Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry 9783527347858, 9783527828159, 9783527828173, 9783527828166

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Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry
 9783527347858, 9783527828159, 9783527828173, 9783527828166

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Applied Organic Chemistry

Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry

Surya K. De

Volume 1

Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry

Surya K. De

Volume 2

Author Dr. Surya K. De

Supra Sciences San Diego, CA United States Cover Image:

© enot-poloskun/Getty Images

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.:

applied for British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2021 WILEY-VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-34785-8 ePDF ISBN: 978-3-527-82815-9 ePub ISBN: 978-3-527-82817-3 oBook ISBN: 978-3-527-82816-6 Typesetting SPi Global, Chennai, India Printing and Binding

Printed on acid-free paper 10 9 8 7 6 5 4 3 2 1

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Contents

Volume 1 Preface xxiii About the Author xxv About the Book xxvii Acknowledgments xxix List of Abbreviations xxxi 1 Rearrangement Reactions 1

Baeyer–Villiger Oxidation or Rearrangement 1 Mechanism 2 Application 2 Experimental Procedure (from patent US 5142093A) 3 Dakin Oxidation (Reaction) 3 Mechanism 4 Application 4 Experimental Procedure (from patent EP0591799B) 4 Bamberger Rearrangement 5 Mechanism 5 Experimental Procedure (from patent CN102001954B) 6 Beckmann Rearrangement 6 Mechanism 6 Application 7 Experimental Procedure (general) 7 Preparation of Caprolactam (from patent US 3437655A) 7 Benzilic Acid Rearrangement 8 Mechanism 9 Application 9 Experimental Procedure (from patent US20100249451B) 9 Baker–Venkataraman Rearrangement 9 Mechanism 10 Application 10 Experimental Procedure (from patent CN105985306B) 10

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Claisen Rearrangement 11 Mechanism 11 Application 12 Experimental Procedure (from patent WO2016004632A1) 13 Eschenmoser–Claisen Rearrangement 13 Mechanism 13 Ireland–Claisen Rearrangement 14 Mechanism 14 Johnson–Claisen Rearrangement 15 Mechanism 15 Overman Rearrangement 15 Mechanism 16 Cope Rearrangement 16 Mechanism 17 Application 17 Experimental Procedure (from patent US 4421934A) 17 Curtius Rearrangement 17 Mechanism 18 Application 18 Experimental Procedure (from patent EP2787002A1) 19 Demjanov Rearrangement 19 Mechanism 20 Application 21 Experimental Procedure (from Reference [14], copyright 2008, American Chemical Society) 21 Tiffeneau–Demjanov Rearrangement 22 Mechanism 22 Application 23 Experimental Procedure (from Reference [10], copyright, The Royal Society of Chemistry) 23 Fries Rearrangement 23 Mechanism 24 Application 24 Experimental Procedure (from patent US9440940B2) 25 Favorskii Rearrangement 25 Mechanism 25 Application 26 Experimental Procedure (from patent EP3248959A2) 26 Fischer–Hepp Rearrangement 26 Mechanism 27 Experimental Procedure (general) 27 Hofmann Rearrangement (Hofmann degradation of amide) 28 Mechanism 28 Application 29 Experimental Procedure (from patent CN105153023B) 29 Hofmann–Martius Rearrangement 29 Mechanism 30

Contents

Experimental Procedure (from patent DD295338A5) 30 Lossen Rearrangement 31 Mechanism 31 Application 32 Experimental Procedure (from patent EP2615082B1) 32 Orton Rearrangement 32 Mechanism 33 Pinacol–Pinacolone Rearrangement 33 Mechanism 34 Application 34 Experimental Procedure (general) 34 Rupe Rearrangement/Meyer–Schuster Rearrangement 34 Rupe Rearrangement 35 Meyer–Schuster Rearrangement 35 Mechanism 35 Application 36 Experimental Procedure (from patent US4088681A) 36 Schmidt Rearrangement or Schmidt Reaction 36 Mechanism 37 Application 37 Experimental Procedure (from patent WO2009026444A1) 38 Wagner–Meerwein Rearrangement 38 Mechanism 38 Application 39 Wolff Rearrangement 39 Mechanism 39 Alternatively 40 Application 40 Experimental Procedure (from patent US9175041B2) 9175041B2 40 Arndt–Eistert Homologation or Synthesis 41 Mechanism 41 Application 42 Experimental Procedure (from patent US9399645B2) 42 Step 1 42 Step 2 42 Zinin Rearrangement or Benzidine and Semidine Rearrangements 42 Mechanism 43 Experimental Procedure (from patent US20090069602A1) 44 References 45 Baeyer-Villiger Oxidation or Rearrangement 45 Dakin Oxidation or Reaction 47 Bamberger Rearrangement 48 Beckmann Rearrangement 48 Benzilic Acid Rearrangement 50 Baker–Venkataraman Rearrangement 51

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Claisen Rearrangement/Eschenmoser–Claisen Rearrangement/Ireland–Claisen Rearrangement/Johnson–Claisen Rearrangement/Overman Rearrangement 52 Cope Rearrangement 53 Curtius Rearrangement 54 Demjanov Rearrangement 56 Tiffeneau–Demjanov Rearrangement 56 Fries Rearrangement 56 Favorskii Rearrangement 58 Fischer–Hepp Rearrangement 58 Hofmann Rearrangement (Hofmann Degradation of Amide) 59 Hofmann–Martius Rearrangement 60 Lossen Rearrangement 60 Orton Rearrangement 61 Pinacol–Pinacolone Rearrangement 62 Rupe Rearrangement/Meyer–Schuster Rearrangement 62 Schmidt Rearrangement or Schmidt Reaction 63 Wagner–Meerwein Rearrangement 64 Wolff Rearrangement 65 Arndt–Eistert Homologation or Synthesis 66 Zinin Rearrangement or Benzidine and Semidine Rearrangements 67 2 Condensation Reaction 69

Aldol Condensation Reaction 69 Application 70 Experimental Procedure (general) 71 Enantioselective Aldol Reaction (from patent US 6919456B2) 71 Mukaiyama Aldol Reaction 72 Mechanism 72 Application 72 Experimental Procedure (from patent DE102013011081A1) 73 Evans Aldol Reaction 73 Mechanism 74 Application 74 Experimental Procedure (from patent WO2013151161A1) 74 Henry Reaction 75 Mechanism 75 Application 76 Experimental Procedure (from patent US 6919456B2) 76 Preparation of Chiral Catalyst 76 Nitro-Aldol Reaction 76 Benzoin Condensation 76 Mechanism 77 Application 77 Experimental Procedure (from patent DE3019500C2) 78 Claisen Condensation 78 Mechanism 78

Contents

Application 79 Experimental Procedure (from patent US9884836B2) 79 Darzens Glycidic Ester Condensation 80 Mechanism 80 Application 81 Experimental Procedure (from patent JP2009512630A) 81 Dieckmann Condensation 81 Mechanism 82 Application 82 Experimental Procedure (from patent US 7132564 B2) 82 Knoevenagel Condensation 83 Mechanism 83 Application 84 Lumefantrine 84 Experimental Procedure (from patent WO2010136360A2) 84 Pechmann Condensation (synthesis of coumarin) (also called von Pechmann condensation) 85 Mechanism 85 Application 86 Experimental Procedure (from patent US7202272B2) 86 Perkin Condensation or Reaction 86 Mechanism 87 Application 88 Experimental Procedure (from patent US4933001A) 88 Stobbe Condensation 88 Mechanism 89 Application 89 Experimental Procedure (from patent US20160137682A1) 90 References 90 Aldol Condensation Reaction 90 Mukaiyama Aldol Reaction 93 Evans Aldol Reaction 96 Henry Reaction 98 Benzoin Condensation 99 Claisen Condensation 101 Darzens Glycidic Ester Condensation 102 Dieckmann Condensation 103 Knoevenagel Condensation 105 Pechmann Condensation 106 Perkin Condensation or Reaction 107 Stobbe Condensation 108 3 Olefination, Metathesis, and Epoxidation Reactions 111

Olefination 111 Corey–Winter Olefin Synthesis 111 Mechanism 112 Application 112

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Experimental Procedure (from patent US5807866A) 112 Horner–Wadsworth–Emmons Reaction 113 Mechanism 113 Application 113 Experimental Procedure (from patent JPWO2015046403A1) 114 Julia–Lythgoe Olefination 114 Mechanism 115 Modified Julia Olefination 115 Mechanism 115 Application 116 Experimental Procedure (from patent CN103313983A) 116 Julia–Kocienski Olefination 117 Application 117 Experimental Procedure (from patent WO2016125086A1) 118 Kauffmann Olefination 118 Mechanism 119 Application 119 Experimental Procedure (from patent WO2014183211A1) 119 Peterson Olefination 119 Mechanism 120 Application 121 Experimental Procedure (from patent WO2017149091A1) 121 Petasis Olefination 122 Mechanism 122 Application 123 Experimental Procedure (from patent US5087790A) 123 Tebbe Olefination 123 Mechanism 123 Application 124 Experimental Procedure (from patent US8809558B1) 124 Wittig Reaction or Olefination 124 Mechanism 125 Application 126 Experimental Procedure (from patent WO2006045010A2) 126 Metathesis 127 Olefin Metathesis 127 Ring-Closing Metathesis 127 Mechanism 128 Experimental Procedure (from patent US20022018351A1) 128 Cross Metathesis 128 Ring-Opening Metathesis 128 Ring-Opening Metathesis Polymerization (ROMP) 129 Asymmetric Epoxidation 129 Sharpless Asymmetric Epoxidation 129 Mechanism 129 Application 130

Contents

Experimental Procedure (from patent DE102014107132A1) (For more experimental procedures see Chapter 15) 130 Jacobsen–Katsuki Asymmetric Epoxidation 130 Mechanism 131 Application 131 Experimental Procedure (from patent US7501535B2) 132 Shi Asymmetric Epoxidation 132 Mechanism 133 Application 133 Experimental Procedure (from patent EP1770095A1) 133 Sharpless Asymmetric Dihydroxylation 134 Mechanism 135 Application 135 Experimental Procedure (from patent US7472570B1) 136 Sharpless Asymmetric Aminohydroxylation 136 Mechanism 137 Application 137 Experimental Procedure (from patent US8987504B2) 137 Woodward cis-Dihydroxylation 138 Mechanism 138 Application 139 Experimental Procedure (from patent WO1997013780A1) 139 Prévost trans-Dihydroxylation Reaction 140 Mechanism 140 Application 141 References 141 Corey–Winter Olefin Synthesis 141 Horner–Wadsworth–Emmons Reaction 141 Julia–Lythgoe Olefination 143 Julia–Kocienski Olefination 144 Kauffmann Olefination 146 Peterson Olefination 146 Petasis Olefination 148 Tebbe Olefination 148 Wittig Reaction or Olefination 149 Metathesis 150 Sharpless Asymmetric Epoxidation 150 Jacobsen–Katsuki Asymmetric Epoxidation 152 Shi Asymmetric Epoxidation 153 Sharpless Asymmetric Dihydroxylation 155 Sharpless Asymmetric Aminohydroxylation 156 Woodward cis-Dihydroxylation 158 Prévost trans-Dihydroxylation Reaction 158 4 Miscellaneous Reactions 161

Alder-Ene Reaction 161 Mechanism 161

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Application 162 Experimental Procedure (from patent WO2015149068A1) 162 Appel Reaction 162 Mechanism 163 Application 163 Experimental Procedure (from patent WO2015134973A1) 163 Barton Decarboxylation 164 Mechanism 164 Application 165 Experimental Procedure (from patent US6080563A) 165 Barton Nitrite Photolysis (Barton nitrite ester reaction) 166 Mechanism 166 Application 167 Experimental Procedure (from patent US3214427A) 167 Brown Hydroboration 167 Mechanism 168 Application 168 Experimental Procedure (from patent WO1995013284A1) 168 Bucherer Reaction 169 Mechanism 169 Application 170 Experimental Procedure (from Reference [7], copyright 2020, American Chemical Society) 170 Chichibabin Reaction 170 Mechanism 171 Application 171 Experimental Procedure Amination of 3-Picoline (from patent EP0098684B1) 171 Chugaev Elimination Reaction 172 Mechanism 173 Application 173 Experimental Procedure (from Reference [10], copyright 2008, American Chemical Society) 173 Cannizzaro Reaction 173 Mechanism 174 Application 175 Experimental Procedure (general) 175 Cope Elimination Reaction 175 Mechanism 175 Application 176 Experimental Procedure (from Reference [3], copyright, Organic Syntheses) 176 Corey–Fuchs Reaction 176 Mechanism 177 Application 177 Experimental Procedure (from patent JP2015500210A) 178 Formation of Compound B 178

Contents

Formation of Compound C 178 Corey–Nicolaou Macrolactonization 178 Mechanism 179 Application 179 Experimental Procedure (patent US20060004107A1) 179 Danheiser Annulation 180 Mechanism 181 Danheiser Benzannulation 181 Mechanism 182 Application 182 Experimental Procedure (from Reference [22], Copyright 2013, American Chemical Society) 182 Diels–Alder Reaction 183 Normal Electron Demand Diels–Alder Reaction 183 Inverse electron Demand Diels–Alder Reaction 183 Hetero–Diels–Alder Reaction 183 Mechanism 184 Application 184 Experimental Procedure (from patent CA 2361682A1) 184 Dutt–Wormall Reaction 185 Mechanism 185 Étard Reaction 185 Mechanism 186 Application 186 Experimental Procedure (US8957255B2) 186 Finkelstein Reaction 187 Mechanism 187 Application 188 Experimental Procedure (from patent WO2019134765A1) 188 Fischer–Speier Esterification 188 Mechanism 188 Experimental Procedure (general) 189 Mukaiyama Esterification 189 Mechanism 190 Application 190 Experimental Procedure (from patent US4206310A) 190 Yamaguchi Esterification 191 Mechanism 191 Application 192 Experimental Procedure (from patent WO 2019033219A1) 192 Grignard Reaction 193 Mechanism 193 Application 194 Experimental Procedure (general) 194 Experimental Procedure (from patent WO1994028886A1) 195 Gabriel Synthesis 195 Mechanism 196

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Application 196 Experimental Procedure (from patent US9540358B2) 197 Hell–Volhard–Zelinsky Reaction 197 Mechanism 198 Application 198 Experimental Procedure (from patent WO199101199A1) 199 Hofmann Elimination or Exhaustive Methylation 199 Mechanism 199 Application 200 Hosomi–Sakurai Reaction 200 Mechanism 201 Application 201 Experimental Procedure (from patent WO2019093776A1) 201 Huisgen Cycloaddition Reaction 202 Click Chemistry 202 Mechanism 203 Experimental Procedure (from patent WO2008124703A2) 203 Hunsdiecker Reaction 203 Mechanism 204 Application 204 Experimental Procedure (from patent WO2017060906A1) 204 Keck Asymmetric Allylation 204 Mechanism 205 Application 205 Experimental Procedure (from patent US6603023B2) 205 Thionation Reaction (Lawesson’s Reagent) 206 Mechanism 207 Application 207 Experimental Procedure (general) 207 Michael Addition or Reaction 208 Mechanism 208 Application 209 Experimental Procedure (Aza-Michael Addition) (from patent CN102348693B) 209 Mitsunobu Reaction 209 Mechanism 210 Application 211 Experimental Procedure (from patent US20170145017A1) 211 Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction) 211 Mechanism 212 Application 213 Experimental Procedure (from patent US20060094739A1) 213 Nozaki–Hiyama–Kishi Reaction 213 Mechanism 214 Application 214 Experimental Procedure (from patent US20190337964A1) 214 Paterno–Büchi Reaction 215

Contents

Mechanism 215 Application 215 Experimental Procedure (from Reference [29], copyright 2019, American Chemical Society) 216 Pauson–Khand Reaction 216 Mechanism 217 Application 217 Experimental Procedure (from patent WO2003080552A2) 217 Reformatsky Reaction 218 Mechanism 218 Application 219 Experimental Procedure (from patent US6924386B2) 219 Ritter Reaction 220 Mechanism 220 Application 221 Experimental Procedure (from patent WO1996036629A1) 221 Robinson Annulation 221 Mechanism 222 Application 222 Experimental Procedure (from patent WO2018226102A1) 223 Sandmeyer Reaction 223 Mechanism 224 Application 224 Experimental Procedure (from patent WO20100234652A1) 224 Schotten–Baumann Reaction 225 Mechanism 225 Amide Formation 225 Ester Formation 225 Application 226 Simmons–Smith Reaction 226 Mechanism 227 Application 227 Experimental Procedure (from patent US7019172B2) 228 Stork Enamine Synthesis 228 Mechanism 229 Application 230 Experimental Procedure (from patent US2773099A) 230 Tishchenko Reaction 230 Mechanism 231 Application 231 Experimental Procedure (from Reference [38], copyright 2012, American Chemical Society) 231 Ullmann Coupling or Biaryl Synthesis 232 Mechanism 232 Application 233 Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation 233

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Ullmann Biaryl Ether Synthesis 233 Goldberg Reaction (biaryl amines) 233 Ullmann-Type Reaction/Ullmann Condensation 234 Mechanism 234 Application 234 Experimental Procedure (from Patent WO1999018057A1) 234 Weinreb Ketone Synthesis 235 Mechanism 236 Application 237 Experimental Procedure (from patent US9399645B2) 237 Step 1 237 Step 2 237 Williamson Ether Synthesis 238 Mechanism 238 Application 238 Experimental Procedure (from patent WO1994028886A1) 239 Wurtz Coupling or Reaction 239 Mechanism 239 Application 240 Wurtz–Fittig Reaction 240 Mechanism 240 References 240 Alder-Ene Reaction 240 Appel Reaction 242 Barton Decarboxylation 242 Barton Nitrite Photolysis (Barton Nitrite Ester Reaction) 244 Brown Hydroboration 244 Bucherer Reaction 246 Chichibabin Reaction 246 Chugaev Elimination Reaction 247 Cannizzaro Reaction 247 Cope Elimination Reaction 249 Corey–Fuchs Reaction 250 Corey–Nicolaou Macrolactonization 250 Danheiser Annulation/Danheiser Benzannulation 251 Diels–Alder Reaction 252 Dutt–Wormall Reaction 253 Étard Reaction 253 Finkelstein Reaction 254 Fischer–Speier Esterification 255 Mukaiyama Esterification 255 Yamaguchi Esterification 256 Grignard Reaction 257 Gabriel Synthesis 258 Hell–Volhard–Zelinsky Reaction 259 Hofmann Elimination or Exhaustive Methylation 259

Contents

Hosomi–Sakurai Reaction 260 Huisgen Cycloaddition Reaction/Click Chemistry 262 Hunsdiecker Reaction 262 Keck Asymmetric Allylation 263 Thionation Reaction (Lawesson’s Reagent) 264 Michael Addition or Reaction 265 Mitsunobu Reaction 266 Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction) 268 Nozaki–Hiyama–Kishi Reaction 270 Paterno–Büchi Reaction 271 Pauson–Khand Reaction 272 Reformatsky Reaction 274 Ritter Reaction 276 Robinson Annulation 277 Sandmeyer Reaction 279 Schotten–Baumann Reaction 280 Simmons–Smith Reaction 281 Stork Enamine Synthesis 282 Tishchenko Reaction 283 Ullmann Coupling or Biaryl Synthesis 285 Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation 286 Weinreb Ketone Synthesis 287 Williamson Ether Synthesis 289 Wurtz Coupling or Reaction 290 Wurtz–Fittig Reaction 290 5 Aromatic Electrophilic Substitution Reactions 293

Bardhan–Sengupta Synthesis 293 Mechanism 293 Bogert–Cook Reaction or Synthesis of Phenanthrene 294 Mechanism 294 Friedel–Crafts Reaction 295 Friedel–Crafts acylation 295 Friedel–Crafts alkylation 295 Mechanism 296 Mechanism for Friedel–Crafts Alkylation 297 Application 297 Experimental Procedure (from patent US4814508A) 298 Gattermann Aldehyde Synthesis 298 Mechanism 299 Experimental Procedure (from patent US2067237A) 299 Gattermann–Koch Aldehyde Synthesis 300 Mechanism 300 Experimental Procedure (from patent WO2002020447A1) 301 Haworth Reaction 301 Mechanism 303

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Experimental Procedure (from patent CN106977377A) 304 Houben–Hoesch Reaction 304 Mechanism 305 Application 306 Experimental Procedure (from patent EP0431871A2) 306 Kolbe–Schmitt Reaction 306 Mechanism 307 Application 307 Experimental Procedure (from patent US7582787B2) 307 Reimer–Tiemann Reaction 308 Mechanism 308 Application 310 Experimental Procedure (from patent US4324922A) 310 Vilsmeier–Haack Reaction 311 Mechanism 312 Application 313 Experimental Procedure (from patent US5599966A) 313 References 313 Bardhan–Sengupta Synthesis 313 Bogert–Cook Reaction or Synthesis of Phenanthrene 314 Friedel–Crafts Reaction 314 Gattermann Aldehyde Synthesis 317 Gattermann–Koch Aldehyde Synthesis 317 Haworth Reaction 318 Houben–Hoesch Reaction 318 Kolbe–Schmitt Reaction 319 Reimer–Tiemann Reaction 319 Vilsmeier–Haack Reaction 320 6 Pd-Catalyzed C—C Bond-Forming Reactions 323

Suzuki Coupling Reaction 323 Mechanism 324 Application 325 Experimental Procedure (General) 325 Heck Coupling Reaction (Mizoroki–Heck Reaction) 325 Mechanism 326 Application 327 Experimental Procedure (from patent WO2008138938A2) 327 Negishi Coupling Reaction 328 Mechanism 328 Application 329 Experimental Procedure (from patent WO2010026121) 329 Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction) 330 Mechanism 330 Application 330 Experimental Procedure (from patent WO2008012440A2) 331

Contents

Sonogashira Coupling Reaction 331 Mechanism 332 Application 332 Experimental Procedure (General) 333 Kumada Cross-Coupling 333 Mechanism 334 Application 335 Experimental Procedure (from patent WO2015144799) 335 Hiyama Coupling Reaction 335 Mechanism 336 Application 336 Experimental Procedure (from patent US20022018351A1) 336 Liebeskind–Srogl Coupling Reaction 337 Mechanism 337 Application 338 Experimental Procedure (from patent WO2008030840A2) 338 Fukuyama Coupling Reaction 338 Mechanism 339 Application 339 Experimental Procedure (from patent US20150336915A1) 339 Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig Amination) 340 Mechanism 340 Buchwald–Hartwig Amination 340 Application 341 Experimental Procedure (from patent US7442800B2) 341 Tsuji–Trost Allylation 341 Mechanism 342 Application 343 Experimental Procedure (from patent US20190270700A1) 343 References 343 Suzuki Coupling Reaction 343 Heck Coupling Reaction (Mizoroki–Heck Reaction) 345 Negishi Coupling Reaction 347 Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction) 349 Sonogashira Coupling Reaction 351 Kumada Cross-Coupling 353 Hiyama Coupling Reaction 355 Liebeskind–Srogl Coupling Reaction 356 Fukuyama Coupling Reaction 357 Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig Amination) 358 Tsuji–Trost Allylation 360

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363 Biginelli Reaction (3-Component Reaction [3-CR]) 363 One of Plausible Mechanisms 364 Application 364 Experimental Procedure (from patent US810606062B1) 364 Gewald Reaction (3-Component Reaction [3-CR]) 365 Mechanism 365 Application 366 Experimental Procedure (from patent US20100081823A1) 366 Hantzsch Pyridine Synthesis 366 Mechanism 367 Application 368 Experimental Procedure (from patent US8106062B1) 368 Mannich Reaction 369 Mechanism 369 Application 370 Experimental Procedure (from patent WO2007011910A2) 370 Passerini Reaction (3-Component Reaction [3-CR]) 370 Mechanisms 371 Ionic Mechanism 371 Concerted Mechanism 372 Lactone Formation [3] 372 Application 372 Experimental Procedure (from patent WO1995002566A1) 373 Strecker Amino Acid Synthesis 373 Mechanism 374 Part 1: Formation of α-Aminonitrile 374 Part 2: Hydrolysis of the Nitrile 374 Application 375 Experimental Procedure (from patent US5169973A) 375 Ugi Reaction (4-Component Reaction [4-CR]) 375 Plausible Reaction Mechanism 376 Application 377 Experimental Procedure (from patent US20150087600A1) 377 Asinger Reaction (4-Component Reaction [A-4CR]) 378 Application 378 References 379 Biginelli Reaction 379 Gewald Reaction 380 Hantzsch Pyridine Synthesis 381 Mannich Reaction 382 Passerini Reaction 384 Strecker Amino Acid Synthesis 385 Ugi Reaction 386 Asinger Reaction 388

7 Multicomponent Reaction

Contents

Volume 2 Preface

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About the Author xxiii About the Book xxv Acknowledgments xxvii List of Abbreviations xxix 8 Oxidations and Reductions 389 9 Nomenclature and Application of Heterocyclic Compounds 449 10 Synthesis of Some Heterocyclic Compounds Using Named Reactions 469 11 Protection and Deprotection of Common Functional Groups 12 Amino Acids and Peptides 519 13 Functional Group Transformation 543 14 Synthesis of Some Drug Molecules 565 15 Common Laboratory Methods 573 16 Common Reagents in Organic Synthesis 603 Appendix A List of Medicines (Partial) and Nutrients 671 Index 737

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Volume 1 Preface xxiii About the Author xxv About the Book xxvii Acknowledgments xxix List of Abbreviations xxxi 1 Rearrangement Reactions 1 2 Condensation Reaction 69 3 Olefination, Metathesis, and Epoxidation Reactions 111 4 Miscellaneous Reactions 161 5 Aromatic Electrophilic Substitution Reactions 293 6 Pd-Catalyzed C—C Bond-Forming Reactions 323 7 Multicomponent Reaction

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Volume 2 Preface xxi About the Author xxiii About the Book xxv Acknowledgments xxvii List of Abbreviations xxix 8 Oxidations and Reductions 389

Oxidation Reactions 389 Corey–Kim Oxidation 389 Mechanism 390

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Application 390 Experimental Procedure (from patent US9212136B2) 390 Dess–Martin Oxidation 391 Mechanism 392 Application 392 Experimental Procedure (General) 392 Experimental Procedure (from patent US9212136B2) 393 Jones Oxidation 393 Mechanism 394 Application 395 Experimental Procedure (General) 395 Swern Oxidation 395 Mechanism 396 Experimental Procedure (from patent US9212136B2) 397 Pfitzner–Moffatt Oxidation 397 Mechanism 398 Application 398 Experimental Procedure (from patent WO2019202345A2) 399 Tamao–Fleming Oxidation 400 Fleming Oxidation 400 Tamao Oxidation 400 Mechanism 400 Application 401 Experimental Procedure (from patent WO2005113558A2) 402 Tamao–Kumada Oxidation 402 Mechanism 402 Oppenauer Oxidation 403 Mechanism 403 Application 404 Experimental Procedure (from patent US3506692A) 404 Riley Oxidation 404 Mechanism 405 Application 405 Experimental Procedure (from patent US20140341799A1) 405 Ley–Griffith Oxidation 406 Mechanism 406 Application 407 Experimental Procedure (from patent WO1998008849A1) 407 Criegee Oxidation (Criegee Glycol Cleavage) 407 Mechanism 408 Application 408 Experimental Procedure (from patent US5208036) 409 Criegee Ozonolysis 409 Mechanism 411 Application 411 Experimental Procedure (from patent US20030232989A1) 411 Reduction Reactions 412

Contents

Birch Reduction 412 Mechanism 412 Application 413 Experimental Procedure (from patent US20090247756A1) 413 Bouveault–Blanc Reduction 414 Mechanism 414 Application 415 Experimental Procedure (from patent US2883424A) 415 Clemmensen Reduction 415 Mechanism 415 Carbanionic Mechanism 416 Carbenoid/Radical Mechanism 416 Application 417 Experimental Procedure (from patent WO1994028886A1) 417 Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey reduction) 417 Mechanism 418 Application 418 Experimental Procedure (from patent WO2013040068A2) 419 Noyori Asymmetric Hydrogenation 419 Mechanism 420 Application 421 Experimental Procedure (from patent US20020173683A1) 421 Luche Reduction 422 Mechanism 422 Application 423 Experimental Procedure (from patent US20180134650A1) 423 Meerwein–Ponndorf–Verley Reduction 423 Mechanism 424 Application 424 Experimental Procedure (from patent US8674120B2) 424 Mozingo Reduction 425 Application 425 Rosenmund Reduction 425 Mechanism 425 Experimental Procedure (from patent US3517066A) 426 Preparation of 3,4,5-Trimethoxybenzaldehyde 426 Wolff–Kishner Reduction 426 Mechanism 427 Application 427 Experimental Procedure (from Patent US20060128691A1) 427 References 428 Corey–Kim Oxidation 428 Dess–Martin Oxidation 428 Jones Oxidation 430 Swern Oxidation 431

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Pfitzner–Moffatt Oxidation 431 Tamao–Fleming Oxidation 432 Tamao–Kumada Oxidation 433 Oppenauer Oxidation 433 Riley Oxidation 434 Ley–Griffith Oxidation 435 Criegee Oxidation (Criegee Glycol Cleavage) 435 Criegee Ozonolysis 436 Birch Reduction 437 Bouveault–Blanc Reduction 438 Clemmensen Reduction 438 Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey Reduction) 439 Noyori Asymmetric Hydrogenation 440 Luche Reduction 443 Meerwein–Ponndorf–Verley Reduction 444 Mozingo Reduction 445 Rosenmund Reduction 446 Wolff–Kishner Reduction 446 9 Nomenclature and Application of Heterocyclic Compounds 449

The Hantzsch–Widman Nomenclature 449 Examples 450 Saturated System 451 Partial Unsaturation 451 Unsaturated System 452 Priority of Heteroatoms for Numbering Purposes When More Than One Heteroatom in the Ring 452 Extra Hydrogen Atom 453 Heterocycles with Fused Rings 453 Common Names 455 The Replacement Nomenclature 456 Application of Heterocyclic Compounds 456 Drugs for Oxirane Derivatives 457 Drugs for Aziridine Derivatives 457 Drugs for Azetidine Derivatives 457 Drugs for Oxetane Derivatives 457 Drugs for Furan Derivatives 458 Drugs for Thiophene Derivatives 459 Drugs for Pyrrole and Pyrrolidine Derivatives 459 Drugs for Imidazole, Imidazoline, and Imidazolidine Derivatives 460 Antibacterial 460 Antifungal 460 Other 460 Drugs for Triazole Derivatives 460 Drugs for Isoxazole Derivatives 461 Drugs for Thiazole Derivatives 461

Contents

Drugs for Pyridine Derivatives 461 Drugs for Pyrimidine Derivatives 462 Drugs for Pyrazine Derivatives 463 Drugs for Piperidine Derivatives 463 Drugs for Quinoline/Isoquinoline Derivatives 463 Drugs for Oxazole/Isoxazole/Thiazole/Thiadiazole Derivatives 463 Drugs for Chromane Derivatives 464 Drugs for Indole Derivatives 464 Drugs for Benzimidazole Derivatives 464 Drugs for Indazole Derivatives 465 Drugs for Azepin/Diazepine Derivatives 465 Drugs for Xanthine Derivatives 465 Drugs for Lactone Derivatives 466 Drugs for β-Lactam Derivatives 466 References 467 10 Synthesis of Some Heterocyclic Compounds Using Named Reactions 469

Bartoli Indole Synthesis 469 Mechanism 470 Application 470 Experimental Procedure (from patent US9567339B2) 470 Bischler–Napieralski Reaction 471 Mechanism 471 Alternative Mechanism 472 Application 472 Experimental Procedure (from patent US6048868A) 472 Combes Quinoline Synthesis 472 Mechanism 473 Application 474 Experimental Procedure (from patent WO2018234184A1) 474 Conrad–Limpach Synthesis 474 Mechanism 475 Application 475 Experimental Procedure (from patent US20120010237A1) 475 Doebner–Miller Reaction 476 Mechanism 476 Application 477 Feist–Benary Synthesis of Furan 477 Mechanism 477 Application 478 Experimental Procedure (from patent CN106243072A) 478 Fischer Indole Synthesis 478 Mechanism 479 Application 479 Experimental Procedure (General) 480 Friedländer Synthesis or Annulation 480 Mechanism 481

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Application 481 Experimental Procedure (General) 481 Knorr Pyrrole Synthesis 482 Mechanism 482 Application 483 Madelung Indole Synthesis 483 Mechanism 483 Application 484 Experimental Procedure (General) 484 Paal–Knorr Furan Synthesis 484 Mechanism 485 Experimental Procedure (General) 485 Paal–Knorr Pyrrole Synthesis 485 Mechanism 486 Application 486 Experimental Procedure (an intermediate for Atorvastatin, from patent WO2009023260A2) 487 Pictet–Gams Isoquinoline Synthesis 487 Mechanism 488 Application 488 Pictet–Spengler Reaction 488 Mechanism 489 Application 490 Experimental Procedure (from patent CN107552089A) 490 Skraup Quinoline Synthesis 491 Mechanism 491 Experimental Procedure (from patent WO2011022928A1) 492 Preparation of 7-Trifluoromethyl-5-nitroquinoline 492 References 493 Bartoli Indole Synthesis 493 Bischler–Napieralski Reaction 494 Combes Quinoline Synthesis 495 Conrad–Limpach Synthesis 495 Doebner–Miller Reaction 496 Feist–Benary Synthesis of Furan 496 Fischer Indole Synthesis 497 Friedländer Synthesis or Annulation 498 Knorr Pyrrole Synthesis 499 Madelung Indole Synthesis 501 Paal–Knorr Furan Synthesis 502 Paal–Knorr Pyrrole Synthesis 502 Pictet–Gams Isoquinoline Synthesis 503 Pictet–Spengler Reaction 503 Skraup Quinoline Synthesis 505

Contents

507 Amines 507 tert-Butyloxycarbonyl (Boc) 507 2-(Trimethylsilyl)ethoxymethyl (SEM) 507 Carbobenzyloxy/Carboxybenzyl/Benzyloxycarbonyl (Cbz or Z) 507 9-Fluorenylmethyloxycarbonyl (Fmoc) 508 Allyloxycarbonyl (Alloc) 508 Benzyl (Bn) 508 p-Methoxybenzyl (PMB) 508 Acetyl (Ac) 508 Trifluoroacetyl 508 Tosyl (Ts) 509 Trityl (Trt) 509 2,2,2-Tricholoethoxycarbonyl (Troc) 509 Methyl Carbamate 509 Formamide 509 Alcohols 509 Methyl Ether 509 Methoxymethyl (MOM) Ether 510 2-Methoxyethoxymethyl (MEM) Ether 510 Benzyloxymethyl (BOM) Ether 510 Tetrahydropyranyl (THP) Ether 510 Benzyl (Bn) Ether 510 tert-Butyl (t-Bu) Ether 510 Silyl Ether 510 Trimethylsilyl (TMS) Ether 510 Triisopropylsilyl (TIPS) Ether 511 tert-Butyldimethylsilyl (TBS or TBDMS) 511 tert-Butyldiphenylsilyl (TBDPS) 511 2-(Trimethylsilyl)ethoxymethyl (SEM) Ether 511 Ester Formation 511 Acetate or Acetyl (Ac) Ester 511 Methanesulfonate (Mesylate) 511 Tosylation 511 Benzoate (Bz) Ester 512 Pivaloate (piv) Ester 512 For 1,2-Diols 512 Acetonide (Isopropylidene Ketal) 512 Carbonate 512 Benzylidene Acetal 512 For 1,3-Diols 512 For Phenols 513 Protection and Deprotection for the Carboxylic Acid Group 514 From Primary or Secondary Alcohol 514

11 Protection and Deprotection of Common Functional Groups

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For tert-Butyl Ester 514 Benzyl Ester 515 Silyl Ester 515 2-(Trimethylsilyl)ethoxymethyl Ester (SEM Ester) 515 Protection and Deprotection of Carbonyl Group 515 Dimethyl Acetals and Ketals 515 1,3-Dioxolane (Cyclic Acetals and Ketals) 515 1,3-Dioxane 516 1,3-Dithiolane (Cyclic Dithioacetals and Ketals) 516 1,3-Dithiane 516 Protection and Deprotection of Terminal Alkyne 516 References 517 Amines 517 Alcohols 517 Protection and Deprotection for the Carboxylic Acid Group Protection and Deprotection of Carbonyl Group 517 Protection for the Terminal Alkyne CH 518

517

12 Amino Acids and Peptides 519

Natural Amino Acids 519 Amino Acids with Nonpolar Side Chain 521 Amino Acids with Polar Side Chain 522 Amino Acids with Positive Charged (Basic) Side Chain 522 Amino Acids with Negatively Charged (Acidic) Side Chain 523 Nonnatural Amino Acids 523 Solution-Phase Peptide Synthesis 525 Experimental 525 Mechanism of DIC–HOBt Coupling Reaction 526 Mechanism of Boc Deprotection with TFA 527 Mechanism of Fluorenyl-9-methoxycarbonyl (Fmoc) Deprotection with Piperidine 528 Solid-Phase Peptide Synthesis 528 Merrifield Resin 528 Solid-Phase Peptide Synthesis Fmoc Strategy 529 Amino Acids with Side-Chain Protecting Groups for Fmoc Strategy 530 General Considerations 530 Standard Fmoc Strategy for SPPS 533 Cleavage Cocktail 533 Cleavage Cocktail A 534 Cleavage Cocktail B 534 Reagents and conditions 535 Covalent Peptides 536 Staple Peptides 537 Building Blocks for Stapled Peptides (Both L and D Analogs of Amino Acids Are Available) 538 Hydrocarbon Stapled Peptide Examples 538

Contents

Experimental Procedure 539 Stapled Peptide by Click Chemistry 539 Building Blocks for Click Chemistry (Both L and D Analogs Are Available) 540 Side-Chain Modification 540 References 540 13 Functional Group Transformation 543

Alcohol to Aldehyde 543 Secondary Alcohol to Ketone 544 Primary Alcohol to Carboxylic Acid 546 1,2-Diol Oxidation 547 Alcohol to Fluoride [11, 14, 15] 547 Alcohol to Chloride 547 Alcohol to Bromide 548 Alcohol to Iodide [13] 548 Alcohol to Ester 549 Alcohol to Ether 549 Alcohol to Sulfonic Ester 550 Alcohol to Methylene 550 Alcohol to Azide 550 Azide to Amine 550 Aldehyde to Alcohol 551 Aldehyde to Carboxylic Acid 551 Aldehyde to Difluoro [14, 15] 551 Ketone to Alcohol 551 Ketone to Ester 552 Ketone to Difluoro [14, 15] 552 Ketone to Methylene 553 Ketone to Thioketone 553 Acid (Carboxylic) to Ester 553 Acid to Amide 554 Acid to Ketone 555 Ester to Acid 555 Ester to Aldehyde 555 Ester to Alcohol 555 Ester to Ketone 556 Nitro to Amine 556 Alkene to Epoxide 557 Alkene to Alkane 557 Alkyne to Alkane 558 Alkyne to Alkene 558 Cyano to Carboxylic Acid 558 Cyano to Amine [16] 558 Cyano to Amide 559 Methyl Phenyl Ether to Phenol [17, 18] 559 Toluene to Benzyl Halides 560

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Contents

Alkylbenzene to Benzoic Acid 560 Aromatic Amine to Azide 560 Aromatic Halide to Aldehyde [21] 561 Aromatic Halide to Benzoic Acid [22] 561 Thioether to Sulfoxide 561 Thioether to Sulfone 561 Thiol to Disulfide [23–25] 562 Unsymmetrical Disulfide 562 Reductive Amination 562 Amine to Urea and Thiourea 562 Urea Formation from Two Amines 563 References 563 14 Synthesis of Some Drug Molecules 565

References 572 15 Common Laboratory Methods 573

Acetylation of Alcohol (patent WO2013040068A2) 573 Deacetylation (patent WO2013040068A2) 573 Tosylation of Alcohol (patent US9399645B2) 574 Benzoylation of Alcohol (patent WO2019093776A1) 574 Pivaloylation of Alcohol (patent WO2019093776A1) 575 Silylation of Alcohol (patent WO1998008849A1) 575 Desilylation (patent WO1998008849A1) 575 Esterification (ester formation) 576 Ester Formation from Acid and Alcohol (patent US9399645B2) 576 Carboxylic Acid to Benzyl Ester (patent WO2019134765A1) 577 Hydrolysis (saponification) of Ester 577 Carboxylic Acid to Acid Chloride (patent US20070197544A1) 577 Acid Chloride to Amide (patent US20070197544A1) 578 Amide Bond Formation Using Carboxylic Acid and PBr3 (patent US20070197544A1) 578 Buchwald–Hartwig Amination (patent US20070197544A1) 579 Ester to Carboxylic Acid (patent WO2019134765A1) 579 Benzyl Ester to Carboxylic Acid (patent WO2019134765A1) 580 Boc- Protection of Amino Group (patent US20090054548A1) 580 Deprotection of Boc Group (patent US20090054548A1) 581 Sulfonation of Aromatic Compound (patent WO2002030878A1) 581 Nitration of Aromatic Compound (mild and noncorrosive conditions) (patent WO1994019310A1) 582 Nitration of Aromatic Compound (regular method) 582 Nitration of Aromatic Compound (regular method) (patent WO2016118450A1) 582 Reduction of Nitro Group (patent WO2018167800A1) 583 Reduction of Nitro Group by Hydrogenation (patent US6329380B1) 583

Contents

Reduction of Nitro Group Using Hydrazine Raney Nickel (patent US20070197544A1) 584 Reduction of Nitro Group Using Fe and NH4 Cl (patent US20070197544A1) 584 Reduction of Ketone with NaBH4 (patent WO2013040068A2) 585 Reduction of Ester to Alcohol (patent US9399645B2) 585 Reduction of Ester to Alcohol with DIBAL-H (patent WO2016037566A1) 586 Ester to Aldehyde (patent US20190337964A1) 586 Selective Oxidation of Primary Alcohol (patent WO2013040068A2) 587 Oxidation of Alcohol Using DMP 587 Oxidation of Primary Alcohol Using TEMPO (patent US10407378B2) 587 Benzylation of Phenol 588 Debenzylation by Hydrogenation (Patent WO1994028886A1) 588 Iodination of Aromatic Compound (patent US7951832B2) 589 Methylation of Phenol 589 Demethylation to Phenol (patent US6924310B2) 590 Bromide to O-Benzyl (patent WO2019134765A1) 590 Tosylate to Fluoride (patent WO2019134765A1) 590 Iodide to Tosylate (patent WO2019134765A1) 591 Ozonolysis of Alkene (patent WO2013040068A2) 591 Asymmetric Dihydroxylation of Alkene (Sharpless Method) (WO2019093776A1) 592 Alcohol to Fluoride (WO2019134765A1) 592 Alcohol to Iodide (patent US9399645B2) 593 Alcohol to Bromide (patent WO2016037566A1) 593 Alcohol to Iodide via Tosylation (patent WO2016037566A1) 594 Alkene to Aldehyde (patent WO1998008849A1) 594 Amine to Azide via Diazotization (patent WO20030135050A1) 595 Azide to Amine (patent US6329380B1) 595 Reductive Amination (patent WO2005118525A1) 596 Asymmetric C-Alkylation (patent WO2005118525A1) 596 Aldehyde to 1,1-Difluoroalkane (WO2018167800A1) 597 Free Radical Reaction (patent WO2013040068A2) 597 Umpolung 598 Silylation of 1,3-Dithiane (C-Silylation) (Model reactions for education purpose only) 598 Alkylation on 2-Diphenylmethyl-1,3-Dithiane 599 Deprotection of 1,3-Dioxolane 599 Preparation of Grignard Reagent and Reaction with an Aldehyde 599 Alcohol to Bromide 600 Deprotection of 1,3-Dithiane 600 16 Common Reagents in Organic Synthesis 603

Acetic Acid (CH3 CO2 H)

603

xv

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Contents

Acetic Anhydride 603 Acetyl Chloride 604 AlkylFluor 605 Aluminum Chloride (Aluminium Chloride; AlCl3 ) 605 Aluminum Isopropoxide (Aluminium Isopropoxide) 605 Ammonium Chloride (NH4 Cl) 605 Ammonium Formate 606 Ascorbic Acid (Vitamin C) Sodium Salt (Sodium l-Ascorbate) 607 9-Azabicyclo[3.3.1]nonane N-Oxyl, (2-Azaadamantane-N-oxyl) (AZADO) 607 Azobisisobutyronitrile (AIBN) 607 [1,1′ -(Azodicarbonyl)dipiperidine] (ADDP) 608 Benzoyl Peroxide 608 [1,1′ -Bis(diphenylphosphino)ferrocene] palladium(II) dichloride, Pd(dppf )Cl2 608 [Bis(triphenylphosphine)palladium(II) dichloride], Pd(Ph3 P)2 Cl2 609 Bismuth Chloride (BiCl3 ) 609 (Bis(trifluoroacetoxy)iodo)benzene 610 9-Borabicyclo[3.3.1]nonane (9-BBN) 610 Boron Tribromide (BBr3 ) 610 Boron Trifluoride Diethyl Etherate (BF3 -OEt2 ) 611 Bromine (Br2 ) 611 N-Bromosaccharin (NBSa) 611 N-Bromosuccinimide (NBS) 612 Burgess Reagent [Methyl N-(triethylammoniosulfonyl)carbamate] 612 tert-Butyldimethylsilyl Chloride (TBDMS-Cl) 613 tert-Butyldimethylsilyl Trifluoromethanesulfonate (TBS-OTf) 613 tert-Butyl Hydroperoxide (TBHP) 613 n-Butyllithium (n-BuLi) 614 tert-Butyllithium 614 tert-Butyl Nitrite (TBN) 615 Carbon Tetrabromide (CBr4 ) 615 Carbonyldiimidazole (CDI) 616 Ceric Ammonium Nitrate (CAN; (NH4 )2 Ce(NO3 )6 ) 616 Cesium Carbonate (Cs2 CO3 ) 617 Cesium Fluoride (CsF) 617 Chloramine-T, N-chloro Tosylamide Sodium Salt 617 m-Chloroperbenzoic Acid (m-CPBA) 618 N-Chlorosuccinimide (NCS) 619 Chromium Trioxide 619 Cobalt Chloride 620 Copper Iodide (CuI) 620 Dess–Martin Periodinane (DMP) 621 (Diacetoxyiodo)benzene (DAIB) 621 1,4-Diazabicyclo[2.2.2]octane (DABCO) 622 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) 622 Diazomethane 622

Contents

Di-tert-butyl Azodicarboxylate (DBAD) 623 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) 623 N,N ′ -Dicyclohexylcarbodiimide (DCC) 624 Diethylaminosulfur Trifluoride (DAST) 624 Diethyl Azodicarboxylate (DEAD) 625 Diiodomethane (CH2 I2 ) 625 Diisobutylaluminum Hydride (DIBAL-H) 626 Diisopropylaminoborane 626 Diisopropyl Azodicarboxylate (DIAD) 626 N,N-Diisopropylethylamine (DIEA) (Hünig’s Base) 627 4-Dimethylaminopyridine (N,N′ -Dimethylaminopyridine) (DMAP) 627 Diphenylphosphoryl Azide (DPPA) 627 Di-tert-butyl Peroxide (DTBP) 628 Ethyl Chloroformate 628 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDC⋅HCl) 628 Formic Acid 629 O-(7-Azabenzotriazol-1-yl)-N,N,N ′ ,N ′ -tetramethyluronium hexafluorophosphate (HATU) 629 Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU) 629 Hexamethylphosphoramide (HMPA) 630 Hydrazine (NH2 NH2 ⋅H2 O) 630 1-Hydroxybenzotriazole (HOBt) 630 Hydrogen Peroxide 631 [Hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s Reagent) 631 Imidazole 632 Iodine (I2 ) 632 Iodobenzene Dichloride 633 N-Iodosuccinimide (NIS) 633 2-Iodoxybenzoic Acid (IBX) 633 Iron(III) Nitrate Nonahydrate 634 Isoamyl Nitrite (Also Called Amyl Nitrite) 634 Isobutyl Chloroformate 634 Jones Reagent 635 Lawesson’s Reagent 635 Lead Tetraacetate (Pd(OAc)4 ) 635 Lithium Aluminum Hydride (LiAlH4 ) 636 Lithium Diisopropylamide (LDA) 637 2,6-Lutidine (2,6-Dimethylpyridine) 637 Manganese Dioxide (MnO2 ) 637 Methanesulfonyl Chloride (Mesyl Chloride) 638 N-Methylmorpholine N-oxide (NMO) 638 Nitrosobenzene 639 Osmium Tetroxide 639 Oxalyl Chloride 640

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Contents

Oxone (Potassium Peroxymonosulfate) 640 Ozone (O3 ) 641 PhenoFluor Mix 642 Palladium on Calcium Carbonate (Pd/CaCO3 ) 642 Palladium on Carbon 643 Phenyltrimethylammonium Perbromide (PTAB) or Phenyltrimethylammonium Tribromide (PTT) 643 Phosphorus Oxychloride 644 Phosphorus Tribromide (PBr3 ) 644 Piperidine 644 Platinum on Carbon 645 Platinum(IV) Oxide 645 Potassium bis(trimethylsilyl)amide (KHMDS) (Potassium Hexamethyldisilazide) 645 Potassium tert-Butoxide 645 Potassium Carbonate 646 Potassium Iodide 646 Potassium Permanganate 647 Potassium Sodium Tartrate Tetrahydrate (Rochelle’s Salt) 647 Propylphosphonic Anhydride (T3P) 648 PyAOP 648 (Benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphate (PyBOP) 648 Pyridine 649 Pyridinium Chlorochromate (PCC) 649 Pyridinium Dichromate (PDC) 649 Pyridinium p-Toluenesulfonate (PPTS) 650 Raney Nickel 651 Ruthenium(III) Chloride (RuCl3 ) 651 Scandium(III) Trifluoromethanesulfonate (Scandium Triflate) 652 Selectfluor 652 Sodium Azide 653 Sodium Bis(trimethylsilyl)amide (NaHMDS) 653 Sodium Borohydride 653 Sodium Cyanoborohydride 654 Sodium Hydride (NaH) 654 Sodium Hypochlorite (Bleach) 654 Sodium Nitrite 655 Sodium Periodate 655 Sodium Sulfide (Na2 S) 655 Sodium Triacetoxyborohydride (STAB) 655 Tetra-n-butylammonium Fluoride (TBAF) 656 Tetra-n-butylammonium Iodide (TBAI) 656 Tetrakis(triphenylphosphine)palladium(0) (Pd(Ph3 P)4 ) 657 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) 657 Tetrapropylammonium Perruthenate (TPAP) 657 Thionyl Chloride 657

Contents

Titanium(IV) Chloride 658 Titanium Isopropoxide 658 p-Toluenesulfonic Acid 659 Tributyltin Hydride 659 Triethylamine (TEA) 659 Triethyl Orthoformate 660 Trifluoroacetic Acid (TFA) 660 Trimethylsilyl Chloride (TMS-Cl) 660 2-(Trimethylsilyl)ethoxymethyl Chloride (SEM-Cl) 661 Trimethylsilyl Cyanide (TMS-CN) 661 Trimethylsilyl Diazomethane 662 Trimethylsilyl Iodide 662 Triphenylphosphine (Ph3 P) 662 Triphosgene [bis(trichloromethyl) carbonate (BTC)] 663 Tris(dibenzylideneacetone)dipalladium(0) 664 Trityl Chloride (Triphenylmethyl Chloride) 664 Urea Hydrogen Peroxide (UHP) 664 Zinc (Zn) 665 Zinc Chloride 665 References 666 Further Reading 668 Organic and Medicinal Chemistry Books Consulted 668 Appendix A List of Medicines (Partial) and Nutrients 671

Antibiotic (antibacterial agent) 671 Antiviral Medicines 673 Antifungal Medicines 678 Antimalarial Medicines 683 Antituberculosis Medicines 685 Medicines for Pain 687 Anticonvulsants Medication (antiepileptic drugs or as antiseizure drugs) 688 Anti-infective Medicines (anthelminthics and antifilarials) 689 Medicines for Migraine 690 Antileprosy Medicines 691 Disinfectant and Antiseptics 692 Antidiabetic Medicines (diabetes medications) 692 Medicines for Anesthetics (anesthetics) 695 Antiallergics and Medicines for Anaphylaxis 696 Cardiovascular Medicines 697 Medicines for Gastrointestinal 700 Medicines for Mental and Behavioral Disorders 701 Medicine for Joint Paints 703 Medicines Affecting the Blood 704 Medicines for Cancer (antineoplastics) 705 Medicines for Parkinson’s Disease 718 Medicines for Ear, Nose, and Throat 720

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Contents

Medicines for the Respiratory Tract 721 Reproductive Health and Perinatal Care Medicines Medicines for Dermatological (topical) 725 Antidotes in Poisonings 727 Vitamins 730 Other Nutrients 734 Medical Advice Disclaimer 735 Further Reading 735 Index 737

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Preface Organic chemistry is a constantly developing and expanding field of science because of its infinite research and application possibilities. Clear understanding of organic chemistry concepts, including the mechanistic aspects of organic reactions, helps chemists design drug molecules with the power to save human lives. This textbook is targeted to advanced undergraduates and postgraduate students in all areas of organic, bioorganic, pharmaceutical, and medicinal chemistry. Professional researchers may utilize it as a handbook due to its references to original literature, recent reviews, and application of named reactions and reagents frequently used in organic synthesis. This book also covers, step by step, the mechanism of selected reactions that are part of undergraduate and postgraduate curricula. The definition of each named reaction with its original reference(s), i.e. the first one or others if applicable, current reviews, and their applications (sourced from Journal of Medicinal Chemistry and others) are also included. Heterocyclic compounds have important biological activities, so the nomenclature and application of heterocyclic compounds have been summarized in Chapter 9. In addition, Chapter 12 presents preliminary concepts regarding solution-phase and solid-phase peptide syntheses. For synthetic stand points, common organic reagents and functional groups transformation are discussed in Chapters 13–16. References included in this book are available on PubMed (https://www.ncbi .nlm.nih.gov/pubmed) or https://pubs.acs.org. The experimental procedure of each reaction can be found on Google Patents (http://patents.google.com). I would like to express great thanks to Dr. Ramkrishna De (Vertex Pharmaceuticals) for reviewing the manuscript and providing valuable suggestions. Also, Dr. Maloy Kumar Parai provided some assistance in preparing the manuscript. I would like to express great thanks to Wiley editors Dr. Anne Brennführer, Dr. Frank Weinreich, Ms. Katherine Wong, as well as their staffs Ms. Pinky Sathishkumar, Ms. Abisheka Santhoshini who helped me to complete this book. Finally, I wish to thank my family members for their continual understanding and support. I welcome and, in fact, earnestly request readers to notify me of any suggestions for improving this book. San Diego, CA, USA March 2020

Surya K. De

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About the Author Surya K. De received his BS degree from Midnapore College and his PhD degree from Jadavpur University. His first book, Cancer & You: What Everyone Needs to Know About Cancer and Its Prevention, was published in 2018. He has published over 100 peer-reviewed papers in reputed international journals, covering a broad array of specialized topics in science, and he holds 15 US patents for his inventions. Due to Dr. De’s abundant research contributions in the areas of cancer, metabolic diseases, organic and medicinal chemistry, and neuroscience, he earned the distinction of Fellow of the Royal Society of Chemistry (London, UK) in 2010; he was subsequently awarded the status of Chartered Chemist in 2011. Furthermore, he is an elected alternate councilor in the American Chemical Society (San Diego section). Dr. De resides in San Diego, California, where he loves the scenic coastline and sunny skies.

xxvii

About the Book This book is unique in that it covers most reactions that are the syllabus of undergraduate and postgraduate students. The reaction mechanisms are shown in details with step-by-step explanation of the processes. Most of the reactions’ applications and experimental procedures are also given. Professional researcher may utilize it as a handbook due to its references to original literature, recent reviews, and application of named reactions and reagents frequently used in organic synthesis.

xxix

Acknowledgments The author would like to extend his gratitude to the original publishers for experimental procedures for granting permission to use in this book. The publishers include the American Chemical Society, Elsevier, the Royal Society of Chemistry, John Wiley & Sons, Wiley VCH-Verlag, Thieme, and the Japan Institute of Heterocyclic Chemistry. I would like to thank all inventors for patent literatures cited in this book.

xxxi

List of Abbreviations

Abbreviation

Name

Chemical structure

Å Ac

Ångström Acetyl

NA

Acac

Acetylacetonyl

AIBN

2,2′ -Azobisisobutyronitrile

Alloc

Allyloxycarbonyl

Aq

Aqueous

With water

Ar

Aryl

Substituted aromatic ring

9-BBN

9-Borabicyclo[3.3.1]nonane

O O

O

NC

N N

CN

O O

BINAL-H



H B



2,2 -Dihydroxy-1,1 binaphthyl lithium aluminum hydride

O

Al

O

BINAP

2,2′ Bis(diphenylphosphino)1,1′ -binaphthyl

PPh2 PPh2

BINOL

1,1′ -Bi-2,2′ -naphthol OH OH

BMS

Borane dimethyl sulfide complex

H3 B • SMe2

H H

Li

xxxii

List of Abbreviations

Abbreviation

Name

Boc

tert-Butoxycarbonyl

BOM

Benzyloxymethyl

b.p.

Boiling point

BPO

Benzoyl peroxide

Chemical structure O O

O

NA O

O O

Bn

Benzyl

br

Broad

Bz

Benzoyl

n-Bu t-Bu

n-Butyl tert-Butyl

NA O

∘C

Degree Celsius

NA

13

Carbon NMR

NA

C NMR

O

CAN

Ceric ammonium nitrate

(NH4 )2 Ce(NO3 )6

cat.

Catalytic

NA

Cbz (Z)

Benzyloxycarbonyl

conc.

Concentrated

NA

COSY

Correlation spectroscopy

NA

CDI

Carbonyldiimidazole

O O

O N

CSA

N

N

N

Camphorsulfonic acid

SO3H

CTAB

Cetyltrimethylammonium bromide

Δ

Chemical shift in ppm

NA

d

Doublet

NA

DABCO

1,4Diazabicyclo[2.2.2]octane

O

N Br

N N

List of Abbreviations

Abbreviation

Name

Chemical structure

DAST

Diethylaminosulfur trifluoride

F F S N F

Dba

Dibenzylideneacetone

Ph

Ph O

DBAD

Di-tert-butyl azodicarboxylate

O

O N N

O

DBU

DCC DCE

1,8Diazabicyclo[5.4.0]undec7-ene N,N′ Dicyclohexylcarbodiimide

O

N N N C N

Cl

1,2-Dichloroethane

Cl

DCM

Dichloromethane

CH2 Cl2

DCU

N,N′ -Dicyclohexylurea

DDQ

2,3-Dichloro-5,6-dicyano1,4-benzoquinone

O N C N H H O Cl

CN CN

Cl O

de

Diastereomeric excess

DEAD

Diethyl azodicarboxylate

NA O O

N

N

O O

DET

OH

Diethyl tartrate

O O

DHP

O O

HO

3,4-Dihydro-2H-pyran O

(DHQ)2 PHAL

Bis(dihydroquinino)phthalazine

H3C H3 C

MeO

N N O

N H N

O H N

H N OMe

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xxxiv

List of Abbreviations

Abbreviation

Name

(DHQD)2 -PHAL

Bis(dihydroquinidino)phthalazine

Chemical structure H3C H

H3C O

N H

MeO

N

O N N MeO

H

N N

DIAD

DAIB (DIB)

Diisopropyl azodicarboxylate

O

O N N

O

O

O

(Diacetoxyiodo)benzene

O I O O

DIBAL-H

Diisobutylaluminum hydride

DIC

Diisopropylcarbodiimide

DIEA (DIPEA)

Diisopropylethylamine

H Al N C N

N

DIPT

Diisopropyl tartrate

OH

O O

DMA

O

HO

O

N,N-Dimethylacetamide N

DMAP

NMe2

4-N,NDimethylaminopyridine

N

DME DMF

O

1,2-Dimethoxyethane

N

DMP

O O

N,N-Dimethylformamide

H O

Dess–Martin periodinane O

O O I O O O

O

O

List of Abbreviations

Abbreviation

Name

Chemical structure

DMPS

Dimethylphenylsilyl

DMS

Dimethyl sulfide

S

DMSO

Dimethyl sulfoxide

O S

DPPA

Diphenylphosphoryl azide

DPS (TBDPS)

tert-Butyldiphenylsilyl

Si

O O P O N3

Si

DTT (DTE)

OH

1,4-Dithioerythritol

SH

HS OH

E1

Unimolecular elimination

NA

E2

Bimolecular elimination

NA

EDC (EDCI)

1-Ethyl-3(3-dimethylaminopropyl)carbodiimide

EDG

Electron-donating group

NA

EDTA

Ethylenediaminetetraacetic acid

HO

NMe2

N C N

O O

ee

Enantiomeric excess

NA

Ei

Intramolecular syn elimination

NA

Et Equiv.

Ethyl Equivalent

EWG

Electron-withdrawing group

Fmoc

9Fluorenylmethoxycarbonyl

O N

N

OH

O

NA NA O O

Fp

Flash point

NA

g

Grams

NA

GC

Gas chromatography

NA

h

Hour

NA

OH

OH

xxxv

xxxvi

List of Abbreviations

Abbreviation

Name

HATU

O-(7-Azabenzotriazol1-yl)-N,N,N′ ,N′ tetramethyluronium hexafluorophosphate

Chemical structure O N N N

N

NMe2

Me2N

PF6

HBTU

Hexafluorophosphate Benzotriazole Tetramethyl Uronium

O N N N NMe2

Me2N

PF6

HFIP

HMDS

1,1,1,3,3,3-Hexafluoro-2propanol (hexafluoroisopropanol) 1,1,1,3,3,3Hexamethyldisilazane

OH F3C

CF3

Si Si N H

HMPA

Hexamethylphosphoric acid triamide (hexamethylphosphoramide)

N N P N O

HMPT

Hexamethylphosphorous triamide

N N P N

HOAt

1-Hydroxy-7azabenzotriazole

N N

N N OH N

HOBt

1-Hydroxybenzotriazole

HOMO

Highest occupied molecular orbital

NA

HPLC

High-performance liquid chromatography

NA

HTIB

[Hydroxy(tosyloxy)iodo]benzene

N N OH

OH I O O

Hz

Hertz

NA

1

Proton NMR

NA

Heteronuclear multiple bond coherence

NA

H NMR

HMBC

S

O

List of Abbreviations

Abbreviation

Name

Chemical structure

HSQC

Heteronuclear single quantum coherence

NA

IBX

o-Iodoxybenzoic acid

O

HO OH

IPA

Isopropyl alcohol

IR

Infrared spectroscopy

NA

J

Coupling constant

NA

KHMDS

Potassium bis(trimethylsilyl)amide

L

Ligand

NA

LAH

Lithium aluminum hydride

LiAlH4

LHMDS (LiHMDS)

Lithium bis(trimethylsilyl)amide

K N Si Si

Li Si

Liq.

Liquid

LiTMP (LTMP)

Lithium 2,2,6,6tetramethylpiperidide

O I O

N Si

NA

N Li

L.R.

Lawesson’s reagent 2,4-Bis(4-methoxyphenyl)1,3,2,4-dithiadiphosphetane-2,4-disulfide

L-selectride

Lithium tri-sec-butylborohydride

MeO S S P P S S H B

Li

LTA

Lead tetraacetate

Pb(OAc)4

LUMO

Lowest unoccupied molecular orbital

NA

Lut

2,6-Lutidine

m

Meta

NA

m

Multiplet

NA

N

OMe

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xxxviii

List of Abbreviations

Abbreviation

Name

Chemical structure

M

Moles/liter

NA

m-CPBA

meta-Chloroperbenzoic acid

O

Me

Methyl

−−

MEM

(2-Methoxyethoxy)methyl

MIC

Methyl isocyanate

O C N

min

Minute

NA

mg

Milligrams

NA

ml

Milliliters

NA

Mol

Moles

NA

O O H

Cl

CH3

O

O

mmol

Millimoles

NA

μl

Microliters

NA

MOM

Methoxymethyl

m.p.

