‐methyl‐2, 3‐diphenylindole (Scheme  12.18). Thus, 2‐ or 3‐phenylation is achieved, respectively, by applying N‐methyl‐3‐methylindole or N‐methyl‐2‐methylindole as substrate by applying 2‐(dialkylphospho)biphenyl as ligand. Reaction of N‐methylpyrrole with chlorobenzene or 1,3‐dichlorobenzene affords het­ eroarylbenzene or 1,3‐diheteroarylbenzene, respectively. Similar results are obtained when furan is the substrate coupling with 3‐chloroanisole or 1,4‐dichlorobenzene. Heterogeneous Pd/C catalyst was applied for arylation of benzothiophenes with aryl chlorides reported by Glorius and coworkers in 2013 [19]. For exam­ ple, treatment of benzothiophene (0.3 mmol, 1 equiv.) with chlorobenzene (2.0 equiv.) in the presence of Pd/C (9.4 mol%), CuCl (10 mol%), and Cs2CO3 (2.0 equiv.) in dioxane (1.5 mL) at 150 °C for 48 h affords the sole 3‐arylation product in 89% yield (Scheme 12.19). On the other hand, direct arylation of polyfluoroarenes with aryl halides was achieved by Fagnou and coworkers in 2006 [20]. For example, treatment of pentafluorobenzene (1.5 equiv.) with either 4‐totyl iodide (1 equiv.), 4‐totyl bromide (1 equiv.), or 4‐totyl chloride (1 equiv.) in the presence of Pd(OAc)2

447

448

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene 5 mol% Pd(OAc)2 10 mol% BuAd2P

+ Cl

N

Me 1.0 mmol

N Me 0.5 mmol

Me

2.0 equiv. Na2CO3 DMA (2 mL), 125 °C, 24 h

N Me 73%

Me N Me

N Me

65%

N Me 8%

5 mol% Pd(OAc)2 10 mol% Cy2P-o-biphenyl

5.0 equiv.

Me

N Me 7%

Ph

N Me 77%

5.0 equiv.

+ HCl

Ph

Ph +

2.0 equiv. K3PO4 NMP (4 mL), 125 °C, 24 h

Me

Ph

N

OMe

Me N

60%

O

O

O 73%

92%

74%

Scheme 12.18  Pd‐catalyzed arylation of heteroarenes with aryl chlorides.

+

9.4 mol% Pd/C 10 mol% CuCl

Cl

S 2.0 equiv.

0.3 mmol

1.1 equiv. Cs2CO3 Dioxane (1.5 mL), 150 °C, 48 h

S 89%

Scheme 12.19  Pd/C‐catalyzed arylation of benzothiophene with aryl chlorides.

F

F +

F F

X

Me

1.1 equiv. K2CO3 DMA, 120 °C

F

1.5 equiv.

F

5 mol% Pd(OAc)2 10 mol% tBu2MeP

1 equiv.

F

F

Me F

F

X: I, Br or Cl Yield: 83, 98, or 57%

Scheme 12.20  Pd‐catalyzed arylation of polyfluoroarenes with aryl halides.

(5 mol%), trialkylphosphine ligand t‐Bu2MeP (10 mol%), and K2CO3 (1.1 equiv.) in DMA at 120 °C affords 4‐perfluorophenyltoluene, respectively (Scheme 12.20). More economical copper salt was available in the arylation of per­ fluoroarenes reported by Daugulis and coworker in 2008 [21]. Treatment of

12.2  Formation of C─C Bond

pentafluorobenzene (1.5 equiv.) with either electron‐rich 4‐totyl bromide in the scale of either 1.0 or 10 mmol (1 equiv.) or electron‐poor 4‐trifluoromethylphenyl bromide (1.0 mmol, 1 equiv.) in the presence of CuI (10 mol%), 1,10‐phenanthroline (10 mol%), and K3PO4 (2.0 equiv.) in mixtures of DMF and xylene at 140  °C affords the corresponding arylation product in high yield, respectively. Reaction of pentafluorobenzene more steric demanding aryl halides exhibits that 2,4,6‐trimethylphenyl iodide is more prone to produce the biaryl structure (Scheme 12.21). F

F

F F

Br

F

1.0 or 10 mmol or

+

F

Me

Br

F F 1.5 equiv.

CF3

Me F F 91 or 88% (2.3 g) or F F

10 mol% CuI 10 mol% 1,10-phen 2.0 equiv. K3PO4 DMF/xylene, 140 °C F

1.0 mmol

CF3 F

F

F

Me +

F F

F

1.5 equiv.

X

Me

Me 1.0 mmol

10 mol% CuI 10 mol% 1,10-phen 2.0 equiv. K3PO4 DMF/xylene, 140 °C

F 88% F

F Me

F

Me F

F Me

X: Br or I Yield: 20 or 87%

Scheme 12.21  Cu‐catalyzed arylation of polyfluoroarenes with aryl halides.

12.2.4 Alkenylation

Direct cross‐coupling of arene and alkene, namely, Fujiwara–Moritani reac­ tion, is an ideal way to form aryl–alkenyl bond. Soon after Moritani and Fujiwara disclosed formation of aryl–alkenyl bond by treatment of palladium(II)·styrene complex in arene in 1967, alkenylation of heteroarenes with alkenes promoted by palladium complex was reported by the same group in 1973 [22]. Treatment of furan (15 mmol, 1 equiv.) or thiophene (15 mmol, 1 equiv.) with styrene (1.0 equiv.) in the presence of Pd(OAc)2 (1.0 equiv.) in mixtures of dioxane (160 mL) and HOAc (40 mL) under reflux for 48 h affords the corresponding 2‐styryl and 2,5‐distyryl heteroarenes as major products. Reaction of N‐methylpyrrole under similar conditions gives 2‐styryl and 3‐styryl N‐methylpyrrole (Scheme 12.22).

449

450

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

O 15 mmol or S 15 mmol or

+

Ph

O

Ph

15% 1.0 equiv. Pd(OAc)2

+ 1.0 equiv.

Ph

S

Ph

36% Ph +

Me

Me 15 mmol

Ph

13% N

N

+

Ph

S

Dioxane (160 mL) HOAc (40 mL) Reflux, 48 h

O 46%

Me

Ph

N

15%

46%

Scheme 12.22  Pd‐mediated cross‐coupling of heteroarenes with alkenes.

Palladium‐catalyzed cross‐coupling of heteroarenes and alkenes using cop­ per acetate as oxidant was established by Fujiwara and coworkers in 1979 [23]. For example, treatment of furan (2.0  mmol, 1  equiv.) with acrylonitrile (1.0 equiv.) in the presence of Pd(OAc)2 (2 mol%) and Cu(OAc)2 (2.0 equiv.) in mixtures of dioxane (20 mL) and HOAc (5 mL) at 100 °C for 8 h affords the cor­ responding 2‐alkenylfuran as major product, along with 2,5‐dialkenylfuran. Alkenylation selectively occurs at 2‐position of furan, and the total TON is up to 30 (Scheme 12.23).

O 2.0 mmol

+

CN 1.0 equiv.

2 mol% Pd(OAc)2 2.0 equiv. Cu(OAc)2 Dioxane (20 mL) HOAc (5 mL) 100 °C, 8 h

O

CN

38%, TON = 19 cis/trans = 33/67

+

NC

O

CN

20%, TON = 10 trans, trans/cis, trans = 55/45

Scheme 12.23  Pd‐catalyzed cross‐coupling of heteroarenes with alkenes.

Catalytic cross‐coupling of indole derivatives with alkenes was reported by Itahara and coworkers in 1984 [24]. N‐(2,6‐dichlorobenzoyl)indole gave the best performance. For example, treatment of this N‐protected indole (1.0 mmol, 1 equiv.) with methyl acrylate (3.0 equiv.) in the presence of Pd(OAc)2 (2 mol%) and 1.0 equiv. of oxidant Cu(OAc)2 or AgOAc under reflux for 16 h affords the corresponding 3‐alkenylindole product in TON of 8 or 5, respectively (Scheme 12.24). Regioselective alkenylation of indoles with alkene at 2‐ or 3‐position was achieved by applying different solvent system reported by Gaunt and cowork­ ers in 2005 [25]. For example, treatment of indole (8.5 mmol, 1 equiv.) with tert‐ butyl acrylate (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol%) and Cu(OAc)2 (1.8 equiv.) in mixtures of DMF and dimethyl sulfoxide (DMSO) (9/1) at 70 °C

12.2  Formation of C─C Bond CO2Me

Cl

N O

+

CO2Me 3.0 equiv.

Cl

2 mol% Pd(OAc)2 1.0 equiv. oxidant reflux, 16 h

N

Cl

O Cl

1.0 mmol

TON = 8 for Cu(OAc)2 TON = 5 for AgOAc

Scheme 12.24  Pd‐catalyzed cross‐coupling of indoles with alkenes.

for 18 h affords 3‐alkenylindole in 91% yield exclusively. 2‐Alkenylindole is selectively obtained in 57% yield by applying peroxide tBuOOBz as oxidant and mixtures of dioxane and HOAc as solvent (Scheme 12.25). CO2tBu N H 8.5 mmol

N H 8.5 mmol

+

CO2tBu 2.0 equiv.

tBu

+

CO2

2.0 equiv.

10 mol% Pd(OAc)2 1.8 equiv. Cu(OAc)2 DMF/DMSO (9/1) 70 °C, 18 h

N H 91% CO2tBu

10 mol% Pd(OAc)2 0.9 equiv. tBuOOBz Dioxane/HOAc (3/1) 70 °C, 18 h

N H

57%

Scheme 12.25  Pd‐catalyzed cross‐coupling of indoles with alkenes.

Regioselective alkenylation of electron‐deficient pyridine at 2‐position using N‐oxide as directing group was reported by Chang and coworkers in 2008 [26]. For example, treatment of pyridine N‐oxide (4.0 equiv.) with ethyl acrylate (0.3 mmol, 1 equiv.) in the presence of Pd(OAc)2 (10 mol%), Ag2CO3 (1.5 equiv.), and pyridine (1.0 equiv.) in dioxane (0.6 mL) at 100 °C for 12 h affords 2‐alkenylpyridine N‐oxide in 91% yield. Pyrazine N‐oxide is also available in this reaction, giving 2‐alkenylation product in 69% yield (Scheme 12.26). Since N‐oxides are prototypical oxidants and have been routinely used in some reactions, an external‐oxidant‐free alkenylation of quinoline N‐oxides was achieved by Cui, Wu, and coworkers in 2009 [27]. For example, reaction of quinoline N‐oxide (1.0 mmol, 1 equiv.) with ethyl acrylate (5.0 equiv.) in the presence of Pd(OAc)2 (5 mol%) in NMP (1 mL) at 110 °C for 20 h affords the

451

452

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

+

N

CO2Et

O 4.0 equiv.