Melting point

Ms

Mesyl (methanesulfonyl)

MS

Mass spectrometry

NA

MS

Molecular sieves

NA

MSA

Methanesulfonic acid

O HO S O

MSDS

Material safety data sheet

NA

MTBE

Methyl tert-butyl ether

MVK

Methyl vinyl ketone

Mv

Microwave

NA

n

Normal (e.g. unbranched alkyl chain)

NA

NaHMDS

Sodium bis(trimethylsilyl)amide Sodium hexamethyldisilazane

O

NA O S O

O

O

NBS

N-Bromosuccinimide

Na Si

N Si

O N Br O

List of Abbreviations

Abbreviation

Name

NCS

N-Chlorosuccinimide

Chemical structure O N Cl O

NIS

O

N-Iodosuccinimide

N

I

O

NMM

N-Methylmorpholine

O N

NMO

N-Methylmorpholine oxide

O N

NMP

O

N-Methyl-2-pyrrolidinone

O N

NMR

Nuclear magnetic resonance

NA

NSAID

Nonsteroidal anti-inflammatory drug

NA

Nuc/Nu

Nucleophile

NA

o

Ortho

NA

p

Para

NA

Pbf

2,2,4,6,7Pentamethyldihydrobenzofuran-5-sulfonyl

31

P NMR

Phosphorus NMR

PBP

Pyridinium bromide perbromide

PCC

Pyridinium chlorochromate

O S O O

NA NH Br3

N H

PDC

O Cl

Pyridinium dichromate NH

Cr

O O

O O O Cr O Cr O O O

HN

xxxix

xl

List of Abbreviations

Abbreviation

Name

Pd2 (dba)3

Tris(dibenzylideneacetone)dipalladium

Chemical structure O Pd2 3

Pd(dppf )Cl2

Ph Ph P



[1,1 Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Cl

Pd

Cl

Fe

P Ph Ph

PdCl2 (PPh3 )2

Bis(triphenylphosphine)palladium(II) dichloride

Pd(PPh3 )4

Tetrakis(triphenylphosphine)palladium(0)

PhI(OH)OTs

[Hydroxyl(tosyloxy)iodo]benzene

Cl P Pd P Cl

(Ph3 P)4 Pd

OH I

O

S O

O

CH3

PEG

Polyethylene glycol

Ph

Phenyl

PHAL

Phthalazine

PIFA

Phenyliodonium bis(trifluoroacetate)

H

O

O n

N N O CF3

O I

O O

Piv

H

Pivaloyl O

PMB

p-Methoxybenzyl

MeO

PMP

4-Methoxyphenyl

MeO

CF3

List of Abbreviations

Abbreviation

Name

Chemical structure

PNB

p-Nitrobenzyl

O2N

ppm

Parts per million

NA

PPTS

Pyridinium p-toluenesulfonate

Pr P.T.

Propyl Proton transfer

PTAB

Phenyltrimethylammonium perbromide

PTSA (TsOH)

O S O HN O

NA N Br

Br

Br

p-Toluenesulfonic acid SO3H

r.t. (rt)

Room temperature

NA

Rf

Retention factor in chromatography

NA

ROM

Ring-opening metathesis

NA

ROMP

Ring-opening metathesis polymerization

NA

RB (Rose Bengal)

2,4,5,7-Tetraiodo3′ ,4′ ,5′ ,6′ tetrachlorofluorescein, disodium salt (a photosensitizer, dye)

Cl Cl

Cl O

Cl ONa I

I O

O I

s

Singlet

SDS

Sodium dodecyl sulfate

ONa I

NA CH3(CH2)10CH2O

Selectfluor

SEM

N-Chloromethyl-N ′ fluorotriethylenediammonium bis(tetrafluoroborate) 2-(Trimethylsilyl)ethoxymethyl

Cl N

BF4

N F

BF4

O

SET

Single-electron transfer

NA

SN Ar

Nucleophilic substitution on an aromatic ring

NA

Si

O S ONa O

xli

xlii

List of Abbreviations

Abbreviation

Name

Chemical structure

SN 1

Unimolecular nucleophilic substitution

NA

SN 2

Bimolecular nucleophilic substitution

NA

SPB

Sodium perborate

NaBO3

t

Triplet

NA

TBAB

Tetra-n-butylammonium bromide N Br

TBAF

Tetra-n-butylammonium fluoride N F

TBAI

Tetra-n-butylammonium iodide N I

TBD

TBDMS (TBS)

Triazabicyclodecene (1,5,7triazabicyclo[4.4.0]dec5-ene tert-Butyldimethylsilyl

TBDPS (BPS)

tert-Butyldiphenylsilyl

N N

N H Si

Si

TBH

tert-Butyl hypochlorite

TBHP

tert-Butyl hydroperoxide

TBP

Tributylphosphine

O Cl O OH

P

TBTH

Tributyltin hydride Sn H

List of Abbreviations

Abbreviation

Name

TBTSP

tert-Butyl trimethylsilyl peroxide

TCCA

Chemical structure O O

Si

Cl N

Trichloroisocyanuric acid O Cl N

O N Cl

O

TCDI

S

Thiocarbonyldiimidazole

TCNE

Tetracyanoethylene

N

NC

CN

NC

TCNQ

TEA

7,7,8,8-Tetracyano-paraquinodimethane

N

N

N

CN

NC

CN

NC

CN

Triethylamine N

TEMPO

Teoc

2,2,6,6-Tetramethyl1-piperidinyloxy free radical

N O

2-(Trimethylsilyl)ethoxycarbonyl

TEP

Triethylphosphite

TES

Triethylsilyl

O

Si

O O O P O

Si

Tf

Trifluoromethanesulfonyl

TFA

Trifluoroacetic acid

O F3C S O O F3C

TFAA

Trifluoroacetic anhydride F3C

TFE

Trifluoromethanesulfonic acid (triflic acid)

O O

F

2,2,2-Trifluoroethanol F

TFMSA

OH O

OH F

O F3C S OH O

CF3

xliii

xliv

List of Abbreviations

Abbreviation

Name

THF

Tetrahydrofuran

Chemical structure

O

THP

2-Tetrahydropyranyl

TIPS

Triisopropylsilyl

O

Si

TIPS

Triisopropylsilane Si H

TMP

2,2,6,6Tetramethylpiperidine

TMS

Trimethylsilyl

TMSA

Trimethylsilyl azide

TMU

Tetramethylurea

N H Si

Si N 3 O N

TPAP

N

Tetra-n-propylammonium perruthenate N O O Ru O O

TPP

Triphenylphosphine P

TPS

Triphenylsilane Si

Trt

Trityl (triphenylmethyl) C

List of Abbreviations

Abbreviation

Name

Chemical structure

T.S.

Transition state

NA

Ts (Tos)

p-Toluenesulfonyl

O S O

TTN

Thallium(III) trinitrate

UHP

Urea–hydrogen peroxide complex

Z (Cbz)

Tl(NO3 )3 O H2N

NH2

H2O2 O

Benzyloxycarbonyl O

xlv

xlvi

List of Abbreviations

Polarity of Solvents Water

Polar

Acetic Acid Ethylene glycol Methanol Ethanol Isopropanol Pyridine Acetonitrile Nitromethane Diehylamine Aniline Dimethylsulfoxide Ethyl acetate 1,4-Dioxane Acetone 1,2-Dicholoroethane Tetrahydrofuran Dicholoromethane Chloroform Diethyl ether Benzene Toluene Xylene Carbon tetrachloride Cyclohexane Petroleum ether Hexane Pentane

Non-polar

List of Abbreviations

Common Solvents in Chemistry

MW

Solubility Boiling point Density in water Dielectric (g/100 g) constant (∘ C) (g/ml)

Solvent

Formula

Acetic acid

C2 H4 O2

60.052 118

1.044

Miscible

6.20

Acetone

C3 H6 O

58.078

56

0.784

Miscible

21.01

Acetonitrile

C2 H3 N

41.052

81

0.785

Miscible

36.64

Benzene

C6 H6

78.110

80

0.876

0.18

1-Butanol

C4 H10 O

74.120 117

0.809

6.3

17.8

2-Butanol

C4 H10 O

74.120

0.806

15

17.26

99

2.28

tert-Butanol

C4 H10 O

74.12

82

0.788

Miscible

12.5

2-Butanone

C4 H8 O

72.11

79

0.799

25.6

18.6

Carbon disulfide

CS2

76.13

46

1.274

1.266

Carbon tetrachloride

CCl4

153.82

76

1.594

0.08

Chlorobenzene

C6 H5 Cl

112.56

131

1.105

0.05

— 5.69

Chloroform

CHCl3

119.38

61

1.478

0.79

4.81

Cyclohexane

C6 H12

84.16

80

0.773

0.005

2.02

1,2-Dichloroethane

C2 H4 Cl2

98.96

83

1.245

0.86

10.42 31.8

Diethylene glycol

C4 H10 O3

106.12

246

1.119

10

Diethyl ether

C4 H10 O

74.12

34

0.713

7.5

4.26

Diglyme

C6 H14 O3

134.17

162

0.943

Miscible

7.23

1,2-Dimethoxyethane

C4 H10 O2

90.12

84

0.863

Miscible

7.3

N,N-Dimethylacetamide (DMA)

C4 H9 NO

87.12

165

0.937

Miscible

37.8

N,N-Dimethylformamide (DMF)

C3 H7 NO

73.09

153

0.944

Miscible

38.24 47

Dimethyl sulfoxide (DMSO) C2 H6 OS

78.03

189

1.092

25.3

1,4-Dioxane

C4 H8 O2

88.11

101

1.033

Miscible

Ethanol

C2 H6 O

46.01

78

0.786

Miscible

Ethyl acetate

C4 H8 O2

88.11

77

0.895

8.7

Ethylene glycol

C2 H6 O2

62.07

195

1.115

Miscible

37.7

Glycerine

C3 H8 O3

42.5

Heptane

C7 H16

92.09

290

1.261

Miscible

100.20

98

0.684

0.01

Hexamethylphosphoramide C6 H18 N3 OP 179.20 (HMPA)

232

1.03

Miscible

Hexamethylphosphorous triamide (HMPT)

163.20

150

0.898

Miscible

C6 H18 N3 P

Hexane

C6 H14

86.18

69

0.659

0.001

Methanol

CH4 O

32.04

65

0.791

Miscible

Methyl t-butyl ether (MTBE)

C5 H12 O

88.15

55

0.741

5.1

2.21 24.6 6

1.92 31.3

1.89 32.6

xlvii

xlviii

List of Abbreviations

MW

Boiling point (∘ C)

Density (g/ml)

Solubility in water (g/100 g)

Dielectric constant

Solvent

Formula

Methylene chloride

CH2 Cl2

84.93

40

1.326

9.08

N-Methyl-2-pyrrolidinone (NMP)

C5 H9 NO

99.13

202

1.033

10

32

Nitromethane

CH3 NO2

61.04

101

1.382

9.5

35.9

Pentane

C5 H12

72.15

36

0.626

0.04

Petroleum ether (ligroine)



0.656





1-Propanol

C3 H8 O

60.10

97

0.803

Miscible

20.1

2-Propanol (isopropyl alcohol)

C3 H8 O

60.10

82

0.786

Miscible

18.3

Pyridine

C5 H5 N

79.10

115

0.982

Miscible

12.3

Tetrahydrofuran (THF)

C4 H8 O

72.106

65

0.883

Soluble

Toluene

C7 H8

92.14

110

0.867

0.05

2.38

Triethylamine

C6 H15 N

101.19

89

0.728

0.02

2.4

Trifluoroacetic acid

C2 HFO2

114.023

8.55

2,2,2-Trifluoroethanol

C2 H3 F3 O 100.04

Water

H2 O

30–60

18.02

72

1.489

Miscible

74

1.384

Miscible

100

0.998



1.6

1.84

7.52

8.56 78.54

Water heavy

D2 O

20.03

101

1.107

Miscible

o-Xylene

C8 H10

106.17

144

0.897

Insoluble

2.57

m-Xylene

C8 H10

106.17

139

0.868

Insoluble

2.37

p-Xylene

C8 H10

106.17

138

0.861

Insoluble

2.27

References 1. Professor Murov’s Organic solvent table. 2. Vogel’s Practical Organic Chemistry. 3. American Chemical Society, Organic Division.

List of Cooling Baths

Cooling agent

Organic solvent or inorganic salt

Temperature (∘ C)

+12

Dry ice

1,4-Dioxane

Dry ice

Cyclohexane

+6

Dry ice

Benzene

+5

Dry ice

N,N-Dimethylformamide

+2

Ice

Water

0

List of Abbreviations

Cooling agent

Organic solvent or inorganic salt

Temperature (∘ C)

Liquid N2

Aniline

−6

Liquid N2

Ethylene glycol

−10

Liquid N2

Cycloheptane

−12

Dry ice

Benzyl alcohol

−15

Dry ice

Ethylene glycol

−15

Dry ice

Tetrahydrofuran

−22

Dry ice

Carbon tetrachloride

−23

Dry ice

1,3-Dichlorobenzene

−25

Dry ice

o-Xylene

−29

Liquid N2

Bromobenzene

−30

Dry ice

m-Toluidine

−32

Dry ice

3-Heptanone

−38

Dry ice

Pyridine

−42

Dry ice

Cyclohexanone

−46

Dry ice

Acetonitrile

−46 −47

Dry ice

m-Xylene

Dry ice

Diethyl carbitol

−52

Dry ice

n-Octane

−56

Dry ice

Diisopropyl ether

−60

Dry ice

Trichloroethylene

−73

Dry ice

Isopropyl alcohol

−77

Liquid N2

Butyl acetate

−77

Dry ice

Acetone

−78

Liquid N2

Isoamyl alcohol

−79

Dry ice

Sulfur dioxide

−82

Liquid N2

Ethyl acetate

−84

Liquid N2

n-Butanol

−89

Liquid N2

Hexane

−94

Liquid N2

Acetone

−94

Liquid N2

Toluene

−95

Liquid N2

Methanol

−98

Liquid N2

Cyclohexene

−104

Liquid N2

Isooctane

−107

Liquid N2

Ethyl iodide

−109

Liquid N2

Carbon disulfide

−110

Liquid N2

Butyl bromide

−112

Liquid N2

Ethanol

−116

Liquid N2

Ethyl bromide

−119

xlix

l

List of Abbreviations

Cooling agent

Organic solvent or inorganic salt

Temperature (∘ C)

Liquid N2

Acetaldehyde

−124

Liquid N2

Methylcyclohexane

−126

Liquid N2

1-Propanol

−127

Liquid N2

n-Pentane

−131

Liquid N2

1,5-Hexadiene

−141

Liquid N2

Isopentane

−160

Liquid N2

None

−196

Liquid He

None

−269

Dry ice is the solid form of carbon dioxide (CO2 ). Ice is the frozen water. Liquid N2 is the liquid state of nitrogen. Liquid He is the liquid state of helium.

Further Reading 1 Rondeau, R.E. (1966). J. Chem. Eng. Data 11: 124. 2 Phipps, A.M. and Hume, D.N. (1968). J. Chem. Educ. 45: 664. 3 Lee, D.W. and Jensen, C.M. (2000). J. Chem. Educ. 77: 629.

1

1 Rearrangement Reactions A rearrangement reaction is a board class of organic reactions in which an atom, ion, group of atoms, or chemical unit migrates from one atom to another atom in the same or different species, resulting in a structural isomer of the original molecule. Rearrangement reactions mostly involve breaking and/or making C—C, C—O, or C—N bonds. The migration origin is the atom from which the group moves, and the migration terminus is the atom to which it migrates.

Baeyer–Villiger Oxidation or Rearrangement The Baeyer–Villiger oxidation is an organic reaction that converts a ketone to an ester or a cyclic ketone to a lactone in the presence of hydrogen peroxide or peroxy acids [1]. The reaction was discovered in 1899 by Adolf von Baeyer and Victor Villiger. It is an intramolecular anionotropic rearrangement where an alkyl group migrates from the carbonyl carbon atom (migration origin) to an electron-deficient oxygen atom (migration terminus). The most electron-rich alkyl group (most substituted carbon) that is able to stabilize a positive charge migrates most readily. The migration order is as follows: Tertiary alkyl > cyclohexyl > secondary alkyl >phenyl >primary alkyl > CH3 > H. Several new catalysts including organics, inorganics, and enzymes have been developed for this reaction [2–76]. Amine or alkene functional groups are limitations, however, because of their easy and undesirable oxidation. O R3 O R1

O

O

H

O

Peroxyacid R2 or H2O2, CH2Cl2

R1

O O

R2

+ R 3

OH

Ester

Ketone

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

2

1 Rearrangement Reactions

O O

R3

O

O

H

O

Peroxyacid

O

or H2O2, CH2Cl2 Cyclic ketone

Lactone O NO2

O

TfOH, m-CPBA

OEt

(R)

OEt O

MeO

CH2Cl2, r.t.

O

MeO

(R)

O

NO2 99% ee

98% ee

Mechanism O O

R3

O

H

H

.. O R1

OH

O Step 1 R1

R2

R1

R2

R1

R2

O O

R3

O R3

OH

Step 2

O

O O

O R3 O

O R3

O

O

+ H

R1

O

R2

R2

Step 3 O O

.. OH

H

Step 4

O R1

O R2

R1

O R2

Step 1: The oxygen atom of the ketone is protonated to form a carbenium ion. Step 2: Nucleophilic attacks by aperoxycarboxylate ion at electron-deficient carbonyl carbon atom. Step 3: One of the alkyls on the ketone migrates to the oxygen of the peroxide group, while a carboxylic acid departs. Step 4: Deprotonation of the oxocarbenium ion produces the desired ester.

Application Zoapatanol and testololactone (anticancer agent) were synthesized using Baeyer–Villiger oxidation reaction conditions. Total syntheses of several natural products such as 9-epi-pentalenic acid [40], (+)-hippolachnin A,

Dakin Oxidation (Reaction)

(+)-gracilioether A, (−)-gracilioether E, (−)-gracilioether F [71], and salimabromide [76] have been accomplished utilizing this reaction. Experimental Procedure (from patent US 5142093A) Preparation of 4-(2,4-Difluorophenyl)-phenyl 4-nitrobenzoate F

F NO2

F

F

NaBO3 . 4 H2O

NO2

TFA

O

O O

A

B

Sodium perborate tetrahydrate (1.5 g, 9.7 mmol) was added to a mixture of 4-(2,4-difluorophenyl)-4-nitro-benzophenone (A) (1 g, 2.9 mmol) and trifluoroacetic acid (9 ml) at 20 ∘ C under stirring and under nitrogen for 24 hours and then poured into a mixture of methylene chloride (10 ml) and water (10 ml). The organic phase was washed with an 8% aqueous solution of sodium bicarbonate. After drying with sodium sulfate and evaporation of the solvent under reduced pressure, a crude (1.03 g) containing a mixture of ester and ketone starting material in the ratio 98 : 2 from 19 F NMR analysis was obtained. The amount of ester (B) (0.946 g, 91.9% yield) in the crude was determined by high-performance liquid chromatography (HPLC) analysis. An analytical sample (0.89 g) of the crude was crystallized from ethyl acetate giving pure product (0.70 g).

Dakin Oxidation (Reaction) Dakin reaction is a redox reaction used to convert an ortho- or para-hydroxylated phenyl aldehyde or a ketone to a benzenediol with alkaline hydrogen peroxide. This reaction, which is named after British chemist Henry Drysdale Dakin, is closely related to Baeyer–Villiger oxidation [1–17]. O

R

OH

O

H2O2 + NaOH, heat OH

O

OH

H

OH O

H2O2 + NaOH, heat OH

R

OH

H

OH

OH

3

4

1 Rearrangement Reactions

Mechanism O

O O O

H

H O

Step 1

O O H Step 2

H

Step 3

O

H OH

OH

O O H OH

OH

OH

OH Step 4 H O O H O H

OH

O

OH

H O

O H

O

+

Step 5 OH

OH

Step 1: Nucleophilic attack by a hydroperoxide anion to the electron-deficient carbonyl carbon atom forms a tetrahedral intermediate. Step 2: Aryl esmigration, elimination of hydroxide, and formation of an aryl ester. Step 3: Nucleophilic addition of hydroxide to the ester carbonyl carbon atom forms a second tetrahedral intermediate. Step 4: The unstable tetrahedral intermediate collapses to eliminate a phenoxide and forms a carboxylic acid. Step 5: Proton transfers from carboxylic acid to phenoxide. Application Catecholamine, a neurotransmitter, and (±)-fumimycin, a natural product [14], were synthesized by Dakin oxidation. Experimental Procedure (from patent EP0591799B) Preparation of Catechol (o-Dihydroxybenzene) O

H2O2

OH

NaOH, CH3CN

OH

H OH A

B

6.1 g (0.05 mol) of salicylaldehyde (A) and 0.01 g (0.25 mol) of NaOH in 50 ml of acetonitrile were introduced and mixed with 17.2 g of a 11.8% strength (0.06 mol) of hydrogen peroxide aqueous solution and stirred at 50 ∘ C for 48 hours. Any remaining peroxide was removed with a dilute sodium sulfite solution. The

Bamberger Rearrangement

reaction mixture was then mixed with essigester, the organic phase separated, and aqueous phase was washed several times with essigester. Then the combined organic phases were dried and freed of solvent in vacuo to obtain 5.4 g, which was 1 H NMR spectroscopy identified by a comparative sample as catechol (B). (Purity was determined by gas chromatography: 98%; yield 96% of theoretical.)

Bamberger Rearrangement The Bamberger rearrangement is an organic reaction used to convert N-phenylhydroxylamine to 4-aminophenol in the presence of strong aqueous acid [1, 2]. The reaction is named after German chemist Eugen Bamberger. Several new catalysts have been developed for the preparation of 4-aminophenol from directly nitrobenzene [3–19]. H N OH

NH2

H2SO4 H2O

HO

Mechanism H N H .. N OH

H H N O H

H

–H2O H Nitrenium ion

Step 2

Step 1

.. H2O

H N H

H .. NH

Step 4 H O H H

H HO

Step 5

.. H2O

H N

Step 3 H

H

.. O

H

NH2 HO

Step 1: Mono-protonation of N-phenylhydroxylamine. Step 2: Elimination of water and formation of carbocation via a nitrenium ion. Step 3: Nucleophilic attack by water at the carbocation. Step 4: Protonation and deprotonation. Step 5: Deprotonation and rearomatization.

5

6

1 Rearrangement Reactions

Experimental Procedure (from patent CN102001954B) Preparation of p-Aminophenol from N-Phenylhydroxylamine H N OH Carbonic acid

NH2 HO

A

B

In a 100 ml reactor, 0.5 mmol N-phenylhydroxylamine (A) was added; in a 50 ml of water, the closed reactor with CO2 substituted three times and then charged with CO2 ; the reaction was heated at 100 ∘ C; in CO2 pressure 8 MPa conditions, the reaction was stirred for one hour. The reaction mixture was extracted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel to afford a pure product (B).

Beckmann Rearrangement The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann, is a conversion of an oxime to an N-substituted amide in the presence of acid catalyst [1]. The acid catalysts are used including HCl, H2 SO4 , PCl5 , SOCl2 , P2 O5 , tosyl chloride, SO3 , BF3 , etc. These catalysts require the excess amounts and produce a large amount of by-products. Most recently, this reaction has been utilized by using a catalytic amount of new types of catalysts such as RuCl3 , BiCl3 , etc. [2–51]. R1 N R2

O

H2SO4

OH

R1

or PCl5

N H

R2

Anti or trans w.r.t. R2 HO

N

O

O NH

H2SO4

NH2OH

Mechanism .. OH

R1

H R1

N R2

Step 1

N

OH2

Step 2

R2

.. H2O

R1

OH2 R2 T.S.

R 1 C N R2 R.D. Step Step 3

O R C N R2 H

Step 5

H O R1 C N R2

Step 4

H O H R1 C N R2

R1 C N R2

Beckmann Rearrangement

Step 1: Protonation of hydroxyl group and formation of a better leaving group Step 2: Migration of R2 group trans or anti to the leaving group and loss of water group leading to formation of carbocation. This trans (1,2) shift predicts the regiochemistry for this reaction. Step 3: Water molecule attacks as a nucleophile with a lone pair of electrons to the carbocation. Step 4: Deprotonation. Step 5: Tautomerization affords an N-substituted amide, the final product. Application The Beckmann rearrangement reaction is used for the synthesis of paracetamol (acetaminophen), benazepril, ceforanide, olanzapine, elantrine, prazepine, enprazepine, etazepine, and other medicines. OH

OH Beckmann rearrangement

HN N OH

O Paracetamol (acetaminophen)

Experimental Procedure (general) Synthesis of Acetanilide N OH

H N

RuCl3 Acetonitrile, reflux

O

A mixture of acetophenone oxime (135 mg, 1 mmol) and RuCl3 (100 mg) or any other catalyst in acetonitrile (10 ml) was refluxed until no starting material was left (thin-layer chromatography [TLC] monitored). The solvent was removed by rotary evaporator, and the residue was purified over silica gel chromatography using 30% ethyl acetate in hexane to yield an acetanilide (m.p. 114 ∘ C). Preparation of Caprolactam (from patent US 3437655A) N

OH

O HCl

N

H

CH3CN, 75 °C A

B

In a 1 l reaction vessel equipped with a stirrer, a reflux cooler, and a gas inlet tube, 113 g of cyclohexanone oxime (A) (1 mol) was mixed with 200 ml of acetonitrile,

7

8

1 Rearrangement Reactions

after which 40 g of gaseous hydrogen chloride (1.1 mol) was introduced at room temperature. Subsequently the temperature was raised and maintained at 75 ∘ C for two hours, after which the rearrangement was completed. After the acetonitrile had been removed by distillation, the reaction product was dissolved in water and the solution neutralized with sodium bicarbonate. The resulting solution, which was saturated with common salt, was extracted with benzene. After removal of the benzene, 81 g of product caprolactam (B) was obtained, 71% yield.

Benzilic Acid Rearrangement The benzilic acid rearrangement reaction is an organic reaction used to convert 1,2-diketones to 2-hydroxycarboxylic acids using strong base (KOH or NaOH) and then acid work-up [1]. Benzil reacts with base to give benzilic acid that bears the name of the reaction. The reaction works well with aromatic 1,2-diketones. Aliphatic diketones with adjacent enolizable protons undergo aldol-type condensation. The aryl groups with electron-withdrawing groups work the best [2–17].

HCl

HO

KOH, H2O

O

OK

HO

O

O

EtOH, heat

O

OH

Benzilic acid Benzil

2-hydroxylcarboxylic acid

1,2-diketone

O O

KOH, H2O

O O

O

OH OK

O

EtOH, heat

O

Furil

O

OH OH

O O

Ferulic acid

Cyclic diketones lead to form the ring contraction products. O

O

HCl

KOH, H2O

OH OH

EtOH, heat HCl

O

Baker–Venkataraman Rearrangement

Mechanism

Step 1

O

O O O

Step 2

HO

HO O

O OH

Step 3

Step 4 OH

OH O

HO

O

O

Step 1: Nucleophilic attack by hydroxide at the electron-deficient carbonyl carbon atom. Step 2: Migration of phenyl group. Step 3: Proton transfer. Step 4: Acidic work-up gives the desired product. Application The natural product preuisolactone A [16] has been synthesized using this reaction. Experimental Procedure (from patent US20100249451B) Synthesis of Benzilic Acid from Benzil HO Triton B

O

OH O

O

A mixture of benzil (0.1 mol) and Triton B (benzyltrimethylammonium hydroxide) (0.2 mol) was heated at 40 ∘ C for two hours with stirring. The mixture was diluted with water and acidified with 10% hydrochloric acid up to pH 3. The solid was filtered and washed with water to obtain benzilic acid in 92% yield.

Baker–Venkataraman Rearrangement The Baker–Venkataraman rearrangement is a base-catalyzed acyl transfer reaction of aromatic ortho-acyloxyketones to aromatic β-diketones (1,3-diketones) [1–3]. The reaction is named after chemists Wilson Baker and Krishnaswami

9

10

1 Rearrangement Reactions

Venkataraman. This reaction has a wide range of applications in organic and medicinal chemistry [4–23]. O O

1. Base

Ph

OH

2. Acid work-up

Ph

O

O

O

Mechanism O O

O

O

Ph

O

Step 1

Ph

O

Step 2

O Ph

H O

OH

O Step 3

H OH

Step 4 Ph

O

H O

O

Ph

H+/H2O

O

O

O

Step 1: The hydroxide abstracts an 𝛼-hydrogen atom to form an enolate. Step 2: The nucleophilic attacks by the enolate to the ester carbonyl to form a cyclic alkoxide. Step 3: Ring opening and transfer of the acyl group. Step 4: Protonation from acidic work-up gives the desired product. Application Total syntheses of natural products including stigmatellin A [9, 10], zapotin [14], houttuynoid B [19], glycosylflavone aciculatin [21], and dirchromone-1 [23] have been accomplished utilizing this reaction. Experimental Procedure (from patent CN105985306B) Synthesis of 2,4-Dimethoxyphenyl-3-(2-hydroxy-4,6-dimethoxyphenyl)-2propyl-1,3-dicarbonyl-benzoate OMe O O

MeO

OMe OBz

OMe O A

NaH

MeO

OMe

OH OBz

THF OMe O

O B

OMe

Claisen Rearrangement

NaH (53 mg, 2.20 mmol) and 400 mg (A) were placed into 20 ml of dry tetrahydrofuran (THF), and the reaction mixture was stirred at 75 ∘ C until starting material disappeared. The reaction mixture was cooled to room temperature, immersed in 30 ml ice water, extracted three times with ethyl acetate, and washed with brine three times. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel column chromatography (PE/EA 6 : 1) to give 330 mg of the product B as a white solid (yield 77%).

Claisen Rearrangement The Claisen rearrangement is a [3,3]-sigmatropic rearrangement of an allyl vinyl ether to form a γ,δ-unsaturated carbonyl compound under heating or acidic conditions. The reaction is a concerted process where bonds are forming and breaking at the same time [1–31]. O

O

Heat R

R

R1

R1

CO2Me OH

CO2Me O

NMP 205 °C, 6 h

Cl O

Cl

OH

O Heat

When 2,6-positions are blocked, rearomatization cannot take place; there are no o-H atoms. In this case the allyl group will first migrate to the o-position, and then second migration will take place to the p-position via tandem Claisen and Cope rearrangement. O

O R1

R2 Step 1 R1

OH

O

R2 Step 2

R2 Step 3 R1

R1

R2

H

Mechanism This rearrangement is an exothermic, suprafacial, concerted, and pericylic reaction.

11

12

1 Rearrangement Reactions

R2

R1

R1

O

H

R3

R1

R2

R2

O

R3

R3

O

Favored chair T.S.

H

R3

R2

R1 O

Disfavored

R2 R1 O R3

When large groups are in equatorial positions, the 1,3-interaction is minimized. When large groups are in axial positions, the 1,3-diaxial unfavorable interaction is maximized. The aromatic Claisen rearrangement undergoes [3,3]-sigmatropic rearrangement accompanied by a rearomatization.

O

OH

O Step 2

Step 1 H

Step 1: [3,3]-Sigmatropic rearrangement. Step 2: Rearomatization gives the desired product.

Application Total syntheses of termicalcicolanone A [6], (+)-flavisiamine F [12], schiglautone A [27], hemigossypol, gossypol [28], hybridaphniphylline B [29], (±)-corymine [25], sanggenons C [21], (+)-antroquinonol, (+)-antroquinonol D [20],(−)-teucvidin [13], (+)-jasplakinolide [10], and many more have been achieved using this reaction.

Eschenmoser–Claisen Rearrangement

Experimental Procedure (from patent WO2016004632A1) OMe OMe OMe

OH OH

O

+

Microwave C

B

A

To a 5 ml microwave vial fitted with a magnetic stirrer was charged with calcium bistriflimide (16 mg) and O-allylguaiacol (A) (438 mg, 2.67 mmol). The vial was then sealed, and the resultant homogeneous mixture was stirred for two minutes at the temperature of 200 ∘ C under an autogenous pressure and a microwave irradiation generated by the Biotage microwave instrument. After cooling to room temperature, the resulting reaction mixture was analyzed by 1 H NMR to determine the conversion ratio (100%) and isomeric composition [76% of ortho-eugenol (B) and 24% of para-eugenol (C)].

®

Eschenmoser–Claisen Rearrangement When an allylic alcohol is heated in the presence of N,N-dimethylacetamide dimethyl acetal to produce a γ,δ-unsaturated amide, the reaction is known as the Eschenmoser–Claisen rearrangement [32, 33]. NMe2 OH R1

R2

+ H3C

R2

O

OMe OMe NMe2

R1

Xylene R2

R1

150 °C

O NMe2

Mechanism MeO H MeO H3C

OMe OMe : NMe2

MeO

Step 1

NMe2 .. OH

MeO NMe2 CH3 H O

Step 3

Step 2

H3C

R1

R2

.. MeO NMe2 CH3 O R1

R2 Step 4

R2

R1

NMe2 R2 R1

O

Step 6 NMe2

Step 5

O R1

R2

Ketene aminal

H Me O NMe2 C H O H2 R1 R2

OMe

13

14

1 Rearrangement Reactions

Step 1: The N,N-dimethylacetamide dimethyl acetal releases one methoxide to form an iminium cation. Step 2: The alcohol attacks at the iminium. Step 3: Methoxide abstracts a proton. Step 4: Protonation. Step 5: Methoxide abstracts a proton from the methyl, and the intermediate releases a methanol to form a 1,5-diene intermediate (ketene aminal). Step 6: The ketene aminal intermediate undergoes a [3,3]-sigmatropic rearrangement via a chair-like transition state to produce the desired product.

Ireland–Claisen Rearrangement The conversion of an allylic ester to a γ,δ-unsaturated carboxylic acid via silyl ketene acetal using lithium diisopropylamide (LDA), TMSCl, and NaOH/H2 O is known as the Ireland–Claisen rearrangement [34–36]. The stereochemical formation of E/Z silyl ketene acetal is possible using hexamethylphosphoramide (HMPA) [37]. O

O Li LDA

O

O Si TMSCl

O

OH NaOH/H2O

O

O

THF, –78 °C [3,3] Silyl ketene acetal

Allyl ester

Mechanism Si Cl N

O O

H R

Li LDA Step 1

Step 3

O

O

O H H

O Si

O Si

O Li

O

OH

O

O R Step 2

R

R

Step4

R Step 5

H OH O R

Step 1: LDA abstracts a proton. Step 2: Nucleophilic substitution reaction. Step 3: [3,3]-Sigmatropic rearrangement. Step 4: Desilylation. Step 5: Proton transfer.

Overman Rearrangement

Johnson–Claisen Rearrangement When an allyl alcohol is heated with an excess of triethyl orthoacetate under mild acidic conditions to yield a γ,δ-unsaturated ester, the reaction is called the Johnson–Claisen rearrangement [38]. R2 HO

R1

MeO

R2

OMe OMe

+

Acid MeO

O

R1

[3,3] Trimethyl orthoacetate

Allyl alcohol

OMe

Heat O

R1 R2

Ketene acetal

Mechanism H3C

OMe OMe OMe ..

Step 1

.. OMe Step 2 H3C OMe O H Me

O Me

R2

MeO Step 3 MeO

OMe

R1

O H

R2

H

.. HO OMe

R2

Step 6

O

R1

[3,3]

R2

MeO

O

Step 4

R1

R1

O Me .. H

R2

MeO

R1

O H O Me H

Step 5

Ketene acetal

Step 1: Protonation one of methoxy groups. Step 2: Elimination of methanol forms an oxonium cation. Step 3: Alcohol attacks at the oxonium intermediate. Step 4: Proton transfer. Step 5: Methanol abstracts a proton and releases another methanol to form a ketene acetal intermediate. Step 6: A [3,3]-sigmatropic rearrangement undergoes to produce γ,δ-unsaturated ester.

Overman Rearrangement The stereoselective conversion of an allylic alcohol to an allylic trichloroacetamide through an allylic trichloroacetimidate intermediate is known as the Overman rearrangement [39–41]. This rearrangement is similar to the Claisen suprafacial, concerted, nonsynchronous, [3,3]-sigmatropic rearrangement. Larry Overman discovered this reaction in 1974. CCl3

CCl3 Cl3C C N

OH R1 Allylic alcohol

R2

NaH, THF

O R1

NH R2

Allylic trichloroacetimidate

O

Heat or Hg(II) salt or PdCl2

R1

NH R2

Allylic trichloroacetamide

15

16

1 Rearrangement Reactions

Mechanism

H O R1

H

Cl3C C N Step 1

R2

– H2

H O

Cl3C

NaH Step 2

O R1

R2

N

O R1

R2

Step 3

Allylic alcohol

Cl3C R2

R1

NH

O R1

R2 Allylic trichloroacetimidate Step 4

CCl3 O R1

H N

NH R2

Cl3C

R2 O

R1

Allylic trichloroacetamide

Step 1: Deprotonation with a strong base. Step 2: The deprotonated alcohol attacks as a nucleophile to trichloroacetonitrile to form an anion intermediate. Step 3: The anion takes a proton from the starting alcohol to give an allylic trichloroacetimidate intermediate. Since anion takes a proton from the starting alcohol, only a catalytic amount of a strong base is required. Step 4: This intermediate undergoes a concerted [3,3]-sigmatropic rearrangement via a six-membered chair-like transition state to give an allylic trichloroacetamide.

Cope Rearrangement The Cope rearrangement is a [3,3]-sigmatropic rearrangement of 1,5-dienes under thermal conditions to produce regioisomeric 1,5-dienes [1]. The reaction mainly proceeds through an intramolecular pathway. R

R

The oxy-Cope rearrangement has a hydroxy group on C-3 (sp3 -hybridized carbon), forming enal or enone after keto–enol tautomerization. HO

HO

O

Several improvements on this reaction using different catalysts have been successfully accomplished [2–32].

Curtius Rearrangement

Mechanism

Chair-like T.S.

Boat-like T.S.

Both chair-like T.S. and boat-like T.S. can follow the reaction pathway. But chair-like T.S. is energetically more favorable than boat-like T.S. Application Total syntheses of amphilectane, serrulatane diterpenoids [26], alkaloids, (+)-sedridine, (+)-allosedridine [20], (−)-acutumine [12, 13], (−)-okilactomycin [15], (±)-trichodermamide B [9], and (±)-actinophyllic acid [10] have been accomplished using this reaction. Experimental Procedure (from patent US 4421934A) HgCl2 HO

THF, H2O

O

A

B

A mixture of 3,5-dimethylhexa-1,5-dien-3-ol (A) (0.126 g) and mercuric chloride (0.270 g) in a mixture of THF and water (1/1 by volume) (5 ml) was kept at a temperature on the order of 20 ∘ C. After a reaction time of four hours, the reaction mixture was filtered to remove the metallic mercury that was formed. The reaction mixture was extracted with diethyl ether (3 × 25 ml). After drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure (20 mm Hg), 6-methylhept-6-en-2-one (B) (0.040 g) was obtained.

Curtius Rearrangement The Curtius rearrangement is the thermal conversion of an acyl azide to an isocyanate [1–3]. The isocyanate is the intermediate of several products such as urea, amine, carbamate-protected amine, amino acid, and other products. Several improvements on this reaction using different reaction conditions and mechanistic studies have been successfully accomplished [4–41]. O R1

Heat N3

–N2

R1 N C O Isocyanate

Acyl azide

17

18

1 Rearrangement Reactions

R1

R2OH

H N

O

R2

O Carbamate

R1

N C O

H2O

R1 NH2 Amine

R3NH2

R1

H N

H N

R3

O Urea derivative O OH

CBz-Cl,NaN3, t-Bu-ONa

NHCBz I

DME, 75 °C

I

O OH

1. PhOCOCl, NaN3, DME, t-BuONa, 75 °C

H N

H N O

2. PhNH2, 75 °C

Mechanism

R

O

O

O N

R

N

N

R N

R N C O

+ N2

N N N

N

N

It involves a concerted degradation of an acyl azide into an isocyanate. Application The Curtius rearrangement has been used for the synthesis of several medicines including oseltamivir, tranylcypromine, candesartan, gabapentin, benzydamine, bromadol, igmesine, tecadenoson, terguride, and others. STol O

CO2Et

STol

Acetic acid

CO2Et

O

N3 O

NO2

Ac2O, r.t.

O

CO2Et

2 Steps O

N H

NO2

O

N H

NH2

(−)-oseltamivir

Demjanov Rearrangement

SB-203207, an altemicidin-type alkaloid that potently inhibits isoleucyl-tRNA synthetase activity [40], and gastroprotective microbial agent AI-77-B [15] were synthesized using this reaction. Total syntheses of several natural products such as (+)-3-demethoxyerythratidinone, (+)-erysotramidine [39], aspeverin, a prenylated indole alkaloid [32], Lycopodium alkaloid (−)-lyconadin C [30], syringolin A [27], (±)-epiquinamide, (±)-epiepiquinamide [21], ningalin D [18], (+)-sinefungin [10], and many more have been accomplished utilizing this reaction. Experimental Procedure (from patent EP2787002A1)

OH O

DPPA NH2 Et3N

HO

HO A

B

Oleanolic acid

Oleanolic acid (A) (2.5 g, 5.5 mmol) was dissolved in chloroform (25 ml), to which diphenylphosphoryl azide (DPPA) (1.8 g, 6.6 mmol) and triethylamine (0.66 g, 6.6 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature, and then 3 M sulfuric acid (15 ml) was added thereto. The reaction mixture was heated at 100 ∘ C, and the stirring continued for six hours. After the reaction was completed, the reaction mixture was cooled to room temperature, adjusted the pH 13 with NaOH (aq. 10%), and then extracted with ethyl acetate (40 ml × 2). The organic layer was combined, dried, and concentrated to give product (B) as a yellow oil.

Demjanov Rearrangement The Demjanov rearrangement is an organic reaction of primary amine with nitrous acid to form rearranged alcohols. The reaction proceeds via diazotization followed by ring expansion or ring contraction. The reaction is named after the Russian chemist Nikolay Yakovlevich Demjanov who discovered it in 1903 [1, 2]. Several improvements and mechanistic studies have been developed on this reaction [3–14]. OH HNO2 NH2

+ Ring expansion product

OH Normal substitution product

19

20

1 Rearrangement Reactions

NH2

OH

OH HNO2 + Ring expansion product OH

HNO2

NH2

Normal substitution product

OH

+ Ring contraction product

Normal substitution product

Mechanism Generation of Nitrosonium Ion H + NO2

HNO2 H

NO .. NH2

H2O

H O N O H

H O N O

Step 1

N O

– HNO2

N H H

N H

Step 2

+ NO

N

.. O

H N H

Step 3

Step 4

Step 8 Step 7 .. O H

NO2

N

Step 6

N

.. N N

OH2

N H

H

OH

N

– N2

.. O H H

H O

– HNO2

H NO2

Normal Substitution Product Step 1: The nitrosonium ion reacts with the primary amine. Step 2: Abstraction of proton from the amine. Step 3: Protonation.

H .. OH

Step 5

Step 9

N

O H

NO2

NO2

O H H

N

OH

N

Demjanov Rearrangement

Step 4: Deprotonation. Step 5: Protonation. Step 6: Elimination of water and formation of diazonium ion. Step 7: Rearrangement and formation of carbocation. Step 8: Nucleophilic attacks by water. Step 9: Deprotonation and formation of the product.

Application Carbocyclic core of cortistatin, the potent antiangiogenic natural product, was synthesized starting from (+)-estrone utilizing this reaction [14]. O

O

H2N

NaNO2, AcOH, H2O-THF

H

HO H

O

Steps

O

H

O

H

Demjanov rearrangement

O

O

O

H

H Core of cortistatin

Experimental Procedure (from Reference [14], copyright 2008, American Chemical Society) O H2N

NaNO2, AcOH, H2O-THF

H H O A

HO

O Demjanov rearrangement

H

O O

O

H B

A 100 ml round bottom flask, equipped with a PTFE-coated stir bar, was charged with compound A (2.23 g, 6.24 mmol, 1 equiv.), THF (22.3 ml), and water (11.25 ml). The resulting mixture was cooled to 0 ∘ C, and first glacial acetic acid (11.25 ml) was added followed by a solution of NaNO2 (2.14 g, 5 equiv.) in water (18 ml). The reaction mixture was then stirred for two hours at 0 ∘ C, and the progress of the reaction was monitored by TLC. When all the starting material was consumed, the reaction mixture was poured into vigorously stirred mixture of aqueous 2 N NaOH (200 ml) and Et2 O (200 ml). The aqueous phase was extracted with Et2 O (2 × 100 ml), and the combined organic layer was washed with saturated aqueous sodium chloride (2 × 100 ml) and evaporated. The crude product (2.21 g) was purified by flash column chromatography (hexane/EtOAc = 4 : 1 → 2 : 1 with 1 v/v% NEt3 ). The product B (1.35 g, 61%) was obtained as a pale yellow viscous oil, which solidified upon standing in the refrigerator m.p. 120–122 ∘ C. [α]20 = +28.80 (c. 0.01, CHCl3 ), Rf = 0.38 D (hexane/EtOAc = 3 : 1).

21

22

1 Rearrangement Reactions

Tiffeneau–Demjanov Rearrangement The carbocation rearrangement of β-amino alcohol (1-aminomethylcycloalkanol) with nitrous acid to form a ring-enlarged cycloketone is known as the Tiffeneau–Demjanov rearrangement [1, 2]. The ring sizes from cyclopropane to cyclooctane can undergo this reaction with ring expansion, although ideal ring size 5–7 provides good yield [3–10]. O

HO

NH2

HO

HNO2

O

NH2

NaNO2

Mechanism Generation of N2 O3 .. H 2O

H .. HO N O

O

HO

N

.. NH2

H O N O

– H2O

H2O N O

O

N

O

N

–H

O

N

O

O

HO Step 1 – NO2

N O N HH

HO Step 2

O N N H

HO

H HO

Step 5 – H2O

.. H2O O

O H Step 7

.. OH2 N N

Step 4

Step 3

NO2

.. OH N N

HO Step 6 – N2

Step 1: Nucleophilic addition of amine to N2 O3 . Step 2: Deprotonation. Step 3: Isomerization. Step 4: Protonation of hydroxyl group. Step 5: Elimination of water and formation of diazonium ion. Step 6: A rearrangement reaction with ring expansion. Step 7: Deprotonation and formation of cycloheptanone.

N N

Fries Rearrangement

Application Spectromycin analog such as a homospectinomycin, an antibiotic useful for the treatment of gonorrhea infections, has been synthesized strategically utilizing this reaction [7]. Experimental Procedure (from Reference [10], copyright, The Royal Society of Chemistry)

H2N

NaNO2

HO

AcOH

O

A solution of the amino alcohols in 10% (v/v) aqueous AcOH at 0 ∘ C was treated with a 1.25 M aqueous solution of NaNO2 . The reaction mixture was stirred for four hours at 0 ∘ C. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with 10% (w/v) solution of NaHCO3 , brine, and water and dried over anhydrous MgSO4 . The solvent was removed in vacuo, and the residue was immediately purified by flash column chromatography to afford the desired product.

Fries Rearrangement Mostly AlCl3 , BF3 , TiCl4 , or SnCl4 catalyzed rearrangement of phenolic esters to 2-hydroxy aryl ketone or 4-hydroxy aryl ketone is called the Fries rearrangement [1], named after the German chemist Karl Theophil Fries. The rearrangement can proceed with other acids such as HF, CF3 CO2 H, and MeSO3 H in an inert solvent or without any solvent. The acids are generally required in excess of the stoichiometric amounts, particularly with the Lewis acids (most common is AlCl3 ) since they form complexes both with the starting materials and the products. Several improvements including photo-Fries and anionic ortho-Fries rearrangement have been accomplished [2–36]. O O

OH

R

OH O 1. AlCl3, heat

R

2. H2O

O o-Acylphenol or 2-Acylphenol

R = Alkyl or aryl group

+ R

p-Acylphenol or 4-Acylphenol

23

24

1 Rearrangement Reactions

The Fries rearrangement is ortho and para selective, and the ratio depends on temperature, solvent, and other reaction conditions. Generally, at low temperature p-products and at high temperature o-products are predominately formed. Mechanism Both intermolecular and intramolecular mechanisms have been reported. Cl Cl Al Cl Cl

.. O O

Cl R

Cl Al O O

Step 1

Cl .. Cl Al O Cl

Cl R

Cl Al

Cl

O

Step 2

R C O

+ R C O

O Step 3

Cl3Al

AlCl3

OH O O

Step 4

H

Step 5 R

R

R C O

O

R

H2O

O

Cl Cl Al O Cl

Cl Al ..Cl Cl O

O AlCl3 Step 4

H O R

C O

OH Step 5

Step 3

H2O

R

O

R O

R

Step 1: AlCl3 forms a complex with phenolic ester. AlCl3 coordinates with carbonyl oxygen atom of carbonyl acyl group as this oxygen atom is more electron rich than phenolic oxygen atom. It is a stable and preferred Lewis base. Step 2: Reversible formation of an acylium carbocation. Step 3: Electrophilic attacks by the acylium carbocation at ortho and para positions of the aromatic ring to give a resonance-stabilized σ-complex. Step 4: Deprotonation and aromatization. Step 5: Hydrolysis liberates an acylphenol (or called hydroxyl aryl ketone). Application Fries rearrangement is applied for the synthesis of antiviral drug ladanein. Total syntheses of natural products such as (+)-balanol [9], rhein, diacerhein [20], brazanquinones [22], antibiotic kendomycin [25], (+)-(R)-concentricolide [26], and muricadienin [32] have been accomplished strategically applying this reaction.

Favorskii Rearrangement

Experimental Procedure (from patent US9440940B2) O AlCl3

O Cl

Cl

O

O

100 °C

O

O OCH3

HO

OCH3

O

B

A

0.01 mol of 7-(2′ -chloroacetyloxy)-8-methoxycoumarin (compound A) was directly heated in the presence of 0.015 mol aluminum chloride at 100 ∘ C for three hours. After cooling and hydrolysis with diluted hydrochloric acid and ethyl acetate extraction, 6-(2′ -chloroacetyl)-7-hydroxy-8-methoxycoumarin (compound B) was obtained after evaporation of the organic phase. The yield was 80%.

Favorskii Rearrangement The Favorskii rearrangement is an organic reaction used to convert an α-haloketone to a rearranged acid or ester using a strong base (hydroxide or alkoxide). In case of cyclic α-haloketone, this reaction gives a ring contracted product [1–21]. The reaction is named after its discoverer the Russian chemist Alexei Yevgrafovich Favorskii [1, 2]. O

NaOH Ph

Cl

Ph

OH

O O

NaOEt Ph

Ph

Cl

OEt

O O

O Cl

OH

NaOH

Mechanism O HO

H

Cl Step 1

O

O

O

Cl

Cl

OH

Step 2

or – H2O Step 3

O

OH

H O

O H

Step 5

O

OH Step 4

OH

25

26

1 Rearrangement Reactions

Step 1: Abstraction of α-H on the side of the ketone away from the chlorine atom forms an enolate. Step 2: SN 2-type reaction and formation of cyclopropanone ring intermediate. Step 3: Hydroxide as a nucleophile attacks at the ketone. Step 4: Ring opening gives an anion. Step 5: Proton transfers from water or solvent gives the final product. Application Total syntheses of naturally occurring products (±)-sterpurene [10], (±)-kelsoene [8], tricycloclavulone [11], and (±)-communiol E [17] have been successfully achieved utilizing this reaction. Experimental Procedure (from patent EP3248959A2) NaOMe O

MeOH MeO

Br A

O B

To a mixture of 2.60 g of α-bromotetramethylcyclohexanone (compound A) (80.4% GC) and 10 g of methanol in a nitrogen atmosphere was added 2.60 g of a 28% solution of sodium methoxide in methanol at room temperature with stirring. After stirring at room temperature for two hours, the reaction mixture was heated with stirring under reflux for two hours and cooled to room temperature. 24 g of diluted hydrochloric acid was added, and an organic layer and an aqueous layer were separated. The separated organic layer was subjected to usual after treatment, i.e. washing, drying, and concentration, to obtain 1.81 g of the envisaged methyl-2,3,4,4-tetramethylcyclopentane carboxylate as a yellowish oil (compound B) (33.2% GC, yield: 36%).

Fischer–Hepp Rearrangement The Fischer–Hepp rearrangement is an acid-catalyzed conversion of N-alkyl-N-nitrosoanilines to N-alkyl-para-nitrosoanilines [1]. This reaction was discovered by the German chemists Otto Philipp Fischer and Eduard Hepp. Several new reaction conditions on this reaction have been developed [2–10]. R

N NO

R

R NH

NH

HCl

NO + NO Major

Minor

Fischer–Hepp Rearrangement

N NO

NH

NH HCl

NO + NO Minor

Major

Mechanism H R N NO

R .. NO N

.. H R N

R N H Step 2

H Cl

Step 3 + NO Cl

H

Step 1 NO NO

R

R NH

H N

Step 4 H

NO

NO

Cl

Step 1: Protonation of amino nitrogen atom by HCl. Step 2: Formation of nitrosonium ion. Step 3: Aromatic electrophilic substitution at para position or intramolecular migration of + NO. Step 4: Abstraction of proton by chloride ion and rearomatization gives the final product.

Experimental Procedure (general) NO

NH

NH

N

NO HCl

+

AcOH NO A

B Major

C Minor

A solution of A (1 g) in acetic acid 20 ml and 35% HCl 4 ml was stirred at room temperature for three hours. The AcOH and HCl solution were removed in vacuo.

27

28

1 Rearrangement Reactions

The residue was diluted with ice-cold water and neutralized with ammonia followed by extraction with ethyl acetate. The organic layer was washed with water, saturated NaHCO3 solution, and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified over silica gel column chromatography (hexane-ethyl acetate) to afford compound B (major) and compound C (minor).

Hofmann Rearrangement (Hofmann degradation of amide) The Hofmann rearrangement is a conversion reaction of primary amide to primary amine with one carbon atom less (via the intermediate isocyanate formation) using alkali (NaOH) and halogen (chlorine or bromine) or hypohalite (NaOCl or NaOBr). This reaction is also referred to as the Hofmann degradation of amide [1–26]. Br2

O

NH2 NaOH

R1

O

H2O

R1 N C O

R1 NH2

NH2

NH2 1. Br2, NaOH 2. H2O

Mechanism O R1

O

O H N H

Step 1 – H2O

R1

NH

R1

H N

Step 2

OH

O

H Step 3 N Br –H O

R1 – Br

O R1

N Br

2

Bromoamide

Br Br OH

Step 4 – Br

H H O

Step 6 R1

O N C O H H

Carbamic acid

O R1 N C O H

R1 N C O OH

Step 5 R1 N C O

Isocyanate

OH

H2O Step 7

R1 NH2

R1 N C O

+ CO2 (g)

Step 1: Hydroxide abstracts an acidic N–H proton. Step 2: The anion reacts with bromine to form an N-bromoamide. Step 3: Hydroxide abstracts another acidic H atom from N–H.

OH

Hofmann–Martius Rearrangement

Step 4: Elimination of bromide and migration of R1 group to nitrogen atom occur simultaneously to form an isocyanate. Step 5: Water or hydroxide reacts with isocyanate. Step 6: Proton transfer produces a carbamic acid. Step 6: Abstraction of proton with hydroxide. Step 7: Carbamic acid loses CO2 and after protonation gives the amine product. Application Total syntheses of (+)-cepharamine [8], capreomycin IB [16], (−)-epibatidine [12], (+)-phakellstatin, and (+)-dibromophakellstatin [14] have been accomplished using this reaction. Experimental Procedure (from patent CN105153023B) Br

Br NaOH, Br2 NH2

N

H2O

N

O

NH2

B

A

Aqueous sodium hydroxide was cooled to 0 ∘ C by the dropwise addition of elemental bromine, cooling to not lower than 10 ∘ C, and was added portion-wise to 4-bromo-pyridine carboxamide (compound A); the addition was complete stirring incubated at least one hour and then heated to 65–90 ∘ C (TLC monitored). The reaction mixture was cooled to room temperature, was centrifuged to obtain a crude product, and was crystallized from toluene to give a pure product, 2-amino-4-bromopyridine (compound B).

Hofmann–Martius Rearrangement This is a rearrangement reaction of N-alkylarylamine to the corresponding orthoand/or para-arylalkylated aniline under thermal conditions [1–13]. R N

H

NH2

NH2 HCl

R +

Heat R Me N

H

NH2

NH2 HCl

Me +

Heat Me

29

30

1 Rearrangement Reactions

When the catalyst is a metal halide (Lewis acid) used instead of a protic acid, the reaction is referred to as the Reilly–Hickinbottom rearrangement [3]. Me N

H

NH2

NH2

Me

ZnCl2

+

Heat Me

Mechanism R .. H N

Cl

H

R HCl

.. NH2

H H N

R Cl

Step 3

Step 2

Step 1

Step 4

NH2 R H

NH2 R

Cl

S N2

.. NH2

NH2

NH2

R

H

R

R Cl Cl

Step 1: Protonation of NH group from HCl. Step 2: Nucleophilic substitution reaction. Step 3: Aromatic electrophilic substitution reaction. Step 4: Deprotonation and rearomatization. Experimental Procedure (from patent DD295338A5) NH2

NH2

HN Catalyst

+

Heat A

C B

Minor

Major

In a reactor filled with Y zeolite in H+ form, N-isopropylaniline (compound A) was introduced to produce p-isopropylaniline (compound B). In the reactor, a pressure of 40 bar and a temperature of 375 ∘ C were maintained. To adjust and maintain said pressure, a gas mixture of 75% by volume of nitrogen and 25% by volume of hydrogen was used. The reactor also contains the aniline obtained during fractionation of the product mixture and also the o- and polyisopropylanilines based on the N-isopropylaniline in threefold amount.

Lossen Rearrangement

In the continuously operating reactor, a volume velocity of 1 dm3 mixture per dm3 of catalyst was set hourly. From the mixture leaving the reactor, the aniline was first distilled off; then the o- and p-isopropylanilines were separated from the polyisopropylanilines. The o- and p-isopropylaniline were separated by fractional distillation. The p-isopropylaniline was obtained in 99% purity and in relation to the fed N-isopropylaniline in a yield of 81%.

Lossen Rearrangement The Lossen rearrangement is the intramolecular conversion of hydroxamic acids or their O-acetyl, O-aroyl, and O-sulfonyl derivatives into isocyanates under thermal or in the presence of acid or base catalysts [1–3]. Isocyanate can be converted to the corresponding primary amine with water. Several reaction conditions and mechanistic studies have been investigated on this reaction [4–22]. O

H+

R1

O R1

N H

O

N H

R1 NH2

H2O

OH

R2

R1 N C O

R1 NH2

O

O R1

H2O

R1 N C O

N OH H

O S O

O

OH

R1 N C O

CH3

H2O

R1 NH2

Mechanism

R1

O

Step 1

O N H

O

R2 O

– H2O

R1

N

R2 Step 2

O O

R1 N C O

– R2CO2–

.. H O H

OH

Step 3 H O

CO2 +

R1 N C O

Step 4

O H

R1 NH

Step 5 – H2O

Step 6 R1 NH2

R1 N H

R1 N C O O H H

O H OH

31

32

1 Rearrangement Reactions

Step 1: Abstraction of the proton from the N atom. Step 2: Migration of R1 group to the N-atom and elimination of carboxylate. Step 3: Hydrolysis of isocyanate and nucleophilic attack by water. Step 4: Proton transfer. Step 5: Decarboxylation and liberation of carbon dioxide. Step 6: Proton transfer and formation of an amine product.

Application HIV maturation inhibitor BMS-955176 [17] was synthesized using this reaction. Total synthesis of the sesquiterpene illudinine [15] was successfully completed utilizing this reaction.

Experimental Procedure (from patent EP2615082B1)

HO

Dimethyl carbonate, TBD

H N

O

MeOH

O

H N

O

B

A

The Lossen rearrangement of N-hydroxyundec-10-enamide (A) (20 g, 100 mmol) with dimethyl carbonate (181 g, 2 mol), methanol (8 ml), and triazabicyclodecene (TBD) (2.79 g, 20 mmol) results in the formation of methyl-dec-9-enylcarbamate. After purification by column chromatography (hexane/ethyl acetate 9 : 1–7 : 3), 12.8 g of pure methyl-N-dec-9-enylcarbamate (B) was obtained as a colorless oil (yield: 60%).

Orton Rearrangement This is a rearrangement reaction of N-chloroanilides to the corresponding orthoand para-chloroanilides in the presence of acid such as HCl. This reaction can proceed in the presence of Lewis acid as well as by light. Both solvents and nature of substrates have major role for this rearrangement reaction. This reaction is useful for the preparation of para-halo anilides [1–17]. O O N

N

Cl

H

O N

HCl

H

+

Cl

Cl Major

Minor

Pinacol–Pinacolone Rearrangement

Mechanism O

O

.. N Cl

N H

O

O

Cl H + Cl

.. NH

Step 2

N H Step 3 + Cl2

HCl

Cl

Step 1 Cl

H Cl

Cl

Step 4 O NH

Cl Major product

O

.. NH

O

O

H Cl

Cl

N

NH

Cl

Cl

H

Cl Minor

Step 1: Protonation. Step 2: Nucleophilic substitution reaction. Step 3: Aromatic electrophilic substitution reaction. Step 4: Deprotonation ensures rearomatization and formation of the desired product.

Pinacol–Pinacolone Rearrangement The pinacol–pinacolone rearrangement is an acid-catalyzed conversion of a 1,2-diol to a carbonyl compound [1–15]. The name of this reaction comes as pinacol rearranges to pinacolone. OH OH H3C CH3 H3C CH3

H2SO4

H3C H3C H3C

O CH3

Pinacolone Pinacol

33

34

1 Rearrangement Reactions

Mechanism If both the –OH groups are not similar, then the one that gives a more stable carbocation participates in the reaction. Subsequently, an alkyl group from the adjacent carbon migrates to the carbocation center. H .. OH OH CH3 H3C CH3 H3C

Step 1

OH2 OH CH3 H3C CH3 CH3

Step 2

H3C

– H2O

H3C

H3C H3C H3C

OH Step 3 CH3 CH3

Step 4

O CH3

H3C H3C

H3C H3C H3C

O

.. O H CH3

H

CH3 CH3

Step 1: Protonation of one hydroxyl group. Step 2: Elimination of water and formation of a carbocation. Step 3: Migration of one methyl group. Step 4: The loss of proton and formation of final product. Application Syntheses of several natural products including (±)-furoscrobiculin B [7], protomycinolide IV [6], 13-keto taxoid compounds [11], and sesquiterpene onitin [15] have been accomplished utilizing this reaction. Experimental Procedure (general) O HO Ph Ph A

OH Ph

Acetic acid

Ph

Reflux

Ph Ph

Ph Ph B

To benzopinacol (1.83 g, 5 mmol) (compound A) in acetic acid (20 ml) was added one crystal of iodine. The reaction mixture was stirred at 118 ∘ C until starting material disappeared (TLC monitored) and then cooled to room temperature. The white benzopinacolone (compound B) was precipitated, filtered, washed with cold ethanol, and dried.

Rupe Rearrangement/Meyer–Schuster Rearrangement The acid-catalyzed rearrangement of tertiary alcohols containing a terminal α-acetylenic group (e.g. tertiary propargylic alcohols) via an enyne intermediate

Rupe Rearrangement/Meyer–Schuster Rearrangement

to give the corresponding α,β-unsaturated ketones is called the Rupe rearrangement [1–3]. The acid-catalyzed rearrangement of secondary and tertiary propargylic alcohols to the corresponding α,β-unsaturated aldehydes or ketones is referred to as the Meyer–Schuster rearrangement [4]. Several protic acids, Lewis acids, and acidic cation exchange resins have been applied on this reaction [5–34].

Rupe Rearrangement O

OH

1. Acid 2. H2O

Meyer–Schuster Rearrangement R1 OH

O

1. Acid (protic or Lewis)

R2

R3

2. H2O

R3

R2 R1

Mechanism

.. OH

.. H2O

OH2

H

Step 3

Step 2 Step 1

– H2O

H

H

–H

Step 4 Enyne

Step 8

O CH3

H H

Step 5 H O H

.. OH

O H

H

H

Step 7

H H

H

Step 6 H –H

Step 1: Protonation of hydroxyl group makes a better leaving group. Step 2: Elimination of water and formation of carbocation. Step 3: 1,2-Shift forms an enyne. Step 4: Protonation. Step 5: Nucleophilic attacks by water to the carbonium ion. Step 6: Deprotonation. Step 7: Tautomerization. Step 8: Proton transfer forms the desired product.

35

36

1 Rearrangement Reactions

Application A new steroidal drug was synthesized in large scale (pilot plant) using this reaction [22].

O OH H O

Experimental Procedure (from patent US4088681A) O OH

HCO2H 95 °C

A

B

16 g of the acetylene alcohol A was added dropwise at 95 ∘ C to 80 ml of 80% strength formic acid. The reaction mixture was kept for one hour at this temperature. The formic acid was then distilled off under reduced pressure, the residue was taken up in ether, and the ether solution was washed with 10% sodium bicarbonate solution, dried (MgSO4 ), and distilled. 6.4 g (corresponding to 40% of theory) of the corresponding β-damascone B (2,2,6-trimethyl-1-(1′ -oxo-3′ -methyl-but-2′ -en-1′ -yl)-cyclohexene) of boiling point 73–76 ∘ C/0.3 mm Hg was obtained.

Schmidt Rearrangement or Schmidt Reaction The Schmidt reaction or rearrangement is an acid-catalyzed reaction of hydrogen azide with a carbonyl compound such as an aldehyde, a ketone, or a carboxylic acid to give an amine, amide, or nitrile, respectively, after a rearrangement and the loss of a molecule of nitrogen gas [1–24]. This reaction is extended with tertiary alcohol or olefin to give an imine. The reaction is named after Carl Friedrich Schmidt [1]. O R

1. H2SO4, HN3 OH

O R1

2. H2O, heat

R NH2

O

1. H2SO4, HN3 R2

2. H2O, heat

R2

N H

R1

Schmidt Rearrangement or Schmidt Reaction

O R1

1. H2SO4, HN3 H

2. H2O heat

OH R

R

R

R1

H N

H

+

R1 CN

O

1. H2SO4, HN3

R N

R

R

R 1. H2SO4, HN3

R R

R

R

R

R

N R

Mechanism

.. O R1

H

O

R2

.. OH Step 2 R1

R2

R1

Step 1

H

N

N N

H N

H .. O H

H H O H

N N N

OH2 Step 3 R1 N N N

R2

+ H3O N N

Step 4

R2

R1 O R2

N H

R1

Step 7 R 2 N

R1

Step 6

R2 N

HO –H

R2

.. H2O

R1

R1 migration + N2 Step 5

N N N

Step 1: Protonation of oxygen atom of the carbonyl compound. Step 2: Nucleophilic attack by an azide to the electron-deficient carbonyl carbon atom. Step 3: Protonation. Step 4: Elimination of water. Step 5: R1 group migration and formation of nitrilium ion. Step 6: Nucleophilic attack by water and deprotonation. Step 7: Tautomerization gives the desired product.

Application Total syntheses of several natural products such as (+)-sparteine [5], stemona alkaloid (±)-stemonamine [10], lepadiformines A and C [13], (−)-FR901483 [15], (±)-stemonamine [19], and (+)-erysotramidine [20] have been accomplished strategically using this reaction.

37

38

1 Rearrangement Reactions

Experimental Procedure (from patent WO2009026444A1) O

O

MeO

NaN3

MeO

NH + S

TFA-H2O (9:1)

S

H N

MeO

S

Major

A

O

Minor

B

C

To a solution of A (0.20 g, 1.0 mmol) in TFA-H2 O (5 ml, v/v 9 : 1) was added NaN3 (50 mg, 0.75 mmol). After being stirred at room temperature for 24 hours under nitrogen, same amount of NaN3 was added to the reaction mixture. After 42 hours, the reaction mixture was then gently poured into a mixture of ice and solid K2 CO3 and basified to pH ∼10. The aqueous solution was extracted with dichloromethane, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The title compound was isolated by column chromatography (dichloromethane/ethyl acetate 1 : 1) in 51% yield of B (major product) and 25% of C.

Wagner–Meerwein Rearrangement The Wagner–Meerwein rearrangement is an acid-catalyzed alkyl group migration of an alcohol to give an olefin with more substituted. This is a cationic [1, 2]-sigmatropic rearrangement reaction. This reaction has been applied to synthesize complex natural products and drug molecules [3–38]. R1

OH

R3

R4

R2

H Acid

R2

R1

R3

R4

Mechanism

R1

.. O H

R3

R4

R2

H H O H Step 1 – H2O

R1

H O H

R2 R3

R4

Step 2 – H2 O

Step 3

R1

H

R3

R4 1,2 shift

R2

R2 R3

R1 H R4 .. O H H Step 4

H3O

R2

R1

R3

R4

+

Wolff Rearrangement

Step 1: Protonation of the alcohol with the acid. Step 2: Elimination of water forms a carbocation. Step 3: A 1,2-shift (R1 group migration) forms a more stable carbocation. Step 4: Deprotonation with water gives a more substituted olefin and regeneration of acid catalyst. Application H1N1 influenza virus strains [27] and salimabromide antibiotic polyketide [35] have been synthesized using this reaction. Talatisamine is a member of the C19 -diterpenoid alkaloid family, exhibits K+ channel inhibitory and antiarrhythmic activities [38], and was synthesized utilizing this reaction. Total syntheses of several natural products such as (+)-quadrone [6], guanacastepene A [14], (−)-isoschizogamine [25], and Lycopodium alkaloid (−)-huperzine A [26] have been accomplished utilizing this reaction.

Wolff Rearrangement The Wolff rearrangement is a conversion of an α-diazoketone to a ketene with the loss of molecular nitrogen accompanying 1,2-rearrangement using a silver oxide catalyst or thermal or photochemical conditions. Generally, these ketenes are not stable to isolate. These can undergo a nucleophilic attack by water or alcohol or amine to form one carbon homologation of acid or ester or amide (having one carbon more from starting material). The German chemist Ludwig Wolff discovered this reaction in 1902 [1, 2]. Several new catalysts or improved reaction conditions have been developed on this reaction [3–21]. H N

R

R1

O R1 NH2 O N2

R

Ag2O

H

H2O C O

or heat or light

OH

R

R

O

Ketene intermediate R2-OH

O

R

R2

O

Mechanism O

O R

N N2

R H

N

O

O R

N

N Step 1 – N2

R

Step 2 CH

H C O R Ketene

Alpha ketocarbene

39

40

1 Rearrangement Reactions

Alternatively O N

R

N

H

Step 1 R C C O H

Step 2

C O R

H R

.. Ketene intermediate H O H

O C O H H

OH C OH

Step 3 H R

Step 4 OH

R O

Step 1: Elimination of a molecule of nitrogen gas, R group migration, and formation of ketene intermediate. Step 2: Water attacks as a nucleophile to the ketene. Step 3: Proton transfer. Step 4: Tautomerization gives the desired product. Application (+)-Psiguadial B is a plant natural product with potent cytotoxicity toward human liver cancer cells that has been synthesized using this reaction [19]. Me

O Me

O Me

N2

Me

hv, cat.

NH

Me N

CHO

Me

Steps

O

OH OH

Tandem Wolf rearrangement– asymmetric ketene addition

Ph (+) Psiguadial B

Total syntheses of natural products including (±)-Δ9(12)-capnellene [12] and diterpene salvilenone [10] have been accomplished utilizing this reaction. Experimental Procedure (from patent US9175041B2)9175041B2 O

Silver benzoate ZHN

N2

TEA, t-Bu-OH

ZHN

O

O

Diazo derivative (0.602 g, 2.19 mmol) was dissolved in t-BuOH (9 ml) under N2 at 70 ∘ C. Silver benzoate (80.2 mg, 0.35 mmol) in TEA (0.94 ml, 685 mg, 6.70 mmol) was added dropwise, and the mixture stirred at 70 ∘ C in the dark for four hours. The mixture was allowed to cool, filtered through a pad of celite, and the solvent was evaporated. The residue was partitioned between EtOAc (100 ml) and saturated NaHCO3 (20 ml). The organic phase was separated; washed with saturated NaHCO3 (20 ml), H2 O (20 ml), and 5 M NaCl (20 ml); and dried, and the

Arndt–Eistert Homologation or Synthesis

solvent was evaporated. The residue was chromatographed (silica gel, 23 g; 9 : 1 hexane/acetone) to provide 0.443 g (63%) product as a colorless oil.

Arndt–Eistert Homologation or Synthesis The Arndt–Eistert reaction is a conversion of carboxylic acid to one-carbon homologated carboxylic acid via α-diazoketone formation and subsequently Wolf rearrangement of the intermediate in the presence of water and silver oxide catalyst or thermal or photochemical conditions [1–28]. The reaction is named after the German chemists Fritz Arndt and Bernd Eistert [1].

R

O

SOCl2

O OH

– SO2, –HCl

R

Cl

Ag2O, or hv

O

CH2N2, Ether

N2

R

– CH3Cl, –N2

OH

R H2O, dioxane, –N2

O

Mechanism O N N

R

O R

O

Step 1 R

Cl

O

Step 2

Cl

N R

N N

– Cl

H2C N N H R

N

H H H 2C N N

O C O H H

Step 5

O

Step 3

N N + H3C N N

R Step 4

Side reaction

H C O R

.. Ketene intermediate H2O

Cl

R C C O H

CH3Cl + N2

Step 6 OH C OH

H R

Step 7 OH

R O

Step 1: Nucleophilic attack by diazomethane into carbonyl carbon atom of acyl chloride forms a tetrahedral intermediate. Step 2: Elimination of chloride and formation of the diazoketone. Step 3: Abstraction of proton. Step 4: Migration of R group and formation of the ketene intermediate. Step 5: Nucleophilic attack by water to the ketene. Step 6: Proton transfer. Step 7: Tautomerization gives the desired product.

41

42

1 Rearrangement Reactions

Application The reaction is used for the preparation of β-amino acids from α-amino acids. Peptides containing β-amino acids have a lower rate of metabolic degradation than regular peptides with α-amino acids. Hence these peptides may have the interest for pharmaceutical drug discovery field. Nonsteroidal anti-inflammatory agent 2-chloroindolecarboxylic acid [6] was synthesized using this reaction. Total syntheses of several natural products such as bellenamine [11], dragmacidin D [17], phenalenone diterpene salvilenone [13], and CP-225917 [14] have been accomplished utilizing this reaction. Experimental Procedure (from patent US9399645B2) O OH O A

O

H

a. Ethyl chloroformate, THF, Et3N b. CH2N2 in ether

Silver benzoate N2

O

O

Et3N, MeOH

B

OMe O C

Step 1 A solution of A (40.0 g, 344.8 mmol) in THF (800 ml) was cooled to −25 ∘ C and treated with TEA (62.4 ml, 448.2 mmol). Ethyl chloroformate (42.4 ml, 448.2 mmol) was then added dropwise at the same temperature. The mixture was stirred for 30 minutes and then filtered. The filtrate was cooled to 0 ∘ C and treated with an excess of diazomethane in ether. The mixture was allowed to stir while warming to room temperature overnight. The solution was treated with HOAc and then concentrated to approximately one-half its volume. The mixture was poured into water (1 l) and extracted with EtOAc (500 ml × 2). The combined organic layers were washed with saturated NaHCO3 and brine, dried (Na2 SO4 ), and concentrated in vacuo to give diazoketone B, which was used as such in the next step. Step 2 A solution of diazoketone B (40.0 g, 285.7 mmol) in MeOH (500 ml) was cooled to 0 ∘ C and treated with a solution of silver benzoate (6.5 g, 28.6 mmol) in TEA (67 ml). The mixture was protected from light and stirred while warming to room temperature. The crude reaction mixture was filtered through a celite pad and concentrated in vacuo. The residue was distilled in vacuum (60 ∘ C, 20 mmHg) to afford ester C ((S)-(tetrahydrofuran-2-yl)-acetic acid methyl ester).

Zinin Rearrangement or Benzidine and Semidine Rearrangements Acid-catalyzed conversion of hydrazobenzene into 4,4′ -diaminobiphenyl (para-benzidine) and 2,2′ -diaminobiphenyl (ortho-benzidine) is called benzidine rearrangement. Similarly, acid-promoted conversion of hydrazobenzene to

Zinin Rearrangement or Benzidine and Semidine Rearrangements

2-phenylaminoaniline (ortho-semidine) and 4-phenylaminoaniline (parasemidine) is called semidine rearrangement. Side product 2,4-diaminebiphenyl is also obtained for this rearrangement reaction. Improvements and mechanistic studies of these types of rearrangements have been reported [1–33]. NH2

NH2

NH2 H HN N

HCl

+

+

H2N Benzidine

Diphenyline NH2

H N

H2N NH2

ortho-Benzidine

HN + H2N

ortho-Semidine

para-Semidine

Mechanism HN

NH H

H2N

NH2 [5,5] sigmatropic

Step 1

NH2

H H H2N

Step 2

Step 3 –H

NH2

H2N

H2N

NH2

NH2

NH2 H

–H

[5,3] sigmatropic rearrangement

H2N

NH2

H2N NH2

NH2

H

NH2

NH2

HH ortho-Benzidine

NH2

43

44

1 Rearrangement Reactions

H2N

NH2

H2N H H N H

H N

NH2

ortho-Semidine

H2N

H NH

NH2

NH2

NH2 HN H

para-Semidine

Step 1: Protonation of two amino groups. Step 2: Sigmatropic rearrangement and formation of several polar transition steps (T.S.). Step 3: Rearomatization through deprotonation and formation of product.

Experimental Procedure (from patent US20090069602A1) CF3

NH2 N H

A

H N

CF3

H2SO4 Toluene

H2N

CF3 CF3 B

4.19 g of compound A was dissolved in 14.0 g of toluene, and the solution was dropped into 15.0 g of 50% sulfuric acid aqueous solution. The rearrangement reaction was conducted for five hours after the dropping. After the reaction was finished, reaction mixture was neutralized and extracted with toluene to obtain 41.4 g of toluene layer. As a result of analysis of the toluene layer, the concentration of 2,2′ -bis(trifluoromethyl)-4,4′ -diaminobiphenyl was 3.11%, and the yield thereof was 31.8% based on purity of starting material 3,3′ -bis(trifluoromethyl)hydrazobenzene. The toluene solution separated above was concentrated for crystallization. A crystallized product was recrystallized to obtain a white crystal. The result of analysis of the crystal showed that it was 2,2′ -bis(trifluoromethyl)-4,4′ -diaminobiphenyl (compound B) having purity of 99.9% and melting point of 183 ∘ C.

Baeyer–Villiger Oxidation or Rearrangement

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Hofmann–Martius Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12 13

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Lossen Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12

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Orton Rearrangement

13 Pedras, M.S., To, Q.H., and Schatte, G. (2016). Chem. Commun. 52:

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Orton Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

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Pinacol–Pinacolone Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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Rupe Rearrangement/Meyer–Schuster Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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Schmidt Rearrangement or Schmidt Reaction

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Schmidt Rearrangement or Schmidt Reaction 1 2 3 4 5 6 7 8 9 10 11

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Wagner–Meerwein Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

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Wolff Rearrangement

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Wolff Rearrangement 1 2 3 4 5 6 7 8

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Arndt–Eistert Homologation or Synthesis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Arndt, F. and Eistert, B. (1935). Ber. Dtsch. Chem. Ges. 68: 200. Bachmann, W.E. and Struve, W.S. (1942). Org. React. 1: 38–62. Huggett, C., Arnold, R.T., and Taylor, T.I. (1942). J. Am. Chem. Soc. 64: 3043. Wilds, A.L. and Meader, A.L. (1948). J. Org. Chem. 13: 763–779. Cohen, B.I., Tint, G.S., Kuramoto, T., and Mosbach, E.H. (1975). Steroids 25: 365–378. Andreani, A., Bonazzi, D., Rambaldi, M. et al. (1977). J. Med. Chem. 20: 1344–1346. Batta, A.K., Salen, G., Tint, G.S., and Shefer, S. (1979). Steroids 33: 589–594. Hiremath, S.V. and Elliott, W.H. (1981). Steroids 38: 465–475. Kuramoto, T., Kawamoto, K., Moriwaki, S., and Hoshita, T. (1984). Steroids 44: 549–559. Yoshii, M., Une, M., Kihira, K. et al. (1989). Chem. Pharm. Bull. 37: 1852–1854. Ikeda, Y., Ikeda, D., and Kondo, S. (1992). J. Antibiot. 45: 1677–1680. Ye, T. and McKervey, M.A. (1994). Chem. Rev. 94: 1091. Danheiser, R.L. and Helgason, A.L. (1994). J. Am. Chem. Soc. 116: 9471–9479. Nicolaou, K.C., Baran, P.S., Zhong, Y.-L. et al. (1999). Angew. Chem., Int. Ed. Engl. 38: 1669–1675. Katritzky, A.R., Zhang, S., and Fang, Y. (2000). Org. Lett. 2: 3789–3791. Patil, N.T., Tilekar, J.N., and Dhavale, D.D. (2001). J. Org. Chem. 66: 1065–1074. Garg, N.K., Sarpong, R., and Stoltz, B.M. (2002). J. Am. Chem. Soc. 124: 13179–13184. Kirmse, W. (2002). Eur. J. Org. Chem. 12: 2193–2256.

Zinin Rearrangement or Benzidine and Semidine Rearrangements

19 Chakravarty, P.K., Shih, T.L., Colletti, S.L. et al. (2003). Bioorg. Med. Chem.

Lett. 13: 147–150. 20 Vasanthakumar, G.R. and Babu, V.V. (2003). J. Pept. Res. 61: 230–236. 21 Rueping, M., Mahajan, Y.R., Jaun, B., and Seebach, D. (2004). Chemistry 10:

1607–1615. 22 Norgren, A.S., Norberg, T., and Arvidsson, P.I. (2007). J. Pept. Sci. 13:

717–727. 23 Karch, F. and Hoffmann-Röder, A. (2010). Beilstein J. Org. Chem. 6: 47. 24 Pace, V., Verniest, G., Sinisterra, J.V. et al. (2010). J. Org. Chem. 75: 5760. 25 March, T.L., Johnston, M.R., Duggan, P.J., and Gardiner, J. (2012). Chem. Bio-

divers. 9: 2410. (review). 26 Haugeberg, B.J., Phan, J.H., Liu, X. et al. (2017). Chem. Commun. 53:

3062–3065. 27 Castoldi, L., Ielo, L., Holzer, W. et al. (2018). J. Org. Chem. 83: 4336–4347. 28 Zarezin, D.P., Shmatova, O.I., and Nenajdenko, V.G. (2018). Org. Biomol.

Chem. 16: 5987–5998.

Zinin Rearrangement or Benzidine and Semidine Rearrangements 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Zinin, N. (1845). J. Prakt. Chem. 36: 93. Ritter, J.J. and Ritter, F.O. (1931). J. Am. Chem. Soc. 53: 670–676. Carlin, R.B. and Forshey, W.O. Jr. (1950). J. Am. Chem. Soc. 72: 793–801. Carlin, R.B. and Foltz, G.E. (1956). J. Am. Chem. Soc. 78: 1992–1997. Snyder, L.C. (1962). J. Am. Chem. Soc. 84: 340–347. Miller, B. (1962). Tetrahedron Lett. 3: 55–56. Shine, H.J. and Chamness, J.T. (1963). J. Org. Chem. 28: 1232–1236. Hammond, G.S. and Clovis, J.S. (1963). J. Org. Chem. 28: 3283–3290. Shine, H.J. and Chamness, J.T. (1963). Tetrahedron Lett. 4: 641–644. Clovis, J.S. and Hammond, G.S. (1963). J. Org. Chem. 28: 3290–3297. Shine, H.J. and Chamness, J.T. (1967). J. Org. Chem. 32: 901–905. Shine, H.J. and Stanley, J.P. (1967). J. Org. Chem. 32: 905–910. Shine, H.J., Balwin, C.M., and Harris, J.H. (1968). Tetrahedron Lett. 9: 977–980. Hartung, L.D. and Shine, H.J. (1969). J. Org. Chem. 34: 1013–1017. Shine, H.J. and Cheng, J.D. (1971). J. Org. Chem. 36: 2787–2790. Olah, G.A., Dunne, K., Kelly, D.P., and Mo, Y.K. (1972). J. Am. Chem. Soc. 94: 7438–7447. Cheng, J.-D. and Shine, H.J. (1975). J. Org. Chem. 40: 703–710. Shine, H.J., Zmuda, H., Park, K.H. et al. (1981). J. Am. Chem. Soc. 103: 955–956. Shine, H.J., Zmuda, H., Park, K.H. et al. (1982). J. Am. Chem. Soc. 104: 2501–2509. Shine, H.J., Zmuda, H., Kwart, H. et al. (1982). J. Am. Chem. Soc. 104: 5181–5184.

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21 Shine, H.J., Habdas, J., Kwart, H. et al. (1983). J. Am. Chem. Soc. 105:

2823–2827. 22 Shine, H.J., Park, K.H., Brownawell, M.L., and Fillippo, J.S. Jr. (1984). J. Am. 23 24 25 26 27 28 29 30 31 32 33

Chem. Soc. 106: 7077–7082. Rhee, E.S. and Shine, H.J. (1986). J. Am. Chem. Soc. 108: 1000–1006. Shine, H.J. (1989). J. Chem. Educ. 66: 793. Park, K.H. and Kang, J.S. (1997). J. Org. Chem. 62: 3794–3795. Benniston, A.C., Clegg, W., Harriman, A. et al. (2003). Tetrahedron Lett. 44: 2665–2667. Ghigo, G., Osella, S., Maranzana, A., and Tonachini, G. (2011). Eur. J. Org. Chem.: 2326. Ghiho, G., Marnzana, A., and Tonachini, G. (2012). Tetrahedron 68: 2161–2165. Hou, S., Li, X., and Xu, J. (2014). Org. Biomol. Chem. 12: 4952. Leung, G.Y.C., William, A.D., and Johannes, C.W. (2014). Tetrahedron Lett. 55: 3950–3953. Yang, Z., Hou, S., He, W. et al. (2016). Tetrahedron 72: 2186–2195. Bouillon, M.E. and Meyer, H.H. (2016). Tetrahedron 72: 3151–3161. Li, J.J. (2003). Name Reaction, 453–454. Springer.

69

2 Condensation Reaction A condensation reaction is a broad class of organic addition reactions in which two or more identical or different molecules combine together typically proceed in a through stepwise fashion to form a single addition product with elimination of water (hence named condensation). Instead of water, the reaction can proceed with elimination of simple units like ammonia, ethanol, or acetic acid. The condensation reaction can occur in acidic, basic conditions or in the presence of other catalysts. This type of reactions is an essential part of our life as it is an important to form peptide bonds in between amino acids in protein and the biosynthesis of fatty acids. R O

H2N O

H

+

R

R1

H

OH

N H

Condensation Reaction

O

O

H N

H2N O

OH + H

O

H

R1

Condensation of two amino acids gives a peptide and water. Here we describe some named condensation reactions and more condensation reactions can be found in other chapters as well.

Aldol Condensation Reaction Ketones with hydrogen on the carbon atom adjacent to the carbonyl group are called as α-hydrogen, and it is very reactive in the presence of base or acid. On treatment with base benzaldehyde and acetophenone undergo a carbon–carbon bond-forming reaction called the aldol condensation [1]. The intermediate further undergoes dehydration to yield the resonance-stabilized α,β-unsaturated ketone. Several catalysts have been developed on this reaction, and total syntheses of numerous natural products have been completed strategically utilizing this reaction [1–71]

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

70

2 Condensation Reaction

OH

O H

CH3

+

O

NaOH Ethanol

O

Aldol –H2O O

Chalcone

Mechanism of base-catalyzed reaction H2 C H O

Step 1

H

Step 2 O

OH

O

O

O H–O–H Step 3

H

Step 4 O

O

OH

Aldol/ketol

Step 1: Enolate formation with the help of a base. Step 2: The enolate attack at the electron-deficient carbonyl carbon atom. Step 3: Proton transfer gives an aldol or ketol. Step 4: Aldol or ketol undergoes spontaneous dehydration (elimination of water) to form α,β-unsaturated carbonyl compound. Application Several drug-like molecules such as camptothecin and 10-hydroxycamptothecin [28], sirtuin 2-selective inhibitors [42], archazolid F, a highly potent V-ATPase inhibitor, antiproliferative polyketide macrolide [66], gastroprotective microbial agent AI-77-B [22], and tetronamide antibiotic basidalin [57] have been synthesized utilizing this reaction. Expeditious total syntheses of rhizoxin D (a potent antimitotic agent) [20], fostriecin [23], alkaloid (±)-vincorine [30], periconiasins A–E [53], steroid drugs

Aldol Condensation Reaction

[35], streptorubin B [38], (−)-reveromycin B [19], tetrodotoxin [24], aspidodasycarpine, lonicerine [54], (±)-scopadulin [18], dracaenones [65], (+)-schweinfurthin B [33], (+)-migrastatin [25], amphidinolide B1 [27], (−)-18-epi-peloruside A [44], lycopodium alkaloid (−)-lycospidine A [52], epothilone A [16], terpenoids (+)-norleucosceptroid A, (−)-norleucosceptroid B, (−)-leucosceptroid K [49], semiconductors [61], trocheliophorolide B [43], (+)-conico [34], (+)testudinariol A [21], (+)-streptazolin, G2/M DNA damage checkpoint inhibitor psilostachyin C [39], (−)-amphidinolide [45], furanoeremophilane sesquiterpene (+)-9-oxoeuryopsin [46], calyciphylline B-type alkaloids [67], antibiotic pamamycin 621A [37], (−)-mesembrine [17], and amipurimycin [64] have been accomplished using this reaction. Experimental Procedure (general) Preparation of Benzalacetophenone (Chalcone)

CH3

+

H

O

NaOH EtOH O

O

A

B

C

A mixture of acetophenone (A, 480 mg, 4 mmol), benzaldehyde (B, 424 mg, 4 mmol), and 10% NaOH solution (2 ml) in ethanol (2 ml) was stirred at room temperature for one hour. The solid was precipitated, filtered, and washed with water to give a pure product (C, 665 mg, 80%). If an oil forms, then try to crystallize it by cooling the reaction mixture and scratching the flask with a glass rod extending into the oil. Enantioselective Aldol Reaction (from patent US 6919456B2)

O

5 mol% Chiral ligand, 10 mol% Et2Zn

H + HO

4 Å MS, THF, –35 °C

OH

O

OH

O A

B

C

Under an argon atmosphere, a solution of diethylzinc (1 M in hexane, 0.2 ml, 0.2 mmol) was added to a solution of chiral ligand (64 mg, 0.1 mmol) in tetrahydrofuran (THF) (1 ml) at ambient temperature, and the solution was stirred at the same temperature for 30 minutes. This solution (0.25 ml) was added to a suspension of powdered 4 Å molecular sieves (100 mg, dried at 150 ∘ C under vacuum overnight), aldehyde A (0.5 mmol), and hydroxymethyl aryl ketone B (0.75 mmol) in THF (1.5 ml) at −35 ∘ C. The mixture was stirred at the same temperature for

71

72

2 Condensation Reaction

one to two days. The reaction mixture was poured onto 1 N HCl and extracted with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography to give a major product C in 70% yield, d.r. 6 : 1, and ee 93%.

Mukaiyama Aldol Reaction Lewis acid-catalyzed aldol-type reaction between silyl enol ethers and aldehydes is known as the Mukaiyama aldol reaction [1–3]. Several chiral Lewis acids [4–74] and heterogeneous catalysts [19] have been developed for this reaction. OSiMe3

O +

H

R1

Aldehyde

O Lewis acid (TiCl4)

R

R

OSiMe3

OH O H2O

R1

R1

R 1,3-ketol

Silyl enol ether

Mechanism H

Cl Cl

Cl

Ti Cl

.. O R1

O

Cl O

Step 1 H

– Cl

R1

TiCl3

R

O

SiMe3 Cl3Ti

H

.. O

O

Step 2 R1

– SiMe3Cl

R

H Step 3

OH O R1

+ TiCl3(OH) R2

Step 1: TiCl4 coordinates with an aldehyde and then nucleophilic displacement of chloride ion. Step 2: Chloride ion attacks on silicon atom to form an enolate in situ; then it attacks to an aldehyde. Step 3: Aqueous work-up gives the desired product. Application Total syntheses of several natural products such as rutamycin B and oligomycin [16], roflamycoin [7], (−)-hennoxazole A [13], immunosuppresant pironetin [17], leucascandrolide A [18], (−)-bafilomycin A [20], (+)-cheimonophyllon E,

Evans Aldol Reaction

(+)-cheimonophyllal [21], (+)-azaspiracid-1 ([27], N-methylmaysenine [30], 1-deoxy-7,8-di-epi-castanospermine [31], (−)-gymnodimine [37], (−)-goniotrionin [41], terpenoid anominine, tubingensin A [42], PSI-6130, the nucleoside core of sofosbuvir [46], rubriflordilactone A [47], spirocurcasone [43], virgatolide A [44], (−)-lyngbyaloside B [48], fidaxomicin [49], tunicamycin [50], sesquiterpene lactone aquatolide [52], 11-saxitoxinethanoic acid [54], nannocystin A [55], cephalotaxus esters [57], tunicamycin V [58], tiacumicin A [59], and (−)-(3 R)-inthomycin C [60] have been completed utilizing this reaction. Experimental Procedure (from patent DE102013011081A1) O

OSiMe3

O H

1. EMIM(FAP) +

O

OH

+

2. H2O C

B

A

OH

D

In a corresponding reaction vessel with reflux condenser and drying tube, 0.025 mmol (0.5 mol%) catalyst was dissolved in 16.18 mmol of 1-ethyl-3methylimidazolium tris(pentafluoroethyl)trifluorophosphate, [EMIM] [FAP], suspended. 5.18 mmol of benzaldehyde and 5.63 mmol of 1-trimethylsiloxycyclohexene were added to the catalyst suspension and stirred for 22 hours. The conversion was determined by 1 H NMR spectroscopy. For isolation, the reaction mixture was extracted with n-hexane and dichloromethane (1 : 1, v : v). The organic phases were combined, and the solvents were removed in vacuo. Optionally, hydrolysis with THF–water (4 : 1, v : v) and renewed extraction with n-hexane followed. After removal of the solvent in vacuo, a mixture of isomers was obtained.

Evans Aldol Reaction The stereoselective aldol reaction between an aldehyde and an oxazolidinone chiral auxiliary in the presence of Et3 N and Bu2 BOTf is known as the Evans aldol reaction [1–6]. The reaction proceeds in two steps: first (Z)-enolate formation and second aldol reaction. Several catalysts and different reaction conditions have been developed to improve yields and stereoselectivity [6–61]. Bu2B

O

O N (S)

O Bu2BOTf, Et3N CH2Cl2, 0 °C

(Z)

N (S)

Z-enolate

O

OH O

O

O

O 1. R1–CHO, –78 °C, DCM R1 2. H2O

(S) (R)

N

O

(S)

syn-Aldol product

73

74

2 Condensation Reaction

Mechanism Bu2B OTf Bu B O O

O Step 1

N

N

H

Bu

O

Bu

O

O

Bu B

H

R1

O

O Step 2

O

Step 3 N

O

N

R1

Bu

H

H

Et3N

O

O

O

B O

Bu

R1

Step 4

Favored T.S.

Aqueous work O

OH O

O

N

R1

syn-Aldol product

Step 1: Deprotonation of α-H by Et3 N and nucleophilic displacement of OTf give a Z-enolate. Step 2: Aldol condensation through favored chair-like transition state. Step 3: An intermediate boron-complex formation and stabilized by coordination with amide Step 4: An aqueous work-up gives a syn aldol product. Application The Evans aldol reaction has been used as an important strategy in the total synthesis of natural products including l-callipeltose [19], bleomycin A2 [11], (−)-FR182877 [21], glucolipsin A [56], sesaminone [13], antibiotic myxalamide A [14], immunosuppressive agent (−)-sanglifehrin A [24], luminacin D [22], (+)-cystothiazole A [29], antitumor macrolide (+)-rhizoxin D [31], salicylihalamides A and B [32], pteridic acid A, a potent plant growth promoter [33], (−)-15-acetyl-3-propionyl-17-norcharaciol [35], nonactin [36], (+)-eremantholide A [37], cruentaren B [38], (+)-azaspiracid-1 [39], (+)-peloruside a, a potent microtubule-stabilizing agent [40], (−)-pironetin [41], the naturally occurring caspase-1 inhibitor (−)-berkeleyamide A [43], lysergic acid [47], gymnothelignan N [49], pericoannosin A ([57], and many more. Experimental Procedure (from patent WO2013151161A1) O

O N

O

A

2.

(E)

(E)

3. Oxidative work-up

(R) (E)

O

(S)

Bn

OH

1. Bu2BOTf (1.2 equiv.), Et3N (1.2 equiv.) (E)

(S)

(R)

O

O N (S)

(R)

H

B

Bn C

O

Henry Reaction

A mixture of A (1.2 equiv.), Bu2 BOTf (1.2 equiv.), and Et3 N (1.2 equiv.) in DCM (0.1 M) was stirred at 0 ∘ C for one hour. The reaction mixture was cooled to −78 ∘ C, and aldehyde B in DCM was added and stirred for one hour. The reaction mixture was brought to 0 ∘ C. Methanol, buffer solution (pH 7), and hydrogen peroxide solution were added to the reaction system and stirred for 30 minutes. Then, saturated sodium thiosulfate aqueous solution was added to stop the reaction, ethyl acetate was added, and the organic layer was separated; then the aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by thin layer chromatography, and (4S)-3-((2R, 3S, 4R, 6E, 8E)-3-hydroxy-2,4-dimethyldeca 6,8-dienoyl)-4-benzyloxazolidinon-2-one (compound C) (273 mg, 94%) was obtained.

Henry Reaction A base-catalyzed carbon–carbon bond-forming reaction between nitroalkanes with α-hydrogen and aldehydes or ketones to form β-nitro alcohols is referred to as the Henry reaction [1, 2]. It is similar to the aldol reaction and also known as the nitro-aldol reaction. Generally, catalytic amounts of alkali metal hydroxides, alkoxides, carbonates, and organic bases such as DBU and piperidine are used successfully for this reaction [3–5, 19]. Several chiral catalysts are developed for the asymmetric Henry reaction [6–31]. NO2

O R

NO2

Nitroalkane

+ R1

R2

Base (cat.)

R

R2 OH

Solvent

Aldehyde or ketone

R1

β-nitro alcohol

Mechanism O OH H R

N O

O

Step 1 R

O N O

R1

R2

R

N O O

NO2

Step 2 R

O

R1 R2

Nitronate H H O Step 3 NO2 R1

R HO

R2

75

76

2 Condensation Reaction

Step 1: Deprotonation of α-hydrogen from a nitroalkane by hydroxide gives a resonance-stabilized anionic intermediate. Step 2: An aldol-type reaction (C-alkylation of nitroalkane); nucleophilic attacks at the electron-deficient carbonyl carbon atom to give an alkoxide. Step 3: Protonation of alkoxide from the conjugated acid of the base (water in this case) gives the desired β-nitro alcohol. Application β-Nitro alcohols can be easily reduced to give β-amino alcohols, which are important scaffolds in drug discovery research. Experimental Procedure (from patent US 6919456B2) O

OH H

Chiral catalyst (5 mol%) +

H3C NO2

A

4 Å M.S.; THF –78 °C

(S)

NO2

B

Preparation of Chiral Catalyst

Under an argon atmosphere, a solution of diethylzinc (0.36 ml, 1.1 M in tol, 0.4 mmol) was added to a stirred and cooled (0 ∘ C) solution of chiral ligand (0.128 g, 0.2 mmol) in THF (2 ml). After the addition the cold bath was removed, and the solution was allowed to stir at room temperature for 30 minutes to make a 0.1 M catalyst solution. Nitro-Aldol Reaction

Under an argon atmosphere, a solution of catalyst (0.5 ml, 0.1 M in THF, 0.05 mmol) was added dropwise to a stirred and cooled (−78 ∘ C) suspension of powdered molecular sieves 4 Å (100 mg, dried at 120 ∘ C under vacuum overnight), aldehyde A (1 mmol), and CH3 NO2 (0.32 ml, 6 mmol) in THF (3 ml). After the addition, the resulting mixture was transferred to a −20 ∘ C cold bath and left to stir for 24 hours. The reaction was quenched by adding aqueous HCl solution (3 ml, 0.5 M), and the resulting mixture was partitioned with Et2 O (10 ml). The organic phase was washed with water and brine, dried over anhydrous MgSO4 , and filtered. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (EtOAc : hexane, 10 : 90) to afford the nitro-aldol product B in 70% yield and 86% ee.

Benzoin Condensation The benzoin condensation is a coupling reaction of two aromatic aldehydes using cyanide catalyst to give a benzoin, α-hydroxyketone [1–4]. This condensation reaction was first reported by Justus von Liebig and Friedrich Wöhler in 1832, and the catalytic version of the reaction using cyanide was discovered by Nikolay Zinin. Several types of catalysts such as inorganic, organic, and enzymes have

Benzoin Condensation

been utilized on this reaction [5–48]. N-Heterocyclic carbene-catalyzed (NHC) benzoin reaction also has been reported [19]. O

O O H

+

H

CN OH

EtOH, H2O

Benzoin Benzaldehyde

Mechanism Electrophilic carbon

Nucleophilic carbon OH

O

O H

H CN

Step 1

OH

C N

Step 2

C N

Umpolung

CN Donor

OH

OH

OH O

C N

Step 3

CN

H

O

H

H O

Step 4

OH

CN

O H

Step 5 Acceptor O

O Step 6

OH

CN

OH Benzoin

Step 1: Nucleophilic addition of cyanide anion to the electrophilic carbon of benzaldehyde. Step 2: Rearrangement to form a carbanion; electrophilic carbon becomes nucleophilic. It is an example of umpolung, reversal of polarity. Step 3: Nucleophilic attacks of the carbanion to the second equivalent of benzaldehyde (acceptor). Step 4: Proton transfers from water. Step 6: Abstraction of proton. Step 5: Elimination of cyanide group gives the desired benzoin. Application Total syntheses of 7′ -desmethylkealiiquinone, 4′ -desmethoxykealiiquinone, 2-deoxykealiiquinone [33], and (±)-glyceollin II [37] have been completed utilizing this reaction.

77

78

2 Condensation Reaction

Experimental Procedure (from patent DE3019500C2) O

O

O

H OH

H H

OH

KCN

+

MeOH

O

O

B

A

Bisbenzoins C

In a 20 l reactor provided with a stirrer and a reflux condenser were added 15 l of methanol and 625 g (4.66 mol) of terephthalaldehyde (compound A). The mixture was stirred until dissolution of the dialdehyde. Then 100 g (1.54 mol) of potassium cyanide was added, which was about 16% of the stoichiometric amount. The cyanide was quick in solution, and the environment assumes a dark red color. Now, it was mixed with 2000 g (18.9 mol) of benzaldehyde (compound B). The mixture was stirred for one hour at room temperature and then heated for five hours at the reflux temperature of the methanol (about 65 ∘ C). After cooling to room temperature the formed light, cream-colored precipitate was separated by filtration, washed with water to remove the cyanide, and dried under reduced pressure. At five identical procedures, the yield of bisbenzoin (compound C) was 83–87%.

Claisen Condensation The Claisen condensation is a carbon–carbon bond-forming reaction between two esters or one ester and another carbonyl compound using an alkoxide base in alcohol to form a β-keto ester or β-diketones [1]. The reaction was discovered by the German chemist Rainer Ludwig Claisen in 1887. This reaction has been employed to synthesize drug-like molecules and natural products [2–52]. O

O

O O

O

O 2. H3O

Two esters

+ Ketone

β-ketoester O

O

O

O

1. NaOEt, EtOH

+

O

1. NaOEt, EtOH O

2. HCl

1, 3-Diketone

Ester

Mechanism The one of two starting materials must have an α-hydrogen that is abstracted by a strong base to form the resonance-stabilized carbanion (enolate). The nucleophilic attacks by the carbanion to another electron-deficient carbonyl carbon

Claisen Condensation

atom and releases EtO− and forms a β-keto ester. The β-keto ester is stronger acid than ethanol. In strong basic conditions, an active α-H was abstracted again from the product β-keto ester to form another enolate intermediate, and acid work-up is required to neutralize the carbanion and regenerate the final β-keto ester. O

OEt

O

O

O H

Step 1

O

Step 2

O

O O

O

OEt β-ketoester

O

Step 4 O

O

HCl Step 6

O

O H

O O

O

(Z)

O

Step 3

O

Step 5 O

– EtOH O O

Step 1: Enolate formation. Step 2: Condensation. Step 3: Elimination of EtO− and formation of β-keto ester. Step 4: Abstraction of active α-H. Step 5: Formation of another enolate. Step 6: Acidified gives the desired product. Application Syntheses of antimicrobial [29, 34], anticancer agent [37, 46], and HER2/EGFR dual inhibitors [45] have been reported using this reaction. Total syntheses of several natural products including (−)-secodaphniphylline [9], justicidin B, retrojusticidin B [12], core structure of the antibiotic abyssomicin C [24], hybocarpone [28], xanthohumol [32], munchiwarin [35], and (−)-kaitocephalin [36] have been completed strategically using this reaction. Experimental Procedure (from patent US9884836B2)

OEt

+ O A

O B

NaH THF O

O C

To a slurry of sodium hydride (4.0 mmol) in refluxing THF was added dropwise the acetophenone A (1.0 mmol) dissolved in 10 ml of THF over 10 minutes. The solution was then allowed to reflux further for one hour. After cooling to room temperature, the ester B (1.5 mmol) was added dropwise over 15 minutes, and the resulting solution stirred for 24 hours. The reaction mixture was then poured over 50 ml of saturated NH4 Cl and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2 SO4 and concentrated to yield the product C.

79

80

2 Condensation Reaction

Darzens Glycidic Ester Condensation The Darzens glycidic ester condensation (also known as Darzens reaction or Darzens condensation) is an organic reaction between a carbonyl compound (ketone or aldehyde) and an α-haloester containing α-H atoms in the presence of a strong base (such as NaOEt, KOtBu, and NaNH2 ) to afford an α,β-epoxy ester (also called as a glycidic ester). This reaction is named after the Russian chemist Auguste George Darzens in 1904 [1–3]. Numerous modification, improvement, theoretical, and mechanistic studies have been reported [4–31]. X

O + R

R2

R1

O

OEt

NaOEt EtOH

O

O O

+ Cl

R

OEt

R1

R2 O

O

NaOEt OEt

O

EtOH

OEt Glycidic ester

Mechanism O Cl

NaOEt Step1

OEt

O

OEt

OEt

–EtOH

H H

O

Cl

Cl

O H

OEt

Step 2 O

O OEt

+

OEt

Cl

Cl

syn

O

O

O

O

Step 3

anti

O

O

OEt

OEt

OEt

cis

Cl

Cl syn

O O

O

O

O O

OEt OEt

Cl anti

Step 3

Cl

O

O

OEt trans

Dieckmann Condensation

Step 1: Deprotonation from an α-haloester with a strong base forms a resonancestabilized α-carbanion. Step 2: The nucleophilic attacks by the carbanion to another electron-deficient carbonyl carbon atom to give syn and anti diastereomers. Step 3: An intramolecular SN 2 reaction undergoes with the loss of chloride to form the epoxides. Generally, the cis/trans ratios of epoxide formation are 1 : 1 to 1 : 2. Application Total syntheses of natural products such as yohimbine [7], (−)-coriolin [19], and (±)-epiasarinin [22] have been accomplished using this reaction. Experimental Procedure (from patent JP2009512630A) O

O

OMe

O Cl + A

MeONa OMe

O

NMP

B

C

β-Ionone (compound A) (212.7 g, 97% purity, 1.07 mol), methyl chloroacetate (compound B) (146.4 g, 1.35 mol), and NMP (75 g, 0.76 mol) were placed in a flash contained and stirred at 0 ∘ C followed by sodium methoxide (87.6 g, 1.62 mol) that was added. After addition of sodium methoxide, the reactor contents were brought to 20 ∘ C and held at that temperature for 20 minutes. After usual work-up, the desired product was obtained.

Dieckmann Condensation The Dieckmann condensation, named after the German chemist Walter Dieckmann, is the intramolecular chemical reaction of diesters containing α-hydrogens in the presence of an alkoxide base in alcohol to afford a cyclic β-keto ester [1]. This reaction is the intramolecular version of the Claisen condensation. Several new catalysts including chiral catalysts have been employed on this reaction [2–43] to synthesize the complex natural products. O

O

O

1. NaOEt,EtOH

OEt O OEt

2. Acidic work-up

OEt

81

82

2 Condensation Reaction

Mechanism One of two ester groups of the starting material must have an α-hydrogen. O O

OEt OEt H

Step1

O

O

O

O OEt

OEt

OEt

5-exo-trig

OEt

O

Ring closing

H O

Step 3

OEt

OEt

Step 2

OEt

Enolate formation

Step 4 O

M O

O

O

OEt OEt H

Stable intermediate

Acidic work up Step 5 O

O OEt

Step 1: Abstraction of proton and formation of an enolate. Step 2: Ring closing; the enolate attacks another carbonyl group. Step 3: Release of − OEt. Step 4: Abstraction of proton and formation of stable intermediate. Step 5: Protonation from acidic work-up gives the desired product. Application Total syntheses of natural products such as mycophenolic acid [15], (±)-sacacarin [13], benanomicin A [9], pseudodistomin B triacetate, pseudodistomin F [10], ABCD-ring system of lactonamycin [14], martinellic acid [16], ningalin D [20], stemona alkaloid (±)-stemonamine [24], (±)-subincanadine F [27], diversonol, lachnone C [28] (−)-fusarisetin A [29], (±)-schindilactone A [31], oseltamivir phosphate [32], epicoccamide D [33], lycopodium alkaloids (−)-lycojaponicumin C, (−)-8-deoxyserratinine, (+)-fawcettimine, (+)-fawcettidine [34], 18,19-di-nor-cholesterol [35], secalonic acid E [36], aurantoside G [37], TAN1251C [38], and aurofusarin [41] have been completed utilizing this reaction as one of the key steps. Experimental Procedure (from patent US 7132564 B2) O

O OEt O

OEt

2. H2SO4

OEt A

O

1. NaOH

B

Knoevenagel Condensation

1336 g of diethyl adipate (compound A) and 472 g of sodium ethoxide were placed in the high-viscosity reactor. After start-up of the kneader and commencement of mixing of the starting materials, a viscous mass was immediately formed. While kneading slowly, the temperature was slowly increased to 120 ∘ C. A vacuum of 10 mbar was slowly built up. The temperature of 120 ∘ C was reached after about 15 minutes. Slow kneading was then continued at a temperature of 120 ∘ C for 30 minutes until a pulverized white solid had been obtained. The powder formed was discharged by means of a transport screw and subsequently hydrolyzed using half-strength sulfuric acid. Phase separation and distillation at 120 ∘ C/10 mbar gave 1021 g of ethyl cyclopentanone-2-carboxylate (compound B) (about 99%). Diethyl adipate could no longer be detected.

Knoevenagel Condensation The Knoevenagel condensation is an organic reaction between an aldehyde or a ketone and an activated methylene compound (such as malonic acid, diethyl malonate, ethyl acetoacetate, and Meldrum’s acid) in the presence of an amine base (e.g. piperidine) to afford a substituted olefin [1–3]. This reaction was discovered by Emil Knoevenagel in 1898, and it is a modification of the aldol condensation. There are several new catalysts also used for this reaction such as InCl3 , bifunctional polymeric amine catalyst, ionic liquid, and many more [4–36]. O R

R1

Z

+

Z1

CH2

Amine base

Z

Z1

R

R1

Z, Z1 (electron-withdrawing groups) = CO2 R, COR, CHO, CN, NO2 , etc. must be strong enough to facilitate the deprotonation to the enolate even with a mild base. Using any strong base, this reaction may induce self-condensation of aldehyde or ketone. Mechanism O

O

EtO

OEt H

H

H

N

H

.. N H

Step 1

O

O

O

EtO

OEt H

O

O

EtO

OEt H

EtO

O OEt

83

84

2 Condensation Reaction

O

O

O

EtO

Step 2

OEt H

EtO

OEt R

O

OH

R H

N

H N H

H

O

O

H

OEt

O

H N.

O

Step 3

EtO

O R

O

O

O

Step 4

EtO

EtO

OEt OH

R

OEt

+ H2O

R

Step 1: The reaction mechanism starts by deprotonation of active methylene compound by piperidine base to give a resonance-stabilized enolate as shown above. Step 2: The enol reacts with an aldehyde to form an aldol. Step 3: Proton transfer. Step 4: Aldol undergoes base-catalyzed elimination of water to form the desired product. Alternatively, the amine catalyst reacts with the aldehyde or ketone to form an iminium ion intermediate, which then gets attacked by the enolate. Application Lumefantrine (benflumetol), an antimalarial drug, was synthesized using Knoevenagel condensation conditions [34]. NBu2

NBu2

O

H

HO Cl

HO NaOH

+

Cl

MeOH

Cl

Cl

Cl

Cl

Lumefantrine

Total syntheses of (±)-leporin A [9], sarcodictyin [10], (±)-gelsemine [8], illudinine [28], and (+)-granatumine A [33] have been completed utilizing this reaction. Experimental Procedure (from patent WO2010136360A2) O

O

O H

O

+

r.t.

O

MeO

O A

B

O

Ti(OiPr)4 MeO

O

O C

Pechmann Condensation (synthesis of coumarin) (also called von Pechmann condensation)

To a solution of 4-methoxybenzaldehyde (compound A) (16.7 g, 0.12 mol) and diisopropyl malonate (compound B) (23.1 g, 0.12 mol) was added Ti(OiPr)4 (47.4 ml, 0.16 mol), and the resulting mixture was stirred at room temperature for two days. The resulting suspension was poured on ice-cold 1 M HCI (280 ml), and the mixture was stirred at 0 ∘ C for 30 minutes. The product was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2 SO4 . The solvent was removed under reduced pressure using a rotary evaporator. Purification by Kugelrohr distillation gave 4-methoxybenzylidene-diisopropylmalonate (compound C) (33.1 g, 90%).

Pechmann Condensation (synthesis of coumarin) (also called von Pechmann condensation) Acid-catalyzed condensation of phenols with β-keto acids or esters to form substituted coumarins is called the Pechmann condensation [1]. Several acids or Lewis acid catalysts [4–20] have been used in the Pechmann condensation reaction including H2 SO4 [1], P2 O5 [2], and AlCl3 [3] to provide coumarin derivatives in good yields. R O

OH +

O

R

Acid O

O

O

Mechanism O R

O O .. O

O

R

Step 2

Step 1 O

H

O

R

H

OEt

O

O

O Step 3

H R .. OH O

O

H

R

OH OH

R

Step 5 H

Step 4 O

OH

.. O

O

Step 6

OH2 O

R

R

R .. O H

Step 8

Step 7 O

O H .. O H

H

O

O

85

86

2 Condensation Reaction

Step 1: Phenol attacks at electron-deficient carbonyl carbon atom of a β-keto ester. Step 2: Elimination of OEt ion and formation of a new ester. Step 3: Keto–enol tautomerization. Step 4: Michael-type addition. Step 5: Rearomatization. Step 6: Protonation of hydroxyl group making a better leaving group. Step 7: Elimination of water. Step 8: Deprotonation gives the desired product. Application Coumarin and its derivatives are widely used as additives in food, perfumes, cosmetics, agrochemicals, dyes, and pharmaceuticals. Experimental Procedure (from patent US7202272B2)

O HO

OH A

O

H2SO4 OEt

+

TFA

B

HO

O

O

C

Resorcinol (compound A) (1.21 g, 11.0 mmol) was dissolved in hot ethyl propionylacetate (1.52 g, 10.0 mmol) (compound B). To this stirred mixture at ice-water temperature was added dropwise a mixture of trifluoroacetic acid (1.70 ml, 22.0 mmol) and concentrated sulfuric acid (2.2 ml, 22.0 mmol) at such a rate that the reaction temperature was kept below 10 ∘ C (about 30 minutes). The reaction mixture was then allowed to warm to room temperature and thereupon stirred for an additional three hours before being quenched cautiously with ice water. After stirring the suspension that formed for one hour, the bright yellow precipitate was collected by suction filtration, washed exhaustively with water, and then redissolved into acetone. The resulting solution was heated with activated charcoal, filtered, and evaporated to give a light orange residue that was dried azeotropically with isopropyl alcohol. The crude product that obtained was purified by recrystallization from acetone/hexane (2 : 3) to give compound C as creamy crystals (806 mg, 4.24 mmol, 42%); m.p. 175–178 ∘ C (Lit. 177 ∘ C).

Perkin Condensation or Reaction The Perkin condensation (also known as Perkin reaction) is an organic reaction between an aromatic aldehyde and an anhydride containing α-hydrogens using sodium acetate to give an α,β-unsaturated carboxylic acid (either E or Z or a mixture of E and Z). The reaction was discovered by the British chemist William Henry Perkin in 1868 [1, 2]. Several new catalysts have been developed for this reaction [3–26].

Perkin Condensation or Reaction

O O

H

O

O

1. CH3CO2Na

O

+ Benzaldehyde

OH

2. Acid work-up

Acetic anhydride

Cinnamic acid

Mechanism O O

O

O

Step 1

H

O

O

Step 2

O

O

O

O O Step 3

H

O O O O O

O

O O

O

O O

H O

O

O Step 5

Step 4

O

O O

O O

O Step 6

O O H

O

O

E2

O

O

O

O

O

O

O

Step 8

O O

O

Step 7

O

O

Step 9

O

O O

Step 10

O

OH Acid work-up

Step 1: Abstraction of an α-hydrogen with the carboxylate leads to the formation of an enolate. Step 2: Aldol-type condensation and nucleophilic addition of the carbanion to the aldehyde. Step 3: Intramolecular nucleophilic addition forms a cyclic intermediate. Step 4: Intramolecular acyl transfer. Step 5: Carboxylate attacks on acetic anhydride. Step 6: Elimination of a carboxylate. Step 7: Abstraction of α-hydrogen and elimination of another carboxylate. Step 8: Acetate attacks to the carbonyl carbon atom. Step 9: Elimination of acetic anhydride.

87

88

2 Condensation Reaction

Step 10: Protonation of the carboxylic group from acidic work-up gives the desired product. Application The dietary supplement resveratrol has been synthesized using this reaction [12]. Total syntheses of combretastatin A-4 [12], coumestrol, and aureole [19] have been completed utilizing this reaction. Experimental Procedure (from patent US4933001A) Synthesis of 5-(2′ -Chloro-5′ -nitrophenyl)-2,4-dimethyl-2,4-pentadienoic acid O

Cl

Cl H

O

+ O

CO2H

Sodium propionate O

140 °C

NO2

NO2

C

B

A

22.6 g of 2-chloro-5-nitro-α-methylcinnamaldehyde (compound A) and 9.6 g of sodium propionate were added to 16.3 g of propionic anhydride (compound B), and the mixture was stirred for 22 hours at 140 ∘ C. After cooling, the reaction mixture was poured into 100 ml of water, brought to pH 10 (NaOH), and extracted with ethyl acetate. The aqueous phase was acidified with concentrated HCl; the precipitate was separated out was filtered off with suction, washed with water, and dried. 18 g (64% of theory) of a yellow solid of melting point 180–182 ∘ C (compound C) was obtained.

Stobbe Condensation The Stobbe condensation is an organic reaction between diethyl succinate and an aldehyde or a ketone under a strong base such as sodium ethoxide or potassium tert-butoxide or sodium hydride to give an unsaturated ester acid. This reaction is named after von Hans Stobbe in 1893 [1]. Several modification, mechanistic, and theoretical studies have been reported [2–27]. O R1

O R2

OEt OEt

+ O

KOt-Bu Heat

R1 R2

CO2K CO2Et

HCl H 2O

R1 R2

CO2H CO2Et

Stobbe Condensation O Ph

O

OEt OEt

+

Ph

CO2K

Ph

KOt-Bu Heat

CO2Et

Ph

CO2H

Ph

HCl H2O

CO2Et

Ph

O

O

OEt OEt

+

CO2H

CO2K

O KOt-Bu

CO2Et

HCl

CO2Et

H2O

Heat

O

Mechanism O

OEt OEt

H O t-BuO

O

O

O

OEt

Step 1

R1

OEt Enolate formation

Aldol addition

O R1

O

Step 2

R2

OEt O

OEt

O

OEt Step 3

Lactone formation

R1 R CO Et 2 2

Step 4

O R2

O O R1 R2

CO2H CO2Et

H Acid work-up

R1 R2

CO2 CO2Et

Ring Opening Step 5

R1

R2 H CO2Et

t-BuO

Step 6

Step 1: Abstraction of an α-hydrogen and formation of resonance-stabilized carbanion Step 2: Aldol addition with the ketone Step 3: Intramolecular cyclization Step 4: Elimination of ethoxide and formation of a lactone Step 5: Reversible ring opening Step 6: Proton transfer from HCl to carboxylic acid Application Painkiller medicine codeine [26] was synthesized using the Stobbe conditions. Syntheses of the core of purpuromycin [21] and natural product schweinfurthins [25] have been completed utilizing this reaction.

89

90

2 Condensation Reaction

Experimental Procedure (from patent US20160137682A1) O OMe OMe

+

HO OMe A

O

O

H

O

OMe

1. Li, MeOH, reflux, 48 h 2. H2SO4, MeOH, reflux, 24 h

B

OMe

HO O

OMe C

To a solution of vanillin (compound A) (14.0 g, 92.1 mmol, 1 equiv.) and dimethyl succinate (compound B) (12.13 ml, 92.1 mmol, 1 equiv.) in MeOH (450 ml) and lithium wire (1.79 g, 257.9 mmol, 2.8 equiv.) was added slowly piecewise with an ice bath to control the exotherm. After the initial lithium had fully dissolved, more lithium (1.98 g, 285.5 mmol, 3.1 equiv.) was added slowly piecewise and stirred until fully dissolved. The reaction mixture was then heated at reflux for 48 hours. After cooling the solution to room temperature, most of the methanol was removed by concentration on rotary evaporator. EtOAc (1000 ml) was added, and the solution was washed with a 2 M aqueous HCl solution (700 ml), H2 O (3 × 1000 ml), and then brine (200 ml). The organic layer was then dried over anhydrous MgSO4 , filtered, and concentrated. The crude was dissolved in MeOH (230 ml), H2 SO4 (1 ml) was added, and the solution was heated at reflux overnight. Upon cooling the next morning, NaHCO3 (3.0 g) was added to quench H2 SO4 , and the solution was mostly concentrated by rotary evaporator. EtOAc (500 ml) was added, and the solution was washed with H2 O (2 × 200 ml) and then brine (100 ml). The organic layer was then dried over anhydrous MgSO4 , filtered, and concentrated to a brown oil. Dissolution in a small amount of CH2 Cl2 and then flash column chromatography (silica gel, 20–50% ethyl acetate in hexane) provided product (18.0 g, 64.2 mmol, 70% yield, unassigned olefin geometry) as an off-white solid, compound C, Rf = 0.17 (silica, ether : hexane 1 : 1).

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91

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Mukaiyama Aldol Reaction

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Perkin, W.H. (1868). J. Chem. Soc. 21: 181–186. Perkin, W.H. (1877). J. Chem. Soc. 32: 660–674. Kalnin, P. (1928). Helv. Chim. Acta 11: 977–1003. Johnson, J.R. (1942). Org. React. 1: 210–265. Dippy, J.F.J. and Evans, R.M. (1950). J. Org. Chem. 15: 451–456. Buckles, R.E. and Bremer, K.G. (1953). J. Am. Chem. Soc. 75: 1487–1489. Rai, M., Krishan, K., and Singh, A. (1977). Indian J. Chem., Sect B 15B: 847–848. Kinastowski, S. and Nowacki, A. (1982). Tetrahedron Lett. 23: 3723–3724. Rosen, T. (1991). The Perkin reaction. In: Comprehensive Organic Synthesis, vol. 2 (eds. B.M. Trost and I. Fleming), 395–408. Oxford: Pergamon Press. Gaukroger, K., Hadfield, J.A., Hepworth, L.A. et al. (2001). J. Org. Chem. 66: 8135–8138. Lee, J.Y., Park, J.H., Lee, S.J. et al. (2002). Arch. Pharm. 335: 277–282. Solladié, G., Pasturel-Jacopé, Y., and Maignan, J. (2003). Tetrahedron 59: 3315–3321. Moreau, A., Chen, Q.H., Praveen Rao, P.N., and Knaus, E.E. (2006). Bioorg. Med. Chem. 14: 7716–7727. Sharma, N., Sharma, A., Shard, A. et al. (2011). Chemistry 17: 10350–10356. Kouznetsov, V.V., Meléndez Gómez, C.M., Derita, M.G. et al. (2012). Bioorg. Med. Chem. 20: 6506–1652. Sarkar, P., Durola, F., and Bock, H. (2013). Chem. Commun. (Camb). 49: 7552–7554. Pu, W., Lin, Y., Zhang, J. et al. (2014). Bioorg. Med. Chem. Lett. 24: 5423. Sánchez, E.L., Santafé, G.G., Torres, O.L. et al. (2014). Biomedica 34: 605–611. Sheng, J., Xu, T., Zhang, E. et al. (2016). J. Nat. Prod. 79: 2749–2753. Kumar, N.P., Sharma, P., Reddy, T.S. et al. (2017). Eur. J. Med. Chem. 127: 305–317.

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21 Ferreira, M., Naulet, G., Gallardo, H. et al. (2017). Angew. Chem. Int. Ed. Engl.

56: 3379–3382. 22 Kumar, N.P., Sharma, P., Reddy, T.S. et al. (2018). Eur. J. Med. Chem. 151:

173–185. 23 Lenz, D., Koeppe, B., Tolstoy, P.M., and Limbach, H.H.J. (2019). J. Labelled

Compd. Radiopharm. 62: 298–300. 24 Kumari, K., Vishvakarma, V.K., Singh, P. et al. (2017). Curr. Med. Chem. 24:

4579. (review). 25 Kurty, L. and Czako, B. (2005). Strategic Applications of Named Reaction in

Organic Synthesis, 338. Elsevier. 26 Kumar, N.P., Sharma, P., Reddy, T.S. et al. (2018). Eur. J. Med. Chem. 151: 173.

Stobbe Condensation 1 Stobbe, H. (1893). Ber. Dtsch. Chem. Ges. 26: 2312–2319. 2 Johnson, W.S., Goldman, A., and Schneider, W.P. (1945). J. Am. Chem. Soc.

67: 1357–1360. 3 Daub, G.H. and Johnson, W.S. (1948). J. Am. Chem. Soc. 70: 418–419. 4 Johnson, W.S., Davis, C.E., Hunt, R.H., and Stork, G. (1948). J. Am. Chem.

Soc. 70: 3021–3023. 5 Newman, M.S. and Linsk, J. (1949). J. Am. Chem. Soc. 71: 936–937. 6 Daub, G.H. and Johnson, W.S. (1950). J. Am. Chem. Soc. 72: 501–504. 7 Johnson, W.S., McCloskey, A.L., and Dunnigan, D.A. (1950). J. Am. Chem. 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Soc. 72: 514–517. Turner, D.L. (1951). J. Am. Chem. Soc. 73: 3017–3021. Johnson, W.S. and Daub, G.H. (1951). Org. React. VI: 1–73. Turner, D.L. (1953). J. Am. Chem. Soc. 75: 1257–1258. Islam, A.M. and Zemaity, M.T. (1958). J. Am. Chem. Soc. 80: 5806–5808. Soffer, M. and Donaldson, A. (1958). J. Org. Chem. 23: 308–309. El-Abbady, A.M., Doss, S.H., Moussa, H.H., and Nossier, M. (1961). J. Org. Chem. 26: 4871–4873. Coombs, M.M., Jaitly, S.B., and Crawley, F.E. (1970). J. Chem. Soc. Perkin 9: 1266. Morreal, C.E. and Alks, V. (1975). Org. Chem. 40: 3411–3414. Reutrakul, V., Kusamran, K., and Wattanasin, S. (1977). Heterocycles 6: 715–719. Gupta, G. and Banerjee, S. (1990). Indian J. Chem., Sect B 29B: 787–790. Boger, D.L., McKie, J.A., Cai, H. et al. (1996). J. Org. Chem. 61: 1710. Liu, J. and Brooks, N.R. (2002). Org. Lett. 4: 3521. Sato, A., Scott, A., Asao, T., and Lee, M. (2006). J. Org. Chem. 71: 4692–4695. Lowell, A.N., Fennie, M.W., and Kozlowski, M.C. (2008). J. Org. Chem. 73: 1911–1918. Miyazaki, H., Ohmizu, H., and Ogiku, T. (2009). Org. Process Res. Dev. 13: 760–763. Miyazaki, H., Sai, H., Ohmizu, H. et al. (2010). Bioorg. Med. Chem. 18: 1968.

Stobbe Condensation

24 Pillay, A., Rousseau, A.L., Fernandes, M.A., and de Koning, C.B. (2012). Org.

Biomol. Chem. 10: 7809–7819. 25 Kodet, J.G. and Wiemer, D.F. (2013). J. Org. Chem. 78: 9291. 26 White, J.D., Hrnciar, P., and Stappenbeck, F. (1999). J. Org. Chem. 4:

7871–7884. 27 Kim, M. and Vedejs, E. (2004). J. Org. Chem. 69: 6945–6948.

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3 Olefination, Metathesis, and Epoxidation Reactions Olefination Corey–Winter Olefin Synthesis Conversion of 1,2-diols to the corresponding olefins (alkenes) using thiophosgene or thiocarbonyldiimidazole and trimethylphosphite is called Corey–Winter olefin reaction [1]. This reaction is a stereospecific reaction such as a trans-diol produces a trans-alkene, while a cis-diol forms a cis-alkene as the product [1–4]. Several modifications and mechanistic studies have been reported [5–16]. R2

OH +

R1

OH

R2

OH OH

Cl

Cl

N

R2

P(OMe)3

S

Heat

R1

S +

R1

DMAP

S

R2 N

S N

R1

P(OMe)3 Heat

R2

H

R1

H

+ SP(OMe)3 + Co2

R2

H

R1

H

+ SP(OMe)3 + CO2

N

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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3 Olefination, Metathesis, and Epoxidation Reactions

Mechanism S N

N

N

N

N R2

N Step 1

ÖH

O

R1

OH

R1

R2

N

N

N

N

Step 2

N S

OH

R2

O

R1

.. OH

S

Step 3

R2 R1

O

N

O

S

Step 4 R2

O

S P(OMe)3

O

R1

Step 6

R2 R1

O

Step 5

R2

O

O S

S P(OMe)3 R1

O P(OMe)3

P(OMe)3 Step 7 O R2

O

S=P(OMe)3 +

H

R1

H

P(OMe)3

O

R1

Step 8 R2

+

O

P(OMe)3

CO2

+ P(OMe)3

Step 1: Nucleophilic addition [4, 5]. Step 2: Elimination of one imidazole group. Step 3: Formation of cyclic intermediate. Step 4: Liberation of another imidazole unit. Step 5: Nucleophilic attack of P(OMe)3 on thionocarbonate. Step 6: Formation of P—S bond. Step 7: Another nucleophilic addition and liberation of (OMe)3 P=S. Step 8: Two C—O bonds breaking from the complex and formation of an olefin. Application Syntheses of several natural products such as (+)-crotepoxide, (+)-boesenoxide, (+)-senepoxide, (+)-pipoxide acetate, (−)iso-crotepoxide, (−)-senepoxide, and (−)-tingtanoxide [8], radiosumin [7], and brassinosteroid [14] have been accomplished utilizing this reaction. Experimental Procedure (from patent US5807866A) CH3 N P N CH3

S N

OH OH

N

DMAP

N N

+ N

N O

CH2Cl2

O

A

C

N

THF, 60 °C

S

Step 1 B

D

Step 2

E

Horner–Wadsworth–Emmons Reaction

Step 1: A mixture of compound A (25.72 mmol), 1,1′ -thiocarbonyldiimidazole (compound B) (6.50 g, 36.47 mmol), and 4-dimethylaminopyridine (0.10 g, 0.82 mmol) in dry dichloromethane (120 ml) was stirred at 25 ∘ C under nitrogen for four hours and adsorbed onto silica (c. 25.0 g). Column chromatography (ethyl acetate-light petroleum [b.p. 40–60 ∘ C], 1 : 4) provided the title compound C (11.66 g, 91%) as a pale yellow oil that crystallized on standing to afford an orange/brown foam. Step 2: A magnetically stirred solution of C (23.39 mmol) in dry tetrahydrofuran (THF) (80 ml) under nitrogen was treated with 1,3-dimethyl-2-phenyl-1,3,2diazaphospholidine (compound D) (10.8 ml, 58.47 mmol) in one portion. The mixture was degassed and flushed with nitrogen (three times) and then heated at 60 ∘ C for seven hours. The cooled solution was adsorbed onto silica gel (c. 30 g) and column chromatography (ethyl acetate-light petroleum to afford compound E in 80% yield).