0.3 mmol

10 mol% Pd(OAc)2 1.5 equiv. Ag2CO3 1.0 equiv. pyridine Dioxane (0.6 mL) 100 °C, 12 h

N

CO2Et

O 91%

N CO2tBu

N O 69%

Scheme 12.26  Pd‐catalyzed cross‐coupling of pyridine or pyrazine N‐oxide with alkenes.

c­ orresponding 2‐alkenylpyridine product in 86% yield (Scheme 12.27). N‐oxide acts as oxidizing reagent to regenerate Pd(OAc)2 from Pd–H species generated from β‐elimination of heteroaryl–Pd(II)–alkyl intermediate to afford alkenylation product.

N

+

CO2Et

O 1.0 mmol

5.0 equiv.

5 mol% Pd(OAc)2 NMP (1 mL), 110 °C, 20 h

N

CO2Et 86%

Scheme 12.27  External‐oxidant‐free Pd‐catalyzed cross‐coupling of quinoline N‐oxide with alkenes.

Alternatively, formation of heteroaryl–alkenyl bond was achieved by addition of alkyne to heteroarene reported by Fujiwara and coworkers in 2002 [28]. Treatment of pyrrole (2.0 equiv.) with ethyl 3‐phenylpropiolate (1.0 mmol, 1 equiv.) in the presence of Pd(OAc)2 (2 mol%) in HOAc (1 mL) at room tem­ perature affords 2‐alkenylpyrrole in 78% yield (Scheme  12.28). Reaction of indole gives 3‐alkenylation product for 24 h. 2‐Position of pyrrole and 3‐posi­ tion of indole are active positions in SEAr process, indicating that either elec­ trophilic metalation by Pd(OAc)2 or SEAr process by alkenyl cation generated from alkyne and Pd(OAc)2 is probably involved. Regioselective addition of alkyne to indole at 2‐position was achieved by Schipper, Fagnou, and coworker in 2010 [29]. For example, treatment of N,N‐dimethyl‐1H‐indole‐1‐carboxamide (0.3 mmol, 1 equiv.) with internal alkyne (1.1 equiv.) in the presence of rhodium catalyst (5 mol%) and PivOH (5.0 equiv.) in isopropyl acetate (0.75 mL) at 90 °C for 16 h affords quantitative

12.2  Formation of C─C Bond CO2Et N H

N H

2.0 equiv. or

+

Ph

CO2Et

2 mol% Pd(OAc)2

or

HOAc (1 mL), rt, 2 h

Ph 78% CO2Et

Ph

1.0 mmol

N H

N H 78%

2.0 equiv.

Scheme 12.28  Pd‐catalyzed addition of alkynes to heteroarenes.

yield of 2‐alkenylindole product (Scheme 12.29). Addition occurs at less steric hindered methyl side instead of more stable phenyl side for generation of ­benzyl alkenyl cation, indicating that insertion of alkyne to heteroaryl–rhodium intermediate is probably involved. Me + Me

N Me2N

Ph

O

5 mol% Cp*Rh(MeCN)3(SbF6)2

O

Me2N

1.1 equiv.

0.3 mmol

Ph

N

5.0 equiv. PivOH iPrOAc (0.75 mL), 90 °C, 16 h

99%

Scheme 12.29  Rh‐catalyzed addition of alkynes to heteroarenes.

Polyfluorobenzene was also available for alkenylation by addition of alkyne reported by Nakao, Hiyama, and coworkers in 2008 [30]. For example, treat­ ment of pentafluorobenzene (1.0 mmol) with di‐n‐propylacetylene (1.5 equiv.) in the presence of Ni(cod)2 (3 mol%) and phosphine ligand (3 mol%) in toluene (1 mL) at 80 °C for 3 h affords the corresponding alkenylation product in quan­ titative yield (Scheme 12.30). F F + F

F

nPr

nPr

1.5 equiv.

3 mol% Ni(cod)2 3 mol% P(c-C5H9)3 Toluene (1mL), 80 °C, 3 h

F 1.0 mmol

Scheme 12.30  Ni‐catalyzed addition of alkynes to polyfluoroarenes.

F

nPr nPr

F F

F F

99%

453

454

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

12.2.5  Carbonylation and Carboxylation

Formation of heteroaryl–carbonyl bond through direct insertion of CO or CO2 to heteroaryl C─H bond offers a convenient way to prepare heteroarylcarbox­ ylic acid compared with traditional deprotonation and carboxylation method. In 1982, Itahara reported carboxylation of N‐acylindoles with CO promoted or catalyzed by Pd(OAc)2 and Na2S2O8 [31]. Treatment of N‐acetylindole (2.0 mmol) with CO (bubbling) in the presence of Pd(OAc)2 (1.0 mmol) and K2S2O8 (3.0 mmol) in HOAc (40 mL) under reflux for 7 h affords N‐acetylindole‐ 3‑carboxylic acid in 37% yield with TON of 0.5. Reaction of N‐benzoylindole under similar conditions gives the corresponding indole‐3‐carboxylic acid in 78% yield with TON of 1.5 (Scheme 12.31). CO2H N

N O

Me 2.0 mmol or

+

Ph 2.0 mmol

CO bubbling

N

O

Me 1.0 mmol Pd(OAc)2 3.0 mmol Na2S2O8 HOAc (40 mL), reflux, 7 h

37%, TON = 0.7 or CO2H

O

N Ph

O

78%, TON = 1.5

Scheme 12.31  Pd‐catalyzed carboxylation of indole derivatives with CO.

Carboxylation of indole with CO to produce indole‐3‐carboxylic acid using air as terminal oxidant was further developed in 2011 by Lei and coworkers [32]. For example, treatment of N‐methylindole (0.2 mmol, 1 equiv.) with ­mixtures of CO and air (balloon, 7/1) and benzyl alcohol (0.2 mL) in the pres­ ence of PdCl2(PPh3)2 (2.5 mol%), PPh3 (5 mol%), and Cu(OAc)2 (10 mol%) in mixtures of DMSO (0.1 mL) and toluene (1.5 mL) at 100 °C for 36 h affords the corresponding indole‐3‐carboxylic ester in 86% yield (Scheme 12.32). CO2 is also available for catalytic carboxylation of heteroarenes. In 2010, Nolan and coworker reported carboxylation of heteroarenes with CO2 cata­ lyzed by carbene Au(I) complex [33]. For example, treatment of oxazole (1.0 mmol, 1 equiv.) or benzoxazole (1.0 mmol, 1 equiv.) with CO2 (1.5 bar) in the presence of NHC‐gold complex (1.5 mmol) and KOH (1.05 equiv.) in THF

12.2  Formation of C─C Bond

N

+

CO/air

+

balloon (7/1)

Me 0.2 mmol

BnOH 0.2 mL

CO2Bn

2.5 mol% PdCl2(PPh3)2 5 mol% PPh3 10 mol% Cu(OAc)2 DMSO (0.1 mL) Toluene (1.5 mL), 100 °C, 36 h

N Me 86%

Scheme 12.32  Pd‐catalyzed carboxylation of indole derivatives with CO using air as terminal oxidant. N

N

O 1.0 mmol or N

CO2H

O +

CO2 1.5 bar

1.5 mol% [IPrAuOH] 1.05 equiv. KOH THF (1.5 mL), 20 °C, 12 h

O 1.0 mmol

89% or N O 94%

CO2H

Scheme 12.33  Au‐catalyzed carboxylation of heteroarenes with CO2.

(1.5 mL) at 20 °C for 12 h affords the corresponding heteroarylcarboxylic acid, respectively (Scheme 12.33). In 2010, copper‐catalyzed carboxylation of benzoxazoles with CO2 was reported by two groups, namely, Hou [34] and Cazin and Nolan [35], respec­ tively. In the work of Hou et al., treatment of benzoxazole (1.0 mmol, 1 equiv.) with CO2 (1 atm) in the presence of NHC–copper complex (5 mol%), t‐BuOK (1.1 equiv.) in THF (5 mL) at 80 °C for 14 h followed by esterification with MeI (2.0 equiv.) in DMF (5 mL) affords the corresponding carboxylic ester in 86% yield [34] (Scheme  12.34). In the example of Cazin, Nolan, and coworkers, treatment of benzoxazole (1.0 mmol, 1 equiv.) with CO2 (1.5 bar) in the pres­ ence of NHC–copper complex (3 mol%), CsOH (1.05 equiv.), and tetradecane (0.1 mL) in THF (2 mL) at 65  °C for 8 h followed by esterification with MeI (1.0 equiv.) and hydrolysis in HCl aq. affords the corresponding carboxylic acid in 90% yield [35] (Scheme 12.35).

N

+

CO2

O 1.0 mmol

1 atm

(1) 5 mol% [IPrCuCl], 1.1 equiv. KOtBu THF (5 mL), 80 °C, 14 h (2) MeI (2.0 equiv.), DMF (5 mL) 80 °C, 5 h

Scheme 12.34  Cu‐catalyzed carboxylation of benzoxazole with CO2(I).

N O 86%

CO2Me

455

456

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

N

+

O 1.0 mmol

CO2

(1) 3 mol% [IPrCuOH], 1.05 equiv. CsOH Tetradecane (0.1 mL), THF (2 mL), 65 °C, 8 h

N

(2) MeI (1.0 equiv.) (3) HCl aq.

1.5 bar

O

CO2H

90%

Scheme 12.35  Cu‐catalyzed carboxylation of benzoxazole with CO2(II).

12.2.6 Alkynylation

Direct cross‐coupling of heteroaryl C─H bond with alkyne provides an ideal way in the formation of heteroaryl–alkynyl bond. In 2010, Miura and cowork­ ers reported copper‐promoted alkynylation of 1,3,4‐oxadiazoles or oxazoles with terminal alkynes [36]. For example, treatment of 5‐phenyloxazole (5.0 equiv.) with 4‐tolylacetylene (0.5 mmol, 1 equiv.) in the presence of CuCl2 (1.0 equiv.), Na2CO3 (2.4 equiv.), and O2 (1 atm) in DMSO (1.5 mL) at 150 °C for 1 h affords the 2‐alkynyloxazole in 51% yield (Scheme 12.36). N Ph

O

+

Me 0.5 mmol

5.0 equiv.