Horner–Wadsworth–Emmons Reaction The Horner–Wadsworth–Emmons reaction is an organic reaction of an aldehyde or ketone with stabilized phosphorus ylide (phosphonate carbanion) to form a predominately E-alkene [1–4]. The by-product dialkyl phosphate salt is easily removed by aqueous extraction. This is an advantage compared with the Wittig reaction. Stereochemistry (E/Z) depends on reaction conditions such as base, reaction temperature, substrates, and others [5–52].

O EtO P EtO

O

1. NaH

O OEt

2. R-CHO

R

OEt

+

O EtO P ONa EtO Water soluble

Mechanism Mechanism is similar to Wittig reaction.

Application Several natural products including stigmatellin A [9], vitamin D3 [15], FR182877 [16], (+)-migrastatin [20], furaquinocin A, B [21], macrolide antitumor agent rhizoxin D [23], (+)-zoapatanol [24], pyranicin [26], (−)-isodomoic acid C [27], (+)-dactylolide [29], (−)-bitungolide F [33], palmerolide A [34], (−)-platensimycin [35], brevenal [36], antibiotic thuggacin A [44], baulamycin A [45], and asperchalasines A, D, E, and H [46] have been synthesized under this reaction condition.

113

114

3 Olefination, Metathesis, and Epoxidation Reactions

Experimental Procedure (from patent JPWO2015046403A1) N O O O P MeO O OMe

1. NaH, THF Ph

O O

N

2.

H

N

A

Ph

N

O

C

O

O

B

O

Synthesis of 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl) acrylic acid (E)-benzyl. To a suspension of sodium hydride (0.125 g, 2.85 mmol, 55%) in THF (3.5 ml) at 0 ∘ C, benzyl dimethylphosphonoacetate (compound A) (0.700 g, 2.71 mmol) in THF (3 ml) solution was added. After stirring at the same temperature for 30 minutes, a solution of tert-butyl 2-(2-formyl-1H-imidazol-1-yl) acetate (0.600 g, 2.85 mmol) (compound B) in THF (3 ml) was added, and the temperature was raised to room temperature. The mixture was stirred for 15 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, n-hexane/ethyl acetate), and 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl) acrylic acid (E)-benzyl (compound C, 0.82 g, 2.39 mmol, 82%) was obtained as a yellow oil.

Julia–Lythgoe Olefination The Julia olefination or called the Julia–Lythgoe olefination is an organic reaction of phenyl sulfone with an aldehyde or ketone using butyllithium and acetic anhydride and finally reductive elimination by Na/Hg to form an E-olefin predominately [1, 2]. Several modifications and improvements on this reaction have been reported [3–22]. 1. n-BuLi Ph R

S O O

2. R1-CHO 3. Ac2O

AcO R

R1 Ph S O O

R1

Na(Hg) EtOH

R E

Julia–Lythgoe Olefination

Mechanism O

n-Bu

R

R1

Step 1

H

H

Ph S O O

S O O

R

SO2Ph R1

Step 2

Ph

R

SO2Ph R1

Step 3 R

O

O

O O

O O

O

O Step 4

R1

Step 7

SET

R1

R

R

OAc

Na(Hg)

R1 R

Step 6

SET

OAc

R

SO2Ph R1 OAc

– PhSO2M Step 5

Step 1: Deprotonation and formation of a carbanion. Step 2: Nucleophilic attacks by the carbanion at electron-deficient carbonyl carbon atom. Step 3: Acyl transfer. Step 4: Loss of acetic acid. Step 5: Single-electron transfer. and loss of PhSO2 M. Step 6: Loss of an acetate group. Step 7: Formation of an alkene. Modified Julia Olefination The modified Julia olefination provides an alkene from a benzothiazol-2-yl sulfone and an aldehyde in a single step. The replacement of phenyl sulfone with benzothiazole sulfone leads the reaction faster pathway. O S O

N S

O

R +

R1

LDA

R1

H

+

R1

R

R

Mechanism N S

O R S O H

LDA

N S

Step 1

O S O

Step 2

R

S

O

Li

R N OLi S

+ SO2

+

R1

Step 5

Li

Step 3

R

O

H

R1

O S O

N

O O N S S

O

R1 Step 4 N

R O

S

R1

S O Li O

R R1

115

116

3 Olefination, Metathesis, and Epoxidation Reactions

Step 1: Abstraction of the H by LDA. Step 2: Nucleophilic addition of carbanion to the electron-deficient carbonyl carbon atom gives an alkoxide intermediate. Step 3: Alkoxide attacks at C=N. Step 4: This intermediate undergoes a rearrangement reaction to give the sulfonate salt. Step 5: The sulfonate salt spontaneously liberates SO2 and forms an alkene. Application

Total syntheses of natural products including (−)-macrolactin A [12], isoprostane [13], JS isoprostane [14], neolaulimalide, isolaulimalide [17], and antitumor agents neolaulimalide [18], bimatoprost [20], and tafluprost [22] have been accomplished utilizing this reaction. Experimental Procedure (from patent CN103313983A) F N S

O S O

O

O

O

NaHMDS

O

O THF, –70 °C

A

+ F

O

O O

N N N SO2Me C

O H

N N N SO2Me B

A mixture of B (5.7 g, 16.3 mmol) and A (8.0 g, 18.1 mmol) in THF (104 ml) was heated until all reagents were dissolved and then the mixture was cooled to –70 ∘ C. At this temperature −70 ∘ C was added 27.2 ml of a solution of NaHMDS (20% solution in THF total 27.2 mmol, 1.5 equiv.) in one hour. When the feed was completed, the reaction mixture was stirred for one hour at −70 ∘ C. HPLC analysis showed 68% product was formed. Quenched with 10% aqueous NH4 Cl (100 ml), the aqueous phase was separated and washed with 10% of the NH4 C1 aqueous solution of the organic phase two times. Subsequently, the organic phase was washed three times with water at pH 12 (using 1M NaOH solution). The organic phase was evaporated to dryness, and the residue was crystallized from isopropanol to give the product as a solid (compound C).

Julia–Kocienski Olefination

Julia–Kocienski Olefination The Julia–Kochienski olefination is a further refinement of the modified Julia olefination. This method gives very good E-selectivity. Benzothiazole sulfone is replaced by tetrazole sulfone [1–3]. Modifications, improvements for E/Z selectivity, and mechanism studies have been reported [4–54]. N N N N Ph

O S O

N N N N

O S Me O

O

R +

R1

O

R1

KN(SiMe3)2 H

R

Me

Me NaHMDS

+

THF, –78 °C OMe

OMe

H H

O H H +

TBSO

Ph O N N S N N O

KHMDS OH

DME

H

OH

H

OTBS TBSO

OTBS

Application Rosuvastatin derivative was synthesized using Julia–Kocienski or Julia modified olefination reaction as mentioned in experimental procedure after deprotection and saponification to give rosuvastatin (a medicine to reduce cholesterol). F

OH OH

O

(E)

N N N SO2Me

(S)

(R)

OH

117

118

3 Olefination, Metathesis, and Epoxidation Reactions

Syntheses of microtubule-stabilizing antitumor agent laulimalide [4], antiviral agent cycloviracin B [5], peridinin [6], mucocin [7], spirotryprostatin B [9], cylindramide [11], (−)-bitungolide F [15], (+)-aspergillide B [17], (+)-aspergillide C [20], laurenditerpenol [22], penaresidin A [23], iriomoteolide [26], jerangolid A [27], (+)-chamuvarinin [28], maresin [29], (+)-mupirocin H [31], (+)-sorangicin A [32], cladospolides A–C [33], (−)-viridiofungin A [35], polyketide apiosporic acid [37], FD-891 [40], brefeldin A [41], mandelalide A [45], and paecilomycin C [51] have been accomplished under Julia–Kocienski conditions. Experimental Procedure (from patent WO2016125086A1)

O

N N O N S N O

O

O F O

A

O

O

O

THF +

O

N

F

NaH

N M SO2Me C

O H

N N M SO2Me B

To a solution of N-[4-(4-fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]N-methylmethanesulfonamide (B) (100 g), compound A (130 g), and NaOH (11.4 g) in THF (2000 ml), sodium hydride was added (28.5 g) lot-wise at −3 to 3 ∘ C. The reaction mixture was maintained for 30 minutes at −3 to 3 ∘ C, and then the temperature was gradually allowed to raise to 25–35 ∘ C and stirred until the reaction completion. The reaction mixture was quenched with 10% potassium carbonate solution (1000 ml) and extracted with ethyl acetate. The organic layer was washed with 10% NaCl solution and concentrated under vacuum. The resulting residue was triturated with methanol (500 ml), filtered the precipitated white solid, and was dried at 55 ∘ C to afford 120 g of the title compound C (HPLC purity: >98% and Z-isomer content: 400 ∘ C). β-H H R1

R2

H

1. NaOH, CS2

OH R3

2. MeI

1°, 2°, or 3° alcohol

R1

O

S

R2

Heat

R2 R3 S

R1

R3

O + C + CH3–SH S

Alkyl xanthate

β-H H OH

S

1. NaOH, CS2 O 2. MeI

Heat S

Alkyl xanthate

O + C + CH3–SH S

Cannizzaro Reaction

Mechanism

S

H O

R1

S

O

Step 1 +

Ei

R1

S H

S

O C + Me–SH S

Step 1: Intramolecular (Ei) syn elimination. Application Total syntheses of (−)-kainic acid [9] and (±)-ferrugine [12] have been completed using this reaction. The drug-like scaffolds cyclohepta[b]indoles [13] were synthesized under the reaction conditions. Experimental Procedure (from Reference [10], copyright 2008, American Chemical Society) S S N Bn

O

NEt2

258 °C Diphenyl ether

A

N Bn

O

B

A solution of dithiocarbamate (compound A) (820 mg, 2.44 mmol) in diphenyl ether (24 ml) was heated at reflux for a period of two hours under an atmosphere of argon. The reaction mixture was purified by column chromatography (2 : 1–1 : 1 pet. ether/diethyl ether), yielding the exocyclic enone (compound B) (394 mg, 86%) as a yellow oil.

Cannizzaro Reaction The Cannizzaro reaction or disproportionation reaction is a redox reaction between aromatic aldehydes or aliphatic aldehydes that do not have α-hydrogen in the presence of hydroxide to form the corresponding primary alcohols and

173

174

4 Miscellaneous Reactions

carboxylic acids [1]. The reaction is named after the Italian chemist Stanislao Cannizzaro, who discovered it in 1853. Several new catalysts such as biocatalyst [35], Fe-chiral catalyst [38], and other conditions have been investigated [2–42]. The enantioselective intramolecular [28] version has been reported. O

O

H

O

OH

H

OH

1. NaOH +

+ 2. Acid work-up

O H

O

1. NaOH

HCH2–OH

+

H

H

H

+

O

H

+

H–CO2H

2. Acid work-up

H

1. NaOH

OH

O

O

O

2. Acid work-up

O

+

OH O

O

Mechanism

O

O

H

H

H O

OH

Step 1

H

H Cl

O O

H OH

H O

O

O

O

O H H H

Step 3 +

Step 2 Dianion

Hydride transfer

O

Step 5

Step 4

OH

OH

Step 1: The reaction starts with a nucleophilic (hydroxide) attack on the electron-deficient carbonyl carbon atom. Step 2: An abstraction of proton gives a dianion. Step 3: The unstable intermediate dianion then transfers a hydride ion to another molecule of aldehyde. In this process the dianion provides to a carboxylate anion and second aldehyde to an alkoxide. Step 4: Alkoxide takes up a proton from the solvent (water) as alkoxide is more basic than water so the reaction can proceed. Step 5: In acidic work-up, the carboxylate is less basic than water. So it cannot take proton from water. It takes proton from an acid.

Cope Elimination Reaction

Application Isofagomine analogs [18] and nigricanin [34] have been synthesized using this reaction. Experimental Procedure (general) O

O 50% KOH

H Cl

OH

OH +

Cl

MeOH A

Cl C

B

4-Chlorobenzaldehyde (compound A) (2 g) was dissolved in methanol (6 ml). 50% KOH solution in water (4 ml) was added to the reaction mixture and stirred at 65 ∘ C for two hours. The reaction mixture was cooled to room temperature, and then 50 ml water was added. The aqueous layer was extracted with CH2 Cl2 (3 × 20 ml). The combined organic layer was washed with brine, dried over anhydrous MgSO4 , and concentrated in vacuo to give 4-chlorobenzyl alcohol (compound B). Aqueous layer was acidified with 6 N HCl and cooled in ice bath to form the precipitation. The solid was filtered and washed with water. The solid was dried under high vacuum. The solid was recrystallized in methanol to give a pure 4-chlorobenzoic acid (compound C).

Cope Elimination Reaction The Cope reaction or Cope elimination, discovered by the American chemist Arthur Clay Cope, is an organic reaction of the N-oxide containing at least one β-H atom to form an olefin and a hydroxylamine via thermally syn elimination [1–5]. The N-oxide is prepared by oxidation of the corresponding tertiary amine [6–22] with an oxidant such as mCPBA or H2 O2 . Solvent effect [12], theoretical [15], and computational study [22] have been reported. H2O2

H N

R

H R

or m-CPBA

O N

Heat +

R

3° amine oxide N-Oxide

Mechanism

H R

O N

Step 1

O H

Heat

R T.S.

N R

+

OH N

OH N

175

176

4 Miscellaneous Reactions

Step 1: Intramolecular (Ei) syn (cis) elimination reaction forms a planar cyclic five-membered transition state. Application 1,4,6,7-Tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists [21] have been synthesized under the reaction conditions. Experimental Procedure (from Reference [3], copyright, Organic Syntheses) H2O2 NMe2 MeOH

NMe2 O

160 °C

In a carefully cleaned 500 ml Erlenmeyer flask, covered with a watch glass, were placed 49.4 g. (0.35 mol) of N,N-dimethylcyclohexylmethylamine (39.5 g, 0.35 mol) of 30% hydrogen peroxide and 45 ml of methanol. The homogeneous solution was allowed to stand at room temperature for 36 hours. After two and five hours, hydrogen peroxide (39.5 g portions each time) was added. The excess hydrogen peroxide was destroyed by stirring the mixture with a small amount of platinum black until the evolution of oxygen ceases. The solution was filtered into a 500 ml round-bottom flask and concentrated at a bath temperature of 50–60 ∘ C, a water aspirator being used initially and an oil pump finally, until the amine oxide hydrate solidified. A Teflon-covered stirring bar was introduced into the flask, which was then connected by a 20 cm column to a trap (reversed to avoid plugging) cooled in dry ice/acetone. The flask was heated in an oil bath to 90–100 ∘ C, and the apparatus was evacuated to a pressure of c. 10 mm with stirring of the liquefied amine oxide hydrate. When the content of the flask resolidified, the temperature of the oil bath was raised to 160 ∘ C. The amine oxide was decomposed completely within about two hours at this temperature. Water (100 ml) was added to the contents of the trap. The olefin layer was removed with a pipette and washed with two 5 ml portions of water, two 5 ml portions of ice-cold 10% hydrochloric acid, and one 5 ml portion of 5% sodium bicarbonate solution. The olefin was cooled in a dry ice/acetone bath and filtered through glass wool. Distillation over a small piece of sodium through a semimicro-column yielded 26.6–29.6 g (79–88%) of methylenecyclohexane, b.p. 100–102 ∘ C.

Corey–Fuchs Reaction One-carbon homologation of an aldehyde to the corresponding terminal alkyne using CBr4 and Ph3 P followed by treatment with n-BuLi is called Corey–Fuchs reaction [1]. The first step is the conversion of an aldehyde to a homologated dibromoalkene. The second step is the conversion of dibromoolefin to a terminal alkyne using n-BuLi and acidic work-up. This reaction is named after American

Corey–Fuchs Reaction

chemists Elias James Corey and Philip L. Fuchs who discovered it in 1972. Different types of terminal alkynes can be synthesized under the reaction conditions [2–17]. R

CBr4, Ph3P

O H

R

Br

1. n-BuLi

H

Br

2. Acid work-up

R

H

Terminal alkyne

Aldehyde

Dibromoolefin

Mechanism Step 2

Step 1 Br3C Br

.. Ph3P

Ph3P Br

Br

SN2

SN2 CBr3

Step 3 PPh3

Br Br

Br

Br PPh3 Br

.. Ph3P

R

PPh3 Br Ylide

O

H Step 4 Li

n-Bu Li

Br Step 7

R

H n-Bu Li

Br

– nBu-Br R

H

Step 6 – Ph3PO

Br

PPh3 O R

Step 5 Br Br R

PPh3 O

Dibromoolefin

Step 8

Li Acid work-up R

Br

Br

H

Step 9 R

Step 1: Nucleophilic substitution reaction. Step 2: Another nucleophilic substitution reaction. Step 3: Formation of ylide. Step 4: Nucleophilic attacks by ylide to the electron-deficient carbonyl carbon atom of the aldehyde. Step 5: Ring closing. Step 6: Cleavage of C—O and C—P bonds gives a dibromoolefin. Step 7: Abstraction of bromide by n-BuLi. Step 8: Abstraction of proton by n-BuLi and elimination of bromide. Step 9: Acidic work-up and transfer of proton from acid gives the desired alkyne.

Application 6,7-Dehydrostipiamide [4] and calcitriol analogs [6] have been synthesized utilizing this reaction.

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4 Miscellaneous Reactions

Experimental Procedure (from patent JP2015500210A) Br

TBDPSO O CBr4, Ph3P

TBDPSO

H

Br

n-Bu-Li

TBDPSO

THF, –78 °C

CH2Cl2

A

C

B

Formation of Compound B

A solution of triphenylphosphine (4.31 g) dissolved in anhydrous dichloromethane (5.5 ml) was cooled to −10 ∘ C, and carbon tetrabromide (2.72 g) was dissolved in anhydrous dichloromethane (2.05 ml). The solution was added all at once. After the solution returned to −10 ∘ C, a solution of compound A (1.34 g) dissolved in anhydrous dichloromethane (3.15 ml) was added dropwise. The reaction mixture was stirred at −10 ∘ C for four hours before it was quenched with aqueous NaHCO3 (5% w/w, 10 ml). The phases were separated, and the organic layer was washed successively with water (10 ml) and brine (10 ml), then dried over anhydrous Na2 SO4 , filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient 0–5% v/v ethyl acetate/heptane as eluent to give compound B (1.3 g). Formation of Compound C

Compound B (1.0 g) was dissolved in anhydrous THF, stirred and cooled in a dry ice/acetone bath to −78 ∘ C, and 2.1 ml of a 2.5 M solution in hexane n-butyllithium was added dropwise. The reaction mixture was stirred at −78 ∘ C for 90 minutes further; it was warmed to 0 ∘ C and quenched with saturated aqueous ammonium chloride (5 ml). The reaction mixture was diluted with heptane (50 ml) and washed successively with 5% w/w aqueous sodium bicarbonate (100 ml) and brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless clear oil (0.9 g). This was then chromatographed on silica gel using gradient 5–40% v/v ethyl acetate/heptane as eluent to give compound C (0.52 g).

Corey–Nicolaou Macrolactonization The formation of lactones from 𝜔-hydroxyl acids using 2,2′ -dipyridyldisulfide and triphenylphosphine is referred to as the Corey–Nicolaou macrolactonization reaction [1, 2]. The lactones with ring sizes 4–48 can be synthesized using this reaction. The reaction rate depends on ring size and nature of substrate [3–16]. The addition of silver salts (AgBF4 ) for the activation of the pyridylthioester was observed to accelerate the reaction dramatically [5].

HO

( )n

Ph3P

O ( )n Hydroxy acid

O

H

+ N

S S

N

2,2′-Dipyridyl disulfide

Benzene, reflux

O O Lactone

Corey–Nicolaou Macrolactonization OH

1. 2,2′-Dipyridyl disulfide, Ph3P, r.t. 2. Benzene, reflux

HO CO2H

OH O O

O THPO

3. AcOH, H2O, THF, 60 °C

O

O

HO (±)-Zearalenone

Mechanism Step 1 N

S S

N

N

S

O

Step 2

+ PPh3

.. Ph3P

( )n

Ph3P O

S

N

O

H

O ( )n

O

N

H

N

( )n

S

Step 3

( )n

Step 4 Ph3P O S

( )n

O

H

N

HO

Step 6

2-Pyridinethiol ester

O O

O S

O

S

N

O

S

H

H

O Step 5

N

O

( )n

Step 7 ( )n

+

O

NH S

O Tetrahedral intermediate

Lactone

2-Pyridinethione

Step 1: Nucleophilic substitution reaction. Step 2: Carboxylate anion attacks at electrophilic phosphorus atom and another nucleophilic substitution reaction. Step 3: 2-Pyridyl thio anion attacks at electron-deficient carbonyl carbon atom. Step 4: Releases a stable Ph3 PO and gives 2-pyridinethiol ester. Step 5: Proton transfer provides a dipolar intermediate. Step 6: Ring closure provides a tetrahedral intermediate. Step 7: Releasing 2-pyridinethione from the intermediate gives the desired lactone. Application Total syntheses of natural products such as (±)-zearalenone [1], tricolorin A [11], batatoside L [13], and depsipeptide LI-F04a [14] have been completed using this reaction. Experimental Procedure (patent US20060004107A1) Preparation of 13,14-dihydro-15-dehydroxy-15-hydroxyethyl-5-oxa-prostaglandin E1 1,15-hydroxyethyl lactone

179

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4 Miscellaneous Reactions

A mixture of 13,14-dihydro-15-dehydroxy-15-hydroxyethyl-5-oxaprostaglandin E1 386.5 mg (1 mmol), triphenylphosphine 393 mg (1.5 mmol), and 2,2′ -dipyridyl disulfide 330 mg (1.5 mmol) and dry oxygen-free xylene 6 ml was stirred under nitrogen atmosphere at room temperature for 24 hours. The reaction mixture was diluted with 250 ml of xylene and heated at reflux for two hours. Xylene was removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and extracted. The ethyl acetate layer was washed with aqueous NaHCO3 and brine, dried over anhydrous MgSO4 , and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g; solvent ethyl acetate/hexane = 40/60 by volume). Fractions were monitored by thin layer chromatography, eluents were collected, the solvent was evaporated under reduced pressure, and resulting residue was dried under reduced pressure to give 13,14-dihydro-15-dehydroxy-15-hydroxyethyl-5-oxa-prostaglandin E1 1,15-hydroxyethyl-lactone.

Danheiser Annulation Lewis acid-promoted [3+2] cycloaddition of allenylsilanes (or propargylsilanes) and electron-deficient alkenes to produce highly substituted cyclopentene derivatives is known as Danheiser annulation [1–3]. The reaction proceeds a regioselective cycloaddition and stereoselective 1,2-silyl-migration pathway to provide unsaturated five-membered carbocycles and heterocycles [3–11]. O

O R2 R3

R1

R5

TiCl4

SiMe3

R1 R4

C

+ R6

R4

CH2Cl2, –78 °C

R7

Me +

C CH2

Me

O +

SiMe3

SiMe3 C CH2

SiMe3 R3

O

O

R2 R 7

R5

H

TiCl4 SiMe3 CH2Cl2, –78 °C

H

O TiCl4 CH2Cl2 , –78 °C

SiMe3

R6

Danheiser Benzannulation

Mechanism .. O

TiCl4 Step 1

Cl

O

TiCl3

TiCl3

Step 2

O

Me

O

SiMe3

TiCl3

Step 3

C CH2

SiMe3 [1,2]- Silyl shift

Allylic carbocation

Step 4 O TiCl3

O TiCl3

O Step 5

SiMe3

SiMe3

SiMe3

Silicon-stabilized cation

Step 1: Complexation of electron-deficient carbonyl group with TiCl4 . Step 2: Leaving chloride anion gives an allylic carbocation. Step 3: Regioselective nucleophilic addition of trimethylsilylallene to allylic carbocation produces a vinyl cation. Step 4: 1,2-Silyl migration through silicon-stabilized cation forms a β-sillylcarbenium ion intermediate. Step 5: Intramolecular nucleophilic addition to the cationic center gives the desired product.

Danheiser Benzannulation The synthesis of highly substituted benzene derivatives from cyclobutenones and acetylenes in one step at high temperature is referred to as the Danheiser benzannulation [12, 13]. A wide range of aromatic substituted rings can be synthesized utilizing this reaction such as phenol, naphthalenes, benzofurans, benzothiophenes, indoles, carbazoles, and others [14–28]. O

R3

R1

Heat

O

C

R1

OH X

R4

R2

X

R3 Cyclobutenone

R3

R4

R2 R2 R1 Highly substituted phenol

Vinylketene X = OR, OSiR3, SR, NR2

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4 Miscellaneous Reactions

Mechanism The mechanism follows through a cascade of four subsequent pericyclic reactions.

O

R1

R3

R2

R4 O Step 1

X C

R2

4 e-electrocyclic cleavage

Cyclobutenone

R1

O Step 2

R4

[2+2]

X

O

R1

R3

Vinylketene

R4

Step 3

R2

C

X

R3 4 e-electrocyclic cleavage

R3 R2

R1 Diphenylketene

2-Vinylcyclobutenone

Step 4 6 e-electrocyclic closure O

OH R4 X

R3

Step 5

R4

R2

Tautomerization

X

H R3 R2

R1

R1

Highly substituted phenol

Cyclohexadienone

Step 1: Upon heating above 80 ∘ C, cyclobutenone undergoes a four-electron electrocyclic cleavage, forming a vinylketene. Step 2: The vinylketene reacts with an alkyne in a regiospecific [2+2] cycloaddition to give a 2-vinylcyclobutenone. Step 3: Reversible a four-electron electrocyclic cleavage undergoes again to yield a dienylketene intermediate. Step 4: The dienylketene undergoes a six-electron electrocyclization to give a cyclohexadienone. Step 5: Rapid tautomerizes to yield a highly substituted phenol. Application Total syntheses of (−)-cylindrocyclophanes A [14], mycophenolic acid [16], Δ-6-tetrahydrocannabinol [15], and (+)-FR900482 [21] have been accomplished utilizing this reaction. Experimental Procedure (from Reference [22], Copyright 2013, American Chemical Society) CH3

O

CH3

Toluene

+ N CO CH 2 3

Bu

OH

A B

80–110 °C

Bu

N CO2CH3 C

Diels–Alder Reaction

A 10 ml, one-necked, round-bottom flask equipped with a reflux condenser fitted with an argon inlet adapter was charged with ynamide B (0.262 g, 1.71 mmol, 1.0 equiv.), cyclobutenone A (0.219 g, 1.76 mmol, 1.0 equiv.), and 2.1 ml of toluene. The yellow solution was heated at 75–90 ∘ C for two hours, at reflux for three hours, and then allowed to cool to room temperature. Concentration provided 0.475 g of an orange solid, which was dissolved in 10 ml of CH2 Cl2 and concentrated onto 2 g of silica gel. The free-flowing powder was added to the top of a column of 48 g of silica gel and eluted with 30% EtOAc in hexane to afford 0.370 g (78%) of product C as a pale yellow solid, m.p. 94–95 ∘ C.

Diels–Alder Reaction The [4+2] cycloaddition of a conjugated diene and a dienophile (an alkene or alkyne) to form a cyclic olefin under thermal conditions is called Diels–Alder reaction [1–4]. The driving force of the reaction is the formation of two new σ-bonds, which are energetically more stable than the π-bonds. For the discovery of this reaction, Otto Diels and Kurt Alder received the Nobel Prize in Chemistry in 1950. This reaction is widely used to synthesize complex molecules in academic and industrial settings [5–38]. Normal Electron Demand Diels–Alder Reaction EDG

EDG EWG +

EWG

Heat

OMe CO2Et + Me3SiO

OMe CO2Et

Heat Me3SiO

Danishefsky diene

Inverse electron Demand Diels–Alder Reaction EWG

EWG EDG +

Heat

EDG

EDG = electron-donating group (alkyl, O-Alkyl, N-Alkyl, etc.) EWG = electron-withdrawing group (CN, NO2 , CHO, COR, COAr, CO2 H, CO2 R, etc.) Hetero–Diels–Alder Reaction An example of hetero-Diels–Alder reaction, after rearrangement pyrrole derivative was obtained [18].

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4 Miscellaneous Reactions

R4

R4

R3

R4

R3

R3

N O

+ N O

N O

O

O

R2

R2

R2

R1

R1

R1

Mechanism The Diels–Alder reaction is a concerted pericyclic reaction with an aromatic transition state. The driving force of the reaction is the formation of two new σ-bonds. The endo product is the kinetic product that is explained by secondary orbital interactions. R

R R1

R R1

R1

Aromatic T.S.

Application The Diels–Alder reaction has been used for the synthesis of vitamin B6, cortisone, prostaglandins, reserpine (medicine for high blood pressure), and other medicines. Several natural products such as (−)-mniopetal E, [14], (−)-reveromycin B [15], (±)-momilactone A [17], (±)-parimycin [26], and (−)-daphenylline [27] have been synthesized under the reaction conditions. Experimental Procedure (from patent CA 2361682A1) O

O +

Heat

OH

OH

In a 1 l pressure reactor were charged acrylic acid (72 g, 1 mol), xylene, and 4-tert-butylcatechol (TBC) (as a polymerization inhibitor) 75 mg. Then while stirring the contents of the reactor, 1,3-butadiene 75 g was introduced into the reactor. After that, a temperature of the resultant mixture was elevated

Étard Reaction

to 120 ∘ C and left to react at this temperature for three hours. Thereafter, the analysis of the reaction product by NMR spectrometry and GC confirmed that 3-cyclohexene-1-carboxylic acid was obtained.

Dutt–Wormall Reaction The conversion of aryl diazonium salts to aryl azides using sulfonamide and sodium hydroxide is called the Dutt–Wormall reaction [1–5].

N2

O N N N S R NaOH H O

Cl

O + R S NH2 O

N3 +

O R S O

Mechanism Step 1 N N .. O H2N S R O

N N N

O N N Step 2 N S R HH O

O N N N S R H O OH

OH

Diazoaminosulfinate Step 3

N N N +

O S R O

Step 4

O .. N N N S R O

N3

Step 1: Nucleophilic attacks by the lone pair electrons of nitrogen atom of a sulfonamide to a diazo compound. Step 2: Deprotonation. Step 3: Abstraction of proton by a hydroxide ion. Step 4: Hydrolysis and formation of an aryl azide and a sulfinic acid.

Étard Reaction The oxidation of aromatic or heterocyclic bound methyl group to the corresponding aldehyde using chromyl chloride is known as the Étard reaction [1]. The reaction is named after the French chemist Alexandre Léon Étard. Unlike other

185

186

4 Miscellaneous Reactions

oxidizing agents such as KMnO4 or CrO3 , chromyl chloride does not oxidize aldehyde to carboxylic acid [2–14]. O CH3

CrO2Cl2

H

CS2 or CCl4

CrO2Cl2 N

H

CH3 CS2 or CCl4

N O

CrO2Cl2 O

CH3

H O

CS2 or CCl4

O

Mechanism One of the plausible mechanisms: Cl H O O Cr Cl Cl

H

Step 1

Step 2 O Cr Cl HO Cl

O Cl Step 3 Cl O Cr OH

H + Cl

Cr-OH

Step 1: Ene-type reaction. Step 2: [2,3]-Sigmatropic rearrangement. Step 3: Liberation of benzaldehyde from the complex. Application Two medicines, ephedrine and phentermine, were synthesized using this reaction. Total syntheses of natural products such as deguelin, tephrosin [11], elliptone, and 12aβ-hydroxyelliptone [12] have been accomplished utilizing this reaction as a key step. Benzaldehyde can serve as a precursor for various compounds including dyes, perfumes, and pharmaceuticals. Experimental Procedure (US8957255B2) O H

Oxidation reactions of toluene by metasl peroxides (ZnO2 and CdO2 ) were carried out in Teflon-lined autoclaves. About 15 ml of toluene (about 139 mmol) and about 3 mmol of metal peroxide (about 300 mg of ZnO2 or about 440 mg of CdO2 ) were sealed in about 20 ml autoclave and kept inside an oven that was

Finkelstein Reaction

preheated and maintained to the desired temperature (about 140–180 ∘ C) for definite time interval (about 1–12 hours). The reaction mixture within the autoclave was thereby maintained at a temperature ranging from about 140 to 180 ∘ C. At the end of the reaction, the autoclave was cooled to room temperature (about 25–30 ∘ C) naturally. The amount of the reaction products in the reaction mixture was estimated, and the reaction products were separated from the oxides by centrifugation or chromatography such as column chromatography using a SiO2 column to yield a pure product. Benzoic acid or other oxidation products were not formed.

Finkelstein Reaction The exchange of one halogen atom in alkyl halide to another halogen using a metal halide salt is known as the Finkelstein reaction [1]. This is an equilibrium reaction, but the reaction can be completed by exploiting on substantial solubility difference of sodium halides in acetone or by using a large excess of the halide salt. Sodium iodide is soluble in acetone, but sodium chloride and sodium bromide are not soluble in acetone, so these are precipitated during the reaction. The conversion of alkyl chlorides and bromides to the corresponding alkyl iodides can be easily accomplished utilizing this reaction. This reaction can be extended to convert the alkyl alcohols to the alkyl fluorides, iodides, bromides, and chlorides via mesylates or tosylates. Several improved methods have been developed [2–23] for this reaction using copper salts [16], photoinduced [17], enzymatic [22], or other conditions. NaX1 +

NaX

R1 X Alkyl halide

Acetone, reflux

R1 X1

Precipitated

New alkyl halide

X = Cl, Br, OMs, OTs; R1 = primary and secondary alkyl, allyl, benzyl When X = Cl then X1 = Br or I; when X = Br then X1 = I NaI

I

Br

+

NaBr

Acetone, reflux O

O

NaI

EtO

Br Acetone, reflux

EtO

I

+ NaBr

Mechanism Na X1 R1—X

S N2

R1—X1 + NaX

Single step: Bimolecular nucleophilic substitution reaction (SN 2) with inversion of stereochemistry if alkyl halide is chiral.

187

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4 Miscellaneous Reactions

Application Several natural products such as alkaloid (−)-stenine [8, 23], sesquiterpenoid nakijiquinones [9], (−)-brefeldin A [10], and δ-trans-tocotrienoloic acid [12] have been synthesized using this reaction. Experimental Procedure (from patent WO2019134765A1) O

O NaI

Cl

I

OBn

OBn

Acetone, reflux A

B

Benzyl 5-chlorovalerate A (3.17 g, 13.98 mmol) was dissolved in acetone. Sodium iodide (2.60 g, 17.35 mmol) was added to the solution. This mixture was heated to reflux under argon for five hours. The white solid was filtered off and the filtrate was removed under vacuum. The residue was diluted with diethyl ether (30 ml) and washed with water (10 ml) and then brine (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to afford product B as a colorless oil (3.51 g, 79%).

Fischer–Speier Esterification A protic acid-catalyzed esterification of carboxylic acid using primary or secondary alcohol is known as the Fischer–Speier or simply Fischer esterification [1]. The reaction was named after Emil Fischer and Arthur Speier in 1895. A variety of carboxylic acids can be esterified using this reaction [2–6].

R

O

Cat. HCl

O OH

+ R1 OH

R

O

R1

+

H2O

Or cat. H2SO4 Heat

Mechanism

H

R

H

H

.. O

O

Step 1 OH

R R1

HO Step 2 R

OH .. O H

OH O H R1

Step 3

HO R

.. OH O R1

Step 4 H O +H

R

OH2 O R1

Cl Step 5 –H H2O +

O R

O

R1

Mukaiyama Esterification

Step 1: Proton transfer from an acid catalyst to carbonyl oxygen makes electrophilic center of carbon atom. Step 2: Nucleophilic attacks with lone pair electrons of oxygen atom of an alcohol to the carbonyl carbon atom. Step 3: Deprotonation. Step 4: Protonation one of the hydroxyl group. Step 5: Elimination of water and formation of ester. Experimental Procedure (general) O

O

MeOH, H2SO4

OMe

OH 65 °C

Benzoic acid (1.22 g) was dissolved in methanol (50 ml). Conc. H2 SO4 (0.2 ml) was added slowly and carefully to the reaction mixture, and the reaction mixture was stirred at 65 ∘ C until completion of reaction. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (200 ml), and the organic layer was washed with saturated sodium bicarbonate solution (2 × 60 ml) (removing if any benzoic acid was present) and brine and dried (MgSO4 ). The organic layer was concentrated in vacuo to afford methyl benzoate (82% yield). This method works only with simple alcohols such as MeOH, EtOH, n-PrOH, etc.

Mukaiyama Esterification The esterification from a carboxylic acid and an alcohol using Mukaiyama reagent is referred to as the Mukaiyama esterification [1–4]. This reagent or polymer-supported Mukaiyama reagent is used for the formation of amides, lactones, β-lactams, 1,3-oxathiolan-5-one, and others [1–11]. Mukaiyama reagent X O R

OH

N R2

+ R1 OH

O R

Base

X = Cl, Br Y = I, BF4 , CH3 CO2 , Tf2 N,

Y

O

R1

189

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4 Miscellaneous Reactions

Mechanism O R

O

Step 1 O

H

R

X

N R2

O

Step 2

Y

.. O N X R2

R

.. NEt3

O

Step 3

O

O

R .. O R1

N R2

H

Step 4

O + O

R

O

R1

O R O R1

N R2

O

Step 5

O

Step 6

O R O H R1

N R2

N R2 .. NEt3

Step 1: Deprotonation of carboxylic acid by Et3 N forms a carboxylate anion. Step 2: Carboxylate anion attacks on the Mukaiyama reagent. Step 3: Aromatic nucleophilic substitution. Step 4: Alcohol attacks as a nucleophile to the electron-deficient carbonyl carbon atom. Step 5: Deprotonation. Step 6: Elimination of 2-pyridone derivative produces the desired ester.

Application Synthesis of prostaglandin F-lactone [4] has been accomplished using this reaction. O N Ph

HO CO2H

O

2,6-Lutidine, BnEt3NCl, DCE reflux

OH

HO

Cl

HO

OH Prostaglandin F-lactone

Experimental Procedure (from patent US4206310A)

Br OH O

+

OH

N Me

I

n-Bu3N, CH2Cl2 reflux

O O

Yamaguchi Esterification

To a suspended CH2 Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of benzyl alcohol (216 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol), and tri-n-butylamine (888 mg, 4.8 mmol) in CH2 Cl2 (2 ml), and the resulting mixture was refluxed for three hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.

Yamaguchi Esterification The reaction of carboxylic acid with an alcohol using Yamaguchi reagent is known as Yamaguchi esterification [1, 2]. The first step is the formation of a mixed anhydride between the Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) and a carboxylic acid in the presence of Et3 N, and the second step is the conversion of the mixed anhydride to an ester upon reaction with an alcohol in the presence of stoichiometric amount of DMAP [3–37]. O

O OH

R1

Et3N

Cl

+

O

R1

Cl

Cl

R2–OH, DMAP

O

THF, r.t. Cl

Carboxylic acid

O

O

Cl

Cl

Step 1

Yamaguchi reagent

Cl

R1

Toluene, reflux Step 2

O

R2

Ester +

Mixed anhydride

O

Cl

HO Cl

Cl

Mechanism O

Cl

Cl Step 1

O R1

Cl

Cl

O

O H

R1

O

O

O R1

Cl

R1

Cl Cl

Step 2

.. NEt3

Cl

O

O

Step 3

O

O

Cl

Cl

Cl

.. N

Mixed anhydride Step 4

NMe2 O

O

O Step 6

R1 N O R2 H

NMe2

O N

R1

+

Cl

O O H

R2

H NMe2

O

Step 8 R1

O

R2

+ N

.. NMe2

N

R1

N

O

Cl

O Cl

Cl NMe2

Step 7

R1

Step 5

O

NMe2

.. R O H

Cl

Cl

191

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4 Miscellaneous Reactions

Step 1: Deprotonation of carboxylic acid by Et3 N forms a carboxylate anion. Step 2: Carboxylate anion attacks to the Yamaguchi reagent. Step 3: Elimination of chloride anion gives a mixed anhydride. Step 4: DMAP attacks as a nucleophile to regioselectively the less hindered electron-deficient carbonyl carbon atom. Due to two chloro substituents another carbonyl is blocked. DMAP is a stronger nucleophile than the alcohol. Step 5: Elimination of the Yamaguchi reagent forms a better leaving group. Step 6: Alcohol attacks to the electrophilic center. Step 7: Elimination of DMAP leaving group. Step 8: Deprotonation yields the desired ester. Application A large number of natural products such as tautomycetin core [4, 36], amphidinolide X [5], (−)-clavosolide A [6], sporiolide A [8], (+)-cladospolide C [9], 2-epi-amphidinolide E [10], sporiolide B [11], 10-deoxymethynolide [12], palmerolide A [13], (−)-ulapualide A [14], core of iriomoteolide 3a [15], iriomoteolide-1a [16], botryolide B [17], (−)-cleistenolide [18], antimicrobial cyclic peptide xenematide [19], 7,8-O-isopropylidene iriomoteolide-3a [20], palmerolide A [21], mycolactones A/B [22], macrodiolide antibiotic pamamycin-649B [23], pikromycin [24], seimatopolide B [26], nhatrangin A [27, 32], ripostatin B [28], cytospolide P [29], amphidinolide C [30], 16-membered macrolide aspergillide D [31], disorazoles A1 and B1 [34], and dendrodolide-L [35] have been synthesized using this reaction as a key step. Experimental Procedure (from patent WO 2019033219A1) O

Cl

Cl Me

Me

BnO

Me

R3CO2H, R1

OMe OH A

OMe OR2

Cl

Et3N, THF, DMAP

Me

Cl

Me

Me

BnO

R1 OMe O B

O

OMe OR2

R3

Anhydrous triethylamine (57.5 μl, 0.413 mmol, 3.0 equiv.) and 2,4,6trichlorobenzoyl chloride (64.5 μl, 0.413 mmol, 3.0 equiv.) were added to a solution of the carboxylic acid (0.413 mmol, 3.0 equiv.) in THF (1.4 ml), and the mixture was stirred at room temperature for two hours. Using a syringe tip filter to remove the precipitated salts, the mixed anhydride solution was then added to a solution of the secondary alcohol A (0.138 mmol, 1.0 equiv.) and DMAP (33.6 mg, 0.275 mmol, 2.0 equiv.) in THF (2.1 ml) at 0 ∘ C. The mixture was stirred at ambient temperature overnight and then concentrated in vacuo to afford the crude product. Purification by flash chromatography (SiO2 , gradient elution with 2–20% ethyl acetate in pentane) furnished the ester B (76.1 mg, 93%).

Grignard Reaction

Grignard Reaction In 1912, French chemist Victor Grignard received the Nobel Prize in Chemistry for his discovery of a carbon–carbon bond-forming reaction between an alkyl magnesium halide and a carbonyl compound [1, 2]. The first step of this reaction involves the preparation of an organomagnesium reagent (called Grignard reagent) through the reaction of an alkyl, an aryl, or a vinyl halide with magnesium metal. R X + Mg

R Mg X

R MgX

The Grignard reagent behaves as both a strong nucleophile and a strong base. Its nucleophilic character allows it to react with the electrophilic carbon in a carbonyl group to form a carbon–carbon bond. Its basic nature allows it to react with acidic compounds such as carboxylic acids, phenols, thiols, and even alcohols and water. Therefore, the reaction conditions for this reaction must be free from acids and strictly anhydrous. Anhydrous diethyl ether is the solvent of choice for the Grignard synthesis; possibly ether molecules coordinate with and help stabilize the Grignard reagent. Other solvent such as THF also uses for this reaction when substrates are not soluble in ether. Et

Et

O R Mg Br Et

Et

The second step involves the reaction between a Grignard reagent and a carbonyl compound and an acidic work-up to form an alcohol product as shown below. MgBr S

S

Me3Si

SiMe3

Me3Si

O H

S THF, HMPA, –78 °C

S

OH

Me3Si

Several aspects on this reaction such as computational study [14, 37], iron catalyzed [15], kinetic study [17], nickel catalyzed [21, 32], copper catalyzed [22], asymmetric version [36], and cobalt catalyzed have been investigated [3–47]. Mechanism R1

Step 1 O

R2

R1 R2 OMgX R

Step 2 H

R1 R

R2 OH

R MgX

Step 1: Nucleophilic attacks by an alkyl ion to the electron-deficient carbonyl carbon atom. Step 2: Acidic work-up gives the desired alcohol.

193

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4 Miscellaneous Reactions

Application The Grignard reaction has been used for the synthesis of tamoxifen, fluconazole, and other medicines. Cl

MgCl

Cl

Grignard

F + Cl O

N N

OH

N N N

F

Reaction

F

N N NH

F

Cl

N

OH

Base, solvent F

F Fluconazole

Total syntheses of several natural products such as delta-8-tetrahydrocannabinol (delta-8-THC) (±)-1-epiaustraline [16], camptothecin analogs [18], (±)-1epiaustraline, and prelactone V [35] have been completed strategically utilizing this reaction as a key step.

Experimental Procedure (general) Synthesis of triphenylmethanol O Br

Mg

MgBr

O-MgBr

Ether H+

OH

In a two-neck 100 ml round-bottom flask equipped with an air condenser (overhead CaCl2 guard tube or argon balloon) in one neck and septum in other neck, 50 mg magnesium turnings and one bead of iodine (catalytic amount) in 1 ml ether were taken. 345 mg of bromobenzene in 4 ml of ether was added dropwise to the reaction mixture using a syringe over 20 minutes so that the reaction does not boil too vigorously. If the rate of boiling subsides, apply a gentle heat to maintain a good rate of boiling until most of magnesium metal had reacted. After one

Gabriel Synthesis

hour, the reaction mixture was cool down to room temperature; 364 mg of benzophenone in 2 ml ether was added to the reaction mixture slowly. The reaction mixture was stirred at room temperature for one hour further, and then 6 ml of 1 N HCl was added to it. The reaction mixture was extracted with ether (100 ml) and washed with brine (50 ml), dried over anhydrous MgSO4 , and concentrated on rotatory evaporator. The crude was washed with hexane, and the remaining residue was the recrystallized with ethanol to give a pure triphenylmethanol. Yield: 312 mg, 60%, m.p. 161–162 ∘ C. Iodine serves two functions: indicator and activator. (1) It is an indicator. The color will disappear when the magnesium is activated and is able to do redox chemistry with bromobenzene. (2) Iodine may able to chemically clean the surface of magnesium so that fresh, active magnesium is exposed so it is an activator Note: If any substrate contains any acid-sensitive group, use mild acid for quenching the reaction such as NH4 Cl solution or 10% citric acid instead of strong HCl. Experimental Procedure (from patent WO1994028886A1) O

H HO

O

Mg +

A

Br B

Ether

O C

Grignard reagent was prepared from magnesium (248 mg) and 1-bromooctane (compound B) (1.8 g) in dry diethyl ether (5 ml). A tiny amount of solid iodine was added to initiate the reaction, and ether (10 ml) was further added. The reaction was stirred until all magnesium dissolved, and 3-benzyloxybenzaldehyde (10 g) (compound A) was then added to the reaction mixture. The reaction was stirred at room temperature for four hours. Ice water was then added. The organic phase was separated and washed with water (20 ml), 1 N hydrochloric acid (20 ml), and brine (20 ml) and dried over anhydrous sodium sulfate. The organic layer was evaporated to obtain a product (compound C) (79%).

Gabriel Synthesis The conversion of alkyl halides to the primary amines using phthalimide and potassium hydroxide is referred to as the Gabriel synthesis [1]. The reaction is named after the German chemist Siegmund Gabriel who discovered this reaction in 1887. The reaction works well in polar solvents such as EtOH, t-BuOH, and dimethylformamide (DMF) [2–19].

195

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4 Miscellaneous Reactions

O

O R X

CO2

KOH or acid

CO2

KOH N K

NH

+ R—NH2

O

O O

O N K

H2N–NH2

NH +R NH

R X

O

NH2

O

Mechanism R X

O

O Step 1

N

N H

OH N R

KOH

SN2

O

O

O

OH

O

OH Step 3

N R

K

KOH O

O Step 2

Step 4

O

O

O Step 7

O R NH + OH O

O H N R O OH

O O H N R

Step 6

O

Step 5

OH N R O

OH

Step 8 O O R NH2

+ O O

Step 1: Abstraction of proton by KOH. Step 2: SN 2-type reaction. Step 3: Hydrolysis with alkali and nucleophilic attacks at carbon atom of amide. Step 4: Cleavage of C—N bond. Step 5: Proton transfer. Step 6: Nucleophilic attacks at carbon atom of amide. Step 7: Cleavage of C—N bond. Step 8: Proton transfer gives a primary amine. Application Drug-like compounds such as inhibitor of tRNA-modifying enzyme tRNAguanine transglycosylase (TGT) [17] and antibacterial agents [19] were synthesized using this reaction.

Hell–Volhard–Zelinsky Reaction

Experimental Procedure (from patent US9540358B2) Synthesis of 4-(2-chloro-10H-phenothiazin-10-yl)butan-1-amine hydrochloride S

S Cl

N

NH2NH2

Cl

N

EtOH, 90 °C, HCl O

N

HCl.H2N

O

A

B

A solution of 2-(4-(2-chloro-10H-phenothiazin-10-yl)butyl)isoindoline-1,3dione (compound A) (2.00 g, 4.60 mmol) in EtOH (10 ml) was treated with hydrazine monohydrate (0.25 ml, 5.05 mmol) and heated to 90 ∘ C for one hour. The mixture was cooled to 25 ∘ C, filtered to remove the white solid that had formed, and concentrated. The residue was dissolved in 1 : 1 EtOH/ethyl acetate (10 ml), and the solution filtered and treated with aqueous 1 M HCl (5 ml). The combined solution was concentrated to dryness to afford a gray solid (compound B) (0.672 g, 42%).

Hell–Volhard–Zelinsky Reaction The conversion of carboxylic acids containing α-H atom to the corresponding α-chloro or α-bromo carboxylic acid derivatives using chlorine or bromine with red phosphorus or a catalytic amount of PX3 (X = Cl or Br) is called Hell–Volhard–Zelinsky reaction [1–3]. This reaction does not proceed with fluorine or iodine. It is an alternative method to prepare racemic alpha amino acids [4–14]. O R

X2, P or PX3 OH

H

H2O

O R

X

O R

OH X

X X = Cl, Br O OH

O

Br2, P or PBr3

O

H2O

OH

Br Br

Br

197

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4 Miscellaneous Reactions

Mechanism If phosphorus is used, it reacts with bromine to form PBr3 . 3∕2 Br2 + P = PBr3 Br Br P Br

.. O R

Br P Br O

Br O Step 1

P

Br

Step 2

R

R

OH

OH

H

H

Br

H

.. O

Step 3

R

O H

H Br Br + O=P-Br

H

+ HBr Step 4

Br

.. OH Br

R

Br O

H

Step 8

OH R

R

H

Br Step 10

OH Br

O H

R

Step 6

R

Br

Br Br

Br

Step 9

O

Step 7

Br O H Br H

.. OH

.. O

H

Br

Br

Step 5

O R

H Br

H Br

H

O R

OH Br

Step 1: The carbonyl oxygen reacts with PBr3 to form a P—O bond and liberates bromide. Step 2: The nucleophilic attacks by a bromide anion to the electron-deficient carbonyl carbon atom to form an unstable tetrahedral intermediate. Step 3: The unstable tetrahedral intermediate rearranges to release acyl bromide, HBr, and phosphine oxide. Step 4: Protonation. Step 5: Abstraction of α-hydrogen gives an enol. Step 6: Bromine addition to an enol forms α-bromo acyl bromide. Step 7: Water attacks as a nucleophile to the electron-deficient carbon center. Step 8: Deprotonation. Step 9: Elimination of bromide. Step 10: Deprotonation gives the desired product. Application Alpha amino acids such as a racemic mixture of alanine were synthesized using this reaction. OH O

Br2/PBr3

Br OH O

NH3

OH

H2N O

Alanine

Hofmann Elimination or Exhaustive Methylation

Experimental Procedure (from patent WO199101199A1) Cl

Cl

1. SOCl2, Br2

O OH

O

2. MeOH

O Br

A

B

A mixture of 4-chlorophenylacetic acid (5.00 g, 29.3 mmol) (compound A) and thionyl chloride (2.67 ml, 1.25 equiv.) was heated at reflux, while bromine (1.51 ml, 1.0 equiv.) was added from a dropping funnel over 15 minutes. The reaction mixture was heated at reflux 19.5 hours and then cooled to room temperature. Methanol (30 ml, 25 equiv.) was then added slowly, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ether, and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5% NaHSO3 , dried over anhydrous MgSO4 , filtered, and concentrated in vacuo. The residue was purified on a silica gel flash column chromatography (170 × 45 mm) eluted with 15% ethyl acetate/hexane to yield 2.89 g (37%) of compound B.

Hofmann Elimination or Exhaustive Methylation The conversion of an amine with a β-hydrogen to an alkene using methyl iodide, silver oxide, and water under thermal conditions is known as Hofmann elimination or Hofmann exhaustive methylation [1–3]. The reaction proceeds in three steps [4–24]. H

R1 N R2

R

Amine with beta-hydrogen

MeI

H

Step 1

R

I R1

Ag2O, H2O

N R2 Me

Step 2

Quaternary ammonium iodide salt

Heat

OH H

R1

N R Me 2

R

R Step 3 – H2O

Alkene

R1 + N R 2 Me Tertiary amine

Quaternary ammonium hydroxide salt

Mechanism H O H I H R

R1 Step 1 H N .. R 2 R Me

I

R1 N R Me 2

Ag O Ag

O Ag OH

Step 2 –AgI

H R

R1 N + AgOH R2 Me

Step 3 R

+

R1 N R2 Me

199

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4 Miscellaneous Reactions

Step 1: The amine attacks on methyl iodide to form a quaternary ammonium iodide salt. Step 2: Iodide reacts with silver oxide to give silver iodide and silver oxide anion. Silver oxide anion takes proton from water to give silver hydroxide and hydroxide ion that forms a quaternary ammonium hydroxide salt. Iodide replaces by hydroxide. Step 3: Hydroxide abstracts a β-hydrogen from the ammonium salt to release a tertiary amine and the desired alkene. Application Several natural products such as 4-demethoxydaunomycin [12], (−)-cryptosporin [13], and (+)-picrasin B [14] have been synthesized using this reaction. Purine derivatives [11] were synthesized using this reaction.

Hosomi–Sakurai Reaction Lewis acid-promoted allylation of various carbon electrophiles with allyltrimethylsilane is known as the Hosomi–Sakurai reaction [1–4] (also referred as Sakurai allylation). Strong Lewis acids such as TiCl4 , SnCl4 , Al(Et)2 Cl, and BF3 . OEt2 are used for this reaction. The carbon electrophiles are aldehydes, ketones, acetals, ketals, epoxide, acyl chlorides, imines, etc. Most recently, several other catalysts [3–37] and catalytic asymmetric versions [10, 11, 15, 17, 31] were developed for this reaction.

O R

OH

2 R1

SiMe3

+ 3

1

1. TiCl4, DCM R 2. H2O

2 1

R1 3

Aldehyde or ketone

The α,β-unsaturated aldehydes react at the carbonyl group, but α,β-unsaturated ketones produce conjugate addition products.

Catalyst

CH3 +

SiMe3

CH3

O O

Hosomi–Sakurai Reaction

Mechanism TiCl4 .. O R

Cl TiCl3 O

Step 1

R R

R1

O

Step 2

TiCl3

O

Step 3

R1

TiCl3 + Me3Si—Cl

R1

R

R1 SiMe3

SiMe3

Step 4 Cl

H2O OH R

R1

Step 1: Lewis acid activates electrophilic carbon of carbonyl group to form a complexation. Step 2: Nucleophilic attacks by an allyltrimethylsilane at electron-deficient carbonyl carbon atom to form the β-carbocation. Silicon stabilizes β carbocation (β effect). Step 3: Chloride anion attacks at silicon to break the C—Si bond. Step 4: Aqueous work releases the desired product. Application Several natural products such as (−)-lemonomycin [18], core of brevetoxin A [19], (−)-oridonin [25], (±)-epi-picropodophyllin [20], trifarienol A [21], (±)-aspidospermidine [22], (−)-heliespirone A [25], (+)-ophiobolin A [27], amphidinolide P [28], (+)-penostatin E [30], and (−)-oridonin [37] have been synthesized using this reaction as a key step. Experimental Procedure (from patent WO2019093776A1) O

MeO BzO

O O

BzO A

BzO TiCl4, Toluene

OH

MeO

Allyltrimethylsilane

BzO

O O B

In a round-bottom flask was charged with 1 M titanium tetrachloride (306 l) and toluene (93.12 l) and cooled to 0 ∘ C or lower. Titanium isopropoxide (30.20 l) was added dropwise while maintaining the temperature below 25 ∘ C. The reaction solution was warmed to room temperature and stirred for 0.5 hours. Compound A (31.04 kg) and toluene (217.28 l) and allyltrimethylsilane (51.87 l)

201

202

4 Miscellaneous Reactions

were added, and the mixture was stirred at room temperature for 10 minutes, cooled to 0 ∘ C. After further stirring at room temperature for one hour, the solution was cooled to −5 ∘ C or lower, 1 N hydrochloric acid (186.24 l) was added at not more than 25 ∘ C, and the mixture was stirred for 15 minutes. The organic layer was separated and washed sequentially with 1 N hydrochloric acid (93.12 l) and water (93.12 l). The organic layer was concentrated, isopropanol (62.08 l) was added, and the mixture was concentrated under reduced pressure. Isopropanol (31.04 l) was added, and the mixture was completely dissolved by stirring at 60 ∘ C and then cooled to 20 ∘ C. Additional stirring was continued for one hour until a solid was formed. Heptane (155.2 l) was added, and the mixture was stirred at 20 ∘ C for one hour. The resulting solid was filtered and dried in vacuo to give compound B (32.33 kg, 32.3%).

Huisgen Cycloaddition Reaction The cycloaddition between an azide and a terminal alkyne to form 1,2,3-triazole is known as the Huisgen cycloaddition reaction [1, 2]. 2 3 N 1 N N O + N

N

98 °C

N

O

4

2 3 N 1 N N 4

5

18 h

5 O

+

This reaction gives a mixture of 1,4- and 1,5-substituted products. There is no regioselectivity. Click Chemistry When above reaction undergoes in the presence of copper(I) catalyst to form 1,4-subsituted product as a sole product, the reaction is referred as copper(I)-catalyzed azide alkyne cycloaddition (CuAAC). The Nobel laureate K. B. Sharpless coined this reaction as a Click Chemistry since reaction gives high yield, wide application, and simple reaction conditions and by-product can be removed without chromatography separation [3–16]. For copper(II) salt such as a CuSO4 , L-sodium ascorbate is used to convert copper(II) to copper(I) in situ. 2 3 N 1 N N O +

N

N

N

Cu(I) catalyst O H2O, t-BuOH

4

5

Hunsdiecker Reaction

Mechanism One of plausible mechanisms [16]

N

N

R1

Cu

Cu R

N

R

H

Step 2

Cu

Step 1

N

R1 Step 3 Step 4 N N N N R1 Cu

R

Cu

N

R

N R

Cu

N

N R1 H

Step 1: Addition of Cu to an alkyne forms copper acetylide and coordination of another copper. Step 2: Cycloaddition gives an unusual six-membered copper metallocycle. Step 3: Ring contraction provides a triazole-copper intermediate. Step 4: Protonolysis gives the desired triazole product. Experimental Procedure (from patent WO2008124703A2) N HO

N

N3 +

SO2NH2

O

O A

S B

CuSO4

HO O

Sodium L-ascorbate t-BuOH, H2O

O

N N N

SO2NH2 S

C

To a round-bottom flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing t-BuOH : H2 O (1 : 1) was placed azide A (1 equiv.). To this solution was added compound B (0.9 equiv.), CuSO4 ⋅5H2 O (0.2 equiv.), and sodium L-ascorbate (0.4 equiv.), and the reaction was allowed to stir at room temperature for until deemed complete by LC-MS. After the reaction was complete, the solvents were removed in vacuo. The residue was diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous MgSO4 , and concentrated. The residue was purified over silica gel using 5–15% MeOH in DCM to give product C (77%).

Hunsdiecker Reaction The conversion of silver carboxylates to the corresponding alkyl, aryl, and unsaturated chlorides or bromides is known as the Hunsdiecker reaction [1–3] (also called Hunsdiecker–Borodin reaction). This is an example of both a decarboxylation and a halogenation reaction through free radical pathway [4–21]. The yield of halide formation is as follows: primary > secondary > tertiary. O R

Br2 O Ag

R Br CCl4

203

204

4 Miscellaneous Reactions

O R

Br Br Step 1 O Ag – AgBr

R

O

Step 2

O O Br

R

Step 3 O

R

Br

+ CO2 Step 4

R Br

R

Br

Mechanism Step 1: Nucleophilic addition of bromine to silver carboxylate forms an unstable intermediate acyl hypobromite. Step 2: Homolytic cleavage gives diradicals. Step 3: Radical decarboxylation liberates carbon dioxide. Step 4: Formation of alkyl bromide by recombining two radicals. Application Perylene dyes [13] and fluoro-functionalized graphene oxide [14] were synthesized using this reaction. Experimental Procedure (from patent WO2017060906A1) NO2

NO2 O O

Ag

Br2

Br

CCl4, 100 °C A

B

In a 25 ml round-bottom flask equipped with Dimroth condenser (chilled to 10 ∘ C) was charged with compound A (1.8 mmol), brominating agent, and solvent (8 ml). The mixture was stirred and heated in an oil bath under fluorescent room light irradiation (FL). The cooled reaction mixture was filtered through a short silica gel pad, washed with 1 M aqueous Na2 SO3 , dried over anhydrous Na2 SO4 , filtered, and concentrated in vacuo to obtain compound B (80%).

Keck Asymmetric Allylation The nucleophilic addition of an allyl group to an aldehyde using allylstannane, Lewis acid, and chiral ligand is known as the Keck asymmetric allylation [1–4]. Several improvements on this reaction and application of this reaction in the synthesis of natural products have been reported [5–25].

Keck Asymmetric Allylation

OH OH O R

H

OH

SnBu3

+

R

Ti(Oi-Pr)4, CH2Cl2

Mechanism

.. O R

Ti(O-iPr)4 (BINOL) H

R

Step 1

O

Ti(O-iPr)4 (BINOL) H

Ti(O-iPr)4 (BINOL) O

H2O

Step 2

OH

Step 3

SnBu3

Step 1: Complexation of oxygen atom of aldehyde with Ti(O-iPr)4 (Binol) (chiral catalyst) makes more electron-deficient center toward nucleophilic attack. Step 2: Nucleophilic addition by an allyl tin to the carbon atom of activated aldehyde. Step 3: Aqueous work-up liberates the product from the complex. Application Several natural products such as (−)-8-epi-swainsonine triacetate [9], C16–C27 segment of bryostatin 1 [17], (+)-dactylolide [19], (−)-tarchonanthuslactone [21], (+)-chamuvarinin [24], and broussonetine M [25] have been synthesized utilizing this reaction. Experimental Procedure (from patent US6603023B2) HO

O H

S-(−)BINOL N

N

SnBu3

+ S A

Ti(O-i-Pr)4,

S

CH2Cl2, –20 °C B

C

A mixture of (S)-(−)-1,1′ -bi-2-naphthol (259 mg, 0.91 mmol), Ti(O-i-Pr)4 (261 μl, 0.90 mmol), and 4 Å molecular sieves (3.23 g) in CH2 Cl2 (16 ml) was heated at reflux for one hour. The mixture was cooled to room temperature, and aldehyde A was added. After 10 minutes the suspension was cooled to −78 ∘ C, and allyl

205

206

4 Miscellaneous Reactions

tributyltin (3.6 ml, 11.60 mmol) was added. The reaction mixture was stirred for 10 minutes at −78 ∘ C and then placed in a −20 ∘ C freezer for 70 hours. Saturated NaHCO3 (2 ml) was added, and the mixture was stirred for one hour, poured over Na2 SO4 , and then filtered through a pad of MgSO4 and celite. The crude material was purified by flash chromatography (hexane/ethyl acetate, 1 : 1) to give compound C as a yellow oil (60%).

Thionation Reaction (Lawesson’s Reagent) The conversion of carbonyl groups of ketones, esters, and amides to the corresponding thiocarbonyl compounds using Lawesson’s reagent is called thionation reaction [1, 2]. The Lawesson’s reagent (LR) 2,4-bis-(4-methoxyphenyl)[1,3,2,4] dithiadiphosphetane, 2,4-disulfide is a mild and simple thionating agent. Reactions of ketones, amides, lactams, and lactones with Lawesson’s reagent are generally faster than reactions of esters [3–20].

MeO

O R2

R1

OMe

S S P P S S

+

S

Heat R1

Toluene

R2

L.R.

MeO

O R1

N R2 H

OMe

S S P P S S

+

S

Heat

N R2 H

R1

Toluene

L.R.

O

S

MeO

OMe

S S P P S S

+

Heat Toluene

L.R.

MeO N H

O

S +

P

OMe

Heat

S S

P S

Toluene

N H

S

Thionation Reaction (Lawesson’s Reagent)

Mechanism MeO S P

OMe

S

P

MeO

MeO 2

S

S P S

Step 1

S

Dithiophosphine ylide

Step 2

S P O S

.. O

R1

R2

R2 R1

Step 3

MeO

MeO

Step 4

S S P

+ O

R1

R2

S P O R2 S R1 Thiaoxaphosphetane intermediate

Step 1: In solution the LR is in equilibrium with a more reactive dithiophosphine ylide intermediate. Step 2: Nucleophilic-type addition. Step 3: C—S bond formation provides a four-membered TS, Wittig-type reaction. Step 4: Breaking of C—O and P—S bonds gives the desired product. The driving force of this reaction is the formation of a stable P=O bond. Application Potential neuropharmacologic agents [4], thiosegetalin A [6], and huperzine B [13] have been synthesized applying this reaction. Experimental Procedure (general) S

O L.R. Toluene, reflux A

B

A mixture of A (1 mmol) and Lawesson’s reagent (1.5 mmol) in toluene (10 ml) was stirred at 110 ∘ C for six hours. The solvent was evaporated, and the residue was dissolved in dichloromethane and organic layer washed with water. Evaporation of the organic layer and purification of a the residue on a silica gel column chromatography (hexane/ethyl acetate) compound B was obtained in 55% yield.

207

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4 Miscellaneous Reactions

Michael Addition or Reaction The Michael reaction or addition is a nucleophilic addition to an α,β-unsaturated system in the presence of base [1, 2]. The reaction is thermodynamically controlled. The reaction donors are active methylene compounds such as malonate and nitroalkanes (also called Michael donor), and the Michael acceptors are activated olefins such as α,β-unsaturated carbonyl compounds. This is one of the most widely used methods for C—C, C—N, and C—S bond-forming reactions, and its asymmetric version is reported [3–47]. EWG EWG

1. NaOEt

EWG

+ EWG

2. Acid work-up

EWG

EWG

Michael acceptor

Michael donor Activated methylene

EWG: electron-withdrawing group Michael donors: O

O

O ,

O OEt ,

EtO

O2N

NO2 , NC

CN

O ,

NO2

EtO

Michael acceptors: O

CO2Et

CO2Et

CN ,

NO2 ,

,

,

Heteroatom nucleophile (Michael donor) R–XH R = Alkyl, aryl; X = O, S, NH, N-R1

Base: NaOEt, NaOH, KOH, KOt-Bu, piperidine, Et3 N Solvent: EtOH, t-BuOH, THF, CH3 CN, etc. Mechanism H

O

O OEt

O

O

EtO

O

Step 1 OEt

EtO NaOEt

H

Step 2

O OEt

OEt Ph

Ph O O

O

OEt

EtO

OEt

OEt Step 3

EtO

Acid work-up

O

Ph O

OEt

Mitsunobu Reaction

Step 1: Abstraction of acidic hydrogen atom by a base. Step 2: Addition of carbanion to the activated double bond. Step 3: Protonation from acid work-up gives the desired product. Application Several natural products such as isishippuric acid B [16], nupharamine [18], (±)-neovibsanin B [19], (±)-vincorine [20], (−)-martinellic acid [25], (−)-kainic acid [27], (±)-subincanadine E [29], (+)-trans-dihydrolycoricidine [31], cannogenol [33], and (+)-vallesamidine [37] have been synthesized using this reaction as a key step. Experimental Procedure (Aza-Michael Addition) (from patent CN102348693B) F3C

N (R) H O

CF3 CF3

Si

CF3 O

N NH (E)

CHO

N A

N

4-Nitrobenzoic acid CHCl3, r.t.

N

N

O

N

SiMe3

C

B

H

N N (R)

Chiral catalyst (R-35)

+

N O

SiMe3

A mixture of A (5 equiv.), chiral catalyst (0.2 equiv.), and 4-nitrobenzoic acid (0.05 equiv.) in CHCl3 was stirred at room temperature for 10 minutes, and then B (1 equiv.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 23 hours; after confirmation of completion by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by CombiFlash (0–80% ethyl acetate in hexane) to give product C (80%).

Mitsunobu Reaction The substitution of primary and secondary alcohols with acidic nucleophiles using diethyl azodicarboxylate (DEAD) and triphenylphosphine is called as the Mitsunobu reaction [1, 2]. Secondary alcohols undergo complete inversion of

209

210

4 Miscellaneous Reactions

configuration, and tertiary alcohols generally do not undergo the reaction conditions. Oyo Mitsunobu, a Japanese chemist, discovered this reaction in 1967. Several modifications and improvements from the original reagent combination have been developed such as resin-bound phosphine simplify the separation of the product [3–47]. Nuc

OH R1

H-Nuc DEAD, Ph3P

N3

HN3

OH R1

R2

R1

R2

R2

R2

R1

DEAD, Ph3P

O

R1

R2

R1

DEAD, Ph3P

OH

NaOH R1

R2

R2

THF, H2O

Ester

Secondary alcohol

Inverted alcohol

Ph3P, DEAD

+

THF OH

R3

O

R3-CO2H

OH

O

OH

Mechanism H Nu CO2Et EtO2C N N .. Ph3P

Step 2 EtO2C

Step 1 EtO2C

Step 3

N N

N N Ph3P

H

CO2Et

Ph3P

CO2Et

PPh3 EtO C H 2 O H N N + CO2Et R2 R1

.. O H R1 Nu Ph3P O

+

R1

R2

Inversion of stereochemistry

Step 4

R2 PPh3 O

Step 5 SN2

R1

R2

EtO2C H N N CO2Et H

+

Nu

Step 1: Ph3 P makes a nucleophilic attack on DEAD to form a zwitterionic intermediate. Step 2: Proton transfers from acidic nucleophile to the intermediate and forms an anionic nucleophile. Step 3: Alcohol activation makes a better leaving group. Step 4: Proton transfer. Step 5: SN 2-type reaction gives the final product with inversion of stereochemistry.

Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction)

Application The Mitsunobu reaction has been used to synthesize oseltamivir (antiviral), morphine (pain medication), quinine (antimalarial), entecavir (hepatitis B virus) [17], and other medicines. Total syntheses of many natural products such as stigmatellin, eudistomin, strychnine (pesticide), nupharamine, polycitone B [11], desferrisalmycin B [12], pyranicin [13], (+)-dibromophakellstatin [14], salicylihalamide [15], (+)-vibsanin A [23], aurantoside G [25], aristeromycin analogs [26], nannocystin A [27], actinoranone [29], (±)-chlorizidine A [30], (+)-aristolactam GI [35], caprazamycin A [36], and (+)-ar-macrocarpene [37] have been accomplished using this reaction. Experimental Procedure (from patent US20170145017A1) OPh OPh NH2

OH CF3

N

+

N

N N

O A

N H

NH2

Ph3P N DIAD, EtOAc

N N

O

N N

CF3

B C

Compound A (39.08 g, 198.2 mmol) in EtOAc, compound B (20.0 g, 65.95 mmol), triphenylphosphine (51.81 g, 198.2 mmol), and THF (500 ml) were added into a four-neck round-bottom flask equipped with a mechanical stirrer and a thermometer under nitrogen at 30 ∘ C. A solution containing diisopropyl azodicarboxylate (40 ml, 198.2 mmol) in THF (40 ml) was slowly added over 1.5 hours period while maintaining the reaction mixture temperature at 30 ∘ C. The solution was stirred for three hours at 20–30 ∘ C. When the reaction was complete as determined by HPLC analysis, the solution was concentrated under reduced pressure and purified over silica gel using 2–10% methanol in dichloromethane to afford C.

Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction) The C—C bond-forming reaction between the α-position of an activated alkene such as α,β-unsaturated carbonyl compound and an aldehyde or activated ketone or other carbon electrophile is known as the Baylis–Hillman or Morita–Baylis–Hillman reaction [1, 2]. DABCO is the most frequently used catalyst, but other tertiary amines or phosphines can be used for this reaction [3–48]. Several chiral amines and chiral phosphines catalysts are developed

211

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4 Miscellaneous Reactions

for the asymmetric version of this reaction [8, 10, 34]. Ionic liquid [15], N-heterocyclic carbine catalyzed [22], palladium catalyzed [23], Zn catalyzed [37], theoretical study [24], computational study [27], and kinetic study [30] have been investigated on this reaction. Y R1

R2

DABCO (cat)

EWG

+

R2

YH EWG

R1 or NR3 or PR3

Y = O, NTs, NCO2R4 EWG = CHO, COR, CN, CONR2, CO2R, NO2, etc R1, R2 = alkyl, aryl, H

N DABCO =

or

N

NN

1,4-Diazabicyclo[2.2.2]octane

NN

O

O H

OH O OMe

OMe +

Mechanism O H O

O OMe Step 1 N

.. N

O

O OMe

Step 2

OH OMe

H

N

O OMe

Step 3

N

N

N

N

N

Step 4

OH O N +

OMe

N

Step 1: Conjugated addition of the catalyst to carbonyl compound forms a stabilized nucleophilic anion. Step 2: This in situ generated nucleophile attacks to an electron-deficient carbonyl carbon center (electrophile). Step 3: Deprotonation and proton exchange gives an intermediate. Step 4: Elimination of catalyst from the intermediate gives the desired product.

Nozaki–Hiyama–Kishi Reaction

Application Total syntheses of natural products such as salinosporamide A [11], (−)-spinosyn A [14], secokotomolide A [25], applanatumol B [35], and melleolide F [36] have been accomplished under the reaction conditions.

Experimental Procedure (from patent US20060094739A1) Synthesis of 3-(trifluoromethyl)phenylmethyl pyridinepropanoate O

O F3C

β-hydroxy-α-methylene-3-

O

+ N

F3C

DABCO

O N

0 °C C

B

A

OH

O H

A mixture of 62 mg (0.27 mmol) of 3-(trifluoromethyl)phenylmethyl acrylate (compound A), 29 mg (0.27 mmol) of pyridine-3-carboxaldehyde (compound B), and 30 mg (0.27 mmol) of DABCO was thoroughly shaken on a vortex mixer and then stored at 0 ∘ C overnight. The product was purified by preparative HPLC (prep HPLC) using a Gilson 210 HPLC/fraction handler to give 47 mg (0.14 mmol, 52% yield) of the desired Baylis–Hillman adduct, 3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate (compound C).

Nozaki–Hiyama–Kishi Reaction The coupling reaction between an aldehyde or a ketone and an allyl or a vinyl halide in the presence of CrCl2 and NiCl2 to form an alcohol is known as the Nozaki–Hiyama–Kishi reaction [1–5]. Aldehyde reacts faster than ketone. The mild reaction conditions tolerate several functional groups such as esters, amides, nitriles, and others [6–46]. O R X

+

Organic halide

R1

OH

CrCl2, NiCl2 R2

Aldehyde or ketone

DMF or DMSO or THF

R1

R

R2

Alcohol

R = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenyl; X = Cl, Br, I, OTf R1, R2 = alkyl, aryl, H

213

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4 Miscellaneous Reactions

Mechanism 2 Cr(II)

2 Cr(III)

Ni(0)

Step 1

Ni(II)

O R1

Step 2 R X

R2

R Cr(III)Cl2

R Ni(II) Cl

OCrCl2

Step 4

Step 3

R1

CrCl3

Ni(0)

R

R2

OH

Step 5 H2O

R1

R

R2

Step 1: Reduction of Ni(II) [NiCl2 ] to Ni(0) with 2 equivalents of CrCl2 produces Cr(III) (CrCl3 ). Step 2: Oxidative addition of Ni(0) into an organic halide forms R-Ni-Cl. Step 3: Transmetalation, exchanging Ni to Cr complex, forms an organochromium(III) nucleophile and regenerates Ni(II) salt. Step 4: Nucleophilic addition to electron-deficient carbonyl carbon atom. Step 5: Aqueous work-up gives the desired alcohol. Application Total syntheses of natural product aspinolide B [11], phomactin A [30], mosin B [12], epothilones B and D [10], narbonolide [18], bipinnatin J [35], (+)-methynolide [36], solandelactones E and F [37], leustroducsin B [38], aspercyclides [39], pestalotiopsin A [40], (−)-apicularen A [41], (+)-lysergol, (+)-isolysergol, (+)-lysergic acid [42], malyngamide W [43], (−)-gymnodimine [44], didemnaketal B [22], (+)-vibsanin A [45], epoxyeujindole A [23], (+)-amphirionin-4 [25, 46], and aquatolide [24] have been accomplished using this reaction. Experimental Procedure (from patent US20190337964A1) O O CO2Et H O

H O

H OH

H

H O

H

Br

SiMe3

CrCl2, NiCl2

B

O O CO2Et H O

SiMe3 O

DMSO, CH3CN A

C

Chromium(II) chloride (100 g) and nickel(II) chloride (1.06 g) were added to dimethyl sulfoxide (210 ml) and acetonitrile (210 ml) and cooled to 0–5 ∘ C. Compound A (30 g) and (2-bromovinyl)trimethylsilane (compound B) (73 ml) were dissolved in acetonitrile (210 ml) and added dropwise. The resulting solution was stirred for 24 hours at room temperature, and the completion of the reaction was confirmed. Methanol (200 ml), water (200 ml), and MTBE (200 ml) were added thereto, followed by stirring for one hour. The organic layer was separated, and the aqueous layer was extracted twice with MTBE (100 ml). The

Paterno–Büchi Reaction

combined organic layer was washed with saturated sodium chloride (200 ml), and sodium sulfate was added to the organic layer, followed by filtration and concentration. The resulting residue was subjected to chromatography (ethyl acetate : hexane = 1 : 2) to give compound C (18.2 g, 48%).

Paterno–Büchi Reaction The photochemical [2+2] cycloaddition of an alkene with a carbonyl to form an oxetane is known as the Paterno–Büchi Reaction [1–3]. Solvent, temperature effect [20], mechanistic study, and substrate scope on this reaction have been investigated [4–32]. O Ph

H

O

hv Ph

+

H

H

O +

Ph

H H

H

Mechanism H hv

O Ph

O

H

Step 1

Ph

O

Step 2 Ph

H

H

Step 3

O Ph H

Diradical

Step 1: Carbonyl ground state photoexcited to form singlet or triplet state and both n–π* and π–π* transition states are possible. Step 2: Radical exchanges to form a diradical intermediate. Step 3: Formation of sigma bond gives an oxetane. Application Synthesis of Taxol, an anticancer agent and oxetane ring-containing drug, has been accomplished. O O O

O

OH

O

NH O O OH

OH

H O O O

O

Paclitaxel (Taxol)

Recently, synthesis of azetidine derivatives via aza-Paterno–Büchi reaction [29] has been reported.

215

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4 Miscellaneous Reactions

N

+

R

hv

N

Aza Paterno–Buchi reaction

R

Azetidine

Total syntheses of natural products such as (±)-5-oxosilphiperfol-6-ene [9] and merrilactone A [14] have been completed using this reaction as a key step. Experimental Procedure (from Reference [29], copyright 2019, American Chemical Society) H

TpCu (catalyst), 100 W Hg lamp

O

O

+ Et2O (0.15 M), 12 h A

H

B

C

In a glove box to a borosilicate culture tube charged with a magnetic stir bar were acetone (compound A) (30 mg, 1.0 equiv.), TpCu (0.1 equiv.), norbornene (3.0 equiv.) (compound B), and diethyl ether (0.15 M). The vial was capped, sealed with electrical tape, and irradiated with a UVP Blak-Ray B-100 A UV lamp in an assembled photoreactor fitted with an exhaust fan and 20′′ box fan. After 12 hours, the reaction mixture was filtered through a glass filter and rinsed with an additional 1 ml Et2 O, and solvent removed under reduced pressure. A 0.6 M solution of durene in C6 D6 added (100 μl) before diluting with additional C6 D6 for 1 H NMR analysis. Compound C was obtained as a white solid in 51% NMR yield determined using durene as an internal standard and 21% isolated yield (>95 : 5, exo : endo as determined by a series of multidimensional NMR experiments).

Pauson–Khand Reaction A [2+2+1] cycloaddition of an alkyne, an alkene, and carbon monoxide in the presence of dicobalt complex catalyst to give an α,β-cyclopentenone is known as the Pauson–Khand reaction [1, 2]. Theoretical study [14], computational study [51], aldehyde as a CO source [15], Mo catalyzed [18], Rh catalyzed [21], Ir catalyzed [25], Fe catalyzed [37], and other conditions have been investigated [3–51]. O R2

R1

R3 + R4

EtO2C EtO2C Intramolecular reaction

R5

CO, Co2(CO)8

R6

Co2(CO)6 (P(OPh3))2 CO

R1 R2

EtO2C EtO2C

R3

R6 R5 R4

O

Pauson–Khand Reaction

Mechanism Co

Step 1 CO Co Co CO R + OC – 2 CO OC CO O OC

CO OC Co OC OC Co OC CO

R1

R Step 2 – CO

CO OC Co OC OC Co OC

R

R1

+ CO

OC

O R

R1

Step 6

R1

CO Co CO

OC CO CO O Co R

Step 5

OC CO OC Co OC OC Co OC O

+ Co2(CO)6

R Step 4

R1

+ CO

Step 3

CO OC Co OC OC Co OC OC

R

R1

Step 1: Addition of alkyne and elimination of two CO provides a hexacarbonyldicobalt complex. Step 2: Substitution of CO by an alkene. Step 3: Alkene insertion and addition of CO. Step 4: CO insertion. Step 5: Ketone formation. Step 6: Reductive elimination gives a cyclopentenone. Application Total syntheses of several natural products such as (−)-alstonerine [20], (−)pentalenene [22], (−)-magellanine, (+)-magellaninone [23], (+)-achalensolide [24], (−)-alstonerine [28], (−)-α-kainic acid [29], (+)-nakadomarin A [30], (±)-meloscine [32], (−)-huperzine Q [33], (±)-axinellamines A and B [34], (+)-indicanone [35], (−)-jiadifenin [36], +)-ileabethoxazole [37], (−)-nakadomarin A [40], (+)-sieboldine A [41], (−)-indoxamycins A and B [42], and (−)-daphlongamine H [44] have been accomplished exploiting this reaction. Experimental Procedure (from patent WO2003080552A2) O H

SiMe3

Co2(CO)8 +

Me3Si H

A

B

C

Under nitrogen at room temperature, a solution of trimethylsilylacetylene (compound A) (1.44 ml, 10.19 mmol, 1 equiv.) in dichloromethane (40 ml) was treated with Co2 (CO)8 (3.50 g, 10.24 mmol, 1 equiv.). Stirring was continued for 24 hours.

217

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4 Miscellaneous Reactions

TLC analysis (hexane) indicated formation of the corresponding cobalt complex. Norbornadiene (compound B) (1.2 ml, 11.12 mmol, 1.1 equiv.) was added, the reaction mixture was cooled to 0 ∘ C, and 4-methylmorpholine N-oxide (11.93 g, 101.84 mmol, 10 equiv.) was added in five portions. Stirring was continued for three days before silica gel (c. 25 g) was added, and the solvent was removed under reduced pressure. Purification by flash column chromatography (hexane/Et2 O, 19 : 1) afforded compound C (1.2 g, 54%) and an endo product (6%).

Reformatsky Reaction The nucleophilic addition of an α-haloester to an aldehyde or a ketone using metallic zinc to form a β-hydroxy-ester is known as the Reformatsky reaction [1, 2]. The reaction was discovered by the Russian chemist Sergey Nikolaevich Reformatsky in 1887. The Reformatsky enolate is formed by treating an α-haloester with zinc dust. This enolate is less reactive than lithium enolate or Grignard reagent. Several modifications and improvements such as asymmetric version [13, 18], Rh-catalyzed [14], Sn-catalyzed [16], Sm-catalyzed [17, 26], ultrasound promoted [19], Fe-catalyzed [20, 43], Ni-catalyzed [21], Ti-catalyzed [22], Ba-catalyzed [23], In-catalyzed [27], and Zn-catalyzed [28] have been developed on this reaction [3–47]. O R1

R2

OR3

+ Br

Br Zn O

Zn Ether or THF

O

R1

OR3

R2

OH O

H3O

O

R1

Acidic work-up

OR3

R2

OH

O +

OEt

Br O

OEt

1. Zn, ether O 2. Acidic work-up

Mechanism O R1 OR3

Br O

R2 BrZn .. O

Zn, ether Step 1

OR3

BrZn

OR3

O

O

H O

Step 2 R1

OR3

R2

ZnBr Step 3

Br OH R1

R2

Step 4

O OR3

Br Zn R1

O

H

R2

O OR3

Reformatsky Reaction

Step 1: Oxidative Zn addition and O-zinc enolate formation. Step 2: Nucleophilic addition of enolate to the carbonyl carbon atom and zinc switches to carbonyl oxygen atom. Step 3: Protonation. Step 4: Elimination of ZnBr2 gives the desired β-hydroxy-ester. Application Natural products such as (±)-chlorizidine A [39], (−)-borrelidin [24], brevetoxin B [26], (−)-stemoamide [31], (+)-acutiphycin [32], (−)-kainic acid [36], (±)-chlorizidine A [37], (±)-chlorizidine A [39], paralemnolide A [40], and aplysiasecosterol A [41] have been synthesized under the reaction conditions.

Experimental Procedure (from patent US6924386B2) O Br

(–)-Sparteine (chiral catalyst) OEt

Zn, TMS-Cl, THF, DMF O

A

OEt

H

S B

S OH O C

At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel, and stirrer under protective nitrogen gas was initially charged with 9 g of zinc dust (138 mmol) in 60 ml of THF. After 2.3 ml of trimethylchlorosilane was added, the mixture was heated to 60 ∘ C for 15 minutes, and 22.4 g of ethyl bromoacetate (compound A) (134 mmol) was subsequently added dropwise undiluted at 45 ∘ C within 7 minutes. The mixture was then stirred for 15 minutes. After cooling to 0 ∘ C, 60 ml of DMF and 32.6 g of (−)-sparteine (139 mmol) were added undiluted, and the temperature rose to 8 ∘ C. After the clear mixture had been stirred at 40 ∘ C for 10 minutes, then it was cooled at 20 ∘ C, and 12.4 g of thiophene-2-carbaldehyde (compound B) (111 mmol) was added. The clear reaction mixture was subsequently stirred at 20 ∘ C for eight hours, then acidified at this temperature to a pH of 2 using 35 ml of 20% hydrochloric acid, and stirred for 10 minutes, and the temperature of the mixture cooled to 0 ∘ C. 150 ml of water was then added. Precipitated sparteine salt was filtered off with suction and washed twice with 40 ml of ethyl acetate each time (>80% of sparteine could be recovered). After removing the organic phase, the aqueous phase was extracted using 50 ml of ethyl acetate, and the organic phase was subsequently removed. The organic phase was then stirred with 20 ml of concentrated ammonia solution at 10 ∘ C for 10 minutes. After phase separation, drying, and removal of solvent under reduced pressure, ethyl (S)-(−)-3-hydroxy-3-(2-thiophene)propionate (compound C) was obtained in a yield of 20.9 g (94% of theory) and a purity of >94% and 89% ee (HPLC).

219

220

4 Miscellaneous Reactions

Ritter Reaction The formation of amides from nitriles and alcohols or alkenes (carbocation precursors) in the presence of strong acids is known as the Ritter reaction [1, 2]. John J. Ritter, an American chemist, discovered this reaction in 1948. Both aromatic and aliphatic nitriles react with carbocation precursors such as secondary alcohols, tertiary alcohols, benzylic alcohols, tert-butyl acetate, alkyl halides, and alkenes in the presence of strong acids to form the corresponding amides. HCN or NaCN can be used for this reaction to make formamides. Generally, any substrate capable of forming a stable carbenium ion (carbocation) is a suitable starting material for this reaction [3–31]. But primary alcohols do not undergo this reaction, with exception of benzylic alcohols. Mostly protic acids such as H2 SO4 [11], HCl, HCO2 H, and MsOH [18] are used for this reaction. Most recently, some Lewis acids such as BF3 .OEt2 , AlCl3 , SnCl4 , CuI [26], and Fe(ClO4 )3 ⋅H2 O [30] are also successfully utilized. O

H2SO4 N +

R

Nitrile

Alkene

O

H2SO4

N +

R

H2O

tert-Alcohol

Nitrile

N H Amide O

H2SO4

OH +

NaCN

N H Amide

OH R

R

H2O

H

H2O

tert-Alcohol

N H

Formamide

Mechanism H

H .. O

Step 1

H

O

H

Step 2 E1

.. N C R

Step 3

R C N

R C N

.. H O H

Alcohol H

Nitrilium ion Step 4

Alkene

H N

R O

Step 8

H O H .. R Step 7 C O H N H

R .. C O H Step 6 N H

R Step 5 C O H N.. O H H H

R H C O H N

H

.. O

H

Robinson Annulation

Step 1: Protonation of alcohol makes a better leaving group. Step 2: Elimination of water gives a carbocation. Both alcohol and alkene give the same carbocation. Step 3: Nitrile attacks as a nucleophile with lone pair electrons of nitrogen atom at the carbocation to form a nitrilium ion. Step 4: Water attacks as a nucleophile to the newly generated carbocation. Step 5: Deprotonation. Step 6: Proton transfer. Step 7: Tautomerization. Step 8: Deprotonation gives the desired amide. Application Crixivan (indinavir) (anti-HIV medicine) [8], amantadine (antiviral and medicine for the Parkinson’s disease) [16], and alkaloid aristotelone [12] have been synthesized utilizing this reaction. Experimental Procedure (from patent WO1996036629A1) N OH

N + N H

CN

A

N

H2SO4 N

H N

AcOH, H2O N H

O B

4-(3-Picolyl)-2-carbonitrile-piperazine (A) 0.283 g (1.4 mmol); Glacial acetic acid 3.5 ml; Sulfuric acid 96% 1.6 ml, tert-butanol 2.5 ml; Water 0.6 ml. To a solution of 4-(3-picolyl)-2-carbonitrile-piperazine (A) in AcOH was added 0.6 ml of H2 SO4 . The resulting precipitate was brought back into solution by the addition of 0.6 ml of H2 O and 1.5 ml of tert-butanol. TLC (EtOAc/MeOH 50/50) indicated only partial conversion after 24 hours; thus, the remainder of the H2 SO4 (1.0 ml) and tert-butanol (1.0 ml) were added. The reaction was complete after an additional 24 hours. 45% aqueous KOH solution was slowly added (to pH >12), and the mixture was extracted with 3 × 15 ml of CH2 Cl2 . The combined organic phases were dried over anhydrous MgSO4 , filtered, and concentrated to dryness to give a brown oil. Chromatography on SiO2 (EtOAc/MeOH 50/50) gave 4-(3-𝜌icolyl)-2-tert-butylcarboxamide-piperazine (compound B) as a low melting solid.

Robinson Annulation The reaction of a cyclic ketone with an α,β-unsaturated ketone in the presence of base (NaOH, KOH, NaOEt, NaNH2 , or others) to form a six-membered

221

222

4 Miscellaneous Reactions

α,β-unsaturated ketone is known as the Robinson annulation [1]. Robert Robinson discovered this reaction in 1935. This reaction is a combination of two reactions: Michael addition and intramolecular aldol condensation. Both cyclic and acyclic ketones react with α,β-unsaturated ketone to form substituted cyclohexanone derivatives. Several new catalysts including asymmetric versions have been developed for this reaction [2–43]. Aza-Robinson annulation [10], chiral phosphoric acid-catalyzed [22], and proline-catalyzed [29] reaction have been reported. O

O

KOH

O

+ R1 Cyclic ketone

R1 α,β-Unsaturated ketone

Mechanism O H O

H

Step 1

R1

O

Step 2

O

R1

R1

Step 3

O

H

OH

OH

O O R1

H O

Diketone Step 4

O Step 7

R1

HO

R1

H

OH O

H O Step 6 R1

O H O

Step 5

O O R1

Step 1: Deprotonation of the α-hydrogen of the ketone by the base forms an enolate. Step 2: Michael addition of the enolate to α,β-unsaturated ketone. Step 3: Protonation from water forms α-1,5-diketones. Step 4: Abstraction of another α-hydrogen with the base forms a new enolate. Step 5: Intramolecular aldol condensation gives a cyclic alkoxide. Step 6: Protonation gives an alcohol. Step 7: Dehydration (elimination of water) gives the desired product.

Application This is an important reaction for the formation of six-membered rings in polycyclic compounds, such as steroids, benzo[c]quinolizin-3-ones [15], and other polycyclic compounds. (+)-Codeine (pain, coughing, and diarrhea) [13] and (−)-morphine (painkiller medicine) [41] have been synthesized using this reaction as a key step.

Sandmeyer Reaction

Natural products such as ring of ouabain [16], (±)-guanacastepene A [15], pseudopteroxazole [14], core of norzoanthamine, platensimycin [19], peribysin E [21], lycoposerramine Z [28], jiadifenolide [31], nardoaristolone B [30], (±)-limonin [33], pallambins C and D [35], pregnanolone [38], (+)-taondiol [39], (−)-daphenylline [40], and (+)-strongylophorines 2 and 9 [43] have been synthesized under the reaction conditions. Experimental Procedure (from patent WO2018226102A1) O

O +

B

A

O

Benzenesulfonic acid CH2Cl2 C

A solution of 2-methylcyclohexanone (A) (52.26 g, 0.46 mol) and methyl vinyl ketone (B) (68.28 g, 0.97 mol) in 850 ml dichloromethane was cooled, and benzenesulfonic acid (150.5 g, 0.952 mol) was added in portions over a five minutes period at −50 to −55 ∘ C. The magnetically stirred mixture was allowed to warm up and placed in a mixture of ice and dry ice when it had reached −20 ∘ C. After overnight stirring, 300 ml water was added, followed by the slow addition of sodium bicarbonate (96 g, 1.142 mol). The mixture was stirred for two hours, the layers were separated, and the cloudy aqueous layer was extracted with 300 ml dichloromethane. Drying and rotary evaporation left a residue to which was added 700 ml heptane with swirling. After standing for 30 minutes, the supernatant was decanted from the residue, which was treated once more with 300 ml heptane. Rotary evaporation of the solution, followed by Kugelrohr distillation at 120–150 ∘ C/0.5 mbar, gave compound C (55.57 g, 73%).

Sandmeyer Reaction The conversion of aryl diazonium salts to aryl halides using copper salts as reagents or catalysts is called the Sandmeyer reaction [1, 2]. The most commonly applied Sandmeyer reactions are the chlorination, bromination, cynation, and hydroxylation using CuCl, CuBr, CuCN, and Cu2 O, respectively [3–35]. The Swiss chemist Traugott Sandmeyer discovered this reaction in 1884. Recently, Ag-promoted converting aromatic amino group into CF3 group [18], trifluoromethylation using other catalysts [16, 19, 21, 34], difluoromethylation [24], aryl trimethylstannanes from aryl amines [20], trifluoroacetylation [29], and aromatic C—P bond from aryl amine [28] have been investigated. N2 X

X = Cl, Br, CN

CuX

X

223

224

4 Miscellaneous Reactions

Cl

CuCl

N N Cl

Mechanism N N Cl

CuCl

Step 3

Step 2 N N

+ N2

+ CuCl2

SET Step 1

CuCl2

Cl + CuCl

Aryl radical

Diazonium radical

Step 1: Single-electron transfer (SET) from CuCl to diazonium salt forms a diazonium radical. Step 2: Formation of aryl radical with rapidly releases of one molecule of nitrogen gas. Step 3: Aryl radical reacts with copper(II) chloride to form chlorobenzene and regenerate copper(I) chloride. Application Drug-like compounds such as triarylisothiazoles [8], thieno[3,2-c]pyran-4-one as anticancer agents [12], thieno[3,4-c]pyrrole-4,6-dione [14], and organic light-emitting diodes [22] have been synthesized employing this reaction. Experimental Procedure (from patent WO20100234652A1) NH2 Me

Br Me

NaNO2

Me

Me

48% aqueous HBr Cl

Cl

To an initial charge of 65 ml of 48% aqueous HBr was added, in portions, 15.56 g (0.1 mol) of 4-chloro-2,6-dimethylaniline. The resulting thick suspension was stirred at 80 ∘ C for 15 minutes. It was then cooled to −10 ∘ C, and a solution of 8 g (0.116 mol) of NaNO2 in 35 ml of water was added dropwise within approx. 40 minutes at such a rate that the temperature did not exceed −5 ∘ C. 80 mg of sulfamic acid was added. Then the suspension of the diazonium salt cooled to −10 ∘ C was metered within about 25 minutes into a solution, heated to 80 ∘ C, 28.6 g (0.103 mol) of FeSO4 × 7H2 O in 65 ml of 62% aqueous HBr. The reaction mixture was then stirred at 80 ∘ C for another one hour, allowed to cool to room temperature, and admixed with 125 ml of water, the phases were separated, and the aqueous phase was extracted three times with 50 ml each time of methylene chloride. The combined organic phases were washed twice with 25 ml each time of water, dried over anhydrous MgSO4 , and concentrated under reduced pressure to give 17.2 g of an oil that, according to GC, contains 95.6% 4-chloro-2,6-dimethylbromobenzene (75% of theory).

Schotten–Baumann Reaction

Schotten–Baumann Reaction The preparation of amide from an amine with an acyl halide or anhydride in the presence of an aqueous base is known as the Schotten–Baumann reaction [1, 2]. The reaction is extended to prepare an ester from an alcohol with an acyl halide or anhydride. Nowadays, organic bases such as DMAP, DIEA, and TEA are used for the amide formation, and Lewis acids such as Sc(OTf )3 , Bi(OTf )3 , NiCl2 , ZnCl2 , RuCl3 , etc. are used for the ester formation in organic solvents [3–21]. O R

X

+ H2N R1

R

O

NaOH +

HO R1

R H2 O

Alcohol

Acyl halide or anhydride

R1

Amide

O X

N H

H2O

Amine

Acyl halide or anhydride

R

O

NaOH

O

R1

Ester

X = Cl, Br, OCOR; R, R1 = alkyl, aryl; amine = primary or secondary; other base = KOH, NHCO3 . Na2 CO3 . Mechanism Amide Formation O

O

Step 1

R

Cl

R1

.. NH2

Cl R H N H R1

O

O

Step 2 R

N H

R1

Step 3 R

N H

H

R1

OH

Step 1: The amine attacks at the electron-deficient carbonyl carbon atom of the acyl chloride to form an unstable tetrahedral intermediate. Step 2: Leaving of chloride gives a protonated amide. Step 3: The hydroxide abstracts the acidic proton to give an amide. A base is required to absorb this acidic proton. Ester Formation O

O

Step 1

R

Cl

R1

.. OH

R

Cl O

R1 H

O

Step 2 R

O O

R1 H OH

Step 3 R

O

R1

225

226

4 Miscellaneous Reactions

Step 1: The alcohol as a nucleophile attacks at the electron-deficient carbonyl carbon atom of the acyl chloride to form an unstable tetrahedral intermediate. Step 2: Leaving of chloride gives a protonated ester. Step 3: A base or hydroxide absorbs the acidic proton to give an ester. Application Syntheses of N-vanillyl nonanamide (also known as synthetic capsaicin; an active component of chili peppers), (−)-tejedine [7], fumiquinazoline G [8], (+)-cannabisativine [11], and chlorocatechelin A [13] were accomplished utilizing this reaction. Drug-like molecules such as tetrahydro-β-carboline diketopiperazines [19], dehydroabietylamine derivatives [14], ceramide analogs [10], and rhodamine B [21] were synthesized. Total syntheses of (+)-cannabisativine [11] and chlorocatechelin A [20] have been completed using this reaction as a key step.

Simmons–Smith Reaction Cyclopropanation of alkenes using diiodomethane in the presence of Zn–Cu is called the Simmons–Smith reaction [1, 2]. This reaction is stereospecific, and a wide range of functional groups such as alcohols, ethers, aldehydes, ketones, esters, carbonate, sulfones, sulfonates, and silanes are well tolerated during cyclopropanation of a variety of alkenes [3–49]. Theoretical study [11, 12, 22, 37, 39], new mechanistic study [14], asymmetric version of this reaction [17, 18], Zn-promoted [33], Ni-catalyzed [46], and Co-catalyzed [48, 49] have been investigated. R

R

CH2I2, Cu-Zn

R1

R1

Ether

cis

Z CH2I2, Cu-Zn

R

Ether

R1 E

R R1 trans

CH2I2, Cu-Zn

OH

OH Ether CH2I2, Cu-Zn Ether

H

H

Simmons–Smith Reaction

O (S)

O

(S)

O

Me2N (Z)

S

OH

O

BBu

Me2N

S

O

H O

(S)

OH

CH2I2, Et2Zn, CH2Cl2-DME

Mechanism 2 Zn 2 ICH2-Zn-I

2 I-CH2-I

(I-CH2)2-Zn

+ ZnI2

Oxidative addition Simmons–Smith reagent

I C ZnI H2 R1 R3 R2

ZnI CH2 R3

I

Concerted

R1

Addition

R2

R4

R2

R4

R1

R3 R4

+

ZnI2

T.S.

The mechanism starts with oxidative addition of Zn to form the Simmons–Smith reagent. The second step follows concerted cycloaddition through a threecentered butterfly-type transition step. Application Curacin A, an anticancer agent for several cancer cell lines such as renal, colon, and breast, has been synthesized using Simmons–Smith reaction [15]. (E)

(R)

(Z)

(E)

H (R)

OCH3

N (Z)

Curacin A H

S (R)(S)

H

Cilastatin, an antibiotic used in combination with imipenem, has been synthesized using this reaction [16].

(S)

O

NH

HO

NH2 S

(Z)

O

OH

(R)

O Cilastatin

227

228

4 Miscellaneous Reactions

Several natural products such as halicholactone [10], longifolene [23], solandelactones A–F [29, 30], core of zoanthenol [31], and (−)-lundurine A [45, 47] and drug-like compounds such as antiviral agents [28] and cyclopropyl nucleosides [24, 26, 27] were synthesized utilizing this reaction. Experimental Procedure (from patent US7019172B2) O O Et2Zn, CH2I2 Hexane, 0 °C OBn A

OBn B

1-Benzyloxy-4-(2-cyclopropylmethoxy-ethyl)benzene (B) To a stirred solution of compound A (12 g, 0.0447 mol) in dry hexane (50 ml), diethyl zinc (1.1 M solution in hexane, 185 ml) was added at 0 ∘ C under nitrogen atmosphere followed by diiodomethane (18 ml, 0.224 mol). The reaction was stirred for six hours at 0 ∘ C and poured over cold aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous layer extracted repeatedly with diethyl ether. The combined organic layer was washed with aqueous solution of sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified over silica gel column using ethyl acetate and light petroleum ether (1 : 50) as an eluent to afford compound B as a colorless liquid (11.365 g, 90%).

Stork Enamine Synthesis The alkylation or acylation of an enamine followed by hydrolysis to give the corresponding carbonyl compound is known as the Stork enamine synthesis [1–3]. The reaction is named after the inventor a Belgian-American chemist Gilbert Stork in 1954. The alkylation or the conjugate addition takes place at the less substituted side of the enamine. Enamines act as nucleophiles similar to enolates. Alkylation of the enamine undergoes in neutral conditions, so acidic and basic sensitive groups can tolerate [4–18]; over-alkylation was not observed, which is an advantage over enolate. The reaction involves three steps: (1) Formation of an enamine from an aldehyde or ketone with a cyclic secondary amine. (2) Addition of enamine to an alkyl halide or an acyl halide or an α,β-unsaturated carbonyl compound. (3) Acidic hydrolysis to generate the desired product.

Stork Enamine Synthesis O

O

H

O

N

Hydrolysis O

1,3-Diketone

Cl

O

O

N

N H

O

H

O

N

Acidic hydrolysis

1,4-Dioxane, reflux

Enamine

O

1,5-Diketone

MeI (excess) MeOH, reflux O N

H

I

Hydrolysis

Mechanism .. N

Step 4 .. N H

O Step 1

N H O

Step 3

.. N

Step 2

N

O

H OH

- OH

Enamine

OH

Step 5

.. H N O H

O

Step 7

Step 8 H .. N H H O

O

.. O H

Step 9

H .. O H

H

Step 6

O O

O

N O

N

O

O

Step 10

Step 1: Nucleophilic attacks with a lone pair electrons of nitrogen atom to electron-deficient carbonyl carbon atom. Step 2: Proton transfer. Step 3: Elimination of hydroxide forms a nitronium ion.

229

230

4 Miscellaneous Reactions

Step 4: Abstraction of an α-hydrogen by the hydroxide gives an enamine. Step 5: Conjugate addition (Michael type) of enamine to α,β-unsaturated ketone. Step 6: Tautomerization. Step 7: Water attacks as a nucleophile to the partially positive charge carbon atom. Step 8: Proton transfer. Step 9: Breaking C—N bond and making more stable C—O double bond. Step 10: Deprotonation gives the desired product.

Application Several natural products such as (−)-8-aza-12-oxo-17-desoxoestrone [9], (±)biatractylolide [8], and anmindenol A [16] were synthesized using this reaction. Drug-like compounds such as antiviral agents [18] and indolo[2,3-a]quinolizidin2-one [14] have been synthesized under the reaction conditions.

Experimental Procedure (from patent US2773099A) O

1.

N H

, Benzene

O Me

2. MeI, MeOH 3. Acidic work-up

The enamine from cyclohexanone was prepared by refluxing 2 g of cyclohexanone with 6.6 ml pyrrolidine in 35 ml of benzene for 30 minutes using a water separator to remove the water formed in the condensation. The benzene was then removed and replaced by 25 ml of methanol. After addition of 10 ml of methyl iodide, the mixture was refluxed for 25 hours, most of the solvent was removed, 25 ml of water was added, and heating was continued for another 30 minutes. The mixture was then worked up by adding 10 ml 10% H2 SO4 and salt solution extraction with ether. The ether layer was washed with salt solution and thiosulfate, dried over anhydrous MgSO4 , and distilled, giving about 60% of 2-methylcyclohexanone.

Tishchenko Reaction The formation of an ester from two equivalents of an aldehyde using aluminum ethoxide, which acts as a Lewis acid, is called Tishchenko reaction [1–3]. This is a disproportion reaction. It is named after the Russian chemist Vyacheslav Evgenevich Tishchenko who discovered this reaction in 1906. Most recently several improvements [3–49] such as thiolate-catalyzed [37], Sm-catalyzed [12, 13], zirconium alkoxide catalyzed [21], Ir-catalyzed [23], lanthanum complex catalyzed [24], Yb(III)-complex catalyzed [26], chiral ytterbium complex catalyzed [27], LiBr-catalyzed [29], organoactinide catalyzed [30], chiral lithium diphenylbinaphtholate [32], Mg-complex [33], lithium diphenylbinaphtholate catalyzed

Tishchenko Reaction

[34], Lewis acidic phosphonium Zwitterions catalyzed [46], cobalt-catalyzed [47], and mechanistic studies [8, 9, 42] have been investigated on this reaction. O

O

R

H

R

H

O

O +

O

Al(OEt)3

+

R

R

O

Al(OEt)3 H

H

O

O

O

O

O H

Al(OEt)3

O

H +

Benzyl benzoate

Mechanism Al(OEt)3

.. O R

O

Step 1 H

R

Al(OEt)3 H

Step 2

.. O R

O R O R

Al(OEt)3 H H

Al(OEt)3 O Step 3 H R O R

O R

O

R

H

H

Step 1: Coordination of Al(OEt)3 with one molecule of aldehyde. Step 2: Nucleophilic attacks by oxygen lone pair electrons of another molecule of aldehyde to the electron-deficient carbonyl carbon atom to form a hemiacetal intermediate. Step 3: An intramolecular 1,3-hydride shifts and elimination of catalyst gives the desired product. Application Several natural products such as luminacin D [15], rhizoxin D [18], (+)-13deoxytedanolide [19], (−)-polycavernoside A [39], (+)-elevenol [44], and hoiamide A [49] have been synthesized using this reaction. Experimental Procedure (from Reference [38], copyright 2012, American Chemical Society) O

O H

Bn2Se2, Bu2Mg

O

THF A

B

231

232

4 Miscellaneous Reactions

To a dry flask charged with 3 Å molecular sieves, a magnetic stirrer, and dibenzyl diselenide (0.48 mmol, 163.3 mg, 2.5 mol%) under a strict atmosphere of argon was added THF (0.2 ml). To this yellow solution was added di-n-butylmagnesium (1 M solution in heptane, 0.24 mmol, 0.24 ml) dropwise while stirring. To the resulting colorless solution, benzaldehyde (19.2 mmol, 1.95 ml) (compound A) was added. The reaction mixture was allowed to stir at 25 ∘ C for 24 hours. The reaction mixture was diluted with ethyl acetate and concentrated in vacuo. The resulting product was purified by column chromatography eluting in gradient 0–20% dichloromethane in hexane to give compound B (2.013 g, 99%) as a colorless oil.

Ullmann Coupling or Biaryl Synthesis The coupling of aryl halides in the presence of copper to form biaryl compounds is known as the Ullmann coupling reaction [1, 2]. The reaction was discovered by the German chemist Fritz Ullmann in 1901. The reactivity order is ArI > ArBr > ArCl [3–23].

X Heat

+

+ Cu

2

2CuX

X = Cl, Br, I

I Heat + Cu

2

Mechanism Both free radical and ionic mechanisms have been reported.

I I + Cu

Step 1

Cu

Cu

CuI

I + CuI

+ Cu Step 4 Step 2 – CuI

Step 1: Oxidative addition of copper. Step 2: Formation of Ph–Cu.

Step 3

Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation

Step 3: Oxidative addition of another iodobenzene. Step 4: Reductive elimination gives a biaryl compound. Application Syntheses of tubulin inhibitors [9], biphenyl chiral materials [11], and natural products aspercyclides [12] and nigricanin [18] have been completed using this reaction.

Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation The copper-promoted conversion of aryl halides to biaryl ethers is known as the Ullmann biaryl ether synthesis [1, 2]. The copper-mediated conversion of aryl halides to aryl amines is called the Goldberg reaction [3]. The scope of this type reaction is extended. The copper or copper(I) salt-promoted conversion of aryl halides to aryl ethers, aryl amines, aryl nitriles, and aryl thioethers is known as the Ullmann-type reaction [3–51]. These reactions require polar solvents such as nitrobenzene, DMF, DMSO, or N-methylpyrrolidone and high temperatures (>200 ∘ C) with excess amounts of copper or copper(I) salts. The reactivity pattern of aryl halide is as follows: I > Br > Cl ≫ F. Generally, aryl fluorides do not react under the reaction conditions. The electron-withdrawing groups in ortho and para positions of aromatic ring provide in good yield. Researchers have extensively applied these reactions in both academic and industrial settings [4–51]. Mechanism study [43], Ni-catalyzed [31], microwave [32], copper(I) siloxane cage complex catalyzed [33], copper nanoparticle catalyzed [36], photoinduced [38], and Pd–Au-catalyzed [40] have been investigated on this reaction. Recently, these types of reactions are replaced by the Buchwald–Hartwig reaction where a catalytic amount of Pd-catalyst is required. Ullmann Biaryl Ether Synthesis OH O2N

Cu or CuI

O2N

+ I

Solvent, heat

O

Goldberg Reaction (biaryl amines) NH2

O2N

Cu or CuI

O2N

+ I

Solvent, heat

N H

233

234

4 Miscellaneous Reactions

Ullmann-Type Reaction/Ullmann Condensation Y Cu or CuI + X

Y

Solvent, heat base

X = I, Br, Cl; Y = OH, SH, NH2 Mechanism Step 1

Ar-Y-M

CuX

M X

Ar-Y-Ar Ar-Y-Cu

Reductive elimination

X Ar

Step 3

Cu

Ar-X

Y Ar

Oxidative addition Step 2

The exact oxidation state of copper is unknown. The radical mechanism is also ruled out based on radical scavenger experiments. The possible Cu(III)-complex formation is intriguing. Step 1: Formation of aryl copper oxide or amide. Step 2: Oxidative addition of Ar-X gives possibly a Cu(III)-complex intermediate. Step 3: Reductive elimination gives the desired product. Application

Total syntheses of natural products such as dihydro-combretastatin D-2 [29], (±)-diepoxin sigma [9], (±)-aspidospermidine [17], santiagonamine [20], and vialinin B [30] have been accomplished utilizing this reaction as a key step. Experimental Procedure (from Patent WO1999018057A1) Cl OMe

Cl

(CuOTf)2-PhH, Cs2CO3

O

OMe

+ I A

MeO

OH

Ethyl acetate OMe

B C

l-Chloro-4-iodobenzene (compound A) (2.5 mmol), 3,4-dimethylphenol (compound B) (3.5 or 5.0 mmol), Cs2 CO3 (3.5 or 5.0 mmol), (CuOTf )2 -PhH

Weinreb Ketone Synthesis

(0.0625 mmol, 5.0 mol% Cu), ethyl acetate (0.125 mmol, 5.0 mol%), and toluene (2.0 ml) were added to an oven-dried test tube, which was then sealed with a septum, purged with argon, and heated to 110 ∘ C under argon until the aryl halide was consumed as determined by GC analysis. The reaction mixture was then allowed to cool to room temperature, diluted with Et2 O, and washed sequentially with 5% aqueous NaOH, water, and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (1% Et2 O/pentane) gave the analytically pure product (compound C) as a clear oil (530 mg, 91% yield).

Weinreb Ketone Synthesis The conversion of acid chlorides, acids, and esters to ketones via Weinreb’s amides and subsequent treatment with organometallic reagent is known as the Weinreb ketone synthesis [1]. The normal amide leads to tertiary alcohols, whereas Weinreb amide gives ketone [2–38] due to chelation effect stops over addition (see mechanism). This method tolerates a wide range of functional groups elsewhere in the molecule such as α-halogen substitution, N-protected amino acids, α-β unsaturation, silyl ethers, lactones, lactams, sulfonates, sulfinates, and phosphonate esters. The Weinreb amide can react with a variety of carbon nucleophiles from lithiates and Grignard reagents such as aliphatic, vinyl, aryl, and alkynyl.

H N

O Cl

R1

+

Me

O Pyridine R1

OMe

H N

O OR3

R1

+

Me

Me3Al OMe

R1

OH

+

H N OMe Me

1. R2Li or R2MgX 2. Acidic work-up

O R1

R2

Weinreb amide

N, O-dimethyl hydroxylamine

O

Me

CH2Cl2

N, O-dimethyl hydroxylamine

N OMe

CH2Cl2

R1

N OMe Me

2. Acidic work-up

R1

R2

Weinreb amide

O

HATU, DIEA DMF

O

1. R2Li or R2MgX

O

R1

O

1. R2Li or R2MgX N OMe Me

Weinreb amide

2. Acidic work-up

R1

R2

235

236

4 Miscellaneous Reactions

The normal reaction forms an alcohol due to over-addition.

R1

OH

R2-Li or R2MgI

O X

R1 THF or ether

R2

R2

Over-addition product X = OH, OR, NR2, halogens

The Weinreb amide can reduce with an excess of LiALH4 to give an aldehyde. O R1

O

Excess LiAlH4

N OMe Me

R1

H

THF

Weinreb amide

Aldehyde

The reaction with sterically hindered nucleophiles or with highly basic conditions or elimination of the methoxide moiety to form formaldehyde can occur as a significant side reaction [6] as shown below. .. B

O R

O

O

H

O C N H2 Me

R

N H

Me

H

+

H

Formaldehyde

Mechanism O R1

Cl

.. N H Me OMe

O

Step 2

O

Step 1

R1

Cl N H OMe Me

R1

O Base

H

N Me OMe Step 3

R1

OMe Step 4 N

Me

M

O

O Me N R1 R Me 2 Stable metal chelate M= Li or Mg

R2-M .. B

O R1

Step 7 R2

Ketone

Step 5

H O R1

+ R2

H N Me OMe

Step 6

H .. O R1

H

OMe N Me R2 H

Step 1: Nucleophilic addition. Step 2: Elimination of chloride. Step 3: Deprotonation by base. Step 4: Strong and stable metal chelation. Step 5: Acidic work-up and protonation of nitrogen atom. Step 6: Elimination of MeNH(OMe) and liberation of protonated ketone from the complex. Step 7: Deprotonation gives the desired ketone.

Weinreb Ketone Synthesis

Application Anticancer agent discodermolide was synthesized using Weinreb amide conditions. Total syntheses of natural products such as amphidinolide J [barbazanges], (−)-spirofungin A [11], (S)-coniine [15], (+)-zoapatanol [17], aculeatins A, B, and D [25], F-ATPase inhibitor cruentaren A [26], and (5R,6R,8R,9S)-(−)-5,9Zindolizidine 221T [27] have been completed using this reaction. Experimental Procedure (from patent US9399645B2)

O

O

N N

N

HCl HN O O

N

O

O

O

n-BuLi, THF, –60 °C

O

N N

N

O O N

N

O

O

A

Weinreb amide

O

B

I N N

C

n-BuLi, THF

O

O

N N

N N

O D

O

N N

O

Step 1 A solution of N,O-dimethylhydroxylamine hydrochloride (2.2 equiv.) in THF (0.8 mol/l) at −60 ∘ C was treated with a solution of n-butyllithium (4.1 equiv.). The mixture was stirred for 15 minutes, and a solution of the ester A (23 g, 48.90 mmol, 1 equiv.) in THF (0.6 mol/l) was added dropwise. The reaction mixture was stirred for 30 minutes, and then AcOH in THF (10%) followed by a saturated aqueous solution of NH4 Cl was added. The layers were separated. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with saturated aqueous NaHCO3 , H2 O, and brine, dried over anhydrous Na2 SO4 , and concentrated under vacuum. The residue was purified by column chromatography using EtOAc in hexane or MeOH in DCM to give the desired product B. Step 2 To solution of compound B (1 equiv.) in THF (0.1 mol/l) was added compound C (4 equivalents). The solution was cooled to −78 ∘ C, a solution of n-butyllithium

237

238

4 Miscellaneous Reactions

(2–3 equiv.) was added dropwise, and the reaction mixture was stirred for 20 minutes. The reaction mixture was poured into NH4 Cl (saturated) solution and extracted with DCM. The organic layer was washed with brine and water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (2–10% methanol in dichloromethane) to afford a pure product D.

Williamson Ether Synthesis The synthesis of symmetrical and unsymmetrical dialkyl and aryl alkyl ethers using aliphatic or aromatic alkoxides with alkyl, allyl, or benzyl halides is known as the Williamson ether synthesis [1, 2]. This reaction was discovered by Alexander William Williamson in 1850. The nucleophilic substitution (SN 2 type) of primary or secondary halides with alkoxides provides the desired ethers [3–24]. The tertiary halides undergo E2-elimination reaction to form the corresponding alkenes. The order of reactivity of alkyl halides or other leaving group is as follows: OTs > I > OMs > Br > Cl. Protic solvents and water can slow the reaction rate as these can react with nucleophiles. Acetonitrile, DMF, acetone, and THF are good solvents for this reaction. This method has a broad scope to synthesize symmetrical and unsymmetrical ethers both in laboratory and in large scale in industry. THF R X

+

R O R1

R1 O Na or DMF

R X

+

Dialkyl ether

THF

Ar O Na

R O Ar or DMF Alkylaryl ether

Mechanism SN2 R1 O

R X

R1 O R

+

X

Step 1

Step 1: Nucleophilic substitution bimolecular pathway Application Peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist [9], sigma receptor inhibitor [10], antiviral agents [12], kanamycin A derivatives [15], fluorinated dendrimers [17], positron emission tomography (PET) imaging agent [20], antibacterial agents [21], and microtubule-stabilizing agent [24] have been synthesized using this reaction.

Wurtz Coupling or Reaction

Experimental Procedure (from patent WO1994028886A1) O

H

O

H

K2CO3, KI +

Cl

OH

Acetone, 56 °C

O

In a 100 ml round-bottom flask were placed 3-hydroxybenzaldehyde (5 g), benzyl chloride (6.2 g), potassium iodide (10 mol%), and potassium carbonate (10 g). The reaction mixture was stirred at 56 ∘ C until completion of the reaction (TLC). Acetone was removed under reduced pressure. The crude product was extracted with ethyl acetate (100 ml). The organic portion was washed twice with distilled water (50 ml) to remove all aqueous soluble materials. The ethyl acetate portion was dried with anhydrous sodium sulfate and evaporated to obtain the crude solid. The residue was chromatographed over silica gel to obtain the desired ether in 87% yield.

Wurtz Coupling or Reaction The coupling of two alkyl halides using sodium metal to form an alkane is known as the Wurtz reaction [1, 2]. This is one of the oldest coupling reactions. Several other metals such as silver, zinc, iron, activated copper, and indium have been used for this coupling reaction [3–18]. +

2 R–X

R R

2 Na

Alkyl halide

+

2 NaX

Alkane

X = Cl, Br, I

Mechanism Step 2

Step 1 R

R X

+ Na X

Step 3 SN2

SET

SET

R R + NaX

R Na R X

Na

Na

Step 1: SET from sodium metal to the alkyl halide produces an alkyl radical and sodium halide. Step 2: The alkyl radical then accepts an electron from another sodium atom (SET) to form an alkyl anion (nucleophile). This intermediate has been isolated in several cases. Step 3: Alkyl anion attacks to another alkyl halide in an SN 2 reaction to give an alkane and sodium halide.

239

240

4 Miscellaneous Reactions

Application Preparation of strained ring compounds through intramolecular Wurtz reaction is not easy to make from other methods. 2 Na Cl

+ NaCl + NaBr

Br

Wurtz–Fittig Reaction This is a coupling reaction between an alkyl halide and an aryl halide in the presence of sodium metal in ether to produce a substituted aryl alkyl, and the reaction is referred to as the Wurtz–Fittig reaction [1, 2]. This reaction is similar to Wurtz reaction. Several improvements [3–15] on this reaction and mechanistic studies [3, 5] have been reported. Br

R 2 Na +

R I

+ NaBr + NaI Ether

Mechanism See the Wurtz reaction.

References Alder-Ene Reaction 1 Alder, K., Pascher, F., and Schmitz, A. (1943). Ber. Dtsch. Chem. Ges. 76:

27–53. 2 Alder, K., Pascher, F., and Schmitz, A. (1943). Ber. Dtsch. Chem. Ges. 76:

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Alder-Ene Reaction

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Weinreb Ketone Synthesis

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Williamson Ether Synthesis

35 Jollymore-Hughes, C.T., Pottie, I.R., Martin, E. et al. (2016). Bioorg. Med.

Chem. 24: 5270–5279. 36 Demkiw, K., Araki, H., Elliott, E.L. et al. (2016). J. Org. Chem. 81: 3447. 37 Sureshbabu, P., Azeez, S., Muniyappan, N. et al. (2019). J. Org. Chem. 84:

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Williamson Ether Synthesis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

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Wurtz Coupling or Reaction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Wurtz, A. (1855). Ann. Chim. Phys. 44: 275–312. Wurtz, A. (1855). Ann. Chem. Pharm. 96: 364–375. Morton, A.A. and Fallwell, F. Jr. (1937). J. Am. Chem. Soc. 59: 2386–2390. Whitmore, F.C. and Zook, H.D. (1942). J. Am. Chem. Soc. 64: 1783–1785. Morton, A.A., Davidson, J.B., and Hakan, B.L. (1942). J. Am. Chem. Soc. 64: 2242–2247. Saffer, A. and Davis, T.W. (1942). J. Am. Chem. Soc. 64: 2039–2043. Morton, A.A. and Brachman, A.E. (1951). J. Am. Chem. Soc. 73: 4368–4367. Skell, P.S. and Krapcho, A.P. (1961). J. Am. Chem. Soc. 83: 754–755. Connolly, J.W. and Urry, G. (1964). J. Org. Chem. 29: 619–623. Vermes, B., Keseru, G.M., Mezey-Vandor, G. et al. (1993). Tetrahedron 49: 4893–4900. Garst, J.F. and Cox, R.H. (1970). J. Am. Chem. Soc. 92: 6389–6391. Ramig, K., Dong, Y., and Van Arnum, S.D. (1996). Tetrahedron Lett. 37: 443–446. Giovannini, R., Stüdemann, T., Dussin, G., and Knochel, P. (1998). Angew. Chem. Int. Ed. 37: 2387–2390. Katz, S.M., Reichl, J.A., and Berry, D.H. (1998). J. Am. Chem. Soc. 120: 9844–9849. Hobbs, C. and Hammann, W. (1970). J. Org. Chem. 35: 4188–4191. Vanden Burg, D. and Price, G.J. (2012). Ultrason. Sonochem. 19: 5–8. Blümke, T.D., Groll, K., Karaghiosoff, K., and Knochel, P. (2011). Org. Lett. 13: 6440–6443. Sun, Q., Cai, L., Ding, Y. et al. (2016). Phys. Chem. Chem. Phys. 18: 2730–2735.

Wurtz–Fittig Reaction 1 Tollens, B. and Fittig, R. (1864). Justus Liebigs Ann. Chem. 131: 303–323. 2 Fittig, R. and König, J. (1867). Justus Liebigs Annalen der Chemie 144: 3 4 5 6 7 8 9 10 11

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Wurtz–Fittig Reaction

12 Campbell, B., Dedinas, R.F., and Trumbower-Walsh, S. (2010). Synlett 20:

3008–3010. 13 Hudrlik, P.F., Arasho, W.D., and Hudrlik, A.M. (2007). J. Org. Chem. 72:

8107–8110. 14 Wang, M. and Ning, Y. (2018). ACS Appl. Mater. Interfaces 10: 11933–11940. 15 Wang, Z. (2010). Comprehensive Organic Name Reactions and Reagents,

3100–3104. Wiley.

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5 Aromatic Electrophilic Substitution Reactions Bardhan–Sengupta Synthesis The synthesis of phenanthrene from phenylethylcyclohexanol with phosphorus pentoxide, an aromatic electrophilic substitution reaction followed by dehydrogenation with selenium at high temperature, is known as the Bardhan–Sengupta synthesis [1]. The reaction is named after Jogendra Chandra Bardhan and Suresh Chandra Sengupta. This reaction has been used to synthesize derivatives of phenanthrene [2–8].

HO

Se

P2O5 140 °C

280–340 °C Phenanthrene

The starting material of this reaction has been synthesized as shown below.

1. 10% KOH K in benzene

Br +

Heat

O CO2Et

HO

O CO2Et 2. Acidified with HCl 3. Heat (decarboxylation) 4. Na/ether

Mechanism See the next reaction.

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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Bogert–Cook Reaction or Synthesis of Phenanthrene The dehydration and isomerization of 1-β-phenylethylcyclohexanol to octahydro derivative of phenanthrene is called the Bogert–Cook reaction [1]. This reaction is similar to the Bardhan–Sengupta reaction. Several modifications and improvements on this reaction have been developed [2–8]. OH MgBr

O Grignard

+

H2SO4

reaction 1-β-Phenylethylcyclohexanol Se Heat

Phenanthrene

Mechanism H .. OH

H

OH2 Step 2

Step 3

H H Step 1 Step 4

– HSO4 Se

Step 5 H

Heat Step 6 Phenanthrene

Step 1: Protonation of hydroxyl group makes a better leaving group. Step 2: Abstraction of proton and elimination of water gives an alkene. Step 3: Protonation forms a carbocation. Step 4: Aromatic electrophilic substitution reaction.

– HSO4

Friedel–Crafts Reaction

Step 5: Deprotonation and aromatization of one ring. Step 6: Dehydrogenation at high temperature gives the desired phenanthrene.