1.0 equiv. CuCl2 2.4 equiv. Na2CO3 O2 (1 atm) Ph DMSO (1.5 mL), 150 °C, 1 h

N

Me

O 51%

Scheme 12.36  Cu‐mediated cross‐coupling of heteroarenes with alkynes.

Catalytic alkynylation of benzoxazole with terminal alkynes was achieved by the same group in 2010, applying nickel catalysis and atmospheric O2 as ­oxidant [37]. For example, treatment of benzoxazole (0.5 mmol, 1 equiv.) with phenylacetylene (2.0 equiv.) in the presence of NiBr2·diglyme (5 mol%), dtbpy (5 mol%), t‐BuOLi (3.0 equiv.), and O2 (1 atm) in toluene (2.5 mL) at 100 °C for 1 h affords the 2‐alkynylbenzoxazole in 48% yield (Scheme 12.37). N

5 mol% NiBr2 diglyme 5 mol% dtbpy

+

O 0.5 mmol

2.0 equiv.

3.0 equiv. LiOtBu, O2 (1 atm) Toluene (2.5 mL), 100 °C, 1 h

N O 48%

Scheme 12.37  Ni‐catalyzed cross‐coupling of benzoxazole with alkynes.

Catalytic alkynylation of indole derivatives with terminal alkynes was achieved by Li and coworkers in 2010, applying palladium catalysis and atmos­ pheric O2 as oxidant [38]. For example, treatment of N‐methyl‐3‐methylin­ dole (0.1 mmol, 1 equiv.) with phenylacetylene (2.0 equiv.) in the presence of

12.2  Formation of C─C Bond Me + N Me 0.1 mmol

Me

10 mol% K2PdCl4 20 mol% Cs2CO3 2.0 equiv. PivOH,O2 (1 atm) DMSO (1 mL), 80 °C, 24 h

N Me 71%

2.0 equiv.

Scheme 12.38  Pd‐catalyzed cross‐coupling of indole derivatives with alkynes.

K2PdCl4 (10 mol%), Cs2CO3 (20 mol%), PivOH (2.0 equiv.), and O2 (1 atm) in DMSO (1 mL) at 80  °C for 24 h affords the 2‐alkynylindole in 71% yield (Scheme 12.38). Catalytic alkynylation of benzoxazole with terminal alkynes was also availa­ ble applying commercial tetrakis(triphenylphosphine)palladium(0) catalyst and atmospheric air as oxidant, reported by Chang and coworkers in 2011 [39]. For example, treatment of benzoxazole (3.0 equiv.) with phenylacetylene (0.5 mmol, 1 equiv.) in the presence of Pd(PPh3)4 (5 mol%) and t‐BuOLi (4.0 equiv.) and air (1 atm) in toluene (3 mL) at 100 °C for 12 h affords the 2‐alky­ nylbenzoxazole in 74% yield (Scheme 12.39). N

+

O 0.5 mmol

3.0 equiv.

5 mol% Pd(PPh3)4

N

4.0 equiv. LiOtBu, air (1atm) Toluene (3 mL), 100 °C, 12 h

O 74%

Scheme 12.39  Pd‐catalyzed cross‐coupling of benzoxazole with alkynes.

Polyfluoroarenes are also available in the cross‐coupling with terminal alkynes to form aryl–alkynyl bond. In 2010, Su and coworkers reported such reaction under copper catalysis using atmospheric O2 as oxidant [40]. For example, treatment of pentafluorobenzene (5.0 equiv.) with phenylacetylene (0.2 mmol, 1 equiv.) in the presence of CuCl2 (30 mol%), 1,10‐phenanthroline (30 mol%), DDQ (15 mol%), and t‐BuOLi (3.0 equiv.) in DMSO (1.5 mL) at 40 °C for 12 h affords the corresponding perfluorophenylacetylene product in 85% yield (Scheme 12.40). F

30 mol% CuCl2 30 mol% 1,10-phen 15 mol% DDQ

F +

F F F 5.0 equiv.

3.0 equiv. LiOtBu DMSO (1.5 mL), 40 °C, 12 h 0.2 mmol

F

F

F

F 85%

F

Scheme 12.40  Cu‐catalyzed cross‐coupling of pentafluorobenzene with alkynes.

457

458

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

Copper‐catalyzed cross‐coupling of polyfluoroarenes with terminal alkynes at room temperature using atmospheric air as oxidant was also reported by Miura and coworkers in 2010 [37]. For example, treatment of pentafluoroben­ zene (3.0 equiv.) with phenylacetylene (0.5 mmol, 1 equiv.) in the presence of Cu(OTf )2 (20 mol%), 1,10‐phenanthroline ·H2O (40 mol%), and t‐BuOLi (1.0 equiv.) in DMSO (1.5 mL) at room temperature affords the corresponding perfluorophenylacetylene product in 60% yield (Scheme 12.41). F

F

20 mol% Cu(OTf)2 40 mol% 1,10-phen H2O

+

F F F 3.0 equiv.

1.0 equiv. LiOtBu, air (1 atm) DMSO (1.5 mL), rt, 6–24 h 0.5 mmol

F

F

F

F 60%

F

Scheme 12.41  Cu‐catalyzed cross‐coupling of pentafluorobenzene with alkynes.

12.2.7 Cyanidation

Catalytic direct cyanation of heteroaryl C─H bond offers a quick access in the preparation of heteroaryl cyanide. One such example was reported by Cheng and coworkers in 2011 with indole as substrate and combination of NH4HCO3 and DMSO as cyanide source in palladium catalysis [41]. Treatment of N‐methylindole (0.2 mmol, 1 equiv.) with NH4HCO3 (1.5 equiv.) and DMSO (1.5 mL) as combinational cyanation reagent in the presence of PdCl2 (10 mol%), Cu(OAc)2 (1.1 equiv.), and O2 (1 atm) at 140 °C for 6 h affords sole 3‐cyanoindole in 85% yield. Isotopic experiment applying 13C‐labeled DMSO in cyanation of N‐methylindole under similar conditions gives 70% of 3‐13CN‐indole product. In the proposed mechanism, Pd(II) catalyst cleaves heteroaryl C─H bond of indole at 3‐position to form heteroaryl–Pd(II) intermediate. Trans­metalation of this heteroaryl–Pd(II) intermediate with cyanide generated from NH4HCO3 and DMSO in situ gives heteroaryl–Pd(II)–cyanide key intermediate. Reductive elimination of heteroaryl and cyanide group affords 3‐cyanoindole product and Pd(0) species, which is oxidized by Cu(OAc)2 and O2 to generate Pd(II) species, fulfilling the catalytic cycle (Scheme 12.42). DMF was available as cyanide source in palladium‐catalyzed cyanation of indoles reported by Jiao and coworker in 2011 [42]. For example, treatment of N‐methyl‐3‐phenylindole (0.2 mmol, 1 equiv.) with DMF (2.0 mL) as cyanation reagent in the presence of Pd(OAc)2 (10 mol%), FeCl2 (10 mol%), CuBr2 (1.1 equiv.), K2CO3 (1.1 equiv.), tetrabutylammonium acetate (1.1 equiv.), and O2 (1 atm) at 130  °C for 29 h affords 3‐cyanoindole derivative in 66% yield. Reaction of 2‐phenylbenzofuran under similar conditions also gives 3‐cyana­ tion product in 66% with longer reaction time (Scheme 12.43). Isotopic experiments clearly demonstrate that both the carbon and the nitrogen atoms incorporated into heteroarenes are derived from DMF.

12.3  Formation of C─N Bond CN N Me

+

+

NH4HCO3

O H3C

1.5 equiv.

0.2 mmol

S

10 mol% PdCl2 CH3

1.1 equiv. Cu(OAc)2 O2 (1 atm), 140 °C, 6 h

1.5 mL

N Me 85%

II

Pd

Cu(OAc)2 O2

N C H cleavage

Oxidation

Me PdII

Pd0

Reductive elimination

CN

N Me

Ligand exchange

–CN

PdIICN

N Me

NH4HCO3 + DMSO

N Me

Scheme 12.42  Pd‐catalyzed cyanation of indole derivatives.

CN Ph N Me O

0.2 mmol or

+ Ph

O

H

N

Me

Me 2.0 mL

10 mol% Pd(OAc)2, 10 mol% FeCl2 1.1 equiv. CuBr2, 1.1 equiv. K2CO3 1.1 equiv. [nBu4N][OAc] O2 (1 atm), 130 °C

0.2 mmol

Ph N Me 66%, 29 h or CN Ph O 66%, 94 h

Scheme 12.43  Pd‐catalyzed cyanation of heteroarenes.

12.3 ­Formation of C─N Bond Catalytic cross‐coupling of heteroaryl C─H bond and N─H bond of amine is an ideal method to form heteroaryl–nitrogen bond. In 2009, Mori and coworkers reported a cross‐coupling of azoles and amines catalyzed by copper salt using atmospheric O2 as oxidant [43]. For example, treatment of

459

460

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

benzothiazole (0.2 mmol, 1 equiv.) with secondary amine (4.0 equiv.) in the presence of Cu(OAc)2 (20 mol%), PPh3 (40 mol%), and O2 (1 atm) in xylene (1 mL) at 140  °C for 20 h affords the corresponding amination product in 81% yield. Benzoxazole is also available to give the 2‐aminobenzoxazole product. In the proposed mechanism, Cu(II)X2 catalyst cleaves heteroaryl C─H bond to form heteroaryl–Cu(II)–X intermediate. Transmetalation of this heteroaryl–Cu(II)–X intermediate with amine gives heteroaryl– Cu(II)–amine key intermediate. Reductive elimination of heteroaryl and amino group affords the corresponding amination product and Cu(0) spe­ cies. Oxidation of this Cu(0) species by O2 (1 atm) fulfills the catalytic cycle (Scheme 12.44).

N + S 0.2 mmol N

+

O 0.2 mmol

Me HN Ph 4.0 equiv.

Me N Ph

N S

20 mol% Cu(OAc)2 40 mol% PPh3

81%

Xylene (1mL) O2 (1 atm), 140 °C, 20 h

HN

N N

O

4.0 equiv.

72% N CuIIX2

O2 Oxidation

O

C H cleavage HX N

Cu0

CuII X

O

N O

Reductive elimination

Ligand exchange

HN

N N O

CuII N

HX

Scheme 12.44  Cu‐catalyzed amination of heteroarenes with amines.