Friedel–Crafts Reaction In 1877, Charles Friedel and James Crafts discovered this electrophilic aromatic substitution reaction between the nucleophilic π electrons of an aromatic ring and a strong electrophile. There are two types of Friedel–Crafts reactions: one is alkylation and another is acylation, which both take place on aromatic ring with alkyl halide and acyl halide, respectively, in the presence of Lewis acid such as aluminum chloride, ferric chloride, etc. [1, 2]. The Friedel–Crafts alkylation is still one of the widely studied and most utilized reactions in organic synthesis even after more than 143 years of its discovery. This reaction has the great versatility in scope and applicability to continue its crucial role in the synthesis of more and more complex molecules [3–67]. After more than a century, the asymmetric version on this reaction has been developed [34, 35, 38, 40–42, 45, 46, 51, 52, 55]. Several catalysts such as carbon monoxide [9], Sc(OTf )3 [12, 17], Cu(OTf )2 [13, 15], Zn(II)-complex [21], In(III)-salts [22], lanthanide triflates [23, 25], gold-catalyst [24], FeCl3 [26], and biocatalyst [53] have been employed on this reaction. Friedel–Crafts acylation O +

R

AlCl3 or other catalyst X

O R

CH2Cl2

X = F, Cl, Br, I, OH, OTf, OCOR R = alkyl, aryl

Friedel–Crafts alkylation AlCl3 or other catalyst +

X = F, Cl, Br, I

R = alkyl

R X

CH2Cl2

R

295

5 Aromatic Electrophilic Substitution Reactions

Mechanism

Step 3

HCl + AlCl3 +

Step 1

R

O:

Cl

AlCl3

Step 2

R

O

R

Step 4

Cl3Al Cl

Acylium ion

H

R

O

O C + AlCl4 R O:

H

R

O

For the Friedel–Crafts acylation, the electrophile is an acylium ion that is formed by a reaction between an acid chloride and an aluminum chloride as shown in the mechanism below.

R

O

Cl:

Cl Al Cl Cl

296

Step 1: The initial step is the coordination between acyl chloride and AlCl3 (complexation). Step 2: The Lewis acid (AlCl3 ) abstracts the chloride from acyl chloride to form an electrophilic acylium and a tetrachloride aluminum anion. Step 3: An aromatic electrophilic substitution reaction results in a cationic intermediate with the loss of aromaticity.

Friedel–Crafts Reaction

Step 4: Deprotonation with aluminum anion ensures the rearomatization to give the final product and regeneration of catalyst. Mechanism for Friedel–Crafts Alkylation R Cl:

AlCl3

Cl AlCl3

Step 1

H R Step 2

R

AlCl3

Cl

R

H R

Step 3

+

AlCl4 Step 4 R HCl + AlCl3 +

Step 1: The initial step is the coordination between alkyl chloride and AlCl3 (complexation). Step 2: The Lewis acid abstracts the chloride from the alkyl chloride to form an electrophilic alkyl cation and a tetrachloride aluminum anion. Step 3: An electrophilic aromatic substitution reaction undergoes where benzene attacks to the alkyl cation to form a sigma complex. Step 4: Deprotonation with aluminum anion gives the desired product and regeneration of catalyst (Lewis acid). Application The Friedel–Crafts reaction has been used for the synthesis of oxcarbazepine, a medicine for the treatment of epilepsy; cosalane for HIV; and others drugs. O OH

N R

Friedel–Crafts cyclization

O

N R

O

N H2N

O Oxcarbazepine

The drug-like (±)-naphthacemycin A9 , possessing antibacterial activity against methicillin-resistant Staphylococcus aureus and circumventing effect of β-lactam resistance, has been synthesized using this reaction [39]. Several natural products including (±)-frondosin B [8], polycitone B [10], alliacol A [11], kendomycin [16], (±)-taiwaniaquinol B [18], myrmicarin [19], (−)-hamigeran B [27], (−)-alstoscholarisine A [30], (−)-daphenylline [33], (+)-haplophytine [37], (+)-asperazine, (+)-iso-pestalazine A [28], estradiol

297

298

5 Aromatic Electrophilic Substitution Reactions

methyl ether [43], mulinane diterpenoid [44], (±)-adunctin B [47], (+)-taondiol [49], salimabromide [50], and (−)-daphenylline [54] have been synthesized utilizing this reaction. Experimental Procedure (from patent US4814508A) F F

F

LiCl, AlCl3 + 1,2-Dichloroethane O O

A

Cl

F

B

C

To an agitated mixture of lithium chloride (3.18 g, 0.075 mol) and aluminum chloride (20 g, 0.15 mol) in 1,2-dichloroethane (20 ml) at −15 ∘ C was added dropwise a mixture of 4-fluorobenzoyl chloride (8 g, 0.05 mol) (compound B) and fluorobenzene (4.8 g, 0.05 mol) (compound A) in 1,2-dichloroethane (7 ml). The reaction mixture was removed from the water bath after one hour and stored at 0 ∘ C for three hours and then at room temperature overnight. The reaction mixture was then slowly added to 100 ml of a stirred mixture of ice and dilute aqueous hydrochloric acid, the organic phase was separated, and the aqueous phase was washed with two 50 ml aliquots of ether. The combined organic phases were then washed with 50 ml of dilute sodium hydroxide solution and then water, separated, and dried over anhydrous magnesium sulfate. The dried solution was filtered to remove the drying agent, and the solvents were removed in a rotary evaporator. 4,4′ -Difluorobenzophenone (10.3 g, 94.5% yield) (compound C) was obtained as a white solid of melting point 106–109 ∘ C.

Gattermann Aldehyde Synthesis The Gattermann aldehyde synthesis is a formylation of certain aromatic compounds with a mixture of hydrogen cyanide (HCN) and hydrochloric acid (HCl) in the presence of a Lewis acid (AlCl3 ) catalyst [1, 2]. The reaction is named after the German chemist Ludwig Gattermann. It is an aromatic electrophilic substitution reaction similar to the Friedel–Crafts reaction. A variety of aromatic compounds can be formylated under this reaction condition [3–18]. CHO HCN, HCl AlCl3, H2O

Gattermann Aldehyde Synthesis

CH3

CH3 Zn(CN)2, HCl H2O

CHO

Mechanism Formation of an electrophile – Cl H

+

N

HCl

+

H

AlCl3

Cl

H

Cl +

H C NH

H N AlCl3

NH

Step 1 +

H

– Cl H C NH

NH

H

H

NH Step 2

NH

H AlCl4

Cl Step 3

H2 O O

NH4Cl

+

H

Step 1: The aromatic compound (here benzene) attacks to the alkyl cation to form a sigma complex. Step 2: Abstraction of hydrogen with a chloride anion gives an aryl imine. Step 3: Hydrolysis of imine with water yields the final product. Experimental Procedure (from patent US2067237A) O AlCl3, HCN

H

HCl, 80 °C

Forty-four parts of cold dry benzene was mixed with 52 parts of dry aluminum chloride. 10.4 parts of anhydrous hydrogen cyanide was slowly added to the reaction mixture with agitation. The mixture was heated to the boiling point under a reflux condenser, while hydrogen chloride was passed through to saturation. The reaction mixture was then poured into a mixture of 400 parts of ice and 40 parts

299

300

5 Aromatic Electrophilic Substitution Reactions

of hydrochloric acid. When interaction had ceased, the oily layer was removed by steam distillation or otherwise the aldehyde was separated by fractional distillation or as its bisulfite compound. The yield was 4.2 parts.

Gattermann–Koch Aldehyde Synthesis The Gattermann–Koch reaction is a formylation of alkylbenzenes with carbon monoxide and hydrochloric acid in the presence of AlCl3 –CuCl mixture as a catalyst [1]. The reaction is named after the German chemists Ludwig Gattermann and Julius Arnold Koch. This reaction is not applicable to phenols and phenol ethers [2–11]. CH3

CH3 CO, HCl

AlCl3, CuCl H

O

Mechanism Formation of electrophile HCl + AlCl3

HAlCl4

C O H C O

H C O

AlCl4

Acylium ion H +

H C O

H O

Step 1

O

+

AlCl4

H Cl AlCl4

Step 2 O H + HCl + AlCl3

Step 1: The aromatic compound attacks to the acylium ion to form a sigma complex (SE Ar). Step 2: Deprotonation gives the final product.

Haworth Reaction

Experimental Procedure (from patent WO2002020447A1) CH3

CH3

F F

HCl, CO

H O

102.13 g of aluminum chloride (765.9 mmol) and about 497.04 g of 2-fluorotoluene (110.13; 4.513 mmol) were charged to a 2 l stainless steel reaction vessel. To this mixture was added five drops of concentrated HCl. The vessel was sealed, heated to 60 ∘ C, and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented, and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 20 hours (the reaction temperature was maintained at 60 ∘ C for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 ml of ice water (which turned the solution a yellow color), to which was added 500 ml of cyclohexane. The top organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluorotoluene, and left about 71.35 g of 4-fluoro-3-methylbenzaldehyde product (mol. wt. 138.14; 516.5 mmol; yield of approximately 67.4%). The 4-fluoro-3-methylbenzaldehyde product generated a highly pleasant aroma.

Haworth Reaction Acylation of an arene with a succinic anhydride followed by reduction and another intramolecular acylation reaction to form a tetralone is known as Haworth reaction [1]. This reaction has been used to synthesize derivatives of naphthalene and phenanthrene [2–9]. O

O +

O

Zn–Hg

AlCl3

HCl

HO

O

H2SO4 HO O

O

O Tetralone

Synthesis of naphthalene Zn–Hg

O Tetralone

Pd–C Heat

HCl Tetralin

Naphthalene

301

5 Aromatic Electrophilic Substitution Reactions

HCl

+

O

O

AlCl3

O

HO

O

HCl

Zn–Hg

Phenanthrene

Heat

O OH

Pd/C

H2SO4

Zn–Hg

O

Synthesis of phenanthrene

O

302

Haworth Reaction

H

O HO .. O

Acylium ion

Step 7

O

Cl

O

Step 9

Acylium ion

O

H

AlCl3 .. O

O

Step 8

O

Step 1

O

O AlCl3

Step 2

C

O

O

O

AlCl3

Step 3

H2O

.. O

Cl3Al

H2SO4

Step 6

O O

O H

Cl

Step 5

Zn–Hg HCl

Step 4

HO

O

O

Mechanism

Step 1: Coordination of succinic anhydride with AlCl3 . Step 2: Formation of an acylium ion or an electrophile. Step 3: Aromatic electrophilic substitution reaction. Step 4: Deprotonation and rearomatization. Step 5: Reduction of ketone. Step 6: Protonation. Step 7: Elimination of water and formation of an acylium ion. Step 8: Intramolecular aromatic electrophilic substitution reaction. Step 9: Abstraction of proton ensures an aromatization.

303

304

5 Aromatic Electrophilic Substitution Reactions

Experimental Procedure (from patent CN106977377A) OCH3

AlCl3, succinic H3CO anhydride

O

HO

HO Zn/HCl

H3CO

O

O HO

AlCl3

Nitromethane

Nitromethane O

A

B

Step 1

C

Step 2

D

Step 3

Step 1: A mixture of 80 g of anhydrous aluminum chloride and 30 g anisole (compound A) in 250 ml nitromethane was stirred at 0–15 ∘ C. 25 g of succinic anhydride was added to the reaction mixture. The reaction mixture was stirred at 10–20 ∘ C for 12 hours. The reaction mixture was poured into 600 ml of water and 100 ml of 30% hydrochloric acid system at the temperature 0–25 ∘ C, stirred and incubated one hour. The solid was filtrated and dried to give 4-(4-methoxyphenyl)-4-oxobutanoic acid (compound B) yield 92%, HPLC purity 99.5% detection. Step 2: Used standard procedure. Step 3: A mixture of 200 ml toluene and 44 g aluminum chloride in nitromethane 10 ml was heated to 60–70 ∘ C; then 20 g 4-(4-methoxyphenyl)butanoic acid (compound C) was added. The reaction mixture was stirred for 10 hours; after that 300 ml of ice water was added to the reaction mixture. The layers were separated out and the aqueous layer was discarded; the organic layer was added water (100 ml), adjusted to pH 13 with caustic soda, and allowed to stand; and the organic layer was discarded and the aqueous layer was adjusted with hydrochloric acid to pH 2 and filtered. 20 ml of methanol and 30 ml of water were added to the filtrate. The mixture was heated to reflux, and then a clear solution was cooled to 0 ∘ C. Crystals were filtered; the filter cake was dried to give the white solid 7-hydroxy-1-tetralone (D) 14.7 g, yield 88%, HPLC purity 99.99%.

Houben–Hoesch Reaction Acetylation of phenols or phenolic ethers using nitriles and hydrochloric acid in the presence of Lewis acid such as AlCl3 or ZnCl2 is called the Houben–Hoesch reaction [1–4]. This reaction is similar to Friedel–Crafts acylation [5–17]. OH

OH

AlCl3 + R-CN

OH

H2O

+ HCl

OH

OH R

NH

OH R

O

Houben–Hoesch Reaction

OH

OH

AlCl3

OH

H2O

+ CH3CN + HCl OH

OH H3C

OH

NH

O

H3C

Mechanism .. R C N

AlCl3

– R C N AlCl3

R C N + HCl

– NH Cl

R

R C NH

– Cl

Complexation and formation of an electrophile .. OH

O H

Step 3

OH

OH R C N AlCl3

OH

OH

Step 2

Step 1

OH

H Cl

R

NH H

.. O

R

H

OH

H

O H R

NH HCl

NH

Step 4 OH OH OH

Step 6 Step 5 OH O

OH R

H O Cl

R

NH3

H

OH HO R

NH2

Step 1: Aromatic electrophilic substitution reaction. Step 2: Deprotonation ensures rearomatization. Step 3: Nucleophilic attacks by water (hydrolysis) to the imine. Step 4: Proton transfer. Step 5: Protonation of amine. Step 6: Abstraction of proton by chloride ion and elimination of ammonia gas forms the final product.

305

306

5 Aromatic Electrophilic Substitution Reactions

Application Total syntheses of (±)-trigonoliimine A [15] and cassiarin F [14] have been completed using this reaction.

Experimental Procedure (from patent EP0431871A2) OH OH AlCl3, HCl gas

NH2. HCl

+ NC

NH2.HCl

Nitrobenzene O

A

B

C

A suspension of aminoacetonitrile hydrochloride (compound B) (50 g) and phenol (62.6 g) (compound A) in nitromethane (250 g) was stirred at 15–20 ∘ C, and aluminum chloride (175 g) was added with stirring and cooling. Hydrogen chloride gas (79 g) was added over a period of three hours while the temperature was maintained at 15 ∘ C. The subsequent clear solution was left to stand for 18 hours at 20 ∘ C and was then poured slowly into 400 ml of water, cooled to prevent the temperature rising above 30 ∘ C. The precipitate of 2-amino-4-hydroxyacetophenone hydrochloride was filtered off, washed with isopropanol, and dried. The yield of 2-amino-4-hydroxyacetophenone hydrochloride (compound C) was 72.7 g (71.8%), having a purity of 97% by nonaqueous titration.

Kolbe–Schmitt Reaction Carboxylation of phenoxide (sodium salt of phenol) with carbon dioxide at high temperature (120 ∘ C) and under pressure (100 atmosphere) is called the Kolbe–Schmitt reaction [1–3]. The reaction is named after Hermann Kolbe and Rudolf Schmitt. For sodium phenoxide, it gives 2-hydroxybenzoic acid (salicylic acid, a precursor of aspirin) as a major product with a small amount of 4-hydroxybenzoic acid [4–18]. But when potassium phenoxide provides 4-hydroxybenzoic acid as a major product with a small amount of salicylic acid due to a large counterion, ortho position is hindered. Solvent effects [11], kinetic studies [18], modeling studies [9, 10], and enzyme catalysts [15] on this reaction have been investigated. OH

OH

ONa CO2 Heat, pressure

CO2 Na

HCl

CO2H

Acidic work-up Salicylic acid

Kolbe–Schmitt Reaction

Mechanism O

O

Na

O C O

OH

O

Step 1

Step 2

ONa

CO2Na

H

Step 3

Acidic work-up

OH CO2H

Step 1: The aromatic compound attacks on the carbon dioxide and an aromatic electrophilic substitution reaction. Step 2: Rearomatization. Step 3: Protonation gives the final product.

Application Aspirin (nonsteroidal anti-inflammatory drug) and other medicines were synthesized using this reaction condition. O O ONa

O

OH Kolbe–Schmitt

O O

CO2H

CO2H

H2SO4

conditions, acid work-up

Aspirin

Total synthesis of (+)-cytosporolide [13] has been accomplished under this reaction conditions.

Experimental Procedure (from patent US7582787B2)

OH

HCl

NaOH ONa

OH

ONa

CO2

OH

O A

B

O C

307

308

5 Aromatic Electrophilic Substitution Reactions

2,4-Di-tert-butylphenol (A, 10 g) was dissolved in 200 ml of a 2% aqueous solution of NaOH and heated to about 70 ∘ C, removing water under reduced pressure. 2,4-Di-tert-butylphenol sodium salt was reacted with carbon dioxide with heating to yield a 2,4-di-tert-butylsalicylic acid sodium salt (B), which was treated in an aqueous solution of hydrochloric acid to precipitate salicylic acid (compound C).

Reimer–Tiemann Reaction The formylation of phenol using chloroform and sodium hydroxide to form 2-hydroxybenzaldehyde (salicylaldehyde) as a major product is called the Reimer–Tiemann reaction [1–3]. The reaction was discovered by Karl Reimer and Ferdinand Tiemann in 1876. The Reimer–Tiemann reaction can occur for other hydroxyaromatic compounds such as naphthols and electron-rich heterocycles such as indoles [4–29]. Dichlorocarbenes formed from this reaction can react with alkenes and amines to form dichlorocyclopropanes and isocyanides, respectively. So the Reimer–Tiemann reaction may not be suitable for substrates containing these types of functional groups. Mechanism of this reaction [6, 7, 13] has been reported. Photo-Reimer–Tiemann reactions [14, 22, 23] have gained current interest. OH CHCl3, 10% NaOH

CHO

HCl

CHO

OH

OH

ONa

ONa

+ +

Acidic work-up CHO

CHO Major product

Mechanism Abstraction of the proton from chloroform with the hydroxide and elimination of chloride ion forms a neutral dichlorocarbene.

OH

Cl H C Cl Cl

Cl C Cl Cl

:C

Cl Cl

Dichlorocarbene

Reimer–Tiemann Reaction

OH

H

O

O

O NaOH

:C

Step 2

Cl

O H

Cl

Step 3 CCl2

Cl

Cl

Step 1 Step 4 O

O CHO

H O

OH O Step 6

Cl OH Step 5 H

H

O

Cl H

OH

Step 7 H

Step 8

Acidic work-up OH CHO

Step 1: Deprotonation. Step 2: The aromatic compound attacks to the dichlorocarbene gives an intermediate. Step 3: Deprotonation and rearomatization. Step 4: Elimination of chloride ion. Step 5: Nucleophilic attacks by a hydroxide (hydrolysis). Step 6: Elimination of another chloride ion. Step 7: Deprotonation and rearomatization again. Step 8: Protonation (acidic work-up) forms the final product. When pyrrole is subjected to this reaction condition, abnormal Reimer– Tiemann reaction product, ring expansion 3-chloropyridine, is formed.

Cl CHCl3 N H

NaOH

CHO N H

+

N Abnormal product

309

310

5 Aromatic Electrophilic Substitution Reactions

Cl .. C Cl

Cl

Cl

Cl N H

N H

N

OH

4-Alkylphenol also gives an abnormal product along with a normal product.

OH

O

OH CHCl3

CHO

NaOH

+

R

R

R

CHCl2

There is no H atom at the 4-position, so rearomatization does not occur, as shown below. O

O H3O

R

CCl2

R

CHCl2

Abnormal product

If CCl4 is used instead by CHCl3 , salicylic acid is formed. OH

OH

ONa O CCl4, NaOH

ONa

O OH

HCl

Application l-DOPA, a medicine for the treatment of Parkinson’s disease, has been synthesized using this reaction [29]. Experimental Procedure (from patent US4324922A)

OH

OH CHCl3, NaOH H2O

OH

O H + O

H

Vilsmeier–Haack Reaction

A solution of 25 g (0.62 mol) of sodium hydroxide, 100 g (5.55 mol) of water, 11.9 g (0.1 mol) of chloroform, and 27 g (0.28 mol) of phenol was added to a pressure reactor equipped with a thermocouple well and with a capacity of 460 ml. The thermocouple well was put in place, and the cap was screwed on the reactor. The reactor vessel was placed in a rack and shaken. While being continuously shaken, the reactor vessel and contents were heated by gas flame to 80–88 ∘ C and maintained at that temperature for about 12 minutes. The reactor vessel and contents were then cooled with water to 18 ∘ C. The cap was unscrewed and the reaction product removed. The recovered products were o-hydroxybenzaldehyde, p-hydroxybenzaldehyde, and insoluble tar. Based on the conversion of chloroform in the process, a 52.0% yield of combined aldehydes was obtained from the 0.1 mol of chloroform.

Vilsmeier–Haack Reaction The Vilsmeier–Haack reaction is a formylation of an electron-rich aromatic ring using DMF, an acid chloride (POCl3 or COCl2 ), and aqueous work-up [1]. The Vilsmeier–Haack reagent chloroiminium salt is formed in situ from DMF and acid chloride (POCl3 ), and it is a weak electrophile. Hence, it works better with electron-rich aromatic or heteroaromatic compounds such as phenol, phenolic ethers, and aromatic amines [2–25]. An alternative to POCl3 such as XtalFluor-E [19] has been reported. CHO

1. DMF, POCl3 2. Aqueous work-up

EDG

EDG Aryl aldehyde

Electron-rich aromatic compounds EDG = OH, OR, NR2 CHO

1. DMF, POCl3 MeO

2. Aqueous work-up

MeO Aryl aldehyde CHO

1. DMF, POCl3 2. Aqueous work-up

Me2N

Me2N Aryl aldehyde O

O N H

POCl3 DMF, 90 °C

H N

Cl

311

312

5 Aromatic Electrophilic Substitution Reactions

Mechanism Formation of Vilsmeier–Haack reagent N

Step 2

O P Cl H Cl Cl O

N –Cl

H

O O P Cl Cl

Step 3

O O P Cl Cl Cl

N .. H

Cl Step 4

Step 1 O P Cl Cl

Cl N ..

O

N

O O P Cl Cl

Cl H

H

Vilsmeier–Haack reagent

Step 1: DMF reacts with POCl3 to form an oxo-anion–iminium intermediate. Step 2: The intermediate releases chloride. Step 3: The chloride anion attacks as a nucleophile to the partially electrondeficient carbon center. Step 4: Formation of Vilsmeier–Haack reagent, chloroiminium ion. .. O

O

O

O Step 2

Step 1 H

Cl

H

Step 3

N

N

Cl

Cl

.. N

Me N Me

.. H O H

Cl

Step 4 Aqueous work-up O

O

O

Step 6

Step 7

O Step 5

–NHMe2 H O .. H N Me Me

H .. O

Me N Me H

H H

Step 8

O H Me O

H

H N

+

Me

O

O H H

Me N Me ..

H .. H2O

O H

Me N Me

Bardhan–Sengupta Synthesis

Step 1: Electrophilic aromatic substitution reaction and the electron-rich aromatic ring attacks at the chloroiminium ion with loss of aromaticity. Step 2: Deprotonation restores aromaticity. Step 3: Elimination of chloride and formation of another iminium intermediate. Step 4: Water attacks as a nucleophile to the iminium intermediate. Step 5: Deprotonation. Step 6: Protonation of N,N-dimethylamine. Step 7: Elimination of –NHMe2 . Step 8: Deprotonation provides the desired product. Application Total syntheses of natural products such as (±)-tashiromine [6] and (±)-caldaphnidine [18] have been accomplished strategically using this reaction as one of key steps. Experimental Procedure (from patent US5599966A) O POCl3, DMF HO

OH

H2O

H HO

OH

A 1 L3 neck flask equipped with a temperature thermocouple and an overhead stirrer was charged with DMF (49.3 g, 0.675 mol) and acetonitrile (150 ml). The flask was treated with POCl3 (88.16 g, 0.575 mol) in acetonitrile dropwise over 20 rain so that the temperature was maintained at 22–28 ∘ C with a water bath. Then it was stirred at ambient temperature for one hour to ensure complete conversion to the Vilsmeier reagent. The solution remained clear throughout. The reaction was cooled in a dry-ice bath to −14 to −17 ∘ C, and a solution of resorcinol (55.06 g, 0.5 mol) in acetonitrile (150 ml) was slowly added to maintain −10 to −17 ∘ C during the addition. The reaction was stirred for an additional two hours at −15 ± 2 ∘ C and then at 28–32 ∘ C for one hour. To water (680 ml) stirred at 40 ∘ C was added the above salt (122.6 g) in three portions. The reaction was heated to 52 ∘ C for 0.5 hour, and the reaction was cooled. When the temperature had reached 35 ∘ C, sodium thiosulfate solution (0.09 M, 1–2 ml) was added to discharge the resulting pink color. The reaction was cooled to 5 ∘ C and stirred for two hours. The mixture was filtered, and the solid was washed with cold water and air-dried for several hours. Vacuum drying at 30 ∘ C at 0.05 mm of Hg yielded an off-white solid, 53.1 g, m.p. 134–136 ∘ C.

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Bogert–Cook Reaction or Synthesis of Phenanthrene 1 2 3 4 5 6 7 8

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Friedel–Crafts Reaction

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Gattermann, L. and Berchelmann, W. (1898). Ber. Dtsch. Chem. Ges. 31: 1765. Gattermann, L. (1906). Ann 347: 347–386. Adams, R. and Levine, I. (1923). J. Am. Chem. Soc. 45: 2373. Adams, R. and Montgomery, E. (1924). J. Am. Chem. Soc. 46: 1518–1521. Ungnade, H.E. and Orwoll, E.F. (1943). J. Am. Chem. Soc. 65: 1736–1739. Niedzielski, E.L. and Nord, F.F. (1943). J. Org. Chem. 8: 146–152. King, W.J. and Izzo, P.T. (1947). J. Am. Chem. Soc. 69: 1220. Fuson, R.C., Horning, E.C., Rowland, S.P., and Ward, M.L. (1955). Org. Synth. 3: 549. Olah, G.A., Ohannesian, L., and Arvanaghi, M. (1987). Chem. Rev. 87: 671–686. Yato, M., Ohwada, T., and Shudo, K. (1991). J. Am. Chem. Soc. 113: 691–692. Aldabbagh, F. (2005). Aldehyde. In: Comprehensive Organic Functional Group Transformation II, vol. 3 (eds. A.R. Katritzky and R.J.K. Taylor), 99–133. Elsevier. Murthy, A.R.K. and Subba Rao, G.S.R. (1981). Indian J. Chem. 20B: 569–571. Agrawal, S.R., Desai, V.B., Kaushik, H.C. et al. (1962). J. Indian Chem. Soc. 39: 759–762. Ahluwalia, V.K., Dass, I., Krishnamurty, H.G., and Seshadri, T.R. (1965). J. Indian Chem. Soc. 42: 279–282. Aslam, F.M., Gore, P.H., and Jehangir, M. (1972). J. Chem. Soc., Perkin Trans. 1 892–894. Huang, Y.T. (1960). Tetrahedron 11: 52–59. Alagona, G. and Tomasi, J. (1983). J. Mol. Struct. 91: 263–281. Sato, Y., Yato, M., Ohwada, T. et al. (1995). J. Am. Chem. Soc. 117: 3037–3043.

Gattermann–Koch Aldehyde Synthesis Gattermann, L. and Koch, J.A. (1897). Chem. Ber. 30: 1622–1624. Crounse, N.N. (1949). Org. React. 5: 290–301. Manchot, W. (1903). Monatsh. Chem. 24: 857–880. Harding, E.P. and Cohen, L. (1901). J. Am. Chem. Soc. 23: 594–606. Crandall, E.W., Smith, C.H., and Horn, R.C. (1960). J. Org. Chem. 25: 329–331. 6 Olah, G.A., Ohannesian, L., and Arvanaghi, M. (1987). Chem. Rev. 87: 671–686. 1 2 3 4 5

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5100–5105. 10 Kantlehner, W., Vettel, M., Gissel, A. et al. (2000). J. Prakt. Chem. 342: 297. 11 Aldabbagh, F. (2005). Aldehyde. In: Comprehensive Organic Functional Group

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Haworth Reaction 1 Haworth, R.D. (1932). J. Chem. Soc. 1125. 2 Wolfrom, M.L., Lemieux, R.U., and Olin, S.M. (1949). J. Am. Chem. Soc. 71:

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Houben–Hoesch Reaction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Hoesch, K. (1915). Ber. Dtsch. Chem. Ges. 48: 1122–1133. Hoesch, K. and von Zarzecki, T. (1917). Ber. Dtsch. Chem. Ges. 50: 462–468. Houben, J. (1926). Ber. Dtsch. Chem. Ges. 59: 2878–2891. Houben, J. and Fischer, W. (1929). J. Prakt. Chem. 123: 89–109. Gulati, K.C., Seth, S.R., and Venkataraman, K. (1935). Org. Synth. 15: 70. Spoerri, P.E. and DuBois, A.S. (1949). Org. React. 5: 387–412. Yato, M., Ohwada, T., and Shudo, K. (1991). J. Am. Chem. Soc. 113: 691–692. Sato, Y., Yato, M., Ohwada, T. et al. (1995). J. Am. Chem. Soc. 117: 3037–3043. Kawecki, R., Mazurek, A.P., Kozerski, L., and Maurin, J.K. (1999). Synthesis 751–753. Udwary, D.W., Casillas, L.K., and Townsend, C.A. (2002). J. Am. Chem. Soc. 124: 5294. Basavaiah, D. and Satyanarayana, T. (2004). Chem. Commun.: 32. Kobayashi, Y., Katagiri, K., Azumaya, I., and Harayama, T. (2010). J. Org. Chem. 75: 2741–2744. Raja, E. and Klumpp, D.A. (2011). Tetrahedron Lett. 52: 5170. Deguchi, J., Hirahara, T., Oshimi, Y. et al. (2011). Org. Lett. 13: 4344–4347. Zhao, B., Hao, X.Y., Zhang, J.X. et al. (2013). Org. Lett. 15: 528–530.

Reimer–Tiemann Reaction

16 Oylaw, V.K. and Townsend, C.A. (2014). Org. Lett. 16: 6334–6337. 17 Stasyuk, A.J., Smole´ n, S., Glodkowska-Mrowka, E. et al. (2015). Chem. Asian

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Kolbe–Schmitt Reaction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Kolbe, H. (1860). Ann. Chem. Pharm. 113: 1125. Kolbe, H. and Lautemann, E. (1860). Liebigs Ann. Chem. 115: 178. Schmitt, R. (1885). J. Prakt. Chem. 31: 397. Feruson, L.N., Holmes, R.R., and Calvin, M. (1950). J. Am. Chem. Soc. 72: 5315. Lindsey, A.S. and Jeskey, H. (1957). Chem. Rev. 57: 583. Chidamabaram, M.V. and Sorenson, J.R.J. (1991). J. Pharm. Sci. 80: 810–811. Rahim, M.A., Matsui, Y., Matsuyama, T., and Kosugi, Y. (2003). Bull. Chem. Soc. Jpn. 76: 2191–2195. Lijima, T. and Yamaguchi, T. (2007). Tetrahedron Lett. 48: 5309–5311. Markovic, Z. and Markovic, S. (2008). J. Chem. Inf. Model. 48: 143–147. Markovic, Z., Markovic, S., and Begovic, N. (2006). J. Chem. Inf. Model. 46: 1957–1964. Stanescu, I. and Achenie, L.E.K. (2006). Chem. Eng. Sci. 61: 6199–6212. Li, Z. and Su, K. (2007). J. Mol. Catal. A: Chem. 277: 180–184. Takao, K.-I., Noguchi, S., Sakamoto, S. et al. (2015). J. Am. Chem. Soc. 137: 16971–15977. Pesci, L., Kara, S., and Liese, A. (2016). ChemBioChem 17: 1845. Ren, J., Yu, S., Dong, W. et al. (2016). ACS Catal. 6: 564–567. Luo, J., Preciado, S., Xie, P., and Larrosa, I. (2016). Chemistry 22: 6798. Eng, A.Y., Sofer, Z., Sedmidubský, D., and Pumera, M. (2017). ACS Nano 11: 1789. Zhang, X.-B., Liu, Y.-X., and Luo, Z.-H. (2019). Chem. Eng. Sci. 195: 107–119.

Reimer–Tiemann Reaction 1 2 3 4 5 6 7 8 9 10 11

Reimer, K. (1876). Ber. Dtsch. Chem. Ges. 9: 423–424. Reimer, K. and Tiemann, F. (1876). Ber. Dtsch. Chem. Ges. 9: 824–828. Reimer, K. and Tiemann, F. (1876). Ber. Dtsch. Chem. Ges. 9: 1268–1278. Arnold, R.T., Zaugg, H.E., and Sprung, J. (1941). J. Am. Chem. Soc. 63: 1314–1316. Dodson, R.M. and Webb, W.P. (1951). J. Am. Chem. Soc. 73: 2767–2769. Wynberg, H. (1954). J. Am. Chem. Soc. 76: 4998–4999. Wynberg, H. and Johnson, W.S. (1959). J. Org. Chem. 24: 1424–1428. Wynberg, H. (1960). Chem. Rev. 60: 169–184. Wiley, R.H. and Yamamoto, Y. (1960). J. Org. Chem. 25: 1906–1909. Hine, J. and Van Der Veen, J.M. (1961). J. Org. Chem. 26: 1406–1407. Kobayashi, S., Tagawa, S., and Nakajima, S. (1963). Chem. Pharm. Bull. (Tokyo) 11: 123.

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2301–2305. 15 Sasson, Y. and Yonovich, M. (1979). Tetrahedron Lett. 20: 3753–3756. 16 Smith, K.M., Bobe, F.W., Minnetian, O.M. et al. (1985). J. Org. Chem. 50:

790–792. 17 Thoer, A., Denis, G., Delmas, M., and Gaset, A. (1988). Synth. Commun. 18:

2095–2101. 18 Wynberg, H. (1991). Comprehensive Organic Synthesis, vol. 2 (eds. B.M. Trost

and I. Fleming), 769–775. Oxford: Pergamon. 19 Lanlois, B.R. (1991). Tetrahedron Lett. 32: 3691–3694. 20 Divakar, S., Maheswaran, M.M., and Narayan, M.S. (1992). Indian J. Chem.,

Sect B 31B: 543–546. 21 Jung, M.E. and Lazarova, T.I. (1995). J. Org. Chem. 62: 1553. 22 Consuelo Jiménez, M., Miranda, M.A., and Tormo, R. (1995). Tetrahedron 51:

5825–5830. 23 Ravichandran, R. (1998). J. Mol. Catal. A: Chem. 130: 1205–1207. 24 Gu, X.-H., Yu, H., Jacobson, A.E. et al. (2000). J. Med. Chem. 43: 4868–4876. 25 Aldabbagh, F. (2005). Aldehyde. In: Comprehensive Organic Functional Group

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Vilsmeier–Haack Reaction 1 2 3 4 5 6 7 8 9 10 11 12

Vilsmeier, A. and Haack, A. (1927). Ber. Dtsch. Chem. Ges. 60: 119–122. Kikugawa, K. and Ichino, M. (1972). J. Org. Chem. 37: 284. Linda, P., Marino, G., and Santini, S. (1970). Tetrahedron Lett. 11: 4223–4224. Guzman, A., Romero, M., Maddox, M.L., and Muchowski, J.M. (1990). J. Org. Chem. 55: 5793–5797. Kantlehner, W. (2003). Eur. J. Org. Chem. 11: 2530–2546. Bélanger, G., Larouche-Gauthier, R., Ménard, F. et al. (2006). J. Org. Chem. 71: 704–712. Pan, W., Dong, D., Wang, K. et al. (2007). Org. Lett. 9: 2421–2423. Nadhakumar, R., Suresh, T., Calistus Jude, A.L. et al. (2007). Eur. J. Med. Chem. 42: 1128–1136. Tang, X.-Y. and Shi, M. (2008). J. Org. Chem. 73: 8317–8320. Jiao, L., Yu, C., Li, J. et al. (2009). J. Org. Chem. 74: 7525–7528. Quiroga, J., Diaz, Y., Insuasty, B. et al. (2010). Tetrahedron Lett. 51: 2928–2930. Kumar, A.S. and Nagarajan, R. (2011). Org. Lett. 13: 1398.

Vilsmeier–Haack Reaction

13 Paul, N. and Muthusubramanian, S. (2011). Tetrahedron Lett. 52: 3743–3746. 14 Vaarla, K., Kesharwani, R.K., Santosh, K. et al. (2015). Bioorg. Med. Chem.

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2832–2842.

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6 Pd-Catalyzed C—C Bond-Forming Reactions Suzuki Coupling Reaction The Suzuki reaction is a famous cross-coupling reaction between a boronic acid and a vinyl or an aryl halide to form a carbon–carbon bond [1–3]. Akira Suzuki shared the Nobel Prize in Chemistry in 2010 with Richard Heck and Ei-ichi Negishi for their discovery and development of palladium-catalyzed cross-coupling reaction. A variety of substrates undergo this reaction [4–51]. Several new catalysts including air-stable catalysts [24], ionic liquids as catalysts [17], cationic chiral palladium(II) complexes [20], dendritic diphosphino Pd(II) catalysts [23], and nickel catalyst [32] have been reported. R1 X

+ R2 B(OH)2

Pd-catalyst Base, solvent

R1 R2

R1 = aryl, allyl, alkenyl, alkynyl, alkyl; R2 = aryl, alkyl, alkenyl; X = Cl, Br, I, OTf; base = Na2 CO3 , K2 CO3 , Cs2 CO3 , NaF, CsF, KF, KOtBu, NaOtBu, K3 PO4 ; solvent = benzene, toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dioxane, toluene-tBuOH, toluene-EtOH, THF-H2 O, etc.; Pd catalyst: Pd(Ph3 P)4 , Pd(dppf )Cl2 ; Pd catalyst + ligand = PdCl2 , Ph3 P; Pd(OAc)2 , Ph3 P, and other combinations Ar X +

Pd(Ph3P)4, Na2CO3

Ar1 B(OH)2

Toluene, 80 °C

Ar Ar1

X = Cl, Br, I, OTf

R2

B(OH)2

I

Pd(Ph3P)4, Na2CO3

+ R1

Toluene, 80 °C

R1

R2

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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6 Pd-Catalyzed C—C Bond-Forming Reactions

Boc N N

B(OH)2

Boc N N

Suzuki coupling +

I

OMe

O

Pd(dppf)Cl2, Na2CO3 Toluene/ethanol 80 °C H N

O

OMe

N 1. LiOH THF, H2O 2. HCl OH

O

Starting material for kinase inhibitors

Mechanism Reductive elimination

LnPd(0)

R2 X

R1 R2 Step 4 (II) L(n–1) Pd R1

Na OtBu HO B OH OtBu

Step 2

Step 3

R1 B(OH)2

NaOtBu

Ln = ligand

LnPd(II) X R2

R2

Transmetalation Na OtBu R1 B OH

Oxidative addition

Step 1

NaOtBu Pd(II)

Ln

OtBu

Metathesis

Base

R2 NaX

OH

Step 1: Oxidative addition of Pd(0) to the organic halide forms the Pd(II) species. Step 2: Exchange of the anion between base and the Pd(II) complex, where alkoxide (base) replaces the halide on Pd(II) complex. Step 3: Addition of the base (here alkoxide) to the organoborane forms a borate and increases the nucleophilicity of the alkyl group. This facilitates transmetalation step where R1 replaces the alkoxide on Pd(II) complex. Step 4: Reductive elimination gives the desired product and regeneration of catalyst. The catalytic cycle can start again.

Heck Coupling Reaction (Mizoroki–Heck Reaction)

Application The Suzuki coupling reaction has been used in the synthesis of pictilisib (PI-3K inhibitor), rucaparib (poly ADP ribose polymerase [PARP] inhibition), and other drugs for the treatment of several cancers. O

O

N S N

N

THF N

N

N + Cl

N

S

1. Suzuki coupling 2. Deprotection

N

N N

B(OH)2 N O S O CH3

N O S O CH3

N NH Pictilisib

Several drug-like or naturally occurring molecules such as aglycone of vancomycin [5], antibiotic (−)-lemonomycin [16], kendomycin [21], ningalin D, (−)-myxalamide A [26], fidaxomicin [27], influenza A virus M2-S31N inhibitors [29], and spliceostatin G [30] were synthesized under Suzuki reaction conditions. Experimental Procedure (General) Synthesis of biphenyl I

B(OH)2 +

Pd(Ph3P)4 K2CO3, toluene 80 °C

A mixture of iodobenzene (1.02 g, 5 mmol), phenylboronic acid (907 mg, 7.5 mmol), and potassium carbonate (2.07 g, 15 mmol) in 5 ml water and Pd(Ph3 P)4 (577 mg, 0.5 mmol) in 25 ml toluene was stirred at 80 ∘ C for 16 hours. The reaction mixture was partitioned between 100 ml of ethyl acetate and 50 ml of water. The organic layer was washed with saturated NaHCO3 solution (3 × 50 ml) (to remove excess boronic acid) and brine (100 ml). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (2–4% ethyl acetate in hexane) to give a pure biphenyl (539 mg, 70%), m.p. 70 ∘ C.

Heck Coupling Reaction (Mizoroki–Heck Reaction) The Heck reaction is a palladium-catalyzed cross-coupling reaction between an activated olefin and a vinyl or an aryl halide or triflate in the presence of

325

326

6 Pd-Catalyzed C—C Bond-Forming Reactions

a base to form a carbon–carbon bond [1–3]. Richard Heck shared the Nobel Prize in Chemistry in 2010 with Akira Suzuki and Ei-ichi Negishi for their discovery and development of palladium-catalyzed cross-coupling reaction. A wide range of alkenes have been used for this reaction [4–52]. Several modifications and improvements on this reaction such as Ru-catalyst [7, 9], milder conditions [5], Pd(0) nanoparticles [10], allyl acetate as a substrate [14], phosphine-free Pd-catalyst, irradiation-induced Heck reaction of unactive alkyl halides [30], kinetic asymmetric version [34, 35, 37, 43, 44], nickel-catalyzed [36, 40], ligand-free [38], iron(II)-catalyzed [39], mechanism perspective [17], and microwave based [18] have been investigated. R X

R

Pd-catalyst

+ Z

Organo halide

Base

Z Substituted alkene

Alkene

X = I, Br, Cl, or OTf, etc.; Z = H, R, Ar, CN, CO, OR, CO2 R, OAc, NHAc, etc. O I

OMe

+

Pd-catalyst

O

OMe

Base

Mechanism HBr/Base Base L Step 6 H Pd Br L Step 5

O O

Br

L (0) Pd L

Oxidative addition Step 1

O

L (II) Pd Br L

L O H Pd Br L Step 4 β hydride elimination

O H H

L = Ligand, generally Ph3P

Step 2

O L Pd Br L Step 3

O

O O L Pd Br L

O Coordination

Insertion

Step 1: The oxidative addition of the aryl bromide to the Pd(0) complex forms the Pd(II) species. Step 2: Pd forms a π-complex with the alkene.

Heck Coupling Reaction (Mizoroki–Heck Reaction)

Step 3: The alkene inserts itself in the Pd—C bond in a syn addition manner to form a Pd-σ intermediate. Step 4: β-Hydride elimination gives a new π-complex. Step 5: The product liberates from the complex. Step 6: Base-mediated reductive elimination regenerates Pd(0) catalyst. Application The Heck reaction has been employed for the synthesis of naratriptan (anti-migraine drug), alverine, tolpropamine, naftifine, etc. N N Br N H

+

O S O HN

H O N S O

Heck reaction

N H Pd/C H2 N H O N S O N H Naratriptan

Natural products such as mycalamide A [12], camptothecin [13], (±)-vincorine [19], archazolids A and B [20], lejimalide B [23], (−)-englerins A and B [41], and (±)-leuconodine D [42] have been synthesized utilizing this reaction as a key step. Experimental Procedure (from patent WO2008138938A2) OMe

O

I

OEt

+ O Br A

B

Pd-catalyst

OMe

EtO

Et3N, toluene, 90 °C Br C

To a suspension of new Pd catalyst (300 mg, 2 mol% Pd) in toluene (2 ml) were added A (313 mg, 1 mmol), ethyl acrylate (B, 220 mg, 2.2 mmol), and triethylamine (202 mg, 2 mmol), and the reaction mixture was heated under N2 with gentle magnetic stirring at 90 ∘ C for 10 hours. The reaction mixture

327

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6 Pd-Catalyzed C—C Bond-Forming Reactions

was passed through a cotton bed to isolate the catalyst and washed it with dichloromethane (DCM). The combined washings were concentrated under reduced pressure, leaving a residue that was purified by column chromatography on silica gel. Elution with ethyl acetate/light petroleum (1 : 10) afforded ethyl-3-(5-bromo-2-methoxyphenyl)acrylate (C) as a colorless solid (256 mg, 90% yield).

Negishi Coupling Reaction The Negishi reaction is a palladium- or nickel-catalyzed cross-coupling reactions between an organozinc compound and a vinyl or an aryl halide or triflate to form a carbon–carbon bond [1–3]. Ei-ichi Negishi shared the Nobel Prize in Chemistry in 2010 with Akira Suzuki and Richard Heck for their discovery and development of palladium-catalyzed cross-coupling reaction. It is a widely employed transition metal-catalyzed organic reaction [4–58]. Several modifications on this reaction such as carboxylic anhydrides as substrates [14], active catalyst [18], Pd-N-heterocyclic carbene (NHC) catalyst [23], Rh catalyst [29], nickel catalyst [37, 46, 47, 50], iron catalyst [31, 37, 40], copper catalyst [48], Ni-NHC [28], mechanism perspective [30], theoretical [39], and stereoselective version [27, 41] have been investigated. R1

X + R2-Zn-X1

Pd or Ni catalyst

R1

R2

R1 = aryl, alkenyl, acyl, propargyl, etc.; X = I, Br, Cl, OTf, OAc; R2 = aryl, alkenyl, allyl, benzyl, etc.; X1 = Cl, Br, I. Mechanism L Pd(0) L

R2 R1

R2 X

Step 4

Oxidative addition Step 1

L L Pd R1 R2

L R2 Pd X L

Step 3 trans/cis isomerization

R2

L Pd R1 L

Step 2 R1 Zn X Transmetalation

ZnX2

Step 1: The oxidative addition of the organohalide to the Pd(0) forms the Pd(II) species.

Negishi Coupling Reaction

Step 2: The transmetalation with the organozinc where R1 group replaces the halide on the Pd(II) complex to form the trans-Pd(II) complex and the zinc halide salt. Step 3: Isomerization of the trans-Pd(II) complex to the cis-Pd(II) -complex. Step 4: The reductive elimination gives the desired product and regeneration of the Pd(0) catalyst. The catalytic cycle can begin again. Application The Negishi coupling reaction has been used in the synthesis of BMS-599793 and other drugs. NC

+

N

N H

Cl

OCH3

ZnI

OCH3

N Negishi N

coupling

O OCH3

O

3 steps N

N H

N

N

N H

N

N

N

N BMS-599793

Total syntheses of natural product such as (−)-salicylihalamide [8], amphidinolide T [15], (+)-trans-195A [19], (±)-spectinabilin [20], (−)-stemoamide [25], myxovirescin A1 [26], anguinomycin C [34], enigmazole A [36], amythiamicin C [38], and (−)-daphenylline [51] have been completed utilizing this reaction as a key step. Drug-like molecules such as cyclin-dependent kinase (CDK) inhibitors [21] and protein kinase C (PKC) inhibitors [22] were synthesized under the Negishi reaction conditions. Experimental Procedure (from patent WO2010026121) S

Br N MeO A

Pd(dppf)Cl2

N +

S B

ZnBr

THF,100 °C microwave

N

N MeO C

A mixture of A (1.0 equiv.), the organozinc bromide B (0.5 M in THF, 2.0 equiv.), and Pd(dppf )Cl2 -DCM (20 mol%) in THF (10 ml) was heated at 100 ∘ C for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and water was added, extracted with ethyl acetate. The organic layer was washed with saturated Na2 CO3 solution and brine. The organic layer

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6 Pd-Catalyzed C—C Bond-Forming Reactions

was dried over anhydrous MgSO4 , concentrated, and purified by silica gel chromatography (20% EtOAc/hexane) to provide the product C in 73% yield.

Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction) The Stille coupling reaction is an organic reaction between an organic halide or triflate and an organostannane catalyzed by palladium [1–7]. A variety of vinyl halides as substrates [8–49] and ionic liquid [18], computational perspective [41], and mechanisms [45] have been investigated. R R1 X + R2 Sn R R

Pd(0), ligand R1

R2

R1 = aryl, alkenyl, allyl; X = Cl, Br, I, OTf; R2 = aryl, alkenyl, acyl; R = alkyl. Mechanism L Pd L

R2 R1

(0)

R2 X

Step 4

Oxidative addition Step 1

L L Pd R1 R2 Step 3 trans/cis isomerization

L R2 Pd X L L R2 Pd R1 L

Step 2 R1 Sn(R3)3 Transmetalation

X Sn(R3)3

Step 1: The oxidative addition of the organohalide to the Pd(0) forms the Pd(II) species, Step 2: Transmetalation with the organostannane in which R1 group from the tin reagent replaces the halide anion on Pd(II) complex. Sn(R3 )-X also forms. Step 3: Isomerization of the trans-Pd(II) complex to the cis-Pd(II) -complex. Step 4: Reductive elimination gives the desired product and regeneration of Pd(0) catalyst. The catalytic cycle can begin over again. Application Several natural products such as amythiamicin C [35], (−)-mycothiazole [13], epidermal growth factor inhibitor reveromycin B [16], epothilone B [17], (−)-ichthyothereol [19], (R)-(−)-pyridindolols [22], (+)-crocacin D [23], antibiotic fostriecin [24], antitumor agent apoptolidin [26], tardioxopiperazine

Sonogashira Coupling Reaction

A [27], iejimalide B [28], (+)-brevisamide [30], ripostatin B (an inhibitor of the bacterial RNA polymerase) [31], (−)-myxalamide A [32], ripostatin A [33], biselyngbyolide A [38], fidaxomicin [39], antibiotic thuggacin A [40], biselyngbyolide B [41], amphidinolide F [42], pre-schisanartanin C [44], and many more have been synthesized using this reaction. Experimental Procedure (from patent WO2008012440A2) Pd(Ph3P)4

N

+ N

N

N

Cl

SnBu3

N

Toluene, reflux

N

A

N N

B

C

In a flask fitted with a condenser under argon were placed A (1 mmol), B (1.2 mmol), and palladium catalyst (0.1 equiv.), and freshly distilled and degassed toluene (10 ml) was cannulated into the reaction medium. The solution was heated and stirred until complete disappearance of the starting material. After returning to ambient temperature, the solvent was evaporated under reduced pressure, and the residue was taken up in DCM. The solution was filtered through a pad of celite and washed with DCM. The organic phase is then washed successively with concentrated ammonia solution (25 N) and a saturated KF solution. The organic phase was dried over anhydrous Na2 SO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel to afford a pure product C (90%).

Sonogashira Coupling Reaction The Sonogashira reaction is a cross-coupling reaction between an aryl or vinyl halide and a terminal alkyne catalyzed by palladium complex, copper(I) iodide, and base [1, 2]. Several conditions have been employed [3–52] such as the reaction in water [4], microwave [9], copper-free [13, 18, 25], and Ni-catalyzed [20]. Computational study [26], kinetic study [29], and multimetallic-catalyzed reaction [35] have been thoroughly investigated. Boc N N I

CuI, Et3N,

+ N

Boc N N

H N N

TFA CH2Cl2

Pd(PPh3)4 CH3CN

N

N PI-3K inhibitor

The rate of reaction depends on nature of substrates for both Suzuki and Sonogashira reactions; however, general trends are as follows:

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6 Pd-Catalyzed C—C Bond-Forming Reactions

Vinyl iodide > vinyl triflate > vinyl bromide > vinyl chloride > aryl iodide > aryl triflate > aryl bromide > aryl chloride. Mechanism R1

(0) LnPd

R2

Reductive elimination

R1 X Oxidative addition

Step 1 Step 3

R1 (II) LnPd X

R1 LnPd

(II)

Cu

Step 2

R2 Et3NH X

R2

Transmetalation

CuX Et3N

+ H

R2

Step 1: The oxidative addition of the organohalide to the Pd(0) complex forms the Pd(II) species. Step 2: Copper reacts with the alkyne in the presence of base to form copper acetylide. Transmetalation with the copper acetylide in which alkynyl anion replaces the halide on Pd(II) complex. Copper halide catalyst regenerates. Step 3: The reductive elimination gives the desired coupled product and regenerates the Pd(0) catalyst. The catalytic cycle can start again. Application The Sonogashira coupling reaction has been used for the synthesis of altinicline (Parkinson’s disease), GRN-529 (autism), filibuvir (hepatitis C), ponatinib (anticancer), and other drugs. O I OMe O F

F

Sonogashira coupling

O

N

Pd(PPh3)2Cl2 CuI, NH4OH NMP

OMe F

O Hydrolysis and amine coupling

F

O

N

N F F

O

GRN-529

Kumada Cross-Coupling

Total syntheses of several natural products such as (−)-callipeltoside A [19], 8-deshydroxyajudazol B [22], (+)-(R)-concentricolide [23], (−)-exiguolide [36], marine macrolide mandelalide A [37], (−)-daphenylline [39], rubriflordilactone B [40], and callyspongiolide [42] have been accomplished utilizing this reaction. Experimental Procedure (General) Synthesis of diphenylacetylene

I +

CuI, Pd(Ph3P)2Cl2 Et3N, CH3CN, r.t.

A mixture of iodobenzene (1.02 g, 5 mmol), phenylacetylene (561 mg, 5.5 mmol), copper(I) iodide (95 mg, 0.5 mmol), Pd(Ph3 P)2 Cl2 (175 mg, 0.25 mmol), and triethylamine (3.5 ml, 25 mmol) in acetonitrile (25 ml) was stirred at room temperature for 16 hours. The solvent was removed in vacuo, and the residue was chromatographed over silica gel (2–5% ethyl acetate in hexane) to give a pure product diphenylacetylene (667 mg, 75%), m.p. 65 ∘ C.

Kumada Cross-Coupling The Kumada cross-coupling reaction is the reaction of a Grignard reagent with an organic halide or triflate catalyzed by palladium or nickel complexes. Makoto Kumada reported this reaction in 1972, and it was first Pd- or Ni-catalyzed cross-coupling reaction [1–4]. Several improvements [5–50] on this reaction such as microwave-based [10], Ni-catalyzed [17, 22, 26, 27, 29, 30, 36], milder conditions functional groups tolerate [20], N-heterocyclic carbene [23, 32], air-stable palladium HASPO complexes [25], bimetallic [33], tetramethylethylenediamine (TMEDA)-Fe catalyzed [35], cobalt-catalyzed [37], reaction in water [38], iron-catalyzed [41, 44], and others have been reported. R1 X1

+ R2 MgX2

Ni(dppb)Cl2 or Pd(Ph3P)4

R1 R2

R1 = aryl, vinyl, alkyl; R2 = aryl, vinyl, alkyl; X1 = Cl, Br, I, OTf; X2 = Cl, Br, I.

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6 Pd-Catalyzed C—C Bond-Forming Reactions

Mechanism L Pd L

R2 R1

(0)

R2 X

Step 4

Oxidative addition Step 1

L L Pd R1 R2 Step 3 trans/cis isomerization

L R2 Pd X L L R2 Pd R1 L

Step 2 R1 MgX Transmetalation MgX2

Step 1: The oxidative addition of the organohalide to the Pd(0) forms the Pd(II) species. Step 2: Transmetalation with the Grignard reagent in which R1 group from the Grignard reagent replaces the halide anion on Pd(II) complex. MgX2 also forms. Step 3: Isomerization of the trans-Pd(II) complex to the cis-Pd(II) -complex. Step 4: Reductive elimination gives the desired product and regeneration of Pd(0) catalyst. The catalytic cycle can begin over again. Nickel-catalyzed reaction follows similar mechanistic pathway. L (0) Ni L

R2 R1

R2 X

Step 4

Oxidative addition Step 1

L L Ni R2

L R2 Ni X L

R1

Step 3 trans/cis isomerization

R2

L Ni L

Step 2 R1 MgX

R1

Transmetalation MgX2

Hiyama Coupling Reaction

Application The Kumada cross-coupling is used for the synthesis of aliskiren (a treatment for hypertension) and ST1535 (drug for Parkinson’s disease). Drug-like molecules such as (S)-macrostomine [24] and anti-breast cancer agent [34] have been synthesized under the Kumada coupling conditions. Experimental Procedure (from patent WO2015144799) MgCl OTBS

OTBS Br

F

F

Pd(dppf)Cl2, THF 50 °C

A

B

Under N2 , to a solution of A[(4-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (6.0 g, 18.8 mmol) in dry THF (50 ml) was added isopropylmagnesium chloride 2 M in THF (47.0 ml, 94.0 mmol) at r.t. The reaction mixture was then purged with N2 , and Pd(dppf )Cl2 (1.54 g, 1.88 mmol) was added. The reaction mixture was purged again with N2 and stirred at 50 ∘ C for five hours. After being quenched with water, the reaction mixture was diluted with Et2 O and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and evaporated in vacuo to afford a brown residue. The residue was purified through a short pad of silica (mobile phase: heptane 90%, Et2 O 10%). The filtrate was collected and evaporated in vacuo to give 5.0 g of B, yellow oil (94%).

Hiyama Coupling Reaction The Hiyama coupling reaction is a palladium-catalyzed organic reaction of organosilicons with organic halides or triflates in the presence of an activating agent such as a fluoride or hydroxide to form carbon–carbon bond [1–5]. Mechanism perspective [21] and other catalysts [6–32] such as Ni [22] and Cu(II) complexes [23] have been investigated. R1 SiR3 + R2

X

Pd-catalyst TBAF

R1 R2

R1 = aryl, vinyl, alkynyl; R2 = aryl, alkenyl, alkynyl, alkyl; X = Cl, Br, I, OTf; R3 = Cl, F, alkyl.

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6 Pd-Catalyzed C—C Bond-Forming Reactions

Mechanism L Pd L

R2 R1

(0)

R2 X

Step 4

Oxidative addition Step 1

L L Pd R1 R2

L R2 Pd X L

Step 3 trans/cis isomerization

L R2 Pd R1 L

Step 2

F F F Si F

R1

NBu4

F3Si

R1 + Bu4NF

Transmetalation F F Si F F

X

NBu4

Step 1: The oxidative addition of the organohalide to the Pd(0) forms the Pd(II) species. Step 2: Activation of the silane with base or fluoride ion (tetra-n-butylammonium fluoride [TBAF]) leading to a pentavalent silicon center, which is labile enough to break C—Si bond during transmetalation step. The R1 group replaces the halide on the Pd(II) complex to form the trans-Pd(II) complex. Step 3: Isomerization of the trans-Pd(II) complex to the cis-Pd(II) complex. Step 4: The reductive elimination in which C—C bond is formed and regeneration of Pd(0) catalyst to begin the catalytic cycle over again. Application Total synthesis of (−)-exiguolide [20] has been accomplished using this reaction. Experimental Procedure (from patent US20022018351A1) OMe OMe Si Cl

I

+ A

B

TBAF Tri(t-butyl)phosphine [allylPdCl]2,THF

C

To a solution of compound A (255 mg, 1.2 mmol, 1.2 equiv.) in THF was added a solution of TBAF (3.6 ml, 1.0 M in THF, 3.6 mmol, 3.6 equiv.). The initial exotherm was allowed to subside, and the solution was stirred until it returned to room temperature (c. 10 minutes). Iodobenzene (B, 204 mg, 1.0 mmol) was added to the solution followed by tri-(t-butyl)phosphine (0.2 ml, 1.0 M in THF, 0.2 mmol, 0.2 equiv.) and [allylPdCl]2 (9.1 mg, 2.5 mol%). The mixture was stirred at 66 ∘ C for one hour. After being cooled to room temperature, the reaction

Liebeskind–Srogl Coupling Reaction

mixture was treated with H2 O (10 ml) and extracted with CH2 Cl2 (3 × 25 ml). The combined organic layers were dried (Na2 SO4 ) and concentrated in vacuo. The crude product was further purified by column chromatography (SiO2 , hexane to hexane/EtOAc, 50/1) to afford 0.167 g (91%) of compound C as a white solid.

Liebeskind–Srogl Coupling Reaction The Liebeskind–Srogl reaction is a palladium-catalyzed cross-coupling reaction between thioesters and organoboronic acids to form ketones [1, 2]. Scope and limitations [16, 20] and application on this reaction have been investigated [3– 26]. Other catalysts such as biocatalysts [23] and Ni catalysts [24] are also used. O R

S

R1

+

O

Pd2(dba)3, TFP

R2 B(OH)2

R

CuTC, THF

R2

TFP = tris(2-furyl)phosphine as an additional ligand and CuTC = copper(I) thiophene-2-carboxylate as a co-metal catalyst Mechanism O R

S ..

R1

O Coordination Step 1

Cu O

R

S

R1

Step 2 Pd(0)L2

O R

Oxidative addition

R1 S

Pd L L

CuTC

CuTC Transmetalation

S

R2-B(OH)2

O

Step 3

O R Step 4

R Pd 2 + Cu-SR1 + TC B(OH)2 L L Reductive elimination

O R

L R2

+ Pd

(0)

L

Step 1: The initial step is the coordination of thioester with copper salt of thiophene 2-carboxylate. Step 2: The oxidative addition of the thioester to the Pd(0) forms the Pd(II) species. Step 3: The transmetalation with the organoborane where R2 group replaces the thiolate on the Pd(II) complex to form a new Pd(II) complex. Step 4: Reductive elimination gives the desired product and regenerates the Pd(0) catalyst. The catalytic cycle can start again.

337

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6 Pd-Catalyzed C—C Bond-Forming Reactions

Application Several molecules such as synthesis of CDP840 (a potential therapeutic agent for asthma) [4] and enigmol (a synthetic, orally active 1-deoxysphingoid base analog that has demonstrated promising activity against prostate cancer) [11] were synthesized using this reaction. Syntheses of several natural products such as triterpenoid triazine derivatives [15], (+)-peganumine A [19], marine macrolide amphidinolide F [21], and borondipyrromethene dyes [22] have been accomplished using this reaction. Experimental Procedure (from patent WO2008030840A2) O TBSO

S NHCbz

Ph +

(HO)2B

B Cu(I)thiophene carboxylate Pd2(dba)3, THF

A

O TBSO NHCbz C

A mixture of thiol ester A (about 1 mmol), boronic acid B (1.5 mmol), Cu(I) thiophene carboxylate (2.0 equiv.), and Pd2 (dba)3 (2.5 mol%,) was placed under an argon atmosphere. THF (10 ml) and triethylphosphite (20 mol%) were added, and the mixture was stirred at about room temperature for about 16 hours. The reaction mixture was diluted with about 50 ml ethyl acetate and washed with saturated NaHCO3 aqueous solution and brine, followed by drying over anhydrous MgSO4 . After filtration and concentration under vacuum, the residue was purified by chromatography on silica gel using about 20 : 3 EtOAc/hexane to give a pure ketone C in 85% yield, thin-layer chromatography (TLC) (Rf = 0.6, silica gel, hexane/ethyl acetate = 5 : 1). ee = about 97–99%, absolute 4,5-E-alkene product; the Z-product was not observed from nuclear magnetic resonance (NMR).

Fukuyama Coupling Reaction The Fukuyama cross-coupling reaction is an organic reaction of thioester with an organic halide catalyzed by palladium to form a ketone [1]. O R1-ZnI

+ R 2

O S

Pd-catalyst

R2

R1

The method is well tolerated with functional groups such as ketones, acetates, sulfides, aromatic bromides, chlorides, aldehydes, protected alcohol, and protected

Fukuyama Coupling Reaction

amine. Advantages are high chemoselectivity, mild reaction conditions, and the use of less toxic reagents [2–18]. Mechanism O (0)

LnPd

O R

R

SEt

R1 Oxidative addition Step 1

Step 3 (II) LnPd

O (II) LnPd

O R

R

SEt Step 2

R1

R1 ZnI Transmetalation EtS Zn

I

Step 1: The oxidative addition of the thioester to the Pd(0) complex forms the Pd(II) species. Step 2: Transmetalation with the organozinc in which R1 group from the zinc reagent replaces the thiolate anion on Pd(II) complex. EtSZnI also forms. Step 3: The reductive elimination gives the desired coupling product and regenerates the Pd(0) catalyst, which can start again in the catalytic cycle. Application Practical syntheses of (+)-biotin [3], phomoidride B [4], and pteridic acid A [7], a key precursor of the natural product isoprekinamycin [10], have been completed using this reaction. Experimental Procedure (from patent US20150336915A1) O

O S NHCbz A

+

IZn

OTBS B

Pd(OAc)2 DMF

OTBS NHCbz C

A mixture of compound A (1 mmol), compound B (1.5 mmol), and Pd(OAc)2 (0.1 equiv.) in DMF was stirred at 50 ∘ C for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over anhydrous MgSO4 . The organic layer was concentrated in vacuo. The residue was purified over silica gel using ethyl acetate/hexane system to provide a pure product C.