12.4  Formation of C─O Bond

12.4 ­Formation of C─O Bond Transition‐metal‐catalyzed direct functionalization of heteroaryl C─H bond is also applied to form heteroaryl–oxygen bond. In 2009, Suna and coworkers reported acetoxylation of indoles with PhI(OAc)2 catalyzed by either Pd(OAc)2 or PtCl2 [44]. For example, treatment of N‐methyl‐2‐ester‐5‐bromoindole (0.5 mmol, 1 equiv.) with PhI(OAc)2 (1.3 equiv.) in the presence of Pd(OAc)2 (5 mol%) or PtCl2 (5 mol%) in HOAc (2 mL) under irradiation of microwave at 100 °C for 1 h affords the corresponding 3‐acetoxylation product in 75 or 91% yield, respectively. Reaction of 2,3‐unsubstituted indole gives mixtures of oxygenation products with 3‐acetoxyindole as major product in the yield of 34% (Scheme 12.45). Br N Me 0.5 mmol

CO2Et + PhI(OAc)2

5 mol% Pd(OAc)2 or PtCl2 HOAc (2 mL) Microwave, 100 °C, 1 h

1.3 equiv. Br

Br N SO2Ph 0.5 mmol

+ PhI(OAc)2

5 mol% Pd(OAc)2

Br

HOAc (2 mL) Microwave, 100 °C, 17 h

1.3 equiv. Br

Br

OAc CO2Et N Me 75 or 91% OAc N SO2Ph 34% + OAc OAc N SO2Ph 5% + O OAc N SO2Ph 13%

Scheme 12.45  Pd‐ or Pt‐catalyzed acetoxylation of indole derivatives with PhI(OAc)2.

Regioselective palladium‐catalyzed acetoxylation of indole with PhI(OAc)2 at 3‐position by applying appropriate base and solvent was reported by Kwong and coworkers in 2011 [45]. For example, treatment of N‐benzylindole (0.5 mmol, 1 equiv.) with PhI(OAc)2 (2.0 equiv.) in the presence of Pd(OAc)2 (2 mol%) and KOAc (1.0 equiv.) in MeCN (2 mL) at 70  °C for 2 h affords the ­corresponding 3‐acetoxylation product in 70% yield (Scheme 12.46). A variety of N‐arylindoles and N‐alkylindoles are also available for this reaction.

461

462

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene OAc + N Bn 0.5 mmol

PhI(OAc)2

2 mol% Pd(OAc)2 1.0 equiv. KOAc MeCN (2mL), 70 °C, 2 h

N Bn

2.0 equiv.

70%

Scheme 12.46  Pd‐catalyzed acetoxylation of indole derivatives with PhI(OAc)2.

Copper‐catalyzed oxygenation of heteroarenes was reported in 2012 by Lei  and coworkers using atmospheric air as oxidant at room temperature [46]. Treatment of benzothiazole (0.5 mmol, 1 equiv.) with air (balloon) in the ­presence of CuCl2 (5 mol%) and t‐BuONa (1.2 equiv.) in DMF (2 mL) at room temperature for 1 h affords the corresponding keto product generated from hydroxylation followed by keto–enol tautomerization in 70% yield. Benzoxazole is also available to give the target keto product in 5 h. Isotopic experiment using 18 O2 clearly demonstrates that oxygen in product comes from air (Scheme 12.47). H N

N S 0.5 mmol or

+

N

Air balloon

5 mol% CuCl2 1.2 equiv. tBuONa DMF (2 mL), rt

O

O

O O 73% (5 h)

0.5 mmol N + S

S 70% (1h) or H N

18O

2

balloon

0.5 mmol

5 mol% CuCl2

H N

1.2 equiv. tBuONa

S

DMF (2 mL), rt, 1 h

65%

18O

Scheme 12.47  Pd‐catalyzed oxygenation of heteroarenes with air.

12.5 ­Formation of C─Halogen Bond 12.5.1 Fluorination

Examples of direct fluorination of heteroaryl C─H bond are rare since there is very limited pathway known for introduction of fluorine atom. Transition‐ metal‐catalyzed fluorination of aryl C─H bond assisted by directing group is also available for heteroaryl C─H bond. One such example was reported by Daugulis and coworkers in 2013 [47]. Applying 8‐aminoquinoline as effective

12.5  Formation of C─Halogen Bond

directing group, indole or pyridine derivative (0.25 mmol, 1 equiv.) reacts with AgF (4.0 equiv.) in the presence of catalytic CuI (10 or 20 mol%), NMO (5.0 equiv.), DMF, or pyridine as solvent (1 mL) at moderate temperature (50 or 65 °C) affords the corresponding 2‐fluoroindole or 3‐fluoropyridine product, respectively. Difluorination of pyridine derivative to produce 3,5‐difluoropyri­ dine derivative is also available applying stronger conditions (Scheme 12.48).

O

NH

O

N

N Me 0.25 mmol or

+

AgF 4.0 equiv.

Cat. CuI 5.0 equiv. NMO Solvent (1 mL)

NH

F N Me 54%, 10 mol% CuI, DMF, 50 °C, 1 h or N

N O

N

O

NH

NH F

N 62%, 20 mol% CuI, pyridine, 65 °C, 2 h

N 0.25 mmol

N O

NH

+

AgF 6.0 equiv.

N

25 mol% CuI 8.0 equiv. NMO Pyridine (1 mL), 85 °C, 1.5 h

O

NH

F

N 0.25 mmol

F N 61%

Scheme 12.48  Cu‐catalyzed fluorination of heteroarenes with AgF.

Nondirecting‐group‐assisted fluorination of pyridine at 2‐position mediated by AgF2 was achieved by Hartwig and coworker in 2013, which is commercially available [48]. Treatment of 2‐phenylpyridine (0.5 mmol, 1 equiv.) with AgF2 (3.0 equiv.) in MeCN (10 mL) at room temperature for 1 h affords 2‐fluoro‐6‐ phenylpyridine product in 82% yield, which is orthogonal in regioselectivity with directing‐group‐assisted transition‐metal‐catalyzed functionalization of 2‐phenylpyridine. Various pyridines are available for 2‐fluorination. Besides, other heteroarenes such as quinolines, pyrazines, etc. also give 2‐fluorina­ tion product, respectively. This 2‐fluorination of pyridine method is applied

463

464

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

for gram‐scale preparation of 2‐(5‐ethyl‐6‐fluoropyridin‐2‐yl)ethyl 4‐methyl­ benzenesulfonate, a precursor of fluoro‐pioglitazone. The fluorination pathway is proposed to be similar with Chichibabin reaction and amination of pyridine at 2‐position with NaNH2 (Scheme 12.49).

N

+

AgF2 3.0 equiv.

N

MeCN (10mL), rt, 1h

0.5 mmol

82% Me

TsO

F

N 5.0 mmol

+

AgF2

Me MeCN, rt, 1 h

3.0 equiv.

TsO

F N 83%, 1.34 g

Scheme 12.49  AgF2‐mediated fluorination of heteroarenes.

12.5.2 Chlorination

Currently, chlorination of heteroarenes with NCS through SEAr process is still the main method in the formation of heteroaryl–chlorine bond practically. Therefore, new powerful chlorinating reagent is still highly desired. In 2014, Baran and coworkers reported invention of a new guanidine‐based reagent, Palau’Chlor (CBMG), for direct electrophilic chlorination of a range of nitro­ gen‐containing heterocycles at room temperature [49]. The guanidine‐based chlorinating reagent, Palau’Chlor (CBMG), is prepared in three steps starting from S‐methylisothiourea sulfate in quantitative yield and in decagram scale. Applying this chlorinating reagent CBMG (1.2 equiv.) with N‐pivalylindole (0.1 mmol, 1 equiv.) in chloroform (1 mL) at room temperature for 12 h affords 3‐chloroindole product in 86% yield, while NCS does not work for this chlo­ rination. Gram‐scale preparation of 3‐chloroindole derivative is available using ethyl 1H‐indole‐2‐carboxylate as substrate, for example (Scheme  12.50). Various other nitrogen‐containing heterocycles including imidazoles, pyr­ roles, pyrazoles, etc. are available for chlorination as well. Alternatively, chlorination of heteroarenes is available with NCS as chlorin­ ating reagent effectively by applying 2,4,6‐trimethylaniline as catalyst, reported by Samanta and Yamamoto in 2015 [50]. For example, treatment of N‐piva­ lylindole (0.5 mmol, 1 equiv.) or ethyl 1H‐indole‐2‐carboxylate (0.5 mmol, 1 equiv.) with NCS (1.2 equiv.) in the presence of 2,4,6‐trimethylaniline (10 mol%) in CH2Cl2 (2 mL) at room temperature affords the corresponding 3‐chloroindole product in almost quantitative yield (Scheme 12.51). It is p ­ roposed that reaction of 2,4,6‐trimethylaniline with NCS generates N‐chloroaniline intermediate, which serves as highly reactive and selective catalytic electrophilic chlorinating reagent.

12.5  Formation of C─Halogen Bond (1) 4.5 equiv. ClCO2Me 4 mol% [nBu4N][Br] 2.0 equiv. Na2CO3 3.0 equiv. NaOH CH2Cl2 (100 mL)

SMe HN

NH2

H2SO4

(2) 3.0 equiv. NH3 MeOH (~400 mL)

2

72 mmol 20 g, $0.146/g

(3) 1.1 equiv. tBuOCl CH2Cl2 (650 mL)

NH2

H2O (120 mL)

N MeO2C

NH

Quantitative (3 steps) [decagram]

CO2Me

32 g

HN N

Cl NH

MeO2C

CO2Me

Palau’chlor (CBMG)

Cl +

CBMG

CHCl3 (1 mL), rt, 12 h

N Piv 0.1 mmol

1.2 equiv.

N Piv 86% NCS (0%) Cl

N H

CO2Et

+

CBMG

CHCl3 (0.1 M), rt, 12 h

1.1 equiv.

1.0 g

CO2Et N H 99% NCS (0%)

Scheme 12.50  Chlorination of heteroarenes by CBMG. Cl

N

N Piv 0.5 mmol or

N H

+

NCS 1.2 equiv.

CO2Et

0.5 mmol

10 mol% 2,4,6-trimethylaniline CH2Cl2 (2 mL), rt

Piv 96%, 16 h or Cl CO2Et N H 98%, 17h

Scheme 12.51  2,4,6‐Trimethylaniline‐catalyzed chlorination of heteroarenes by NCS.

12.5.3 Bromination

Oxidative bromination of heteroarenes with bromide salt as bromine source utilizing atmospheric O2 as oxidant is an ideal way for the formation of hetero­ aryl–bromine bond. One such example was reported by Stahl and coworkers [51] in 2009. Treatment of benzothiophene (0.3 mmol, 1 equiv.) or N‐tosylin­ dole (0.3 mmol, 1 equiv.) with LiBr (2.0 or 1.0 equiv.) in the presence of CuBr2

465

466

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

(25 mol%) and O2 (1 atm) in HOAc (1 mL) or mixtures of toluene (1 mL) and HOAc (1 mL) at 60 or 40 °C for 24 h affords the corresponding 3‐bromination product, respectively (Scheme  12.52). It is proposed that bromination is accomplished by electrophilic bromination, and copper catalyst mediates the aerobic oxidation of bromide to molecular bromine. Br S

S

0.3 mmol or

+

LiBr 2.0 or 1.0 equiv.

25 mol% CuBr2 O2 (1 atm), 24 h

N Ts

77% HOAc (1mL), 60 °C or Br

N Ts 66%, Toluene (1 mL) HOAc (1 mL), 40 °C

0.3 mmol

Scheme 12.52  Cu‐catalyzed bromination of heteroarenes by LiBr and O2 (1 atm).

Oxidative bromination of heteroarenes with bromide anion was also achieved using DMSO as oxidant reported by Jiao and coworkers [52]. For example, treatment of N‐benzylindole (0.5 mmol, 1 equiv.) or ethyl 1H‐indole‐2‐carbox­ ylate (0.5 mmol, 1 equiv.) with hydrogen bromide (1.2 equiv., 48% aq.) in the presence of DMSO (1.2 equiv.) in ethyl acetate (2 mL) at 60 °C for 0.5 h affords the corresponding 3‐bromoindole product in quantitative yield (Scheme 12.53). It is proposed that bromination is occurred by electrophilic bromination, and DMSO oxidizes bromide to molecular bromine or DMS·Br2 species. Br

N Bn 0.5 mmol or

N H

+

CO2Et

HBr 1.2 equiv. (48% aq.)

1.2 equiv. DMSO EtOAc (2 mL), 60 °C, 0.5 h

0.5 mmol

Scheme 12.53  Bromination of heteroarenes by HBr and DMSO.

N Bn 98% or Br

N H 98%

CO2Et

12.5  Formation of C─Halogen Bond

Besides, it is also available for bromination with NBS using 2,4,6‐trimethylaniline as catalyst, reported by Samanta and Yamamoto in 2015 [50]. For example, treatment of N‐acetylindole (0.5 mmol, 1 equiv.) with NBS (1.1 equiv.) in the presence of 2,4,6‐trimethylaniline (2 mol%) in CH2Cl2 (2 mL) at 0  °C for  24 h affords the corresponding 3‐bromoindole product in 81% yield (Scheme 12.54). Br N Ac 0.5 mmol

+

NBS

2 mol% 2,4,6-trimethylaniline CH2Cl2 (2 mL), 0 °C, 24 h

1.1 equiv.

N Ac 81%

Scheme 12.54  2,4,6‐Trimethylaniline‐catalyzed bromination of heteroarenes by NCS.

12.5.4 Iodination

Direct iodination of heteroaryl C─H bond provides a quick access in the ­preparation of heteroaryl iodide. Oxidative bromination of heteroarenes with bromide anion using DMSO as oxidant reported by Jiao and coworkers was also applied in the iodination [52]. For example, treatment of 2‐methylbenzothiophene (0.5 mmol, 1 equiv.) or ethyl N‐methyl‐2‐phenylindole (0.5 mmol, 1 equiv.) with ammonium iodide (2.0 or 1.2 equiv.) in the presence of DMSO (6.0 or 3.6 equiv.) and conc. H2SO4 (3.0 or 1.8 equiv.) in ethyl acetate (2 mL) at 80 or 60 °C for 10 or 5 h affords the corresponding 3‐iodoindole product in almost quantitative yield (Scheme 12.55). The conditions for oxidative iodination are harsher than oxidative bromination. Besides, polyfluoroarene is iodinated promoted by base reported by Daugulis and coworker in 2009 [53]. For example, treatment of pentafluorobenzene I Me

Me

S 0.5 mmol or

+ Ph

NH4I 2.0 or 1.2 equiv.

6.0 or 3.6 equiv. DMSO 3.0 or 1.8 equiv. conc. H2SO4 EtOAc (2 mL), 80 or 60 °C, 10 or 5 h

N Me 0.5 mmol

Scheme 12.55  Iodination of heteroarenes by NH4I and DMSO.

S 98% or I Ph N Me 94%

467

468

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

(1.5 equiv.) with molecular iodine (1.0 mmol, 1 equiv.) in the presence of K3PO4 (2.0 equiv.) in DMF (1 mL) at 130 °C for 2 h affords perfluorophenyl iodide in 85% yield (Scheme 12.56). Deprotonation of pentafluorobenzene followed by nucleophilic substitution forms aryl–iodine bond. F

F

F +

F F F 1.5 equiv.

I2

2.0 equiv. K3PO4 DMF (1 mL), 130 °C, 2 h

F I

F F

1.0 mmol

F 85%

Scheme 12.56  Iodination of polyfluoroarenes by I2.

12.6 ­Cross‐Coupling of Dual Aryl sp2C─H Bonds on Directing‐Group‐Containing Arenes, Heteroarenes, or Polyfluoroarenes As described in Chapters 9–12, aryl sp2C─H bonds of directing‐group‐containing arenes, heteroarenes, or polyfluoroarenes are cleaved more selectively and effectively in their oxidative reactions compared with those of simple arenes. Thus, some novel cross‐coupling reactions of dual aryl sp2C─H bonds have been established to form unsymmetrical biaryls, one of the most common and important motifs in organic compounds, utilizing directing‐group‐containing arene, heteroarene, or polyfluoroarene as one cross‐coupling partner. These reactions are more convenient and environmentally friendly than the tradi­ tional cross‐couplings such as the Suzuki, Stille, Negishi, or Ullmann reaction. Catalytic cross‐coupling of arene having directing group with simple arene was established by Sanford and coworkers in 2007 [54]. For example, treatment of benzo[h]quinoline (0.43 mmol, 1 equiv.) with excess benzene (98 equiv.) in the presence of Pd(OAc)2 (10 mol%), BQ (0.5 equiv.) promoting reductive elim­ ination of two aryl partners, Ag2CO3 (2.0 equiv.) as terminal oxidant, and DMSO (4.0 equiv.) to stabilize the Pd(0) species from aggregation to Pd black at 130 °C for 12 h affords the ortho‐phenylation product in 89% yield. Applying benzene in large excess as solvent, homocoupling of neither benzo[h]quinoline nor benzene is observed. Anisole is also an available coupling partner, giving mixtures of ortho‐arylation product in 88% yield with o/m/p regioselectivity of 1/2.9/3.3. In the proposed mechanism, Pd(II) catalyst coordinates with pyri­ dine and cleaves ortho‐aryl C─H bond to form aryl–Pd(II) complex, which cleaves phenyl C─H bond subsequently to give aryl–Pd(II)–phenyl key inter­ mediate. Reductive elimination of aryl and phenyl group affords biaryl product and Pd(0) species, which is oxidized to Pd(II) species to fulfill the catalytic cycle (Scheme 12.57).

12.6  Cross‐Coupling of Dual Aryl sp2C─ H Bonds

10 mol% Pd(OAc)2

+

N 0.43 mmol

N

0.5 equiv. BQ, 2.0 equiv. Ag2CO3 4.0 equiv. DMSO, 130 °C, 12 h 98 equiv.

89%

N PdII

Ag2CO3 Oxidation

Metalation

H

N

Pd0

PdII Reductive elimination

Metalation

N N

H

PdII

Scheme 12.57  Cross‐coupling of benzo[h]quinoline with benzene.

This kind of catalytic cross‐coupling was expanded to aniline derivatives, reported by Shi et al. [55] and Buchwald et al. [56] in 2008. In the work of Shi et  al., for example, treatment of aniline derivative (0.3 mmol, 1 equiv.) with excess benzene (1.0 mL) in the presence of Pd(OAc)2 (10 mol%), Cu(OTf )2 (1.0 equiv.), and O2 (1 atm) in EtCO2H (1.5 mL) at 120  °C for 7 h affords the ortho‐phenylation product in 66% yield [55]. Toluene is also available, giving ortho‐arylation product in 78% yield with m/p regioselectivity of 1/1.1 (Scheme 12.58). In the example of Buchwald et al., reaction of aniline derivative (0.3 mmol, 1 equiv.) with slightly excess benzene (11 equiv.) in the presence of Pd(OAc)2 (10  mol%), DMSO (10  mol%), O2 (1  atm), and CF3CO2H (5.0 equiv.) at 90 °C for 18 h affords the ortho‐phenylation product in 92% yield [56]. Anisole or toluene is also available, giving ortho‐arylation

469

470

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

Me

N

NAc

10 mol% Pd(OAc)2

+

1.0 equiv. Cu(OTf)2, O2 (1 atm)

O

EtCO2H (1.5 mL), 120 °C, 7 h

0.3 mmol

1.0 mL

66%

Scheme 12.58  Cross‐coupling of aniline derivative with benzene using Cu(OTf )2/O2 (1 atm).

­ roduct in 82 or 77% yield with o/m/p regioselectivity of 1/2/12 or 1/16/16, p respectively (Scheme 12.59). Me Me

H Me N

Me Me

NHPiv

10 mol% Pd(OAc)2

+

10 mol% DMSO, O2 (1 atm) CF3CO2H (5.0 equiv.), 90 °C, 18 h

O 11 equiv.

0.3 mmol

92%

Scheme 12.59  Cross‐coupling of aniline derivative with benzene using O2 (1 atm).

O‐Phenylcarbamates were also available in the catalytic cross‐coupling reported by Dong and coworkers in 2010 [57]. For example, treatment of mmol, 1  equiv.) with excess benzene O‐phenylcarbamate derivative (0.2  (1.0 mL) in the presence of Pd(OAc)2 (10 mol%), Na2S2O8 (3.0 equiv.), and CF3CO2H (5.0 equiv.) at 70 °C for 39 h affords the ortho‐phenylation product in 90% yield (Scheme 12.60). Me

Me

Me O

N

Me

10 mol% Pd(OAc)2

+

3.0 equiv. Na2S2O8 CF3CO2H (5.0 equiv.), 70 °C, 39 h

O 0.2 mmol

OCONMe2

1.0 mL

90%

Scheme 12.60  Cross‐coupling of O‐phenylcarbamate derivative with benzene.