339

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Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig Amination) The Buchwald–Hartwig amination is a palladium-catalyzed coupling reaction between organic halides or triflates and amines to form carbon–nitrogen bond. This reaction extended to form carbon–oxygen bond [1–4]. Various compounds [5–51] such as indole derivatives [13, 14, 22], quinoline derivatives [17], pyridine derivatives [18], pyrimidine derivatives such as antifolates [23], diazadithia[7]helicenes [27], coumarin [28], indolin-3-yl acetate [30], and cyclic peptide [15] have been synthesized using this reaction. New catalysts such as NHC [9, 32], nano-Pd–Au [31], and Ni [33] have been reported. R1 X +

H N R R1 2

N

R2

Pd-catalyst Ligand, base

X = Cl, Br, I, OTf; R1 = aryl, alkyl, H; R2 = aryl, alkyl. Pd-catalyst

Ar-X + Ar1-OH

Ar O Ar1

Mechanism Buchwald–Hartwig Amination Ar

R1 N R2

(0)

LnPd

Reductive elimination

Ar

Step 4

X

Oxidative addition Step 1

Ar LnPd NaX + tBuOH

Ar LnPd

R1 N R2 Ar

Step 3

LnPd

Step 2 X Coordination

NaOtBu R1

X

N R 2 H

H N R1

R2

Step 1: The oxidative addition of the aryl halide to the Pd(0) complex forms the Pd(II) species. Step 2: The amine coordinates with the Pd(II) -complex. Step 3: The base abstracts the proton from amine and leaves the halide to form the Pd—N bond.

Tsuji–Trost Allylation

Step 4: The reductive elimination gives the desired aryl amine and regenerates the catalyst, which can begin over again in the catalytic cycle. Application Total syntheses of (−)-variabili, (−)-glycinol [20], Lycopodium alkaloid (−)-huperzine A [21, 29], and (−)-indolactam V [26] have been accomplished using this reaction as a key step. Experimental Procedure (from patent US7442800B2) H N

Cl +

Me

O A

B

O N

(IPr)Pd(acac)Cl, KOtBu DME

Me C

In a glove box, (IPr)Pd(acac)Cl (0.01 mmol, 6.3 mg), potassium tert-butoxide (1.1 mmol, 124 mg), and anhydrous dimethoxyethane (DME) (1 ml) were added in turn to a vial equipped with a magnetic bar and sealed with a screw cap fitted with a septum. Outside the glove box, morpholine (compound B) (1.1 mmol) and 4-methylchlorobenzene (compound A) (1 mmol) were injected in turn through the septum. If one of the two starting materials was a solid, it was added to the vial inside the glove box, and DME and the second starting material were added outside the glove box under argon. The reaction mixture was then stirred at room temperature unless otherwise indicated. When the reaction reached completion (one hour) or no further conversion could be observed by gas chromatography (GC), water was added to the reaction mixture, the organic layer was extracted with tert-butylmethyl ether (MTBE), dried over magnesium sulfate, and the solvent was evaporated in vacuo. The product was purified by flash chromatography on silica gel to afford compound C (97%).

Tsuji–Trost Allylation The Pd-catalyzed allylation of carbon nucleophiles such as active methylenes, enolates, amines, and phenols with allylic substrates that contain a leaving group in an allylic position is known as the Tsuji–Trost reaction [1–5]. Several leaving groups (X) such as halides, acetates, ethers, sulfones, carbonates, phenols, carbamates, epoxides, and phosphates perform this reaction via π-allylpalladium complexes [6–25]. If allylic substrates are chiral, then soft nucleophiles undergo the substitution reaction with the retention of configuration, but hard nucleophiles undergo the substitution reaction with the inversion of configuration. Soft nucleophiles are derived from conjugate acids with pK a < 25. These add directly to ally moiety. Hard nucleophiles have conjugate acids with pK a > 25; these first attack

341

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6 Pd-Catalyzed C—C Bond-Forming Reactions

the metal center followed by reductive elimination to provide the allylation products if chiral compounds give inversion of configuration.

R

Nu H

Pd(0) or Pd(II), phosphine ligand

X

or Nu Pd(II) X

Allylic compound

R

R

R Base, solvent

R1 Nuc

Pd-catalyst R

Substituted product

R1 Pd-catalyst

R

R1 Nu

Hard Nu

X

Soft Nu

Nu

Inversion of configuration

Retention of configuration R, R1 = alkyl, aryl, H

X = Cl, OAc, Br, OCO2Me etc.

Pd- catalyst : Pd(PPh3)4, Pd2(dba)3 , Pd(COD)Cl2, Pd2(acac)3 etc. Solvent: THF, DMSO, DMF, DME, Et2O, etc Base: TEA, DIEA, KHMDS, NaHMDS, K2CO3, Cs2CO3 etc.

The most common nucleophiles are malonates, enolates, phenoxides, carboxylates, primary alkoxides, carboxylates, amines, azides, sulfonamides, sulfones, imides, etc. Mechanism Nu Step 1

X

Step 2

X Pd(0)L2

Step 3

L Pd(0) L

L Pd(II) X

+L, –X

L Pd(II) L Step 4 Nu

L Pd(0) L

+

Nu Product

Step 5 (0) L Pd L

Catalyst regeneration

Step 1: The palladium coordinates to the alkene forming a η2 π-allyl-Pd0 Π complex. Step 2: Oxidative addition of leaving group forms η3 π-allyl-Pd(II) complex.

Suzuki Coupling Reaction

Step 3: Ligand exchanges X to L, forming Pd(II) + center. Step 4: Nucleophile attacks at allylic center to form Pd(0) complex. Step 5: Reductive elimination gives the desired product and regeneration of catalyst, which can start again in the catalytic cycle. Due to regeneration of Pd catalyst, all Pd-catalyzed reactions require a small amount of catalyst (1–5 mol%). Application The formation of C—C, C—N, and C—O bonds utilizing this reaction has a wide range of applications in drug discovery research as well as natural product synthesis. Experimental Procedure (from patent US20190270700A1)

NC

CN O

Pd(PPh3)4

O

NC NC

O Ph

O

Ph + B

THF, 40 °C C

A

Tetrakis(triphenylphosphine)palladium(0) (1 mol%) was charged in a flame-dried Schlenk flask under a nitrogen atmosphere and dissolved in THF (0.5 M with respect to the limiting reagent). Allyl carbonate (B) (1.1 equiv.) derivative was then added to the reaction mixture directly followed by the substrate A (1 equiv.). The reaction mixture was stirred at 40 ∘ C until completion. After completion of the reaction, the crude mixture was concentrated in vacuo and purified via column chromatography (hexane/ethyl acetate) to afford the product C in 82% yield.

References Suzuki Coupling Reaction 1 Miyaura, N., Yamada, K., and Suzuki, A. (1979). Tetrahedron Lett. 20: 2 3 4 5

3437–3440. Miyaura, N. and Suzuki, A. (1979). J. Chem. Soc., Chem. Commun.: 866–867. Miyaura, N. and Suzuki, A. (1995). Chem. Rev. 95: 2457–2483. Littke, A.F. and Fu, G.C. (1998). Angew. Chem. Int. Ed. 37: 3387–3388. Nicolaou, K.C., Takayanagi, M., Jain, N.F. et al. (1998). Angew. Chem. Int. Ed. 37: 2717–2719.

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13088–13093. 34 Inoue, F., Kashihara, M., Yadav, M.R., and Nakao, Y. (2017). Angew. Chem. Int.

Ed. 56: 13307–13309. 35 Ahneman, D.T., Estrada, J.G., Lin, S. et al. (2018). Science 360: 186–190. 36 Weber, P., Scherpf, T., Rodstein, I. et al. (2019). Angew. Chem. Int. Ed. 58:

3203–3207. 37 Shukla, J., Ajayakumar, M.R., and Mukhopadhyay, P. (2018). Org. Lett. 20:

7864–7868. 38 Mitsudo, K., Shigemori, K., Mandai, H. et al. (2018). Org. Lett. 20:

7336. 39 Ganesh, B.S., Balakumar, E., Jerome, P., and Karvembu, R. (2017). Catal. Lett. 40 41 42 43 44 45 46 47

147: 2619. Peixoto, D., Locati, A., Marques, C.S. et al. (2015). RSC Adv. 5: 99990. Nowak, M., Malinowski, Z., Fornal, E. et al. (2015). Tetrahedron 71: 9463. Hartwig, J.F. (1997). Synlett 329–340 (review). Baranano, D., Mann, G., and Hartwig, J.F. (1997). Curr. Org. Chem. 1: 287–305. (review). Hartwig, J.F. (1998). Acc. Chem. Res. 31: 852–860. (review). Hartwig, J.F. (1998). Angew. Chem. Int. Ed. 37: 2046–2067. (review). Wolfe, J.P., Wagaw, S., Marcoux, J.-F., and Buchwald, S.L. (1998). Acc. Chem. Res. 31: 805–818. (review). Muci, A.R. and Buchwald, S.L. (2002). Top. Curr. Chem. 219: 131–209. (review).

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48 Sherwood, J., Clark, J.H., Fairlamb, I.J.S., and Slattery, J.M. (2019). Green

Chem. 21: 2164. (review on solvent effect for the coupling reaction). 49 Mphahlele, M.J. and Maluleka, M.M. (2014). Molecules 19: 17435. (review). 50 Dorel, R., Grugel, C.P., and Haydl, A.M. (2019). Angew. Chem. Int. Ed. 58:

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Tsuji–Trost Allylation 1 Tsuji, J., Takahashi, H., and Morikawa, M. (1965). Tetrahedron Lett. 6:

4387–4388. 2 Tsuji, J. (1969). Acc. Chem. Res. 2: 144. (review). 3 Trost, B.M. and Fullerton, T.J. (1973). J. Am. Chem. Soc. 95: 292–294. 4 Godleski, S.A. (1991). Nucleophiles with allyl-metal complexes. In: Compre-

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

hensive Organic Synthesis, vol. 4 (eds. B.M. Trost and I. Fleming), 585–662. Oxford: Pergamon. Trost, B.M. and Van Vranken, D.L. (1996). Chem. Rev. 96: 395–422. Saitoh, A., Achiwa, K., Tanaka, K., and Morimoto, T. (2000). J. Org. Chem. 65: 4227–4240. Seki, M., Mori, Y., Hatsuda, M., and Yamada, S. (2000). Org. Lett. 2: 2467–2470. Kimura, M., Horino, Y., Mukai, R. et al. (2001). J. Am. Chem. Soc. 123: 10401–10402. Kinoshita, H., Shinokubo, H., and Oshima, K. (2004). Org. Lett. 6: 4085–4088. Trost, B.M., Tang, W., and Toste, F.D. (2005). J. Am. Chem. Soc. 127: 14785–14803. Mohr, J.T., Behenna, D.C., Harned, A.M., and Stoltz, B.M. (2005). Angew. Chem. Int. Ed. 44: 6924–6927. Ibrahem, I. and Córdova, A. (2006). Angew. Chem. Int. Ed. 45: 1952–1956. Adak, L., Chattopadhyay, K., and Ranu, B.C. (2009). J. Org. Chem. 74: 3982–3985. Wang, L., Li, P., and Menche, D. (2010). Angew. Chem. Int. Ed. 49: 9270–9273. Sha, S.-C., Zhang, J., Carroll, P.J., and Walsh, P.J. (2013). J. Am. Chem. Soc. 135: 17602–17609. Li, Y.-X., Xuan, Q.-Q., Liu, L. et al. (2013). J. Am. Chem. Soc. 135: 12536–12539. Kurti, L. and Czako, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis, 458–459. Academic Press. Suzuki, Y., Seki, T., Tanaka, S., and Kitamura, M. (2015). J. Am. Chem. Soc. 137: 9539–9542. Wang, K., Ping, Y., Chang, T., and Wang, J. (2017). Angew. Chem. Int. Ed. 56: 13140–13144. Kalek, M. and Himo, F. (2017). J. Am. Chem. Soc. 139: 10250–10266. Parisotto, S. and Deagostino, A. (2018). Org. Lett. 20: 6891–6895. Burtea, A. and Rychnovsky, S.D. (2018). Org. Lett. 20: 5849–5852.

Tsuji–Trost Allylation

23 Wang, Z.J., Zheng, S., Romero, E. et al. (2019). Org. Lett. 21: 6543–6547. 24 Ma, X., Yu, J., Zhou, Q. et al. (2019). J. Org. Chem. 84: 7468–7473. 25 Martínez-Gualda, A.M., Cano, R., Marzo, L. et al. (2019). Nat. Commun. 10:

2634.

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7 Multicomponent Reaction A multicomponent reaction is a chemical reaction where at least three or more compounds react together in a single vessel to form a new product. A new product contains portions of all starting components, and generally by-product is only water. Therefore, the multicomponent reaction is an important atom-economy and eco-friendly reaction. Using multicomponent reactants, target compounds can be synthesized in one pot with fewer steps. Multicomponent reactions have been applied in various research fields, such as the discovery of lead compounds, manufacture of final drug, or making combinatorial compounds’ library.

Biginelli Reaction (3-Component Reaction [3-CR]) The Biginelli reaction is a three-component reaction from an aldehyde, β-keto ester (ethyl acetoacetate), and urea to produce 3,4-dihydropyrimidin-2(1H)-ones [1–3]. The reaction was discovered by the Italian chemist Pietro Biginelli in 1893. Instead of urea, thiourea can be used to provide the corresponding 3,4-dihydropyrimidin-2(1H)-thiones. The reaction proceeds in the presence of Bronsted acid (HCl) or Lewis acid (FeCl3 , RuCl3 , Cu(OTf )2 , Sc(OTf )3 , Yb(OTf )3 , NiCl2 , CuCl2 , InCl3 , or other catalysts) in ethanol or without solvent at high temperature [4–37]. Dihydropyrimidinones and their sulfur analogs have been reported as antibacterial, antiviral, antitumor, anti-inflammatory, analgesic, antihypertensive, calcium channel modulator, and other biological activities. O O R-CHO + 1

2

Catalyst

X

O

+ O

H2N

NH2 3

Heat Ethanol or no solvent

R

EtO

NH X

N H 4

X = O or S

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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7 Multicomponent Reaction

One of Plausible Mechanisms Step 2 O

Step 1

O H

+ H 2N

Ph

OH

HN

NH2

H NH2

O

– H2O

Ph

H

H

NH2

N O

O

O OEt

Step 3 Ph

Ph EtO2C

– H2O

NH N H

O

EtO2C

Step 4

NH O NH2

O

Step 1: Nucleophilic addition of the urea to the aldehyde, which is the rate-determining step. Step 2: Acid-catalyzed formation of the imine. Step 3: The enol of the ethyl acetoacetate reacts with the imine. Step 4: Ring closure by the nucleophilic attacks of the amine of urea into carbonyl group followed by second condensation to give the desired product [5–8]. Application Wipf et al. reported the first example of a solid-phase Biginelli reaction using a resin-bound urea to make a combinatorial library [22]. O

O N H

H2N

O

1. THF, 55 °C

+

O Ar-CHO +

O

Wang resin

O

O

NH R1

2. TFA, CH2Cl2

O

R1

Ar

O R

R

N

O

HO O

Several procedures have been developed for the asymmetric synthesis of enantioenriched dihydropyrimidines using chiral catalysts [24, 26, 37]. Experimental Procedure (from patent US810606062B1)

O O

C15H31

+

OEt

A

HCl NH2

H2N

THF, 66 °C

H

O

+

C B

C15H31

O

O

O

EtO2C

NH N H

O D

A solution of ethyl acetoacetate (compound B) (1.13 g, 8.6 mmol), 2-methoxy-6pentadecyl benzaldehyde (compound A) (3 g, 8.6 mmol), and urea (compound C)

Gewald Reaction (3-Component Reaction [3-CR])

(1.04 g, 17.3 mmol) in tetrahydrofuran (20 ml) was stirred at 66 ∘ C in the presence of hydrochloric acid (30%) for seven hours. The reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for five minutes. The viscous liquid was extracted with ethyl acetate (40 ml) and was washed with 1 N hydrochloric acid, water, sodium bicarbonate, and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by flash column chromatography and recrystallized from hexane to get white crystalline solid of compound D (50%).

Gewald Reaction (3-Component Reaction [3-CR]) The synthesis of 2-amino thiophene derivatives from α-methylene carbonyl compounds, α-active methylene nitriles, and elemental sulfur in the presence of base is known as the Gewald reaction [1]. This is a versatile multicomponent reaction to synthesize tetrasubstituted thiophene derivatives [2–26]. O

R1

O

N

R2

R2

Base + S8

OR3

+

NH2

R1

NH2

S

O

Mechanism B .. O

O NC

Step 2

O

Step 1 OR3

NC

OR3 + BH

O

O

Step 3

R2

OR3

R2 H

O

.. B

CN

R1

R1

R2

R1

OR3

HO

CN

H

Step 4

O O O

O OR3

R2 R1 S S

R2

Step 7

N .. S S S S S S S S

R1

N

S S

OR3

S S S S

O Step 6

R2

OR3 Step 5

R2

R1

N S8

R1

N

.. B

S S S S

OR3

H

S S S S

Step 8

O OR3

R2 R1

S

O Step 9

N H B

R1 .. B

H

S

O

O OR3

R2

NH

R2

Step 10 R1

OR3 S

NH H B

Step 11

R2 R1

OR3 S

NH2

365

366

7 Multicomponent Reaction

Step 1: Abstraction of α-H by base from the α-cyano ester. Step 2: Knoevenagel condensation between the ketone and α-cyano ester. Step 3: Proton transfer. Step 4: Elimination of water produces the stable intermediate. Step 5: Abstraction of α-H by base. Step 6: Addition of the elemental sulfur. The mechanism of this part is still unknown. Step 7: Nucleophilic-type addition of the sulfur to the cyano group. Step 8: Leaving the S7 . Step 9: Proton transfer. Step 10: Abstraction of proton gives thiophene. Step 11: Proton transfer gives the desired 2-amino-3,4,5-substituted thiophene [3, 11]. Application Thiophene derivatives are used as human leukocyte elastase [2], antitumor agents [9, 13, 20], and antimicrobial agents [11, 25]. Experimental Procedure (from patent US20100081823A1) O O + H A

OEt

Diethyl amine

CO2Et + S8 CN B

C

S

Reflux

NH2

D

Diethylamine (8 ml) was added to a solution of equimolar quantities of phenylacetaldehyde (A) (12.0 g, 0.10 mol) and ethylcyanoacetate (B) (11.4 g, 0.10 mol) in ethanol and was refluxed for 10 minutes; then elemental sulfur (C) (3.53 g, 0.11 mol) was added, and the solution was refluxed for further three hours. The pale yellow precipitate formed was filtered and washed with cooled ethanol to give compound D as a pale yellow powder (4.70 g, 19% yield), m.p. 124–125 ∘ C.

Hantzsch Pyridine Synthesis The Hantzsch pyridine synthesis is a multicomponent organic reaction between an aldehyde, 2 equiv. of a β-keto ester (ethyl acetoacetate), and ammonia to produce dihydropyridine [1, 2]. Subsequent oxidation provides pyridine-3,5-dicarboxylate. This reaction was discovered by Arthur Rudolf Hantzsch in 1881. Dihydropyrimidones have gained a considerable amount of

Hantzsch Pyridine Synthesis

attention due to the interesting pharmacological properties associated with this type of heterocyclic scaffold [3–40]. R

O

H

+ 2

O

R

O

EtO2C

C2Et

HNO3

+ NH3

OEt

N H

R CO2Et

EtO2C

or FeCl3

N

O

O

O

O

R CO2Et

Catalyst

+ R CHO +

OEt + NH4OAc

EtOH, heat

N H

O

Mechanism O

O

O

Step 1 O

OEt .. NH3

NH3

HO Step 2

O

O

H

OEt

OEt NH2

R

Enamine H O

O

OEt

OEt

O

Step 4

Enol

EtO2C

Step 5 R H O

O

.. NH3

O

OH O OEt

.. NH2

OEt O

R

EtO2C

Step 7

R

OEt Step 6

R

O OEt

O

O

R

O H

R

NH2

– H2 O

O O

OEt

Step 3

CO2Et

Step 8

CO2Et

EtO2C O

O NH 2

NH2 ..

Step 9 ..NH3 R

R CO2Et

EtO2C N

HNO3 Step 12

EtO2C

CO2Et N H

H EtO2C Step 11

R

R

N HO H

CO2Et

CO2Et

EtO2C Step 10 O

N H H

Step 1: Nucleophilic attacks by the lone pair of nitrogen ammonia to the carbonyl carbon atom Step 2: Proton transfer Step 3: Elimination of water and formation of enamine Step 4: Aldol condensation Step 5: Proton transfer Step 6: Elimination of water to form 𝛼,β-unsaturated carbonyl compound Step 7: Conjugate addition (Michael type) Step 8: Proton transfer and enamine formation

367

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7 Multicomponent Reaction

Step 9: Nucleophilic addition of amine to the carbonyl carbon atom Step 10: Proton transfer Step 11: Elimination of water and formation of 1,4-dihydropyridine derivative Step 12: Oxidation to form pyridine derivative Application The Hantzsch reaction has been used for the synthesis of nifedipine (brand name Adalat), a drug for the treatment of angina, high blood pressure, Raynaud’s phenomenon, and premature labor.

CHO

O

O2N

NO2

O

+ 2

OMe

+

MeO2C

NH3

CO2Me N H

Nifedipine

Several drug-like molecules such as Ca channel blockers [10–12, 15, 17, 19], antimicrobial agents [33, 34], antagonist activity against platelet-activating factor [16], and amythiamicin D [24] were synthesized using this reaction. Experimental Procedure (from patent US8106062B1)

O O

O

C15H31 + O A

OEt

+

OEt

H B

AcOH, piperidine

NH2 O

C

n-BuOH

O

C15H31

EtO2C

CO2Et N H D

2-Ethoxy-6-pentadecyl benzaldehyde (compound A) (3 g, 8.3 mmol) and ethyl acetoacetate (compound B) (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 ml). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for three to four hours. Ethyl-3-aminocrotonate (compound C) (1.08 g, 8.3 mmol) was then added and refluxed for 10 hours. n-Butanol was evaporated, and reaction mixture was washed with distilled water and extracted with dichloromethane (10 ml). Organic layer was dried over sodium sulfate and evaporated, and compound was purified by column chromatography using silica gel (100–200 mesh) with hexane/EtOAc (94 : 6) solvent system to give diethyl 1,4-dihydro-4-(2′ -ethoxy-6′ -pentadecyl phenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (compound D) as a white powder.

Mannich Reaction

Mannich Reaction The Mannich reaction is a three-component organic reaction of an aldehyde (non-enolizable carbonyl compound such as formaldehyde or benzaldehyde), a primary or secondary amine, and an enolizable carbonyl compound (such as acetophenone) in the presence of an acid or base catalyst to afford a β-amino carbonyl compound, also called as a Mannich base [1, 2]. A variety of substrate can participate for this reaction [3–41]. Asymmetric version [4, 13–16], Zn-catalyzed [18], proline-catalyzed [23], and phosphonium salt-catalyzed [25, 31] have been investigated on this reaction. O O H

+

H

R

H N

R

R2

+

H

Amine

Non-enolizable carbonyl compound

H

Catalyst R

R1

R N

R2 R1

O β -Amino carbonyl compound (Mannich base)

Enolizabe carbonyl compound

Mechanism Acid catalyzed

.. O H

H H O

H

H O

Step 1

H

H H

+H

R2

H H

N H RR

H

Step 4

O

Step 3

.. H N R H R

+H, –H

Step 5

.. H O

H O

R1 H H

Step 6

R N R

O

Iminium ion

R2

H

H

R N R

R N R

R1

R1

H H .. H2O

Enolized carbonyl compound

O Step 7

H

H

R2 R1

H

– H2O

.. HN R R

H H

R2

H

H H O H

.. O

H .. O

Step 2

R2

H

R1 N R R

.. H O H Step 8

O R2

R1 N R R

Step 1: Protonation of formaldehyde from acid catalyst. Step 2: Nucleophilic attacks by amine to the electron-deficient carbonyl carbon atom. Step 3: Proton transfer. Step 4: Elimination of water gives an iminium ion intermediate.

369

370

7 Multicomponent Reaction

Step 5: Protonation of another enolizable carbonyl compound. Step 6: Abstraction of acidic proton and formation of the enol. Step 7: The enol intermediate attacks to the iminium ion intermediate. Step 8: Deprotonation gives the desired product. Application The Mannich reaction has been used in the synthesis of a wide range of organic compounds such as peptides, nucleotides, antibiotic, agrochemicals, polymers, soap and detergents, and pharmaceutical drugs such as rolitetracycline, fluoxetine (antidepressant), tramadol, tolmetin (anti-inflammatory drug), azacyclophanes, and others. Dipeptidyl peptidase 4 (DPP-IV) inhibitor [17], chiral α-amino acids [20], nupharamine [22], (−)-hippodamine [27], lyconadin A [28], and naucleofficine [33] were synthesized using this reaction. Experimental Procedure (from patent WO2007011910A2)

H N HO O

(+) Cinchonine

O

OMe

O HN

H OMe

A

O

C

OMe

N O

N

+ CH2Cl2, –35 °C

F

MeO

B

F

O D

In an oven-dried 25 ml round-bottom flask, (+)-cinchonine (C, 15 mg, 0.050 mmol) was dissolved in 1.0 ml CH2 Cl2 . The solution was cooled down to −35 ∘ C. The imine B (0.50 mmol) and methyl acetoacetate (A, 0.060 ml, 0.50 mmol) were added successively. The reaction mixture was stirred at −35 ∘ C for 16 hours. The solution was then passed through a plug of silica gel and eluted with 5 ml ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (elution with 15–30% ethyl acetate in hexanes) to give the product D (87%).

Passerini Reaction (3-Component Reaction [3-CR]) The Passerini reaction is a three-component condensation reaction that involves an aldehyde or a ketone, a carboxylic acid, and an isocyanide to

Passerini Reaction (3-Component Reaction [3-CR])

give an α-acyloxycarboxamide. This reaction was discovered [1–4] by Italian chemist Mario Passerini in 1921. Metal-promoted [12], asymmetric version [13, 14, 16, 17, 26], TiCl4 catalyzed [27], mechanism study [20], and preparation of polymers [21, 24, 25], dendrimers [22], and photo-cleavable polymers [23] have been investigated on this reaction [5–40].

+

OH

R2

H

R1

O

O

O

+

R3 NC

R2

R1

H N

O

R3

O

α-Acyloxycarboxamide

Variation of the Passerini reaction R1 MeOH R1 CHO

+ R2 NC +

HO

TMS-N3

R2 N N N N

Mechanisms Ionic Mechanism

In ionic mechanism, reaction in polar solvent such as methanol or ethanol or water proceeds by the following steps [3–6]. O R2

O H

R1 1

H

OH

Step 1

R3 Step 2 N

O R1

H

O

R1

C

O

OH N

2

R2

R3

3 Step 3 R1 O R2

R1

H N

O O 5

Step 4 R3

N

HO O

R3

O R2 4

Step 1: Protonation of the aldehyde. Step 2: Nucleophilic attacks by the isonitrile at the electron-deficient carbonyl carbon atom. Step 3: Addition of carboxylate ion to nitrilium ion intermediate. Step 4: Acyl group transfer and amide tautomerization give the desired product.

371

372

7 Multicomponent Reaction

Concerted Mechanism

In nonpolar solvents and at high concentration, a concerted mechanism is likely. O H R2

O H

R1

O

O

C N R3

1

R2

R2

H

OH

O R1

N TS

O

O

O

R1

N

2

R3

O R2

R3

R1

H N

O

R3

O 3

This scheme involves a trimolecular reaction between the isocyanide, the carboxylic acid, and the carbonyl in a sequence of nucleophilic additions (third-order rate law). The transition state (TS) is shown as a five-membered ring with partial covalent and/or double bonding. The next step of the reaction is an acyl transfer to the hydroxyl group. Lactone Formation [3] O

O NC OH

+

O

O

N H

O

Bifunctional compound

Application The Passerini reaction has been used for the synthesis of hydrastine [16] and polymers from renewable materials [19]. 4-Fluoro-glutamines as potential metabolic imaging agents for tumors [19] were synthesized under the reaction conditions.

Strecker Amino Acid Synthesis

Experimental Procedure (from patent WO1995002566A1)

O

O CN Ph

O OH O

OMe N

A (E/Z mixture)

Pyridine

O

H N

O

OMe

O +

H

+ B

N

Ph

CH2Cl2, r.t.

C

D

+

O

H N

O O

N

O OMe Ph

E

Pyridine (35 μl, 0.441 mmol), butyraldehyde (C, 330 μl, 3.67 mmol), and 1-naphthoic acid (B, 63 mg, 0.367 mmol) were added sequentially to a r.t. CH2 Cl2 (3 ml) solution of isocyanide 107 (A, 90.0 mg, 0.367 mmol, Z/E=1 : 1.4). The mixture was stirred under N2 for 12 hours after which the solvent was removed under reduced pressure. The crude oil was immediately purified by flash silica gel (deactivated with 5% Et3 N) chromatography (gradient eluted with 100% hexane to 1 : 1 hexane/EtOAc) affording two fractions: D (54.5 mg, 31%) and E (44.5 mg, 26%) for a 57% overall yield (Z/E=1.2 : l).

Strecker Amino Acid Synthesis The Strecker amino acid synthesis was discovered by German chemist Adolph Strecker. It is a three-component organic reaction of an aldehyde (or ketone) and an amine in the presence of metal cyanide to afford α-aminonitrile, which is subsequently hydrolyzed to give the desired α-amino acid [1, 2]. Trimethylsilyl cyanide is safer and easily handled reagent than other cyanide ion sources. Various catalysts have been used such as HCl, AcOH, BiCl3 , InCl3 , Sc(OTf )3 , RuCl3 , I2 , aluminum complex [25], photo [27], and others for the synthesis of α-aminonitriles – the intermediate of amino acids [3–35]. Addition of a

373

374

7 Multicomponent Reaction

water-absorbing salt such as MgSO4 and molecular sieve often helps in the formation of the imine, as it helps to lead the equilibrium toward the imine. An enantioselective Strecker reaction is also possible [9].

Catalyst R CHO

HN

NaCN

+ R1 NH2 +

R

CH3CN, r.t.

R1

HCl

CN

H2O

α-Aminonitrile

R1

HN

OH

R O

α-Amino acid

Mechanism Part 1: Formation of 𝛂-Aminonitrile .. O

H+

O H

Step 1 R

H

R

OH

Step 2

H

.. R1 H2N

Step 3

R N 1 H H

R

OH2 N H

R

(Protonated aldehyde more electrophilic)

R1

Step 4

HN

H

CN

R1

Step 5

N

R

R1 H

R

N

Iminium ion

α-Aminonitrile

protonated imine

Step 1: Protonation of the aldehyde Step 2: Nucleophilic attacks by the amine at the electron-deficient carbonyl carbon atom Step 3: Proton transfer Step 4: Elimination of water molecule to form an iminium ion Step 5: Addition of cyanide ion Part 2: Hydrolysis of the Nitrile R1 HN R1 H

R

+

HN R1

Step 1

R

N: H R1

R1

NH

Step 7 OH

R O

R

.. O

N

HN R1

Step 2

R

H

O H

N H

R H

HO

O H .. NH3 OH

Step 6

R1

NH

R HO

H

:O

NH N H

H

H

Step 4

H

NH

Step 1: Protonation of nitrile

Step 3

.. OH NH3

Step 5

R1 R

NH OH2 HO

NH2

Ugi Reaction (4-Component Reaction [4-CR])

Step 2: Addition of water molecule Step 3: Proton transfer Step 4: Addition of water molecule Step 5: Proton transfer Step 6: Elimination of ammonia Step 7: Deprotonation and formation of the desired product Application l-DOPA, a drug for the treatment of Parkinson’s disease, was synthesized using the Strecker reaction conditions. OH

OH OH

Strecker

HO

O + NH4CN

HO

H

reaction

H2N

CN

OH

1. Acid, water, heat 2. Chiral resolution

H2 N

OH O L-DOPA

Several natural products such as (−)-lintetralin [14], (−)-quinocarcin [15], muraymycin D1 [29], and unnatural amino acids [26] were synthesized using this reaction. Experimental Procedure (from patent US5169973A)

H

NH2

+

+ TMS-CN

O A

B

C

N H

CN D

To 1.37 g of benzaldehyde (compound A) (12.9 mmol) and 1.80 ml of trimethylsilyl cyanide (compound C) (13.5 mmol, 5% excess) was added at room temperature 1.15 ml of n-propylamine (14 mmol) (compound B) in a closed flask in a nitrogen atmosphere. A very exothermic reaction took place, and the mixture was further stirred for three hours. Then, dichloromethane was added to the mixture, and the organic phase was washed with water (2 × 10 ml). Drying with sodium sulfate and evaporation of the solvent afforded 2 g of an almost pure N-propyl-α-cyanobenzylamine (compound D) (yield 90%, containing 3.5% of N-propyl benzylidene).

Ugi Reaction (4-Component Reaction [4-CR]) The Ugi reaction is a four-component reaction (4-CR) involving an amine (primary or secondary), an isocyanide, a ketone, or an aldehyde to form a

375

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7 Multicomponent Reaction

bis-amide [1–4]. The reaction was discovered by Ivar Karl Ugi in 1959. The reaction is exothermic, and it works well in polar solvent such as DMF, methanol, or ethanol. This reaction has a high atom economy as only water is lost and yield of the reaction is generally moderate to good [5–40]. Acids or Lewis acids and heat can accelerate the reaction. An enantioselective Ugi reaction is also possible [27]. O

O

R1

+

H

R2

NH2

+ R 3

O

–H2O

+ R4 NC

R3

OH

R1 N R2

H N

R4

O

Variation of Ugi reaction [7, 39] R2 MeOH + R2 CHO

R1 NH2

+ R3 NC +

R1

TMS-N3

N H

R3 N N N N

HO

N H N H

O

N

N

OH

N N N

MeOH

+

+ TMS-N3 +

CHO

50 °C

NC

N H

O

Plausible Reaction Mechanism Except Mumm rearrangement (step 5), all steps are reversible. The mechanism follows linear and parallel sequences: first-order and second-order reactions. O R3

O R1

Step 1 H + R NH2 2

OH

R1 Step 2

R1

O

H N R 2

+

R3

O

N R 2 C N R4

Step 3

O R3

R1 N R2

H N O

R4 N

Step 6 R4

O O

H

R1

N R3 R

2

H R2 ..N

Step 5 R3

O

R1

Step 4

C N R 4

O

Step 1: Amine and aldehyde form an imine with loss of water. Step 2: Proton exchanges from carboxylic acid to imine. Step 3: A nucleophilic addition of isocyanide.

R1

N

H R2

C N R 4

O O

R3

Ugi Reaction (4-Component Reaction [4-CR])

Step 4: Another nucleophilic addition of carboxylic acid. Step 5: This step is a Mumm rearrangement with transfer of the R3 acyl group from oxygen to nitrogen. Step 6: Protonation of the imine and completion of the acyl group transfer gives the desired product. Application Applying Ugi reaction, there were several drugs synthesized such as Crixivan, epelsiban, lacosamide, indinavir, omuralide, retosiban, and others.

O O

OH +

NC

Ugi reaction

+

H +

O

N

N H

O Chiral separation

NH2

Chiral auxiliary removal H N

O N H

O

R-Lacosamide

Atorvastatin (Lipitor), the best-selling cardiovascular drug of all time [18], was synthesized using this reaction. Experimental Procedure (from patent US20150087600A1) F F H

O

NH2

O F

O +

+

OH

F F

F

A

B

MeOH

+

Cl

NC r.t.

C

D

N

N H F

Cl O

F E

A mixture of 2,4-difluorobenzaldehyde (A, 500 mg, 3.5 mmol) and 3,4difluoroaniline (B, 455 mg, 3.5 mmol) in MeOH (8 ml) was stirred at r.t. for 30 minutes. 2-Chloroacetic acid (C, 294 mg, 3.5 mmol) was added, and the reaction mixture stirred for 10 minutes. Cyclohexyl isocyanide (D, 382 mg, 3.5 mmol) was then added, and the reaction mixture was stirred at r.t. overnight. The resulting mixture was partitioned between EA and H2 O. The organic layer was separated, washed with brine, dried over Na2 SO4 , filtered, and concentrated.

377

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7 Multicomponent Reaction

The residue was purified by column chromatography to afford the desired product E (1.1 g, 67% yield) as a white solid.

Asinger Reaction (4-Component Reaction [A-4CR]) The Asinger reaction is a four-component organic reaction of ketones or aldehydes, ammonia, and sulfur to afford 3-thiazoline derivatives [1–17]. The reaction is named after Austrian chemist Friedrich Asinger. –2H2O

O

O R

H

+ H

N

+S

+ NH3

R

R

R

S

Asinger reaction with aldehydes O

O N

–2H2O +

+

NH3

+S

S

Asinger reaction with ketones

Application Penicillin derivative was synthesized using combination of Asinger + Ugi reaction. Penicillamine [5, 6] was synthesized under this reaction conditions.

O R

Asinger

CHO N H

+ NH3 + NaSH + Br CO2Me

CHO

O

S N

reaction

N

HN

R

THF, H2O

O

O

S

NaOH

OMe

OH HN

R O

C6H11NC

R

H N

O O

S N NHC6H11 O

A- Seven-component reaction, Asinger reaction + Ugi reaction [8] S Br

+ NaSH CHO

+ NH3 +

+ MeOH + CO2 CHO

+ NC

H N

N O

O O

Thiazolidine

Biginelli Reaction

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Mannich Reaction

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Passerini Reaction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

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Strecker Amino Acid Synthesis

29 Wang, Q., Wang, D.X., Wang, M.X., and Zhu, J. (2018). Acc. Chem. Res. 51:

1290. 30 Yue, T., Wang, M.X., Wang, D.X. et al. (2009). J. Org. Chem. 74: 8396. 31 Váradi, A., Palmer, T.C., Dardashti, R.N., and Majumdar, S. (2016). Molecules

21: 19. 32 Pirali, T., Galli, U., Serafini, M. et al. (2019). Methods Mol. Biol. 1987: 207. 33 Weber, L. (2002). Curr. Med. Chem. 9: 1241. (review). 34 Dömling, A. and Ugi, I. (2000). Angew. Chem. Int. Ed. 39: 3168–3210.

(review). Hulme, C. and Gore, V. (2003). Curr. Med. Chem. 10: 51–80. (review). Banfi, L. and Riva, R. (2005). Org. React. 65: 1–140. (review). Giustiniano, M., Moni, L., Sangaletti, L. et al. (2018). Synthesis 3549 (review). Kazemizadeh, A.R. and Ramazani, A. (2012). Curr. Org. Chem. 16: 418. (review). 39 De Moliner, F., Banfi, L., Riva, R., and Basso, A. (2011). Comb. Chem. High Throughput Screening 14: 782–810. (review). 40 Llevot, A., Boukis, A.C., Oelmann, S. et al. (2017). Top. Curr. Chem. (Cham) 375: 66. (review). 35 36 37 38

Strecker Amino Acid Synthesis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Strecker, A. (1850). Ann. Chem. Pharm. 75: 27–45. Strecker, A. (1854). Justus Liebigs Ann. Chem. 91: 349–351. Duthaler, R.O. (1994). Tetrahedron 50: 1539–1650. Iyer, M.S., Gigstad, M., Namdev, N.D., and Lipton, M. (1996). J. Am. Chem. Soc. 118: 4910. Sigman, M.S. and Jacobsen, E.N. (1998). J. Am. Chem. Soc. 120: 5315. Arend, B., Westermann, N., and Risch, N. (1998). Angew. Chem. Int. Ed. 37: 1044. Ishitani, H., Komiyama, S., and Kobayashi, S. (1998). Angew. Chem. Int. Ed. 37: 3186–3188. Takamura, M., Hamashima, Y., Usuda, H. et al. (2000). Angew. Chem. Int. Ed. 39: 1650–1652. Ma, D. and Ding, K. (2000). Org. Lett. 2: 2515–2517. Ishitani, H., Komiyama, S., Hasegawa, Y., and Kobayashi, S. (2000). J. Am. Chem. Soc. 122: 762–766. Vachal, P. and Jacobsen, E.N. (2002). J. Am. Chem. Soc. 124: 10012–10014. Enders, D. and Moser, M. (2003). Tetrahedron Lett. 44: 8479–8481. Masumoto, S., Usuda, H., Suzuki, M. et al. (2003). J. Am. Chem. Soc. 125: 5634–5635. Enders, D., Del Signore, G., and Berner, O.M. (2003). Chirality 15: 510–513. Kwon, S. and Myers, A.G. (2005). J. Am. Chem. Soc. 127: 16796–16797. De, S.K. and Gibbs, R.A. (2004). Tetrahedron Lett. 45: 7407. Royer, L., De, S.K., and Gibbs, R.A. (2005). Tetrahedron Lett. 46: 4595. Ranu, B.C., Dey, S.S., and Hajra, A. (2002). Tetrahedron 58: 2529.

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7 Multicomponent Reaction

19 Yadav, J.S., Reddy, B.V., Eeshwaraiah, B., and Srinivas, M. (2004). Tetrahedron 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

60: 1767. Groger, H. (2003). Chem. Rev. 103: 2795. Huang, J. and Corey, E.J. (2004). Org. Lett. 6: 5027–5029. Das, B., Balasubramanyam, P., Krishnaiah, M. et al. (2009). Synthesis 3467. Pan, S.C. and List, B. (2007). Org. Lett. 9: 1149–1151. Prakash, G.K., Mathew, T., Panja, C. et al. (2007). Proc. Natl. Acad. Sci. U.S.A. 104: 3703–3706. Abell, J.P. and Yamamoto, H. (2009). J. Am. Chem. Soc. 131: 15118–15119. Zuend, S.J., Coughlin, M.P., Lalonde, M.P., and Jacobsen, E.N. (2009). Nature 461: 968–970. Rueping, M., Zhu, S., and Koenigs, R.M. (2011). Chem. Commun. (Camb) 47: 12709–12711. Yan, H., Suk Oh, J., Lee, J.W., and Eui Song, C. (2012). Nat. Commun. 3: 1212. Mitachi, K., Aleiwi, B.A., Schneider, C.M. et al. (2016). J. Am. Chem. Soc. 138: 12975–12980. Miyagawa, S., Yoshimura, K., Yamazaki, Y. et al. (2017). Angew. Chem. Int. Ed. 56: 1055–1058. Fuentes de Arriba, Á.L., Lenci, E., Sonawane, M. et al. (2017). Angew. Chem. Int. Ed. 56: 3655–3659. Miyagawa, S., Aiba, S., Kawamoto, H. et al. (2019). Org. Biomol. Chem. 17: 1238. Ager, D.J. and Fotheringham, I.G. (2001). Curr. Opin. Drug Discovery Dev. 4: 800–807. (review). Kampen, D., Reisinger, C.M., and List, B. (2010). Top. Curr. Chem. 291: 395–456. (review). Kouznetsov, V.V. and Galvis, C.E.P. (2018). Tetrahedron 74: 773. (review).

Ugi Reaction 1 Ugi, I., Meyr, R., Fetzer, U., and Steinbrückner, C. (1959). Angew. Chem. 71:

386. 2 Ugi, I. (1960). Angew. Chem. 72: 267–268. 3 Ugi, I. (1962). Angew. Chem. Int. Ed. 74: 89–22. 4 Tsai, C.Y., Park, W.K., Weitz-Schmidt, G. et al. (1998). Bioorg. Med. Chem.

Lett. 8: 2333–2338. 5 Ugi, I. (2001). Pure Appl. Chem. 73: 187. 6 Wehlan, H., Oehme, J., Schäfer, A., and Rossen, K. (2015). Org. Process Res.

Dev. 19: 1980. Bottini, A., De, S.K., Baaten, B.J. et al. (2012). ChemMedChem 7: 2227. Rossen, K., Pye, P.J., DiMichele, L.M. et al. (1998). Tetrahedron Lett. 39: 6823. Gilley, C.B., Buller, M.J., and Kobayashi, Y. (2007). Org. Lett. 9: 3631. Borthwick, A.D., Davies, D.E., Exall, A.M. et al. (2005). J. Med. Chem. 48: 6956. 11 Domling, A. and Ugi, I. (2000). Angew. Chem. Int. Ed. 39: 3168. 12 Turner, C.D. and Ciufolini, M.A. (2012). Org. Lett. 14: 4970–1473. 7 8 9 10

Ugi Reaction

13 Zhao, W., Huang, L., Guan, Y., and Wulff, W.D. (2014). Angew. Chem. Int. Ed.

53: 3436–3441. 14 Bach, M., Lehmann, A., Brünnert, D. et al. (2017). J. Med. Chem. 60:

4147–4160. 15 Xie, L.G. and Dixon, D.J. (2018). Nat. Commun. 9: 2841. 16 Wiemann, J., Fischer Née Heller, L., Kessler, J. et al. (2018). Bioorg. Chem. 81:

567–576. 17 Shaabani, S. and Dömling, A. (2018). Angew. Chem. Int. Ed. 57:

16266–16268. 18 Zarganes-Tzitzikas, T., Neochoritis, C.G., and Dömling, A. (2019). ACS Med.

Chem. Lett. 10: 389–392. 19 Zeng, L., Sajiki, H., and Cui, S. (2019). Org. Lett. 21: 5269–5272. 20 Jovanovi´c, M., Zhukovsky, D., Podolski-Reni´c, A. et al. (2019). Eur. J. Med.

Chem. 181: 111580. 21 Wang, Q., Mgimpatsang, K.C., Konstantinidou, M. et al. (2019). Org. Lett. 21:

7320–7323. 22 Ricardo, M.G., Vasco, A.V., Rivera, D.G., and Wessjohann, L.A. (2019). Org.

Lett. 21: 7307–7310. 23 Oh, J., Kim, N.Y., Chen, H. et al. (2019). J. Am. Chem. Soc. 141: 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

16271–16278. Zhao, Z.Q., Zhao, X.L., Shi, M., and Zhao, M.X. (2019). J. Org. Chem. 84: 14487–14497. Ojeda, G.M., Ranjan, P., Fedoseev, P. et al. (2019). Beilstein J. Org. Chem. 15: 2447–2457. Pachón-Angona, I., Martin, H., Chhor, S. et al. (2019). Future Med. Chem. 11: 3097–3108. Zhang, J., Yu, P., Li, S.-Y. et al. (2018). Science 361: 6407. Dömling, A. (1998). Comb. Chem. High Throughput Screening 1: 1–22. (review). Ugi, I. and Heck, S. (2001). Comb. Chem. High Throughput Screening 4: 1–34. (review). Hulme, C. and Gore, V. (2003). Curr. Med. Chem. 10: 51–80. (review). Tempest, P.A. (2005). Curr. Opin. Drug Discovery Dev. 8: 776–788. (review). De Moliner, F., Banfi, L., Riva, R., and Basso, A. (2011). Comb. Chem. High Throughput Screening 14: 782–810. (review). Sharma, U.K., Sharma, N., Vachhani, D.D., and Van der Eycken, E.V. (2015). Chem. Soc. Rev. 44: 1836–1860. (review). Llevot, A., Boukis, A.C., Oelmann, S. et al. (2017). Top. Curr. Chem. (Cham) 375: 66. (review). Patil, P., Mishra, B., Sheombarsing, G. et al. (2018). ACS Comb. Sci. 20: 70–74. (review). Ismaili, L. and do Carmo Carreiras, M. (2017). Curr. Top. Med. Chem. 17: 3319–3327. (review). Shaabani, S. and Doemling, A. (2018). Angew. Chem. Int. Ed. 57: 16266. (review). Giustiniano, M., Moni, L., Sangaletti, L. et al. (2018). Synthesis 3549 (review).

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39 Neochoritis, C.G., Zhao, T., and Doemling, A. (2019). Chem. Rev. 119:

1970–2042. (review). 40 Gazzotti, S., Rainoldi, G., and Silvani, A. (2019). Expert Opin. Drug Discovery

14: 639–652. (review).

Asinger Reaction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Asinger, F. (1956). Angew. Chem. 68: 413. Asinger, F. and Offermanns, H. (1967). Angew. Chem. Int. Ed. 6: 907. Asinger, F. and Thiel, M. (1958). Angew. Chem. 70: 667. Ugi, I. and Wishofer, E. (1962). Chem. Ber. 95: 136. Drauz, K., Koban, H.G., Martens, J., and Schwarze, W. (1985). Liebigs Ann. Chem. 448–452. Weigert, W.M., Offermanns, H., and Scherberich, P. (1975). Angew. Chem. 87: 372–378. Martens, J., Offermanns, H., and Scherberich, P. (1981). Angew. Chem. 93: 680–683. Domling, A. and Ugi, I. (1993). Angew. Chem. Int. Ed. 32: 563. Kröger, D., Franz, M., Schmidtmann, M., and Martens, J. (2015). Org. Lett. 17: 5866–5869. Chandgude, A.L., Narducci, D., Kurpiewska, K. et al. (2017). RSC Adv. 7: 49995. Rainoldi, G., Begnini, F., de Munnik, M. et al. (2018). ACS Comb. Sci. 20: 98. Kröger, D., Franz, M., Schmidtmann, M., and Martens, J. (2015). Org. Lett. 17: 5866. Zumbrägel, N. and Gröger, H. (2018). Bioengineering (Basel) 5, pii: E60. Zumbrägel, N. and Gröger, H. (2019). J. Biotechnol. 291: 35. Khalesi, M., Halimehjani, A.Z., Franz, M. et al. (2019). Amino Acids 51: 263–272. Zhi, S., Ma, X., and Zhang, W. (2019). Org. Biomol. Chem. 17: 7632–7650. Liu, Z.-Q. (2015). Curr. Org. Synth. 12: 20. (review).

389

8 Oxidations and Reductions Oxidation Reactions Corey–Kim Oxidation The Corey–Kim reaction is an organic oxidation reaction of alcohol to an aldehyde or a ketone using N-chlorosuccinimide (NCS), dimethyl sulfide (DMS), and triethylamine (TEA) [1, 2]. The reaction is named after the American chemist and Nobel laureate Elias James Corey and Korean-American chemist Choung Un Kim in 1972. Several modifications and improvements [3–17] such as odorless reaction [8] and scope and mechanism [6] have been investigated. O

OH R1

R2

OH R1

1.

S

,

N Cl O O

R2

R1

2. Et3N

1. C12H25

S

O

, NCS R1

R2

R2

2. Et3N

An odorless reaction [8] when dodecyl methyl sulfide is used instead of DMS

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

390

8 Oxidations and Reductions

Mechanism R2

R1 O Step 1

.. S

N Cl

O +

N

O

OH ..

O

Step 2

Cl S

N S

O

Cl

O Corey–Kim reagent Step 3

Step 5 O S

+

R1

H R2

O R1

Step 4

S

R1

R2

H

O S

.. Et3N +

R2

O NH + Cl O

Step 1: Nucleophilic substitution-type reaction. Step 2: Formation of the Corey–Kim reagent. Step 3: Alcohol attacks as a nucleophile to the electrophilic center, the Corey–Kim reagent. Step 4: Abstraction of proton by base. Step 5: Intramolecular rearrangement provides the desired product. Application

Total syntheses of 16-epi-vellosimine, (+)-polyneuridine [11], and (+)-macusine A [12] have been accomplished using this reaction as a key step. Experimental Procedure (from patent US9212136B2) H OH O

H H H

1. NCS, Me2S, CH2Cl2

MeO 2. Et3N

H

MeO

OTBS OTBS A

B

To a stirred solution of NCS (2.21 g, 2.5 equiv.) in CH2 Cl2 (60 ml), cooled in an ice bath to 0–5 ∘ C, Me2 S (1.68 ml, 3.5 equiv.) was added. During the addition, the temperature was maintained in the range of 0–8 ∘ C. The obtained suspension was stirred for 30 minutes and was then cooled to −28 ∘ C. To this mixture, a

Dess–Martin Oxidation

solution of compound A (3.0 g, 1 equiv.) in CH2 Cl2 (30 ml) was slowly added. The reaction mixture was stirred for one hour at −28 ∘ C. Then Et3 N (1.98 g, 3 equiv.) was added dropwise. The reaction was completed after stirring for additional 10 minutes (TLC monitored). Saturated aqueous NaHCO3 solution (50 ml) was added, increasing the internal temperature to 0 ∘ C. Then CH2 Cl2 (150 ml) and brine (30 ml) were added, and the phases were separated. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to reach a volume of approx. 50 ml, which were then dried azeotropically with toluene (50 ml). Removal of the solvents in vacuo gave a yellowish oily residue (c. 5 g) from which the desired product was isolated by column chromatography on silica gel (60 g), mobile-phase cyclohexane/AcOEt (100 : 0 to 90 : 10), yield of B 1.62 g (54%).

Dess–Martin Oxidation The Dess–Martin oxidation is a mild oxidation reaction for the conversion/ transformation of a primary alcohol to aldehyde and secondary alcohol to ketone using Dess–Martin periodinane (DMP) reagent [1–5]. The reaction is named after the American chemists Daniel Benjamin Dess and James Cullen Martin who discovered the periodinane reagent in 1983. The DMP is a hypervalent iodine reagent (similar to IBX) and is a mild oxidizing agent for the converting alcohols to aldehydes or ketones [6–47]. OAc I OAc O

AcO

O DMP

O

I OH O O

IBX AcO OAc I OAc O OH R1

R2

O O CH2Cl2

R1

R2

391

392

8 Oxidations and Reductions

AcO

OAc I OAc O

OH R1

O

R2

O R1

R2

CH2Cl2, water

Acceleration of the Dess–Martin oxidation was observed using water [10]. OH R1

O

DMP or IBX

R2

Ionic liquid

R2

R1

Recyclable second-generation ionic liquids as green solvents are used for the oxidation of alcohols with hypervalent iodine reagents (7). Mechanism

AcO OAc I OAc O O

AcO

Step 1 .. H O

R1

OAc R2 I O O H R1

AcO OAc R2 I O H O R1

Step 2

OAc

O

O

OAc

R2

Step 3

OAc

O

I O

+ CH3CO2H

+

R1

R2

O

Step 1: Nucleophilic substitution reaction. Step 2: Deprotonation. Step 3: Deprotonation liberates the desired product. Application Several drug-like molecules such as new platelet aggregation-inhibiting γ-lactam PI-091 [15], antimalarial agents [23],inhibitors of hepatitis C virus NS3 serine protease [32], and natural products such as (+)-coronarin A [36], rubifolide [17], and (+)-lycoricidine [39] were synthesized under the reaction conditions. Experimental Procedure (General) OH

O DMP CH2Cl2

H

Jones Oxidation

To a solution of benzyl alcohol (540 mg, 5 mmol) in DCM (10 ml) was added DMP (2.54 g, 6 mmol) at 0 ∘ C. The reaction mixture was stirred at 0 ∘ C for two hours. The reaction mixture was extracted with DCM, washed with saturated NaHCO3 solution and brine, dried (anhydrous MgSO4 ), and concentrated in vacuo. The residue was chromatographed over silica gel to afford a pure product. Experimental Procedure (from patent US9212136B2) H AcO OAc I OAc O

OH H H

O H

O

MeO

H MeO

CH2Cl2 , r.t. OTBS OTBS B

A

DMP (2.16 g) was added to a stirred solution of A (236 mg, 1 equiv.) in CH2 Cl2 (1.5 ml) at room temperature (20–25 ∘ C.). After stirring for two hours, an in-process TLC analysis showed a complete conversion. The reaction mixture was added to a mixture of saturated aqueous NaHCO3 solution (20 ml), CH2 Cl2 (20 ml), and 1.0 g Na2 S2 O3 . The organic phase was separated, dried over anhydrous MgSO4 , and concentrated in vacuo to give 0.28 g (product B) as a yellow oil.

Jones Oxidation The Jones oxidation is an organic reaction used to convert primary alcohols to carboxylic acids and secondary alcohols to ketones using chromium trioxide, sulfuric acid, and water in acetone [1]. The reaction is named after Sir Ewart Jones who discovered this reaction. Chromium trioxide reacts with sulfuric acid to form chromic acid or dichromic acid. A variety of alcohols can be oxidized with chromic acid to form the corresponding carboxylic acids or ketones [2–23]. O

CrO3, H2SO4, H2O R1

OH

Acetone

OH

R1

Primary alcohol OH

O CrO3, H2SO4, H2O

R1

R2

Acetone

Secondary alcohol

R1

R2

393

394

8 Oxidations and Reductions

Mechanism Part 1: Formation of chromic acid or dichromic acid H O

Cr ..O

Step 1

O

H H O

O

O ..

H

H Step 2

Cr O O H

H ..O Step 3

H O H O Cr O OH

O HO Cr OH O Chromic acid H2O

H

Step 4 O O HO Cr O Cr OH O O Dichromic acid

Step 1: Chromium trioxide reacts with acid (aqueous H2 SO4 ), protonation. Step 2: Water molecule attacks at the protonated chromium center. Step 3: Deprotonation forms chromic acid. Step 4: Formation of dichromic acid. Part 2: Formation of ketone H H O ..O O HO HO Cr OH Cr OH H O Step 2 O O .. Step 1 H O R1 R2 R1

R2

O Cr OH Step 3 O O

O Cr OH O O

HO

R2

R1

R1

H

H

R2

.. O

H

Step 4 OH O Cr O

O +

R1

R2

H2O

HO

OH Cr O

Step 1: Nucleophilic attacks by the alcohol at the chromic acid. Step 2: Deprotonation. Step 3: Elimination of hydroxide. Step 4: Abstraction of proton liberates the product from the chromium complex. Aldehyde that can form hydrates in the presence of water and are further oxidized to carboxylic acid.

Swern Oxidation

O R

H2O H

HO

OH

R

H

O HO Cr OH O

HO R

O O Cr OH HO

O R

OH + HO Cr OH O

Application Syntheses of folic acid [7], C-nor-9,11-secoestradiol [8], aromatase inhibitor 5-androstene-4,17-dione [9], and labdane-type diterpenoid [18] have been accomplished under this reaction conditions.

Experimental Procedure (General)

OH

O CrO3, H2SO4

OH

H2O, acetone To a solution of CrO3 (10 equiv.) in water (6 ml) at 0 ∘ C, H2 SO4 (1 ml) was added dropwise with stirring. To this mixture benzyl alcohol (1 equiv.) in acetone was added dropwise. The reaction mixture was stirred at room temperature until all starting materials were consumed. After almost completion of the reaction, isopropyl alcohol was added to the reaction mixture and stirred for 30 minutes (to destroy excess amounts of chromic acid, isopropyl alcohol was oxidized to acetone). The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with NaHSO3 solution, brine, and water successively. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified over silica gel column to afford a pure product.

Swern Oxidation The Swern oxidation is a mild oxidation reaction of primary alcohol and secondary alcohol using oxalyl chloride, dimethyl sulfoxide (DMSO), and TEA as a base to form an aldehyde and a ketone, respectively [1–3]. Upon quenching with base, the intermediates rearrange intramolecularly to aldehydes or ketones, respectively. The reaction is named after the American chemist Daniel Swern. The reaction conditions are very mild and tolerate a wide range of functional groups [4–20].

395

396

8 Oxidations and Reductions

O

R

Cl

Cl

1.

O

, DMSO

O

OH

R

H

2. Et3N

Primary alcohol

O OH R1

1.

Cl

Cl

O

, DMSO

O

R2

R1

R2

2. Et3N

Secondary alcohol

Mechanism

O S

O S

O Cl Cl

O

O

Step 1 Cl

O

Cl

Step 2

Cl

O S

O O S

O

Cl Step 3 .. Et3N

H

S O R1

Cl Step 5 R2

H O S R1

Step 4

Cl S

+ CO2 + CO

.. OH

R2 R1

R2

Step 6

H R1

S O

+ R2

O

Step 7 Et3N HCl

R1

R2

+

S

Sulfur ylide

Step 1: The mechanism starts with the activation of DMSO with the oxalyl chloride, and then a nucleophilic addition occurs. Step 2: The chloride anion leaving gives an intermediate. Step 3: The chloride anion attacks at the sulfonium salt to form a chlorosulfonium cation and liberate both CO gas and CO2 gas. Step 4: The alcohol attacks as a nucleophile to the chlorosulfonium intermediate. Step 5: The chloride anion abstracts a proton to form an alkoxysulfonium cation.

Pfitzner–Moffatt Oxidation

Step 6: The second phase starts with trimethylamine, which deprotonates the alkoxysulfonium at the alpha position to form alkoxysulfonium ylide. Step 7: Upon rearrangement the intermediate intramolecularly releases a DMS gas and the final aldehyde or ketone product depending the starting alcohol. Experimental Procedure (from patent US9212136B2) H OH O

H H H

1. DMSO, (COCl)2, Py, CH2Cl2 H

MeO 2. Et3N

MeO

OTBS OTBS A

B

To a mixture of DMSO (3.18 g, 2.5 equiv.) in CH2 Cl2 (50 ml), cooled to −78 ∘ C, oxalyl chloride (3.21 g, 1.5 equiv.) was added dropwise, keeping the internal temperature below −60 ∘ C. Thereafter, the mixture was stirred 45 minutes at an internal temperature ranging from −60 to −78 ∘ C. After the addition of pyridine (3.24 g, 2.5 equiv.), the mixture was stirred for 15 minutes before a solution of A (36.37 g, 1 equiv.) in CH2 Cl2 was added (the addition was exothermic) while keeping the internal temperature below −60 ∘ C. The mixture was stirred for 30 minutes, and Et3 N (9.1 ml) was added at a temperature below −50 ∘ C (the addition was exothermic). Additional CH2 Cl2 (45 ml) was added facilitating the stirring, and the reaction mixture was stirred for 2.5 hours (TLC monitored). Then water (75 ml) was added, and the internal temperature was allowed to warm first to 0 ∘ C and then room temperature (20–25 ∘ C). The organic phase was separated and the aqueous phase was extracted with CH2 Cl2 (50 ml). The combined CH2 Cl2 phases were concentrated under reduced pressure, leaving an oily residue. The oil was dissolved in methyl tert-butyl ether (MTBE) (60 ml), and the solution was washed with saturated aqueous NaHCO3 solution (60 ml) and brine (2 × 60 ml). The organic phase was dried over anhydrous MgSO4 , concentrated under reduced pressure, dried azeotropically with toluene (50 ml), and concentrated in vacuo again. The product was isolated by column chromatography on silica gel (75 g), mobile-phase cyclohexane/EA (100 : 0 to 90 : 10), yield of B 6.92 g (92.6%).

Pfitzner–Moffatt Oxidation The oxidation of primary and secondary alcohols to aldehydes and ketones, respectively, using dicyclohexylcarbodiimide (DCC) and DMSO in the presence

397

398

8 Oxidations and Reductions

of catalytic amounts of H3 PO4 is known as Pfitzner–Moffatt oxidation or simply Moffatt oxidation [1–6]. This reaction tolerates most of the functional groups. The reagents of this reaction are inexpensive, and yield is very high [7–12]. OH

O

DCC, DMSO R1

R2

R1

R2

Acid (catalytic)

Mechanism H Step 1 N C N ..

HX (acid)

Step 2

H N C N

N C N O H S

DMSO

DCC O S

H

.. H O Step 3 X

O S

+ R

Step 5 R1

S CH2 Step 4 O H R R1

Alkoxysulfonium ylide

H S O

R

R1

H H

R

R1

O

+ N H

N H

1,3-Dicyclohexylurea

Step 1: DCC is protonated. Step 2: Nucleophilic attacks by DMSO on the electron-deficient carbon center of protonated DCC. Step 3: Alcohol attacks as a nucleophile to the electron-deficient S atom to form a 1,3-dicyclohexylurea. Step 4: Deprotonation gives an alkoxysulfonium ylide. Step 5 : Abstraction of hydrogen atom gives an aldehyde or a ketone and a DMS. Application Beraprost as vasodilator and antiplatelet agent was synthesized using this reaction.

Pfitzner–Moffatt Oxidation

OMe O

ONa

OMe O

O DCC, DMSO

O

H

(S) (S)

AcO

H

(S) H

(R)

(S) (S)

(S)

OH

AcO

(R)

H

(R)

O

H

Steps

O (S)

AcO

H

(R)

(R) (E)

O

H (S)

HO Beraprost sodium

Total syntheses of rofleponide [9] and desmycosin [10] have been accomplished using this reaction. Experimental Procedure (from patent WO2019202345A2) MeO

MeO

O

O

DCC, DMSO, H3PO4 Toluene

O

O

OH A

O

O O H B

28.2 g of compound A was dissolved in 100 ml of distilled toluene under inert atmosphere. The reaction mixture was cooled to 13 ∘ C, then 47.3 g of DCC dissolved in 150 ml of toluene, and 23.8 ml of 1 M phosphoric acid in DMSO solution added. After the addition, the reaction mixture was heated to 45 ∘ C and agitated at that temperature. After reaching the desired conversion, the reaction mixture was cooled to room temperature and washed with water (2 × 300 ml); the organic phase was dried from water by concentration in vacuum at 50 ∘ C to approx. 80 ml

399

400

8 Oxidations and Reductions

volume. The toluene concentrate was purified by chromatography using silica gel column and toluene–diisopropyl ether (3 : 1 and 1 : 1) eluent mixtures. The fractions containing the pure product were combined and evaporated to give compound B (23.82 g, 85%).