Phenylacetamides were used as substrates by the same group in 2010 [58]. For example, treatment of phenylacetamide derivative (0.2 mmol, 1 equiv.) with excess benzene (1.0 mL) in the presence of Pd(OAc)2 (10 mol%), Na2S2O8 (3.0 equiv.), and CF3CO2H (5.0 equiv.) at 70  °C for 24 h affords the ortho‐ phenylation product in quantitative yield. Anisole is also available, giving ortho‐arylation product in quantitative yield as well with o/m/p regioselectivity of 9/13/78 (Scheme 12.61).

12.6  Cross‐Coupling of Dual Aryl sp2C─ H Bonds Me

Me

H N O

CONHiPr

10 mol% Pd(OAc)2

Me +

3.0 equiv. Na2S2O8 CF3CO2H (5.0 equiv.), 70 °C, 24 h

Me

0.2 mmol

1.0 mL

99%

Scheme 12.61  Cross‐coupling of phenylacetamide derivative with benzene.

The regioselectivity problem of monosubstituted simple arene such as ani­ sole or toluene to give mixtures of regioisomers was enhanced to give para‐ arylation as major product enabled by F+ oxidant, reported by Yu and coworkers in 2011 [59]. For example, treatment of benzamide derivative (0.2 mmol, 1 equiv.) with excess toluene (2.0 mL) in the presence of Pd(OAc)2 (10 mol%), NFSI (1.5 equiv.), and DMF (2.0 equiv.) at 90 °C for 24 h affords the ortho‐aryla­ tion product in 73% yield with m/p regioselectivity of 1/17 (Scheme 12.62). F F F

F

CF3

CF3 Me

HN

+

F O

F

2.0 mL

10 mol% Pd(OAc)2

HN

1.5 equiv. NFSI 2.0 equiv. DMF 90 °C, 24 h

F O

F

0.2 mmol

Me 73% (p/m = 17/1)

Scheme 12.62  Cross‐coupling of benzamide derivative with toluene.

N‐methoxybenzamide was also available in the cross‐coupling with toluene followed by cyclization to give phenanthridinone product [60]. For example, treatment of N‐methoxybenzamide (0.7 mmol, 1 equiv.) with excess toluene (25 equiv.) in the presence of Pd(OAc)2 (10 mol%), K2S2O8 (2.0 equiv.), and CF3CO2H (20 equiv.) at room temperature for 16 h affords the phenanthridi­ none product in 92% yield (Scheme 12.63). O O N H

OMe

0.7 mmol

Me +

25 equiv.

10 mol% Pd(OAc)2 2.0 equiv. K2S2O8 20 equiv. CF3CO2H rt, 16 h

Scheme 12.63  Cross‐coupling of benzamide derivative with toluene.

N

92%

OMe

Me

471

472

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

In addition, cross-coupling of weak coordinating ethyl benzoate with electrondeficient arenes such as nitrobenzene or trifluoromethylbenzene was achieved by Lu and Zhou in 2012 by applying Pd(OAc)2/K2S2O8/CF3CO2H ­oxidative catalytic system [61]. Treatment of ethyl benzoate (1.0 mmol, 1 equiv.) with nitrobenzene (5.0 equiv.) or trifluoromethylbenzene (5.0 equiv.) in the presence of Pd(OAc)2 (10 mol%), K2S2O8 (2.0 equiv.), and CF3CO2H (10 equiv.) at 90 °C for 40 h affords the corresponding ortho‐arylation product in moderate yield with m/p regioselectivity of 4.4/1 or 3.5/1, respectively. Utilizing weak coordi­ nating ester group as directing group and reaction of electron‐deficient arene is probably due to the high electrophilic characteristics of Pd(OCOCF3)+ ­cation generated in situ (Scheme 12.64). CO2Et NO2

CO2Et

5.0 equiv. +

or CF3

1.0 mmol

NO2

10 mol% Pd(OAc)2 1.0 equiv. K2S2O8 10 equiv. CF3CO2H 90 °C, 40 h

55% m/p = 4.4/1 or CO2Et CF3

5.0 equiv.

56% m/p = 3.5/1

Scheme 12.64  Cross‐coupling of ethyl benzoate with electron‐deficient arenes.

On the other hand, catalytic cross‐coupling of heteroarenes such as indole, ­ enzofuran, etc. with arenes was also established successfully. In 2007, Fagnou and b coworker reported Pd(II)‐catalyzed cross‐coupling of indoles with arenes [62]. For example, treatment of N‐acetylindole (0.6 mmol, 1 equiv.) with excess benzene (1.5 mL) in the presence of Pd(OCOCF3)2 (10 mol%), 3‐nitropyridine (10 mol%), CsOPiv (40 mol%), Cu(OAc)2 (3.0 equiv.), and PivOH (0.4 mL) under microwave irradiation at 140 °C for 5 h affords the 3‐phenylation product in 87% yield, along with minor 2‐phenylation, and 2,3‐diphenylation products (Scheme 12.65).

+

N Me 0.6 mmol

10 mol% Pd(OCOCF3)2 10 mol% 3-nitropyridine

O

1.5 mL

40 mol% CsOPiv 3.0 equiv. Cu(OAc)2 mw, PivOH (0.4 mL), 140 °C, 5 h

N Ac 87%

Scheme 12.65  Catalytic cross‐coupling of indole with benzene at 3‐position.

12.6  Cross‐Coupling of Dual Aryl sp2C─ H Bonds

Catalytic cross‐coupling of indole at 2‐position with benzene was reported by them in the same year, applying AgOAc instead of Cu(OAc)2 as oxidant [63]. For example, treatment of N‐pivalylindole (0.45 mmol, 1 equiv.) with excess benzene (2.7 mL) in the presence of Pd(OCOCF3)2 (5 mol%), Ag(OAc)2 (3.0 equiv.), and PivOH (6.0 equiv.) at 110 °C for 3 h affords the 2‐phenylation product in 84% yield, along with minor 3‐phenylation, and 2,3‐diphenylation products (Scheme 12.66).

N Piv

5 mol% Pd(OCOCF3)2

+

2.7 mL

0.45 mmol

3.0 equiv. AgOAc 6.0 equiv. PivOH 110 °C, 3 h

N Piv 84%

Scheme 12.66  Catalytic cross‐coupling of indole with benzene at 2‐position.

Aerobic catalytic cross‐coupling of benzofuran with benzene applying hetero­poly acid was disclosed by DeBoef and coworkers in 2007 [64]. For example, treatment of benzofuran (0.4 mmol, 1 equiv.) with excess benzene (3.0 mL) in the presence of Pd(OAc)2 (10 mol%), HPMV (10 mol%), and O2 (3 atm) in HOAc (2 mL) at 120 °C for 1.5 h affords the 2‐phenylation product in 84% yield. Reaction of N‐acetylindole also gives 2‐phenylation product as major product (Scheme 12.67). 10 mol% Pd(OAc)2 10 mol% HPMV

+ O 3.0 mL

0.4 mmol

O 84%

20 mol% Pd(OAc)2 1.0 equiv. Cu(OAc)2

+ N Ac 0.4 mmol

O2 (3 atm) HOAc (2 mL), 120 °C, 1.5 h

3.0 mL

O2 (3 atm) HOAc (2 mL), 120 °C, 3 h

N Ac 45% (C2/C3 = 5/1)

Scheme 12.67  Catalytic cross‐coupling of benzofuran or indole with benzene at 2‐position.

Catalytic cross‐coupling of electron‐deficient pyridine N‐oxides with simple arenes was achieved by Chang and coworkers [26] in 2008. For example, treat­ ment of pyridine N‐oxide (0.6 mmol, 1 equiv.) with excess benzene (40 equiv.) in the presence of Pd(OAc)2 (10 mol%) and Ag2CO3 (2.2 equiv.) at 130 °C for 16 h affords the 2‐phenylation product in 59% yield (Scheme 12.68). Catalytic cross‐coupling of polyfluoroarenes with simple arenes was also available. In 2010, Su and coworker reported, for example, that reaction of

473

474

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene O N

10 mol% Pd(OAc)2

+

2.2 equiv. Ag2CO3 130 °C, 16 h

40 equiv.

0.6 mmol

O N

59%

Scheme 12.68  Catalytic cross‐coupling of pyridine N‐oxide with benzene at 2‐position.

­ entafluorobenzene (0.2 mmol, 1 equiv.) with excess benzene (0.8 mL) in the p presence of Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.0 equiv.), Na2CO3 (0.75 equiv.), and PivOH (1.5 equiv.) in DMA (2 mL) at 110  °C for 24 h affords the corre­ sponding phenylation product in 83% yield [65] (Scheme 12.69). F

F 10 mol% Pd(OAc)2

+

F F F 0.2 mmol

0.8 mL

2.0 equiv. Cu(OAc)2 0.75 equiv. Na2CO3 1.5 equiv. PivOH DMA (2 mL), 110 °C, 24 h

F

F

F

F 83%

F

Scheme 12.69  Catalytic cross‐coupling of pentafluorobenzene with benzene.

Catalytic cross‐coupling of polyfluoroarenes with simple arenes was also reported by Shi and coworkers in 2011 [66]. For example, treatment of ­pentafluorobenzene (0.6 mmol, 1 equiv.) with excess benzene (4.0 mL) in the presence of Pd(OAc)2 (10 mol%), Ag2CO3 (1.5 equiv.), i‐Pr2S (1.0 equiv.), and HOAc (1.0 equiv.) at 120  °C for 20 h affords the corresponding phenylation product in 91% yield (Scheme 12.70). F

F 10 mol% Pd(OAc)2

+

F F F 0.6 mmol

4.0 mL

1.5 equiv. Ag2CO3 1.0 equiv. iPr2S 1.0 equiv. HOAc 120 °C, 20 h

F

F

F

F 91%

F

Scheme 12.70  Catalytic cross‐coupling of pentafluorobenzene with benzene.

In previous text, catalytic cross‐coupling of directing‐group‐containing arene, heteroarene, or polyfluoroarene with simple arene to afford

12.6  Cross‐Coupling of Dual Aryl sp2C─ H Bonds

unsymmetrical biaryl product via dual C─H bond cleavages is described. One common feature for these cross‐coupling reactions is that simple arene is used in large excess (often as solvent), probably due to their low reactivity for C─H activation. Mixtures of cross‐coupling regioisomers are usually obtained when monosubstituted arene such as toluene, anisole, etc. is used. Besides, electron‐ deficient simple arenes are rarely reported. In addition, aerobic catalytic cross‐ coupling of dual aryl C─H bonds utilizing atmospheric O2 or air as terminal oxidant has not been achieved. Nevertheless, these examples of establishing catalytic cross‐coupling of directing‐group‐consisting arene, heteroarene, or polyfluoroarene with simple arene in usable yield and chemoselectivity exhibit promising potential toward the ideal formation of aryl–aryl bonds. In addition, catalytic cross‐couplings of directing‐group‐containing arenes or heteroarenes have also been achieved recently. Catalytic cross‐ coupling of two different arenes with directing groups was reported by Shi and coworkers [67]. For example, treatment of benzoic acid (0.2 mmol, 1 equiv.) with benzyl methyl thioether (3.0 equiv.) in the presence of [(Cp*RhCl)2]2 (2.5 mol%), AgSbF6 (40 mol%), and AgNO3 (4.0 equiv.) in toluene (2 mL) at 160 °C for 12 h affords the dibenzo[c,e]oxepin‐5(7H)‐one product in 63% yield, which is the privileged core in natural products and bioactive molecules. In the proposed mechanism supported by mecha­ nism studies simplified herein, Rh(III) catalyst generated from [(Cp*RhCl)2]2 and AgSbF6 in situ coordinates and metalates ortho‐aryl C─H bond of benzyl thioether to form aryl–Rh(III) species, which coordi­ nates and metalates ortho‐aryl C─H bond of benzoic acid subsequently to give aryl–Rh(III)–aryl species. Reductive elimination of two different aryl groups affords Rh(I) species and unsymmetrical biaryl product followed by cyclization to produce dibenzo[c,e]oxepin‐5(7H)‐one core. Oxidation of Rh(I) species by AgNO3 to Rh(III) species fulfills the catalytic cycle (Scheme 12.71). Also in 2015, Li and coworkers [68] gave an example of cross‐coupling of two benzoic acids in rhodium catalysis. Reaction of 2‐methoxybenzoic acid (0.2 mmol, 1 equiv.) with 2‐chlorobenzoic acid (5.0 equiv.) in the presence of [Rh(nbd)Cl]2 (10 mol%) and MnO2 (3.0 equiv.) in H2O (1 mL) at 150 °C for 24 h affords the cross‐coupling product in 72% yield (Scheme 12.72). Catalytic cross‐coupling of dual heteroaryl C─H bonds in palladium cataly­ sis was achieved by Hu, You, and coworkers [69]. For example, treatment of caffeine (0.5 mmol, 1 equiv.) with benzothiophene (3.0 equiv.) in the presence of Pd(OAc)2 (2.5 mol%), Cu(OAc)2·H2O (1.5 equiv.), and pyridine (1.0 equiv.) in dioxane (0.6 mL) at 120 °C for 20 h affords the cross‐coupling product in 93% yield (Scheme 12.73).

475

476

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene CO2H

2.5 mol% [(Cp*RhCl)2]2 40 mol% AgSbF6

MeS +

0.2 mmol

3.0 equiv.

O

4.0 equiv. AgNO3 Toluene (2 mL), 160 °C, 12 h

O

63%

SMe RhIII

AgNO3

Oxidation

Metalation

H SMe RhIII

RhI O

SMe

O

Reductive elimination

CO2H

Metalation

SMe

HO2C

RhIII CO2H

H

Scheme 12.71  Catalytic cross‐coupling of benzyl thioether with benzoic acid.

MeO

MeO

CO2H

CO2H

10 mol% [Rh(nbd)Cl]2

+ HO2C 0.2 mmol

Cl

3.0 equiv. MnO2 H2O (1 mL), 150 °C, 24 h

HO2C

5.0 equiv.

72%

Scheme 12.72  Catalytic cross‐coupling of benzoic acids.

O Me O

N N

Me N N

Me 0.5 mmol

O +

2.5 mol% Pd(OAc)2

Me

1.5 equiv. Cu(OAc)2H2O O 1.0 equiv. pyridine 3.0 equiv. Dioxane (0.6 mL), 120 °C, 20 h S

N

Me N

N N Me 93%

Scheme 12.73  Catalytic cross‐coupling of caffeine with benzothiophene.

S

Cl

12.7 ­Summary

12.7 ­Summary In this chapter, alkylation, trifluoromethylation, arylation, alkenylation, car­ bonylation, alkynylation, cyanidation, and formation of aryl C─heteroatom bond (heteroatom = N, O, F, Cl, Br, or I) via either indirect SEAr or radical process or direct C─H functionalization pathway in the oxidations of ­heteroarenes or polyfluoroarenes are described. Basically, these described reactions lie in between reaction types two and three, which are able to occur but not so well with working mechanism but not fully clarified, as mentioned in Chapters 9–11. One major concern is the reactivity of electron‐deficient heteroarenes such as pyridine. Oxidation of electron‐deficient heteroarenes is less reported compared to electron‐rich heteroarenes such as indole, benzoxazole, etc. Another major concern is the regioselectivity of heteroarenes such as pyri­ dine to afford one specified regiomer. Arylation of pyridine with aryl halides at 3‐position to give meta‐arylation product catalyzed by Pd(OAc)2 and fluorination of pyridine with AgF2 at 2‐position to afford ortho‐fluorination product are the two examples combining both reactivity and regioselectivity. Besides, linear alkylation of heteroarenes including indole, pyrrole, benzo­ furan, furan, etc. with alkenes to afford anti‐Markovnikov product by apply­ ing nickel–NHC catalytic system gives an example of reversed regioselectivity for alkene addition. Stereoselective alkylation of heteroarenes has been explored, but one major concern is that the alkylating reagents are limited to activated alkenes, c­ arbonyl compounds, and imines. Despite this progress, much more versatile methods for oxidation of heter­ oaryl C─H bonds such as fluorination, amination, etc. are still highly desired. In addition, further improvement of the established oxidative reactions to apply atmospheric O2 or air as terminal oxidant is always the pursuit for an ideal oxidation. Finally, it is described that unsymmetrical biaryl products are obtained ­elegantly by transition‐metal‐catalyzed cross‐coupling of directing‐group‐containing arene, heteroarene, or polyfluoroarene. More exploration is urgently desired on both reactivity and selectivity in this kind of oxidative reaction to form car­ bon–carbon bond via dual C─H bond cleavages, based on understanding the nature of bond cleaving and forming in organic transformation [70]. Oxidative cross‐coupling of simple aryl C─H bonds with inert C─H bonds is described in the next chapter.

477

478

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene Amines

H2N

Aryl

12.3

12.1

12.2.1 O2

HO

Aryl

12.4

Introduction

Aryl

Alkyl

R FG H2C CHR

PhI(OAc)2

AcO

Aryl 12.2.2

AgF, AgF2

F

CBMG, NCS

Cl

Br–, NBS

Br

Aryl

Aryl

Aryl

12.5.1

12.5.2

Heteroand polyfluoro arenes

12.2.3

12.2.4

I

Aryl

Aryl Summary

FG CF3

X

Aryl

H

Aryl

Aryl

12.5.4

12.6 12.7

O

CO or CO2

OH 12.2.6

H

CF3

12.5.3 12.2.5

NH4I or I2

Aryl

12.2.7

Aryl

Aryl

N

CN source

­References [1] Vechorkin, O.; Proust, V.; Hu, X. Angew. Chem. Int. Ed. 2010, 49, 3061. [2] Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 12307. [3] Schramm, Y.; Takeuchi, M.; Semba, K.; Nakao, Y.; Hartwig, J. F. J. Am. Chem.

Soc. 2015, 137, 12215.

[4] (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem.

[5] [6] [7] [8]

[9]

Int. Ed. 2001, 40, 160; (b) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903. Parans, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. Eur. J. 2011, 17, 6039. Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14411. Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature, 2012, 492, 95. Nagib, D. A.; MacMillan, D. W. C. Nature, 2011, 480, 224.

­Reference

[10] (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.

2006, 128, 4972; (b) Wagner, A. M.; Sanford, M. S. Org. Lett. 2011, 13, 288.

[11] Modha, S. G.; Greaney, M. F. J. Am. Chem. Soc. 2015, 137, 1416. [12] (a) Do, H.‐Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404; (b) Do,

H.‐Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.

[13] Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673. [14] Larivée, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52. [15] Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.

2008, 130, 14926.

[16] Ye, M.; Gao, G.‐L.; Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]

J.‐Q. J. Am. Chem. Soc. 2011, 133, 19090. Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org. Chem. 2011, 76, 471. Tang, D.‐T. D.; Collins, K. D.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 7450. (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754; (b) René, O.; Fagnou, K. Org. Lett. 2010, 12, 2116. Do, H.‐Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. Asano, R.; Moritani, I.; Fujiwara, Y.; Teranishi, S. Bull. Chem. Soc. Jpn. 1973, 46, 663. Maruyuama, O.; Yoshidomi, M.; Fujiwara, Y.; Taniguchi, H. Chem. Lett. 1979, 1229. Itahara, T.; Kawasaki, K.; Ouseto, F. Bull. Chem. Soc. Jpn. 1984, 57, 3488. Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem. Int. Ed. 2005, 44, 3125. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888. Oyamada, J.; Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Chem. Lett. 2002, 20. Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6910. Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170. (a) Itahara, T. Chem. Lett. 1982, 1151; (b) Itahra, T. Chem. Lett. 1983, 127. Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem. Eur. J. 2011, 17, 9581. Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132, 8858. Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem. Int. Ed. 2010, 49, 8670. Boogaerts, I. I. F.; Fortman, G. C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem. Int. Ed. 2010, 49, 8674 Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 1772. Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358.

479

480

12  Oxidation of Aryl sp2C─H Bond on Heteroarene or Perfluoroarene

[38] Yang, L.; Zhao, L.; Li, C.‐J. Chem. Commun. 2010, 46, 4184. [39] Kim, S. H.; Yoon, J.; Chang, S. Org. Lett. 2011, 13, 1474. [40] Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010,

132, 2522.

[41] (a) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 6725;

[42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54]

[55] [56] [57] [58] [59] [60] [61] [62] [63] [64]

[65] [66]

(b) Liu, B.; Wang, J.; Zhang, B.; Sun, Y.; Wang, L.; Chen, J.; Cheng, J. Chem. Commun. 2014, 50, 2315. Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607. Mutule, I.; Suna, E.; Olofsson, K.; Pelcman, B. J. Org. Chem. 2009, 74, 7195. Choy, P. Y.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2011, 76, 80. Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A. Angew. Chem. Int. Ed. 2012, 51, 4666. Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342. Fier, P. S.; Hartwig, J. F. Science, 2013, 342, 956. Rodriguez, R. A.; Pan, C.‐M.; Yabe, Y.; Kawamata, Y.; Eastgate, M.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 6908. Samanta, R. C.; Yamamoto, H. Chem. Eur. J. 2015, 21, 11976. Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 45, 6460. Song, S.; Sun, X.; Li, X.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2886. Do, H.‐Q.; Daugulis, O. Org. Lett. 2009, 11, 421. (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904; (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651; (c) Sanhueza, I. A.; Wagner, A. M.; Sanford, M. S.; Schoenebeck, F. Chem. Sci. 2013, 4, 2767. Li, B.‐J.; Tian, S.‐L.; Fang, Z.; Shi, Z.‐J. Angew. Chem. Int. Ed. 2008, 47, 1115. Brasche, G.; García‐Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1, 331. (a) Wang, X.; Leow, D.; Yu, J.‐Q. J. Am. Chem. Soc. 2011, 133, 13864; (b) Xu, H.; Shang, M.; Dai, H.‐X.; Yu, J.‐Q. Org. Lett. 2015, 17, 3830. Karthikeyan, J.; Cheng, C.‐H. Angew. Chem. Int. Ed. 2011, 50, 9880. Zhou, L.; Lu, W. Organometallics 2012, 31, 2124. (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Itahara, T. J. Org. Chem. 1985, 50, 5272. Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137; (b) Potavathri, S.; Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef, B. Tetrahedron Lett. 2008, 49, 4050; (c) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676. Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. Li, H.; Liu, J.; Sun, C.‐L.; Li, B.‐J.; Shi, Z.‐J. Org. Lett. 2011, 13, 276.

­Reference

[67] Zhang, X.‐S.; Zhang, Y.‐F.; Li, Z.‐W.; Luo, F.‐X.; Shi, Z.‐J. Angew. Chem. Int.

Ed. 2015, 54, 5478.

[68] Gong, H.; Zeng, H.; Zhou, F.; Li, C.‐J. Angew. Chem. Int. Ed. 2015, 54, 5718. [69] Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem.

Soc. 2010, 132, 1822.

[70] (a) Arndtsen, B. A.; Bergman, R. G.; Mobley, A.; Peterson, T. H. Acc. Chem.

Res. 1995, 28, 154; (b) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879; (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633; (d) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507; (e) Bergman, R. G. Nature 2007, 446, 391; (f ) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976; (g) Yagamuchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51 8960; (h) Wencel‐Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369; (i) Zhou, L.; Lu, W. Chem. Eur. J. 2014, 20, 634; (j) Labinger, J. A.; Bercaw, J. E. J. Organomet. Chem. 2015, 793, 47.

481

483

13 Oxidative Cross‐Coupling of Aryl sp2C─H Bond with Inert C─H Bond 13.1 ­Introduction An intermolecular oxidative cross‐coupling of two different C─H bonds to form a new C─C bond is one of the most convenient, economical, and useful methods in chemical synthesis. However, in the alkylation, alkenylation, and arylation of simple arenes mainly including benzene, toluene, aniline, anisole, chlorobenzene, nitrobenzene, naphthalene, etc., the classic Friedel–Crafts reaction (aryl sp2C─H with alkyl sp3C─Cl or Br), Heck coupling (aryl sp2C─I or Br with alkenyl sp2C─H), Suzuki coupling, and others (aryl sp2C─I or Br with aryl sp2C─M (M = B, Mg, Zn, Sn, etc.)) are still popular and powerful approaches at present, but not avoiding prefunctionalization of substrates and production of halogen wasters. One reason is that aryl sp2C─H bonds of sim­ ple arenes are very stable with high BDEs and low pKa values as mentioned before, excluding heteroaromatic compounds, special aromatic compounds with directing groups for coordination with metals, polyfluoroarenes, etc. Meanwhile, the simple alkyl sp3C─H and alkenyl sp2C─H bonds are also inert to break. In addition, to enhance the chemo‐, regio‐, and stereoselectivities for cross‐coupling products via the dual cleavages of different C─H bonds is a big challenge especially in the cases of two similar C─H bonds, while other side‐ reactions such as homocoupling must be blocked. All these factors determine that it is more difficult to provide an effective cross‐coupling reaction of aryl sp2C─H bond with another inert C─H bond under mild conditions compared with those traditional couplings. However, the aryl sp2C─H, alkyl sp3C─H, and alkenyl sp2C─H bonds are indeed different in their cleavages according to the established reactions. For example, the simple aryl sp2C─H bonds on electron‐rich rings can be broken easily in the electrophilic aromatic substitution such as the Friedel–Crafts reaction. In contrast, the alkyl sp3C─H bonds especially secondary and tertiary sp3C─H bonds are favorable to form their alkyl radicals through homolytic cleavage as described in Chapter 3. It is known well that the alkenyl sp2C─H Oxidation of C─H Bonds, First Edition. Wenjun Lu and Lihong Zhou. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

484

13  Oxidative Cross-Coupling of Aryl sp2C─H Bond with Inert C─H Bond

bonds are cleaved by β‐hydride elimination after their insertions into the C─M bonds, like in the Heck coupling. Moreover, inert aryl and alkyl C─H bonds can also be activated by transition‐metal complexes to generate the corre­ sponding C─M bonds under mild conditions. Thus, based on the accumulated understandings of the characters of C─H bonds and reaction mechanisms in the past years, researchers have developed some effective or promising cross‐ couplings of simple arenes with alkanes, alkenes, or their arene partners though they cannot replace the current methods completely now.

13.2 ­Oxidative Coupling of Simple Arenes with Alkanes (Alkylation of Arenes) The aromatic electrophilic substitution is the essential of the Friedel–Crafts alkylation, in which an alkyl cation attacks on the electron‐rich aromatic ring to form an arenium ion, Wheland intermediate, followed by deprotonation to give an alkylated arene. The alkyl cation is often generated via the cleavage of an alkyl sp3C─halogen in the presence of a strong Lewis acid AlCl3 or FeCl3 (Scheme 13.1). Thus, theoretically, any substrates containing alkyl sp3C atoms can undergo alkylations of simple arenes if they are transformed to be the elec­ trophiles such as alkyl cations. The substrates are not only alkyl halides but also alcohols, alkenes, and even common alkanes. In 1973, Schmerling and Vesely disclosed that the tertiary alkyl sp3C─H bond of isopentane could be converted readily to form its tertiary carbon cation in the presence of AlCl3 with CuCl2 as oxidant at room temperature [1]. Then, it underwent the Friedel–Crafts alkyla­ tion with benzene to afford tert‐pentylbenzene and the isomerization products, sec‐isopentylbenzene and neopentylbenzene (40% yield based on CuCl2) (Scheme 13.2). A small amount of by‐products was also found, such as ethyl­ benzene, isopropylbenzene, 1,1‐diphenylethane, and polymerization products of benzene. Two years later, Olah and coworkers used anhydrous superacidic fluoroantimonic acid (HF‐SbF5) as catalyst to attack on the alkyl sp3C─H bonds from methane, ethane, and other light alkanes to form the corresponding alkyl cations with releasing hydrogen gas at room temperature (CH4 at 80  °C) [2] (Scheme 13.3). Of course, these carbon cations could subsequently react with The Friedel–Crafts alkylation R-Cl + FeCl3 +

R+

R+

+ FeCl4–

+ FeCl4– R H +

R + HCl + FeCl3

Scheme 13.1  Cross‐coupling of arenes with alkyl halides (Friedel–Crafts alkylation).

13.2 ­Oxidative Coupling of Simple Arenes with Alkanes (Alkylation of Arenes

+ CuCl2

+

AlCl3 17–21 °C 40% based on Cu

Scheme 13.2  Cross‐coupling of benzene with isopentane.

+

CH4 2 equiv.

1 equiv.

+ HF-SbF5

+ H2

80 °C, 3 h

20 equiv.

0.1%

Scheme 13.3  Cross‐coupling of benzene with methane.

benzene to form the alkylation products under the same conditions, but the yield and selectivity were not good. For example, toluene was obtained from methane and benzene only in 0.1% yield, and in the case of isopentane, the yield of pentylbenzenes having five isomers was 9.6% (tert : sec : iso : neo : n = 16.6 : 13.0 :  7.0 : 4.2 : 1.0). Since solid catalysts such as acidic zeolites modified with metals (Pt, Pd, Re, Ga, or Zn) are environmentally benign and halide‐free, many researchers have studied their performance in the alkylation of simple arenes with light alkanes including ethane, propane, and others in the gas phase for three decades. For example, in the presence of Pt/H4SiW12O40/SiO2 catalyst, a bifunctional catalyzed pathway is proposed, which involves the cleavage of alkyl sp3C─H bonds to form alkenes at metal sites and the alkylation of arenes with alkenes at acid sites [3] (Scheme 13.4). In the case of methane, an oxidant such as dioxygen is often necessary to transform CH4 to methoxy species in the pres­ ence of ZnZSM‐5 catalyst followed by a methylation of arene to give the cou­ pling product. However, the operation temperatures are very high (over 250 °C), and either the yield or the selectivity is still not good enough [4] (Scheme 13.5).

Cat Pt/H4SiW12O40/SiO2

+

+ H2

300 °C 1 equiv.

9 equiv. (1bar)

90–93% selectivity, 6–8% conversion

Scheme 13.4  Pt‐catalyzed cross‐coupling of benzene with propane.

+

CH4

+ O2

Cat ZnZSM-5 > 250 °C

Solid-OCH3

Scheme 13.5  ZnZSM‐5‐catalyzed cross‐coupling of benzene with methane using O2 as oxidant.

485

486

13  Oxidative Cross-Coupling of Aryl sp2C─H Bond with Inert C─H Bond

In 2011, Li and Guo developed a catalytic oxidative cross‐coupling of ben­ zene derivatives with cycloalkanes to afford para‐selective products. Based on the previous results on the formation of secondary alkyl radicals and aryl radical‐charactered intermediates, they attempted to use di‐tert‐butyl ­peroxide (TBP) as oxidant in the coupling of benzoic acid (1 equiv.) with cyclohexane (solvent), and a trace amount of target products was found. When 10  mol% Ru3(CO)12 was employed with 5  mol% dppb (bis(diphenylphosphino)butane) as ligands in this reaction, p‐cyclohexyl benzoic acid was obtained in 65% yield under air at 135 °C. Other benzene rings with various electron‐deficient groups including ester, ketone, nitrile, amide, bromine, and chlorine gave their corresponding coupling products in 45–95% yields and in 45–96% para‐selectivities. For benzene and anisole, both yields were