Tamao–Fleming Oxidation The Tamao–Fleming oxidation is an organic reaction used to convert a carbon–silicon bond to carbon–oxygen bond using peroxy acid [1–5]. This reaction is a stereospecific with retention of configuration at the carbon–silicon bond [6–35]. Fleming Oxidation OH

m-CPBA, HX

Si

R1 R1

R2

Base, hydrolysis

R2 Retention of configuration

Tamao Oxidation H SiR′ X 3 R1

R2

H2O2, KHF2

H OH

DMF

R1

R2

Mechanism

Step 1 X

Si R1

R2

X Si

Step 2

H Si

R1

H X R1

R2

R2

R1 .. H O O

R1

O

O Cl

Step 3 X

O Si

Cl

R2

Si O O

Step 5

O

.. H O O

R2

Cl

Step 4 R1

H Si O O R2

O Cl

Tamao–Fleming Oxidation Step 6 O Si

Step 7

O

O

O Si O

Cl R1

O

.. H O O

Cl

O

O Cl

Step 8

R2

O

Si O O R2

R1

O

R2

R1

O O O O Si OH O

Cl

R2

R1

O O O O Si Step 11 O OH R2 R1

Step 9 Cl O

Step 10

O Si

O R1

O O

Cl

R2

Step 12

R1

OH

Acidic work-up

O R2

Step 13

R1

R2

Step 1: Electrophilic aromatic substitution reaction. Step 2: Removal of phenyl group and formation of the halosilane. Step 3: The displacement of the halide by m-chloroperoxybenzoic acid. Step 4: Deprotonation. Step 5: A rearrangement forms the silanol. Step 6: m-Chloroperoxybenzoic acid reacts with the silanol intermediate. Step 7: A rearrangement gives a methylsilanol intermediate. Step 8: Another m-chloroperoxybenzoic acid reacts with the silanol intermediate. Step 9: A rearrangement forms the dimethylsilanol intermediate. Step 10: Another m-chloroperoxybenzoic acid reacts with the dimethylsilanol intermediate. Step 11: In alkaline hydrolysis, hydroxide attacks at the electron-deficient carbonyl carbon atom. Step 12: The alkoxide liberates from the complex. Step 13: Acidic work-up gives the desired alcohol. Application Total syntheses of natural products such as (+)-1-epiaustraline [9], (±)-deoxymannojirimycin [14], (+)-hyacinthacine A [16], Casuarina [17], (+)-australine [19], and amphidinolide N [23] have been completed using this reaction as a key step.

401

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8 Oxidations and Reductions

Experimental Procedure (from patent WO2005113558A2) PMB CO2Me N H O H

MeOH O Si Me Me

KF, KHCO3 , H2O2

PMB CO2Me N H O H

THF–MeOH (1:1), r.t., 18 h

A

MeOH OH OH B

dr = 20:1

To a solution of compound A (0.974 g, 2 mmol) in tetrahydrofuran (THF) (5 ml) and MeOH (5 ml) at 23 ∘ C was added KHCO3 (0.8 g, 8 mmol) and KF (0.348 g, 6 mmol). Hydrogen peroxide (30% in water, 5 ml) was then introduced to this mixture. The reaction mixture was vigorously stirred at 23 ∘ C, and additional hydrogen peroxide (2 ml) was added after 12 hours. After 18 hours, the reaction mixture was quenched carefully with NaHSO3 solution (15 ml). The mixture was extracted with ethyl acetate (3 × 25 ml), and the combined organic layers were washed with water and dried over anhydrous Na2 SO4 . The solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate) to give the pure triols B (0.82 g, 92%). ∶ +5.2 (c. 0.60, CHC13 ). Rf = 0.15 (in ethyl acetate), m.p. 83–84 ∘ C; [α]23 D

Tamao–Kumada Oxidation The Tamao–Kumada oxidation is an organic reaction used to convert an alkyl fluorosilane to an alcohol using hydrogen peroxide, potassium fluoride, and potassium bicarbonate [1–9]. F F Si R R

KF, H2O2

2 R-OH

KHCO3, DMF

Mechanism The Tamao–Kumada oxidation uses the more reactive fluoro- or chlorosilanes. In this reagent silicon is a stronger Lewis acid and more metallic character than the substrates used in the Tamao–Fleming oxidation. Moreover, activation of fluoride ion forms a pentavalent intermediate, which is able to bind hydrogen peroxide. The transition state is stabilized through hydrogen bonding between fluorine and hydrogen.

Oppenauer Oxidation F F Si R R

RF Si F O F R O H

F F R Si R F

F

.. H O O H

F F O Si R R F

F F RO Si OR F

2 R-OH

Oppenauer Oxidation The Oppenauer oxidation is an alkoxide-catalyzed selective oxidation of secondary alcohols to ketones in excess acetone [1]. The reaction was discovered by Rupert Viktor Oppenauer. This method used the relatively inexpensive and nontoxic reagents [2–27].

R1

O

Al(O-i-Pr)3

OH R2

R2

R1

O

OH +

Mechanism The aluminum-catalyzed hydride shifts from the α-carbon of an alcohol component to the carbonyl carbon of a second component, which proceeds over a six-membered transition state.

.. OH R1

R O O R Al O R

OR O Al OR

Step 1 R1

R2

O H Step 2

OR R1 O Al OR O R2

O OR O Al OR

R1

R2

R2 Step 3

Hydride transfer

Six-membered cyclic transition state OH

O R1

+ R2

403

404

8 Oxidations and Reductions

Step 1: Nucleophilic substitution reaction. Step 2: Aluminum coordinates with ketone to make a six-membered cyclic transition state. Step 3: Hydride transfer gives the desired products ketone and alcohol. Application Codeinone (a painkiller medicine) was synthesized using this reaction. MeO

MeO

, Al(O-i-Pr)3 O

O

O N Me

N Me

O

HO

Codeinone

Codeine

Experimental Procedure (from patent US3506692A) O

O Al(O-i-Pr)3 , cyclohexanone Toluene, 110 °C HO A

O B

To a solution of 30 ml of dry toluene and 10 ml of cyclohexanone was added 1 g of compound A. From the mixture was distilled out 5 ml of the toluene in order to remove a trace of water. To this reaction mixture was added dropwise over about 20 minutes under refluxing and stirring a solution of 0.45 g of aluminum isopropoxide in 20 ml of dry toluene, while about 20 ml of toluene was distilled out. Stirring was continued for further 50 minutes under reflux, and then the reaction mixture was cooled. Excess aluminum isopropoxide in the mixture was decomposed by addition of water. The mixture was subjected to steam distillation. The residue was extracted with ether, and the extract was washed with water and dried over anhydrous sodium sulfate. The ether was evaporated from the extract to obtain 0.91 g of a crude crystalline substance. The crude crystalline substance was recrystallized from a mixture of ether and n-hexane to give the pure desired product B with m.p. 146 ∘ C.

Riley Oxidation The Riley oxidation is a selenium dioxide-mediated oxidation of activated methylene adjacent carbonyl to 1,2-dicarbonyls [1]. This reaction was reported by Harry

Riley Oxidation

Lister Riley in 1932. The substrate scope [2–17] and mechanism [2, 3, 7] of this reaction have been reported. O

O

SeO2

R2

R1

R2

R1

H2O

+

H2O + Se

O

Mechanism The mechanism starts with attack by the enol tautomer at the electrophilic selenium center. After rearrangement and loss of water, a second equivalent of water attacks at the alpha position. In the last step selenic acid (or selenium and water) liberates and produces the 1,2-dicarbonyl.

Step 1

O R2

R1

.. OH

H R2 +/– H+

R1 O Se O

O H R1

Step 2

O

R2 –H O 2

R1 Se O OH Step 3

O ..

H +/-H+

R2 Se

Step 4

O

R1

.. O OH R2 O

SeH

–H2SeO Step 5 O

O

Step 6 R2

R1

R2

R1 O

O

H H

.. O H

Step 1: Tautomerization. Step 2: Michael-type addition. Step 3: Elimination of water. Step 4: Water attacks as a nucleophile at the electrophilic center and deprotonation. Step 5: Elimination of H2 SeO. Step 6: A deprotonation step produces the desired product. Application Total syntheses of natural products such as strychnine [3], (+)-ingenol [15], and (+)-ryanodol [17] have been accomplished using this reaction. Experimental Procedure (from patent US20140341799A1) O

O SeO2 O

AcOH, 118 °C A

B

Benzil

405

406

8 Oxidations and Reductions

Selenium dioxide (5 equiv.) was dissolved in 10 ml glacial acetic acid, and deoxybenzoin (A, 1 equiv.) was added. The mixture was heated to 118 ∘ C for three hours. The cooled solution was decanted, and the elemental selenium was washed with diethyl ether. Acetic acid was removed under reduced pressure, and the residue was extracted with diethyl ether. The combined organic layers were washed with ultrapure water, a saturated solution of sodium bicarbonate, and then again with brine, after which it was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired benzil (compound B).

Ley–Griffith Oxidation Oxidation of primary and secondary alcohols to aldehydes and ketones, respectively, using N-methylmorpholine-N-oxide (NMO) in the presence of catalytic amounts of tetrapropylammonium perruthenate (TPAP) is called the Ley–Griffith oxidation reaction [1–3]. The oxidation reaction produces water that can be removed by using molecular sieves 4 Å. The reaction conditions are mild and tolerate several functional groups [4–17]. A variety of other synthetic transformations can be employed under this reaction conditions (e.g. diol cleavage, isomerization, imine formation, and heterocyclic synthesis). OH R1

O

Pr4N RuO4

R2 NMO, DCM, 4 Å MS

R1

R2

O N O NMO

Mechanism Part 1: Oxidation of alcohol with RuO4 .. O H R1

R2

O O H Ru O O Step 1 O O O O Ru O R1 R2

–H+ Step 2

R1

O O Ru O O O R2 H

O

Step 3 R1

R2

+ RuO4H H+ RuO3 + H2O

Step 1: Nucleophilic attacks of oxygen lone pair electrons of alcohol to an electrophilic center RuO4. Step 2: Deprotonation. Step 3: Abstraction of proton generates a carbonyl compound.

Criegee Oxidation (Criegee Glycol Cleavage)

Part 2: RuO4 regeneration O O Ru O

O

N

Step 1

O

O Ru O N O O

Step 2 O

O O O Ru O

N + O

Step 1: Nucleophilic addition of NMO to the electrophilic center of RuO3 . Step 2: Elimination of N-methylmorpholine regenerates the RuO4 . Application Natural products such as 9-epi-sessilifoliamide J [11], (+)-minifiensine [16], and quinine [17] were synthesized using this reaction as a key step. Experimental Procedure (from patent WO1998008849A1)

OH O

O

TPAP, NMO

O

O

O

4° M.S.; CH2Cl2 r.t. A

B

To a mixture of 70 mg (0.32 mmol) of the alcohol (compound A) and 4 Å M.S. (1 g) in CH2 Cl2 (5 ml), 66 mg (0.48 mmol, 1.5 equiv.) of 4-methylmorpholine N-oxide (NMO) was added. After stirring for 10 minutes, 6 mg of TPAP (0.016 mmol, 0.05 equiv.) was added and stirred for four hours at room temperature. The reaction mixture was concentrated on a rotary evaporator and directly purified by column chromatography with pentane–ether to afford ketone B (60 mg, 86%).

Criegee Oxidation (Criegee Glycol Cleavage) The oxidative cleavage of 1,2-diols (vicinal diols, glycol) to the corresponding two carbonyl compounds using lead tetraacetate (Pb(OAc)4 , LTA) is known as the Criegee oxidation [1, 2]. This oxidation reaction can be employed with β-amino alcohols, 1,2-diamines, α-hydroxy aldehydes and ketones, α-diketones, and α-keto aldehydes, and all undergo similar type of cleavage [3–15]. Other oxidizing agents such as sodium bismuthate, manganese(III) pyrophosphate, nickel peroxide, silver(I) salts, chromic acid, and phenyliodoso acetate are used for this type of glycol cleavage, but the rate of reaction is slower than lead tetraacetate. HIO4 or NaIO4 is an alternative to lead tetraacetate. The rate of reaction depends on geometry of vicinal diols. Cis-diols are cleaved faster than trans-diols.

407

408

8 Oxidations and Reductions

HO OH R1 R3 R2 R4

O

O

Pb(OAc)4 R1

+

R2

R4

R3

O

O Pb(OAc)4 H

OH

HO

H

+

H

H

Ethylene glycol

Mechanism If the oxygen atoms of the two hydroxy groups are conformationally close enough to form a five-membered ring with the lead atom, the reaction proceeds via a cyclic five-membered intermediate as shown below. AcO .. HO

Pb(OAc)3 OH

R1 R2 R4

AcO Step 1

R3

AcO Pb(OAc)3 H O OH R1 R3 R2 R4

Pb(OAc)2 .. O OH Step 3 R1 R3 R2 R4

Step 2

AcO OAc Pb O O H R1 R3 R2 R4

OAc

Step 4

O

O Pb(OAc)2 +

R4

R3

+

R1

AcO OAc Pb O O R3 R1 R2 R4

Step 5 R2

Five-membered intermediate

Step 1: Nucleophilic substitution reaction. Step 2: Proton transfer. Step 3: Another nucleophilic substitution reaction. Step 4: Proton transfer to give a cyclic five-membered intermediate. Step 5: Breaking the five-membered cyclic intermediate gives the desired products. If two hydroxyl groups are not close enough (trans-diols or bicyclic trans-diols), then an alternative mechanism is possible as shown below. HO OH R1 R3 R2 R4

AcO Pb(OAc)4 - AcOH

CH3 OAc Pb O O .. O O H

R1 R2 R4

R3

O

O R1

R2

+

R3

R4

+ Pb(OAc)2 + AcOH

Application Total synthesis of antibiotic X-206 [7] has been accomplished using this reaction.

Criegee Ozonolysis

Experimental Procedure (from patent US5208036) OH OR2 R1 O

O

Pb(OAc)4

OR1

2 R O 1

CHCl3, r.t.

OR2 OH

H OR2

A

B

The diols (compound A) were dissolved in chloroform (500 ml), and lead tetraacetate (11.8 g, 26.0 mmol) was added. This mixture was stirred for two hours, and then ethylene glycol (5 ml) was added (for quenching the excess oxidant) followed quickly by addition of water (100 ml). The water phase was drawn off, and the organic phase was washed once with saturated sodium chloride solution, dried (magnesium sulfate), and concentrated to an oil to give the aldehyde (compound B).

Criegee Ozonolysis The unsaturated bonds of alkenes and alkynes compounds are oxidative cleaved with ozone to carbonyl compounds is known as the Criegee ozonolysis [1, 2]. The formation of products depends on nature of substrate and work-up conditions [3–18]. Reductive work-up conditions using Ph3 P, Me2 S, or zinc dust produce aldehydes or ketones, while the use of NaBH4 furnishes two alcohols or alcohols and ketones. Oxidative work-up conditions using H2 O2 produce two acids or acids and ketones.

R1 R2

R3 R4

O3

O

O

O

R1

R3

R1

R2

R2 R 4

CH2Cl2

O O

Molozonide

O

R4

O

O

Ph3P

R3

R2

R1

Work-up

+ R 3

R4

Secondary ozonide

R1, R2, R3, R4 = alkyl or aryl

Alkenes to carbonyl compounds

R1

R3

H

R4

R1

R3

H

H

O3

R1

CH2Cl2

O3 CH2Cl2

O O O

H

R1

O

O R3

Reductive work-up R1

R4

+

H

R3

Ketone

Aldehyde

O O H

O

R3 H

O

O

Reductive work-up R1

R4

H

Aldehyde

+

R3

H Aldehyde

409

410

8 Oxidations and Reductions

Alkenes to alcohols and ketones O3

R1

R3

H

R4

CH2Cl2

O

O O

R1

O

H

NaBH4

R3

R1

R4

+

OH

R4

R3

Ketone

Alcohol

Alkenes to alcohols R1 H

O3

R3 H

O O

R1

CH2Cl2

R3

O

H

NaBH4 R1

H

+

OH

R3

OH

Alkenes to acid and ketones O

O R1 H

R3 R4

O3

O O

R1

CH2Cl2

R3

O

H

Oxidative work-up

R4

R1

H2O2

OH

R3

+

Acid

R4 Ketone

Alkenes to acids R1 H

R3

O3

H

CH2Cl2

R1

O O H

O

Oxidative work-up R3

H2O2

H

O

O R1

OH

+

R3

OH Acid

Acid

Cyclic alkenes produce the dialdehydes. 1. O3, DCM

CHO CHO

2. Ni/H2

Alkynes to 1,2-diketones

R1

R2

O

O3 CH2Cl2

R1

O R2

Alkynes can give two carboxylic acids. O R1

R2

O

CH2Cl2

R1

O

R2

Acid anhydride

O

O

H2O

O3

R1

OH

+

R2

OH

Criegee Ozonolysis

Mechanism O O O R1 R2

R3 Step 1

.. O O O

O R3

R1

R1

R2 R4

R4

O

Step 2

Molozonide (1,2,3- trioxolane)

R4

R3

Step 3

O

R2

R2

O

R3 R4

Secondary ozonide (1,2,4-trioxolane) Reductive work-up Step 4

Carbonyl + carbonyl oxide Criegee intermediate or Criegee zwitterion O R3

O O

R1

O R4

+

R1

R2

Step 1: A 1,3-dipolar cycloaddition of ozone to alkene gives a molozonide (also called primary ozonide, 1,2,3-trioxolane). Step 2: The molozonide decomposes to give a carbonyl oxide and a carbonyl compound, also called the Criegee intermediate or the Criegee zwitterion. Step 3: The carbonyl oxide is similar to ozone (1,3-dipolar) that undergoes a retro 1,3-dipolar cycloaddition to form a relatively stable intermediate secondary ozonide (1,2,4-trioxolane). A mixture of three possible secondary ozonides can form if R1 , R2 , R3 , R4 are different groups. Step 4: Reductive work-up gives two carbonyl compounds. Application Total syntheses of mayurone, thujopsenes [6], and core of halichondrin B [8] have been accomplished using this reaction. Experimental Procedure (from patent US20030232989A1) F F

OH O

1. O3, metanol O O

O

2. Me2S

H

O N

N A

B

Ozone was passed with stirring into a solution of 4.0 g (9.1 mmol) of the aromatic alkene (A) in 160 ml of methanol, cooled to −40 ∘ C. An ozone generator from Fis-

411

412

8 Oxidations and Reductions

cher was used here. The rate of addition of ozone was 301 of O2 /h and about 2 g of O3 /h. After 17 minutes (corresponding to 11 mmol of O3 ), the ozonolysis was terminated, as a slight blue coloration of the reaction mixture had taken place. The reaction mixture was flushed with nitrogen at −40 ∘ C and treated with 600 mg (9.67 mmol) of DMS at this temperature. The reaction mixture was allowed to warm to 20 ∘ C in the course of 30 minutes, and the mixture was allowed to stand for a further 2.5 hours. The solvent was then removed by distillation, and the residue was dissolved in a little methylene chloride, treated with 10 g of silica gel, and freed of the methylene chloride. The silica gel loaded with the desired product was shaken with 100 g of silica gel on a frit and eluted with 12, 50 ml fractions of cyclohexane/ethyl acetate (volume ratio 20 : 1) to afford product B (83%).

Reduction Reactions Birch Reduction The Birch reduction, named after Arthur John Birch, is an organic reaction where aromatic rings undergo a 1,4-reduction to produce unconjugated cyclohexadienes [1, 2]. The reduction undergoes with sodium or lithium metal in liquid ammonia and in the presence of an alcohol. The reduction proceeds depending on an electron-donating group (EDG) or an electron-withdrawing group (EWG) on aromatic ring [3–42]. Ammonia-free Birch reduction [26], low temperature in plasma [27], mechanism [32], SmI2 -promoted Birch reduction [33], inorganic electride [Ca2 N]+• e− promoted the Birch reduction [40] have been investigated. OMe

OMe Na or Li, liquid NH3 EtOH EDG

O

O

OH Na or Li, liquid NH3 EtOH EWG

Mechanism M

Liquid NH3

M+

+

e

OH

Reduction Reactions OMe

OMe

OMe

e SET

Step 2

Step 1 H

OMe H

H Et-OH H

OMe H

e

H H

Et-O-H H

Step 3 H H

Step 4

H

H

Et-O-H Radical anion

Step 1: Single-electron transfer (SET) from metal to the aromatic ring. Step 2: Proton transfer from the alcohol to the aromatic ring. Step 3: Another SET. Step 4: Proton transfer ensures the desired product. Application

Several natural and drug-like molecules such as Galbulimima alkaloid GB 13 [11], (±)-secosyrin 1 [14], himandrine skeleton [15], (±)-1-epiaustraline [16], (+)-zoapatanol [19], proteasome inhibitor clasto-lactacystin β-lactone [22], mulinane [34], tyrosine kinase inhibitor XR774 [35], and (−)-quinagolide [41] have been synthesized under the reaction conditions. Experimental Procedure (from patent US20090247756A1) MeO

HCO2H NH

MeO NH3, Li

NH

HO iPrOH/THF – 60 °C

MeO

HO MeO

A

B

To a 5 l dried reaction flask were added compound A (392.5 g, 1.14 mol), isopropyl alcohol (500 ml, anhydrous), and THF (1.0 l, anhydrous, inhibitor-free). The obtained slurry was cooled to −60 ∘ C. Anhydrous ammonia (approximately 1.5 l) was condensed into the slurry. The mixture was stirred for 30 minutes while maintaining the temperature at −60 ∘ C. Then, lithium metal (30.2 g, 4.35 mol) was added to the reaction mixture in five portions over an hour period. After the last addition, the color of the reaction was blue. HPLC analysis indicated the reaction was complete. Then, anhydrous methanol (400 ml) was added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature (approximately eight hours with good stirring), allowing excess ammonia to evaporate. Distilled water (750 ml) was added to the mixture. After stirring for 30 minutes, glacial acetic acid was added slowly to a pH of 9.5–10. After stirring for one hour, the product, compound B [330.1 g, 96% yield, 98.6% ee (R)], was isolated by filtration after washing the solid with distilled water (1 l) and drying under vacuum (30 ∘ C, 30 in Hg, 48 hours).

413

414

8 Oxidations and Reductions

Bouveault–Blanc Reduction The reduction of an ester to the corresponding primary alcohol using sodium in ethanol is called the Bouveault–Blanc reduction [1–4]. Louis Bouveault and Gustave Louis Blanc discovered this reaction in 1903. This reaction is used as an alternative to lithium aluminum hydride reduction in industry [5–10]. O R1

Na R1

OEt

OH

EtOH Primary alcohol

Ester

Mechanism Sodium metal is a single-electron reducing agent. It means the sodium metal will transfer electrons one at a time. Four sodium atoms are needed to fully reduce each ester to alcohol. Ethanol is proton donor.

EtO H O Et O R1

O

Na° OEt

SET

OEt

R1

OEt

R1

OH

+e

OH

Step 2

Step 3

R1

OEt

R1

O H

Step 4

OEt H

Step 1 Et O H

Step 5

Et O H OH R1

H H

Step 9

OH R1

Et O H

OH

Step 8

H Na° +e

R1

H

Na°

O

Step 7 R1

H

+e Step 6

Step 1: SET from sodium metal to the ester. Step 2: Proton transfer from ethyl alcohol. Step 3: SET from sodium metal and formation of carbanion. Step 4: Abstraction of proton from ethyl alcohol. Step 5: Elimination of EtOH and formation of aldehyde. Step 6: SET. Step 7: Proton transfers from ethyl alcohol. Step 8: Formation of carbanion. Step 9: Proton transfer from ethyl alcohol forms the desired product.

O R1

H

Clemmensen Reduction

Application Total synthesis of (±)-antroquinonol D [8] has been accomplished using this reaction. Experimental Procedure (from patent US2883424A)

MeO2C

Na, Ethanol HO

HO

HO A

B

Compound A (3 g) was dissolved in 100 ml of absolute ethyl alcohol. About 10 g of sodium was placed in 200 ml of dry toluene, and the mixture was heated until the sodium was melted and cooled to about 60 ∘ C at which time the alcoholic solution of steroid was added. An additional 100 ml of absolute ethyl alcohol was added, and the mixture was then heated on a steam bath until all of the sodium had dissolved. The mixture was washed with water and acidified with dilute hydrochloric acid. The toluene and ethyl alcohol were removed by steam distillation, and the residue was extracted with ether, and the ether extract was dried over anhydrous magnesium sulfate. The ether was evaporated to give compound B.

Clemmensen Reduction The Clemmensen reduction, named after the Danish chemist Erik Christian Clemmensen, is an organic reaction used to convert an aldehyde or ketone to the corresponding methylene compound using amalgamated zinc and concentrated hydrochloric acid [1–3]. The strong acidic conditions cannot tolerate several functional groups, the main disadvantage of this reaction [4–20]. Zn (Hg)

O R1

R2

HCl

Aldehyde or ketone

H R1

H R2

Alkane

Mechanism The mechanism of the Clemmensen reduction is not exactly clear. There are two proposed mechanisms for this reaction. One is carbanionic mechanism and another is radical mechanism.

415

416

8 Oxidations and Reductions

Carbanionic Mechanism

.. O

H

R1

O

Step 1

R2 HCl

H

Step 2

Step 3 R1

R2

R1

Zn

.. Zn

H R1

R1

R2

H

R2

R1

Zn Cl

R2

H R1

O H Zn

Step 5

H Step 7

Zn

R2

Step 6 R1

.. R1

R2

Cl

Cl

H

Step 8

H .. O H Step 4

O H

Zn

R1

R2

:Zn

R2

Zn

R2

Cl .. Zn

Carbanion

Cl

Step 9 H R1

H

R2

Step 1: Protonation. Step 2: The zinc attacks at the electron-deficient carbonyl carbon atom. Step 3: The chloride attacks on zinc. Step 4: Protonation of hydroxyl group makes it a better leaving group. Step 5: Elimination of water forms a carbocation. Step 6: Zinc abstracts the cation of chlorine to give a carbanion intermediate. Step 7: The carbanion abstracts the proton. Step 8: The chloride attacks on zinc to give another carbanion. Step 9: The carbanion abstracts the proton to give the desired product. Carbenoid/Radical Mechanism O R1

Zn

Step 1 R2

Zn

O R1

Zn

Step 2 R2

R1

R2

Zinc carbenoid

H

Zn

Step 3 R1

H

R2

H

Step 4 – Zn 2+

R1

H

Step 1: SET from zinc metal to the carbonyl compound. Step 2: Elimination of ZnO gives a zinc carbenoid intermediate. Step 3: The zinc carbenoid takes a proton from the acid. Step 4: The proton replaces the metal zinc to produce the desired product.

H

R2

Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey reduction)

Application Total syntheses of (25R)-26-hydroxycholesterol [14] and (±) thielocin A1β [20] have been accomplished under this reaction conditions. Experimental Procedure (from patent WO1994028886A1) OH

O

OH Zn (Hg) HCl, AcOH, 118 °C B

A

Amalgamated zinc (10 g) was placed in a 100 ml round-bottom flask fitted with a stirrer and a reflux condenser. A mixture of acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) was added and then a solution of 2-octanoylphenol (A, 2 g) in acetic acid (5 ml). The mixture was agitated and refluxed for two days. Aqueous 20% w/v NaCl solution (20 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered, and purified by short column chromatography (hexane/ethyl acetate) to afford compound B in 82% yield.

Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey reduction) Itsuno and coworkers first reported in 1981 the enantioselective reduction of ketone to chiral secondary alcohol using chiral alkoxy-amine-borane complexes as a catalyst [1, 2]. Corey, Bakshi, and Shibata developed this reaction further and reported in 1987 using chiral oxaborolidines as catalyst [3–6]. The CBS reduction has been employed as an important procedure for the asymmetric reduction of achiral ketones [6–20].

H

Ph O N B H Catalytic

O R1

Ph

R2

BH3, THF

OH R1

R2

Secondary alcohol

417

418

8 Oxidations and Reductions

H

Ph

Ph O N B H Catalytic

O

OH

BH3, THF Secondary alcohol

Mechanism This CBS catalyst acts as both a Lewis acid and a chiral auxiliary. BH3 coordinates with oxazaborolidine to form a complex that acts as a hydride donor as shown below. H Ph N

Ph

O

BH3 .THF

B R

Step 1

H Ph N

H Ph

Ph Step 2

O B

N

R BH3

H Ph

Ph

Step 3

O B R

H2B H

O

RL

Ph

N O B R H2B O H RS RL

RS

Step 4

HO RL

H RS

Step 5 HCl, MeOH

H2BO RL

H Ph

H RS

+ N

Ph

O B R

Step 1: This step is the coordination of BH3 to the nitrogen atom of the oxazaborolidine CBS catalyst. Step 2: The endocyclic boron of the catalyst coordinates to the ketone at the sterically more accessible electron lone pair (i.e. the lone pair closer to the smaller substituent, RS ). Step 3: The face-selective hydride transfers from BH3 -chiral catalyst complex to the ketone. Step 4: The chiral catalyst regeneration gives the chiral alkoxyborane intermediate. Step 5: Acidic work-up gives the desired chiral alcohol. Application Total syntheses of kanamienamide [16], prostaglandin E1 [19], dysidiolide [10], and okadaic acid [18] have been accomplished utilizing this reaction.

Noyori Asymmetric Hydrogenation

Experimental Procedure (from patent WO2013040068A2) CO2Me

CO2Me R-CBS, BH3.THF O

THF, –70 °C

O

O

OAc

OH

OAc

A

B

A 500 ml three-neck RBF equipped with a magnetic stirrer, a N2 inlet, temperature probe, and a dry ice–acetone bath, charged with 100 ml of THF, 22.73 g (50 mmol) of hydroxyl protected A, and 5 ml of (R)-(+)-2-methyl-CBS-oxazaborolidine, 1 M in THF. The solution was cooled to −78 ∘ C, followed by the addition of 50 ml of BH3 –THF complex 1 M in THF over one hour maintaining the temperature below −70 ∘ C. TLC analysis (hexane/EtOAc, 1 : 1) indicated complete reaction. To the stirring solution slowly was added 50 ml of methanol and allowed to warm to 0 ∘ C for one hour. At this temperature the reaction was further quenched with 150 ml of 1 N hydrochloric acid. The reaction mixture was diluted with 150 ml of MTBE, and the organic layer was separated. The aqueous was back-extracted with 150 ml of MTBE, and the combined layers were, successively, washed with 150 ml of water and 150 ml of brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography to afford 21.7 g (95.3% yield) of diester Beraprost B as a single isomer.

Noyori Asymmetric Hydrogenation The enantioselective hydrogenation of ketones, aldehydes, imines, and functionalized alkenes using chiral ruthenium catalyst is known as the Noyori asymmetric hydrogenation [1–3]. He received the Nobel Prize in Chemistry in 2001 for this reaction. For the asymmetric hydrogenation of functionalized ketones BINAP-Ru catalyst and for the asymmetric hydrogenation of simple ketones BINAP-diamine-Ru catalyst are used, respectively. Several new catalysts and substrates scope have been investigated for this type of reaction [4–80].

O

O

H2 , RuCl2 -(R)-BINAP O

OH O (R)

CH3OH

O

419

420

8 Oxidations and Reductions

O

O

OH O

H2, RuCl2 -(S)-BINAP O

O

(S)

CH3OH

> 99% ee OH

O H2, (S)-BINAP-diamine-Ru

(S)

CH3OH

Mechanism The oxidation state of the ruthenium remains +2 within the catalytic cycle, unlike that of rhodium catalysts that changes back and forth between +1 and +3 [10]. Cl [R-BINAP]Ru Cl 2 MeOH

Step 1

H Cl O Me [R-BINAP]Ru O Me Cl H H2 Step 2 HCl H H O Me [R-BINAP]Ru O Me Cl H

MeOH

O O O

Step 6 Step 3

H2

O O

2 MeOH

OMe H O Me [R-BINAP]Ru O Me Cl H

HO

Step 5 2 MeOH

Me

H O O [R-BINAPH]Ru Cl O H

O

H O [R-BINAP]Ru Cl O MeOH Step 4

O

Noyori Asymmetric Hydrogenation

Step 1: The catalyst coordinates with methanol. Step 2: The catalyst gets hydride from hydrogen and removes HCl. Step 3: The catalyst coordinates with β-keto ester and replaces methanol. Step 4: Hydride transfers from the complex to the keto group. Step 5: Product releases from the complex and methanol coordinates again. Step 6: The complex takes hydride from hydrogen and regenerates the catalyst. Application Industrial uses of this reaction include levofloxacin (antibiotic), carbapenem (antibiotic) [73], l-azatyrosine (antibiotic), BMS 181100 (antipsychotic agent), sitagliptin (treatment for the type 2 diabetes) [62], l-DOPA (medicine for Parkinson’s disease) [31], and pregabalin (Lyrica, an anticonvulsive agent for the treatment of epilepsy, neuropathic pain, anxiety, and social phobia) [43]. F

N F

N N

O

H2, (S)-BINAPRu-diamine

N

OH

N

N

N

(S)

Base

N

F BMS 181100

F

F

(S,R)-t-Bu-JOSIPHOS

F

NH2 O (Z)

F

N

NH2 O

[RhCl(cod)2], H2

N

N

F F

N

(R)

NH4Cl, MeOH

N

F Sitagliptin

CF3

N

N

N CF3

Total syntheses of natural products such as (−)-isowondonin A [65], (−)-melanthiodine [66], decytospolide A [68], (+)-nivetetracyclate A [70], and Dysoxylum alkaloids [71] have been accomplished utilizing this reaction. Experimental Procedure (from patent US20020173683A1) O

(S)-Ru-oxazoline-DPEN

OH (S)

t-Bu-OK, i-Pr-OH

Hydrogenations of acetophenone by the Ru-oxazoline-DPEN complexes were carried out under standardized conditions of 0.0055 mmol catalyst (4 mg, 1 equiv.), 11.1 mmol acetophenone (1.33 g, 2000 equiv.), and 0.11 mmol potassium t-butoxide (20 equiv.) in 3 ml isopropanol at 50 ∘ C under 5 bar H2 with vigorous stirring. Hydrogen consumption was monitored under isobaric conditions and displayed a short induction time, followed by a broad plateau, and then, typically after 24–60 hours, by a rapid falloff as acetophenone was completely consumed. Crude product analysis was performed by thin-layer chromatography on Merck Kieselgel plates with 1 : 5 t-butyl methyl ether/hexane. Hydrogenation was

421

422

8 Oxidations and Reductions

carried out until no further hydrogen consumption was noted; 1-phenylethanol was isolated in 95% yield based on acetophenone consumed. Optical purity of the 1-phenylethanol (enantiomeric excess [ee]) was measured by capillary gas chromatography with a chiral column (CE Instruments GC8000 TOP, 30 m × 0.25 mm Supelco β-DEX 120 column, injector at 200 ∘ C, FID detector at 250 ∘ C).

Luche Reduction The Luche reduction is a chemoselective organic reduction reaction used to convert an α,β-unsaturated ketone to an allylic alcohol with cerium trichloride and sodium borohydride in methanol or ethanol [1–3]. This reduction reaction chemoselectively reduces α,β-unsaturated ketone in the presence of the similar type aldehyde or nonconjugated ketone [4–34]. O

CeCl3, NaBH4

OH

MeOH

Mechanism The cerium coordinates to the alcohol, making its proton more acidic. The proton is abstracted by the carbonyl oxygen of the ketone. The NaBH4 reagent reacts with the cerium-activated alcohol to form a series of alkoxyborohydrides, making harder reducing agent. These hard reagents undergo in the 1,2-hydride attack on the protonated carbonyl to provide selectively an allylic alcohol product. H3C O H

Ce+3

NaBH4

+ MeOH

Na B(OMe)3 H

H3C O H

Ce+3

OH

O

MeO B H MeO OMe

OMe

Meerwein–Ponndorf–Verley Reduction

Application Several drug-like compounds and natural products such as anti-HIV agent (±)-calanolide A [7], d-, l-deoxymannojirimycin [8], (+)-cannabisativine [11], hispanane [12], swainsonine [13], 8a-epi-d-swainsonine [15], tetrasaccharide [16], (±)-axamide-1 [19], puromycin [20], phomactins [21], neopeltolide [24], seven-membered ring scaffold [25], microcosamine A [26], eupalinilide E [27], (−)-1-deoxyaltronojirimycin [29], and acutifolone A [31] were synthesized using this reaction as a key step. Experimental Procedure (from patent US20180134650A1)

O

CO2Et

(R)

CeCl3 7H2O, NaBH4

HO

MeOH, 0 °C

(Z)

(R)

CO2Et

(Z)

B

A

A solution of A (200 mg, 1.02 mmol) in dry methanol was cooled to 0 ∘ C, added CeCl3 ⋅7H2 O (418 mg, 1.12 mmol), followed by sodium borohydride (77 mg, 2.04 mmol), and stirred at room temperature for one hour. The reaction mass was cooled to 0 ∘ C and quenched with saturated NH4 Cl solution, and methanol was removed in rotary evaporator. Ethyl acetate was added, and the aqueous layer was extracted, dried over anhydrous Na2 SO4 , and concentrated to give the product a colorless liquid (200 mg, quantitative).

Meerwein–Ponndorf–Verley Reduction The reduction of aldehydes and ketones to the corresponding alcohols using aluminum isopropoxide in isopropyl alcohol is known as the Meerwein–Ponndorf– Verley reduction [1–3]. The reverse reaction oxidation of alcohols to aldehydes or ketones is called Oppenauer oxidation or depending on which component is the target product. Several new methods [4–48] such as Al-free Sn-zeolite [14], photo-catalyzed base free [24], Mg alkoxide [30], LiBr [25], and In-tri(isopropoxide) catalyst [35] have been used for this reaction. Mechanism [9, 20, 27] and kinetic control [31] have been investigated on this reaction.

O R1

OH R2

+

Aldehyde or ketone

MPV reduction Al(O-i-Pr)3 R1

Isopropyl alcohol

Oppenauer oxidation

O

OH R2

+ Acetone

Alcohol

423

424

8 Oxidations and Reductions

Mechanism

.. O R1

O

Al(OiPr)3

R2

O Al O O R1

Step 1

R2

Step 2

O O O Al H O R1

H

O O Al O

Step 3 R1

R2

O +

R2

T. S.

Acidic work-up Step 4 H OH R1

R2

Step 1: The initial step is the coordination of ketone or aldehyde with aluminum isopropoxide. Step 2: The hydride transfers through a cyclic six-membered chair-like transition state. Step 3: Acetone is separated from the complex. Step 4: Acidic work-up gives the desired alcohol. Application Total synthesis of bryostatin [26] has been completed using this reaction. Experimental Procedure (from patent US8674120B2) OH O

OH O

Al(O-i-Pr)3

O HO

O

2-Propanol

O HO

OH B

+

A

OH O O HO

OH C

Aluminum isopropoxide (300 g, 1.468 mol) was added to a solution of zearalenone (compound A, 100 g, 0.314 mol) in 1270 ml of 2-propanol. The mixture was stirred at 75 ∘ C for 24 hours; then the mixture was distilled to a volume of about 500 ml, cooled to ambient temperature; 400 ml of water and 550 ml of 6 N HCl were added, ensuring that the reaction temperature was maintained below 40 ∘ C. The reaction was cooled to ambient temperature, and 990 ml of ethyl acetate was added. The aqueous layer was separated, and the ethyl acetate layer

Rosenmund Reduction

was washed with water (2 × 325 ml) and brine (1 × 325 ml). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified over silica gel (hexane/ethyl acetate) to give α-zearalenol (B) and β-zearalenol (C).

Mozingo Reduction The Mozingo reduction is an organic reaction used to convert an aldehyde or ketone into corresponding alkane [1]. The reaction works in two steps: first the carbonyl compound is converted into thioacetal or thioketal, and second it is reduced to corresponding alkane using hydrogen and Raney nickel [2–11].

SH

O

H2

SH S

R

R1

Catalyst

R

S

R

R1

R1

Raney nickel

This method is milder (neutral condition) than either the Clemmensen (run under acidic conditions) or Wolff–Kishner reductions (run under basic conditions), which might interfere with other acid or basic sensitive functional groups. Application Total synthesis of (−)-mangiferaelactone [9] has been accomplished using this reaction.

Rosenmund Reduction The Rosenmund reduction is an organic reaction used to reduce an acid chloride to an aldehyde using hydrogen and Pd-BaSO4 [1]. It is a hydrogenolysis reaction [2–12]. Barium sulfate has a higher surface area that can reduce the activity of the palladium, hence preventing over-reduction. O R1

O

H2 Cl

R1

Pd-BaSO4

H

Mechanism O R1

O

Pd(0) Cl

Step 1

R1

Pd Cl

O

H-Pd-H Step 2

R1

Pd H

O

Step 3 R1

H

+ Pd(0)

425

426

8 Oxidations and Reductions

Step 1: Oxidative addition of Pd. Step 2: Ligand exchanges (Cl to H). Step 3: Reductive elimination gives the desired product. Experimental Procedure (from patent US3517066A) O

O

MeO Cl MeO OMe

H2, Pd-BaSO4

MeO

Xylene

MeO

H

OMe

A

B

Preparation of 3,4,5-Trimethoxybenzaldehyde

Into a 600 ml capacity glass liner of a rocking autoclave was placed in order 150 ml of dry xylene and 24.6 g. (0.30 mol) of freshly fused sodium acetate. The mixture was cooled to 10–15 ∘ C under dry nitrogen, and 23.4 g. (0.10 mol) of freshly prepared 3,4,5-trirnethoxybenzoyl chloride (A) was added. After shaking, 6 g of pre-dried 10% palladium barium sulfate catalyst was added to the vessel, and the total volume was brought to 300 ml by the addition of dry xylene. The mixture was hydrogenated at 36 ∘ C under initial hydrogen pressure of 65 psi. At the end of 1.5 hours, a steady pressure was reached, which corresponded to adsorption of 130% of the theoretical amount of hydrogen. The catalyst was filtered, and the xylene filtrate was evaporated to dryness at reduced pressure. The residue was dissolved in ethyl acetate, and organic layer was washed with brine and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified over silica gel column chromatography (hexane/ethyl acetate) to give compound B.

Wolff–Kishner Reduction The Wolff–Kishner reduction is a reaction used to reduce an aldehyde or ketone to the corresponding alkane using hydrazine, base, and thermal conditions [1–32].

R1

N

NH2NH2

O R2

NaOH

R1

NH2 R2

Heat –N2

H H R1

R2

Wolff–Kishner Reduction

Mechanism OH O

O

Step 1

R2 R1 N H H NH2

R2

R1

Step 2

.. NH2NH2

OH R1 H N

H N N H

Step 3

R2 R1

NH2

R2 H O H

Step 4 H O H H

Step 6

H

R1

H

R1

–N2

R2

R1

N N H

R2 Step 5

H

OH

R2

Step 1: Nucleophilic attacks by hydrazine to the electron-deficient carbonyl carbon atom. Step 2: Proton transfer. Step 3: Elimination of water and formation of hydrazone. Step 4: Proton abstracts by hydroxide ion to form diimide ion. Step 5: Loss of N2 and formation of carbon anion. Step 6: Proton transfer from water or solvent alcohol and formation of the final product. Application Total syntheses of (−)-methyl atis-16-en-19-oate [11], brevisamide [20], palmarumycin CP17 [25], cyrneine A [28], (±)-aspidospermidine [29], and α-cedrene [32] have been accomplished using this reaction as a key step. Experimental Procedure (from Patent US20060128691A1) O

N

H

N

N NH2NH2, KOH

N

F N

N

Diethylene glycol N

F

H H

N

N

N A

H

B

427

428

8 Oxidations and Reductions

To a suspension of 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carbaldehyde (compound A, 332 mg, 1.25 mmol) in diethylene glycol (3.6 ml) were added potassium hydroxide (140 mg, 2.5 mmol) and hydrazine monohydrate (486 μl, 10.0 mmol). The white suspension was stirred for 17 hours at 150 ∘ C before it was cooled to ambient temperature, diluted with water (50 ml), and extracted with ethyl acetate (150 ml). The organic layers were washed with brine (150 ml) and dried over anhydrous sodium sulfate. Purification of the residue by chromatography (SiO2 , hexane : ethyl acetate : dichloromethane : methanol = 75 : 15 : 10 : 0 to 0 : 80 : 10 : 10) afforded the title compound 3-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine (compound B, 68 mg, 21%) as a white solid.

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Bouveault–Blanc Reduction 1 2 3 4 5 6 7 8 9 10

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Clemmensen Reduction 1 2 3 4 5 6 7 8 9

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Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey Reduction)

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Luche Reduction

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743–745. 11 Campbell, H., Zhou, H., and Nguyen, S.T. (2001). Org. Lett. 3: 2391–2393. 12 Ooi, T., Ichikawa, H., and Maruoka, K. (2001). Angew. Chem. Int. Ed. 40:

3610–3612. 13 Ooi, T., Miura, T., Itagaki, Y. et al. (2002). Synthesis 2: 279–291. 14 Corma, A., Domine, M.E., Nemeth, L., and Valencia, S. (2002). J. Am. Chem.

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4515–4517. 17 Zhu, Y., Chuah, G., and Jaenicke, S. (2003). Chem. Commun. 2734–2735. 18 Cohen, R., Graves, C.R., Nguyen, S.T. et al. (2004). J. Am. Chem. Soc. 126:

14796–14803. 19 Fukuzawa, S.I., Nakano, N., and Saitoh, T. (2004). Eur. J. Org. Chem.:

2863–2867. 20 Klomp, D., Maschmeyer, T., Hanefeld, U., and Peters, J.A. (2004). Chemistry

10: 2088–2093. 21 Yin, J., Huffman, M.A., Conrad, K.M., and Armstrong, J.D. (2006). J. Org.

Chem. 71: 840–843. 22 Dong, S. and Paquette, L.A. (2005). J. Org. Chem. 70: 1580–1596. 23 Yin, J., Huffman, M.A., Conrad, K.M., and Armstrong, J.D. III, (2006). J. Org.

Chem. 71: 840–843. 24 Herance, J.R., Ferrer, B., Bourdelande, J.L. et al. (2006). Chemistry 12:

3890–3805.

Mozingo Reduction

25 Linghu, X., Satterfield, A.D., and Johnson, J.S.J. (2006). Am. Chem. Soc. 128:

9302–9303. 26 Manaviazar, S., Frigerio, M., Bhatia, G.S. et al. (2006). Org. Lett. 8: 4477–4480. 27 Boronat, M., Corma, A., and Renz, M. (2006). J. Phys. Chem. B. 110:

21168–21174. 28 Zapilko, C., Liang, Y., Nerdal, W., and Anwander, R. (2007). Chemistry 13:

3169–3176. 29 Fernández, I., Sierra, M.A., and Cossío, F.P. (2007). J. Org. Chem. 72:

1488–1491. 30 Mojtahedi, M.M., Akbarzadeh, E., Sharifi, R., and Abaee, M.S. (2007). Org.

Lett. 9: 2791–2793. 31 Dilger, A.K., Gopalsamuthiram, V., and Burke, S.D. (2007). J. Am. Chem. Soc.

129: 16273–16277. 32 Kim, J.W., Koike, T., Kotani, M. et al. (2008). Chemistry 14: 4104–4109. 33 Bisogno, F.R., García-Urdiales, E., Valdés, H. et al. (2010). Chemistry 16:

11012–11019. 34 Lee, J., Ryu, T., Park, S., and Lee, P.H. (2012). J. Org. Chem. 77: 4821–4825. 35 Battilocchio, C., Hawkins, J.M., and Ley, S.V. (2013). Org. Lett. 15: 2278–2281. 36 Nandi, P., Tang, W., Okrut, A. et al. (2013). Proc. Natl. Acad. Sci. U. S. A. 110:

2484–2489. 37 Kondo, Y., Sasaki, M., Kawahata, M. et al. (2014). J. Org. Chem. 79:

3601–3609. 38 McNerney, B., Whittlesey, B., Cordes, D.B., and Krempner, C. (2014). Chem-

istry 20: 14959–14964. 39 Song, J., Zhou, B., Zhou, H. et al. (2015). Angew. Chem. Int. Ed. 54:

9399–9403. 40 Wu, W., Zou, S., Lin, L. et al. (2017). Chem. Commun. 53: 3232–3235. 41 Fukui, M., Tanaka, A., Hashimoto, K., and Kominami, H. (2017). Chem. Com-

mun. 53: 4215–4218. 42 Xiao, M., Yue, X., Xu, R. et al. (2019). Angew. Chem. Int. Ed. 58:

10528–10536. 43 Boit, T.B., Mehta, M.M., and Garg, N.K. (2019). Org. Lett. 21: 6447–6451. 44 Bruneau-Voisine, A., Wang, D., Dorcet, V. et al. (2017). Org. Lett. 19:

3656–3659. 45 Wilds, A.L. (1944). Org. React. 2: 178–223. (review). 46 Nishide, K. and Node, M. (2002). Chirality 14: 759–767. (review). 47 Chuah, G.K., Jaenicke, S., Zhu, Y.Z., and Liu, S.H. (2006). Curr. Org. Chem.

10: 1639–1654. (review). 48 Wang, B. and Tu, Y.Q. (2011). Acc. Chem. Res. 44: 1207–1222. (review).

Mozingo Reduction 1 Mozingo, R., Spencer, C., and Folkers, K. (1944). J. Am. Chem. Soc. 66:

1895–1860. 2 Wolfrom, M.L. and Karabinos, J.V. (1944). J. Am. Chem. Soc. 66: 909–911. 3 Mosettig, E. and Mozingo, R. (2011). Org. React. 4: 362.

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4 Carey, F.A. and Sundberg, R.J. (2007). Advanced Organic Chemistry: Reactions

and Synthesis, 452–454. Springer. 5 Mithcell, R. and Lai, Y.H. (1980). Tetrahedron Lett. 21: 2637. 6 Woodward, R.B. and Brehm, W.J. (1948). J. Am. Chem. Soc. 70: 2107–2115. 7 Alcaide, B., Casarrubios, L., Dominguez, G., and Sierra, M.A. (1994). J. Org.

Chem. 59: 7934–7936. 8 Nishide, K., Shigeta, Y., Obata, K. et al. (1996). Tetrahedron Lett. 37:

2271–2274. 9 Kumar, R., Rej, R.K., and Nanda, S. (2015). Tetrahedron: Asymmetry 26:

751–759. 10 Rentner, J., Kljajic, M., Offner, L., and Breinbauer, R. (2014). Tetrahedron 70:

8983–9026. (review). 11 Zhao, G., Yuan, L.Z., Alami, M., and Provot, O. (2017). Chem. Select. 2:

10951–10959. (review).

Rosenmund Reduction 1 2 3 4 5 6 7 8 9 10 11 12

Rosenmund, K.W. (1918). Ber. Dtsch. Chem. Ges. 51: 585. English, J.E. Jr. and Velick, S.F. (1945). J. Am. Chem. Soc. 67: 1413–1414. Burger, A. and Hornbaker, E.D. (1953). J. Org. Chem. 18: 192–195. Sellers, J.W. and Bissinger, W.E. (1954). J. Am. Chem. Soc. 76: 4486. Boothe, J.H., Kende, A.S., Fields, T.L., and Wilkinson, R.G. (1959). J. Am. Chem. Soc. 81: 1006–1007. White, H.B. Jr., Sulya, L.L., and Cain, C.E. (1967). J. Lipid Res. 8: 158. Burgstahler, A.W., Weigel, L.O., and Shaefer, C.G. (1976). Synthesis 12: 767–768. Ward, J.P. (1965). Tetrahedron Lett.: 3905–3908. Yadav, V.G. and Chandalia, S.B. (1997). Org. Process Res. Dev. 1: 226–2232. Tsuji, J., Ohno, K., and Kajimoto, T. (1965). Tetrahedron Lett. 6: 4565–4568. Chimichi, S., Bocaalini, M., and Cosimelli, B. (2002). Tetrahedron 58: 4851. Ancliff, R.A., Russell, A.T., and Sanderson, A. (2006). J. Chem. Commun. 25: 12055.

Wolff–Kishner Reduction 1 Kishner, N. (1911). J. Russ. Phys. Chem. Soc. 43: 582. 2 Wolf, L. (1912). Justus Liebigs Ann. Chem. 394: 86–108. 3 Herr, C.H., Whitmore, F.C., and Schiessler, R.W. (1945). J. Am. Chem. Soc. 67:

2061–2063. 4 Soffer, M.D., Soffer, M.B., and Sherk, K.W. (1945). J. Am. Chem. Soc. 67:

1435–1436. 5 Huang, M. (1949). J. Am. Chem. Soc. 71: 3301–3303. 6 Kupchan, S.M. and Abushanab, E. (1965). Tetrahedron Lett.: 3075–3081. 7 Khuong-Huu, F., Herlem, D., and Simes, J. (1969). J. Bull. Soc. Chim. Fr.:

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Wolff–Kishner Reduction

8 Mazzocchi, P.H. and Kim, C.H. (1982). J. Med. Chem. 25: 1473–1476. 9 Taber, D.F. and Stachel, S.J. (1992). Tetrahedron Lett. 33: 903–906. 10 Hartmann, R.W., Bayer, H., Grün, G. et al. (1995). J. Med. Chem. 38:

2103–2111. 11 Toyota, M., Wada, T., and Ihara, M. (2000). J. Org. Chem. 65: 4565–4570. 12 Sendelbach, S., Schwetzler-Raschke, R., Radl, A. et al. (1999). J. Org. Chem.

64: 3398–3408. 13 Szendi, Z., Forgó, P., Tasi, G. et al. (2002). Steroids 67: 31–38. 14 Shih, H., Cottam, H.B., and Carson, D.A. (2002). Chem. Pharm. Bull. 50:

364–367. 15 Marino, J.P., Rubio, M.B., Cao, G., and de Dios, A. (2002). J. Am. Chem. Soc.

124: 13398–13399. 16 Bashore, C.G., Samardjiev, I.J., Bordner, J., and Coe, J.W. (2003). J. Am. Chem.

Soc. 125: 3268–3272. 17 Furrow, M.E. and Myers, A.G. (2004). J. Am. Chem. Soc. 126: 5436–5445. 18 Wang, W., Poudel, B., Wang, D.Z., and Ren, Z.F. (2005). J. Am. Chem. Soc.

127: 18018. 19 Unciti-Broceta, A., Pineda de las Infantas, M.J., Gallo, M.A., and Espinosa, A.

(2007). Chemistry 13: 1754–1762. 20 Ghosh, A.K. and Li, J. (2009). Org. Lett. 11: 4164–4167. 21 Kedrowski, S.M. and Dougherty, D.A. (2010). Org. Lett. 12: 3990–3993. 22 Yamabe, S., Zeng, G., Guan, W., and Sakaki, S. (2014). Beilstein J. Org. Chem. 23 24 25 26 27 28 29 30 31 32

10: 259–270. Cranwell, P.B., Russell, A.T., and Smith, C.D. (2016). Synlett 27: 131. Dai, X.-J. and Li, C.-J. (2016). J. Am. Chem. Soc. 138: 5433–5440. Wang, R., Liu, G., Yang, M. et al. (2016). Molecules 21, pii:: E600. Tang, J., Lv, L., Dai, X.J. et al. (2018). Chem. Commun. 54: 1750–1753. Raj, V., Rai, A., Singh, A.K. et al. (2018). Anticancer Agent Med. Chem. 18: 719. Wu, G.J., Zhang, Y.H., Tan, D.X. et al. (2019). J. Org. Chem. 84: 3223–3238. Kawano, M., Kiuchi, T., Negishi, S. et al. (2013). Angew. Chem. Int. Ed. 52: 906. Kuethe, J.T., Childers, K.G., Peng, Z. et al. (2009). Org. Process Res. Dev. 13: 576. Lewis, D.E. (2013). Angew. Chem. Int. Ed. 52: 11704–11712. Green, J.C. and Pettus, T.R.R. (2011). J. Am. Chem. Soc. 133: 1603–1608.

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9 Nomenclature and Application of Heterocyclic Compounds Heterocyclic compounds mean at least one element other than carbon in the ring system. There are three systems for naming of heterocyclic compounds [1–8]. The International Union of Pure and Applied Chemistry (IUPAC) widely accepted three nomenclatures are as follows: 1. The Hantzsch–Widman nomenclature 2. Common names/trivial names 3. The replacement nomenclature

The Hantzsch–Widman Nomenclature The Hantzsch–Widman method provides a systematic naming of heterocyclic compounds. It depends on three major factors as follows: Y

(CH2)n n = 2, 3, 4, and so on

A. Type of the heteroatom (Y such as N, O, S, Si, P, etc.) is used as a prefix (see Table 9.1). B. The ring size (n) is denoted by stem and used after prefix. C. Nature of the ring such as it is aromatic or nonaromatic or saturated or unsaturated or partially unsaturated. It is used after stem. So in summary, heteroatom is as a prefix, ring size as a stem, and nature of ring (ending) as a suffix; thus naming is as follows: prefix + stem + suffix (see Table 9.2). This rule may follow from 3- to 10-membered heterocyclic rings. A. Type of Heteroatom (Y)

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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9 Nomenclature and Application of Heterocyclic Compounds

Table 9.1 Type of heteroatom described by prefix. Heteroatom

Prefix

Order of priority

O

Oxa

1

S

Thia

2

Se

Selena

3

N

Aza

4

P

Phospha

5

Si

Sila

6

Ge

Germa

7

B

Bora

8

Hg

Mercura

9

Table 9.2 Ring size and nature of ring (saturation and unsaturation). Unsaturated stem + suffix

Saturated with nitrogen stem + suffix

-irane

-irine

-iridine

-etane

-ete

-etidine

-olane

-ole

-olidine

-inane

-ine

ep

-epane

-epine

oc

-ocane

-ocine

9

on

-onane

-onine

10

ec

-ecane

-ecine

Ring size

Stem

3

ir

4

et

5

ol

6

in

7 8

Saturated stem + suffix

B. Ring Size (n) The ring size is described by a stem. Some of the stems are obtained from Latin numerals, such as ir from tri, et from tetra, ep from hepta, oc from octa, on from nona, and ec from deca. C. Nature of Ring The heterocyclic compounds are named by combining suitable prefix, stem, and suffix from Table 9.2. The stem indicates the ring size (Table 9.2), and suffix or an ending indicates degree of unsaturation or saturation in the ring (Table 9.2). So in summary, heteroatom is as a prefix, ring size is as a stem, and nature of ring (ending) is as a suffix. So, naming is as follows: prefix + stem + suffix (see Tables 9.1 and 9.2). Examples Prefix + stem + suffix The letter “a” in the prefix is omitted in the most cases.

The Hantzsch–Widman Nomenclature

Saturated System (The letter “a” is omitted) Oxa + irane = Oxirane O

S

H N

Oxa + irane = Oxirane

Thia + irane = Thiirane

Aza + iridine = Aziridine

O

S

NH

Oxa + etane = Oxetane

Thia + etane = Thietane

Aza + etidine = Azetidine

O

S

Oxa + olane = Oxolane

Thia + olane = Thiolane

N H Aza + olidine = Azolidine

O

S

N H

Oxa + inane = Oxinane

Thia + inane = Thiinane

Aza + inane = Azinane

O Oxa + epane = Oxepane

N H Aza + epane = Azepane

S Thia + epane = Thiepane

Partial Unsaturation If less than the maximum double bonds, then use fully unsaturated name with dihydro, tetrahydro, etc. Numbering starts with heteroatom then from saturation (see below). 5 3

3

2

N H 1 2,3-Dihydroazepine

N H Azepine

4

N H

2

1 2,5-Dihydroazepine

For numbering, give priority to saturated atoms first regardless of substituents. 4 3

5

3

2 1

4

5

N

1-Ethyl-4-methyl-4,5-dihydrazepine

N 1

2

1-Ethyl-5-methyl-2,3,4,5-tetrahydroazepine

451

452

9 Nomenclature and Application of Heterocyclic Compounds

Unsaturated System O

S

H N

Oxa + irine = Oxirine

Thia + irine = Thirine

Aza + irine = Azirine

O Oxa + ete = Oxete

S Thia + ete = Thiete

N Aza + ete = Azete

O

S

N H

Oxa + ole = Oxole (common name furan)

Thia + ole = Thiole (common name thiophene)

Aza + ole = Azole (common name pyrrole)

Two or more similar heteroatoms (di, tri, tetra, etc.) are used by prefixes. N

N N Azine (pyridine)

N N 1,2-Diazine (pyridazine) 4 N

N 2 N H 1 1,2-Diazole

5

N 1,3-Diazine (pyrimidine)

N 1,4-Diazine (pyrazine)

3 N 2 N 1 H

1,2,4-Triazole

N

N N

1,3,5-Triazine

3 N N2 N H 1 1,2,3-Triazole or 1-H-1,2,3-triazole

Priority of Heteroatoms for Numbering Purposes When More Than One Heteroatom in the Ring These are included as main group from the periodic table, within each group by increasing atomic number, as high a group in the periodic table and as low an atomic number in that group. (Group VI) O > S > Se > Te > (Group V) > N > P > As > (Group IV) > Si > Ge > (Group III) > B Commonly found heteroatoms: O > S > N If more than one different heteroatoms in the ring, then the heterocycle is named by combining the appropriate prefixes with the ending in Table 9.2 in order of their preference, O > S > N (Table 9.1).

The Hantzsch–Widman Nomenclature

4 H N O

N

2

5 S 1

Oxaziridine

O

3

N H 4

5-Methyl-1,3-thiazole (S > N)

4 Br 3 N N 2 5 O 1

1 2 3

2-Methy-1,4-oxazine (O > N)

3-Bromo-5-ethyl-1,2,4-oxadiazole

Give priority to heteroatoms first regardless of substituents (examples below). 4 S

5

6 O 1

4 N

N 3 2

5 6

O 1

S 2

5-Methyl-1,2,4-oxathiazine

6-Methyl-1,4,3-oxathiazine

4

3

S

3

2 5 O 1 5-Methyl-1,3-oxathiolane

Extra Hydrogen Atom Extra hydrogen is given a priority, and numbering starts from there (see some examples below). 4

3

4

N 2

5

5

N H 1

1,2-Diazole

N 3 2

N H 1

1,3-Diazole

4 N N 3 5 N 2 N H 1

4 N N 3 5N N2 N H 1

1H-Tetrazole

1H-Pentazole

3 N N 2

3

4N

N 2

N 1 H

N H

1,2,3-Triazole

1,2,4-Triazole

1

If ring size is more than 10, use carbocyclic monocyclic name, and heteroatom is mentioned by prefixes such as oxa, thia, aza, etc. 12 1S 2

10 11

9 8 7

NH 3 4 5 6

1-Thia-6-azacyclododecane

Heterocycles with Fused Rings When naming fused ring systems, the side of the heterocyclic ring is labeled by the letters a, b, c, etc., starting from the atom numbered 1. Hence side “a” is between atoms 1 and 2, side “b” between atoms 2 and 3, side “c” between atoms 3

453

454

9 Nomenclature and Application of Heterocyclic Compounds

and 4, and so on as shown in the examples below. Heterocyclic ring is the parent compound. The naming of prefix of fused heterocycles is used as such: furan, furo; thiophene, thieno; pyridine, pyrido; pyrrole, pyrrolo; quinoline, quino; benzene, benzo; naphthalene, naphtho; pyrimidine, pyrimido; pyrazine, pyrazino; imidazole, imidazo. 4

5

5

4a

6

7 8

3 c d b e a f 2 8a N 1

6

10 9 h 8

b

7

8a

8

e a f

3 N2

1

Benzo[c]pyridine comon name isoquinoline

2 N a b 3 c d 4

gf

8 7

e

6 5

5

6

7

d c

Benzo[b]pyridine common name quinoline 1

4

4a

9

1

c b de a N 10

2 3 4

Benzo[b]quinoline dibenzo[b,e]pyridine acridine

Benzo[h]-quinoline (quinoxaline)

5 6 7

4a

4

b a O 8a 8 1

3 2

Benzo[b]pyran-2-one coumarin

Nitrogen-containing ring is the parent ring, the largest ring is also the parent ring (two rings contain N or contain O, and another contains N as shown below), and the parent ring name is used in the last of compound’s name.

a N

b 3 2 1 N H

2

1 O 12 3

b

H N 6 a 5 4

3

Pyrrolo[2,3-b]pyridine

6-H-furo[2,3-b]pyrrole (N-ring is the parent)

The ring having the greatest number of heteroatoms or variety of heteroatoms (priority) is the parent ring. 4 5 6

6

N 1 3 d5 2 4 ba c 2 N N 3 1

Pyrido[2,3-d]pyrimidine

1 S a d b 2 4 c N N 3 3

1 HN 2

O

5

Imidazo[4,5-d]thiazole (S,N preferred to only N,N)

Common Names

N

b

d a O

1

S

c

3 N

2

5 N

4

2 a S b

N 1

3

Imidazo[2,1-b]thiazole

[1,3]Thiazolo[5,4-d]oxazole O>S>N O,N preferred to S,N

5 6 N

4 O a b d c

3 NH 4

2

N 1 5

1-H-Pyrazolo[4,3-d]oxazole O,N preferred to N only 4-Heteroatoms lowest locants (1,2,4,6), if starting oxazole, locants (1,3,4,5) or (1,3,5,6)

Common Names H N

S

Aziridine

Thiirane

O

O

Ethylene oxide Oxirane

4 5

4

3 5

2

O 1

5

N

4

3

2 N H 1

Imidazole

5

S 1

5

S 1

N3 2

5

N H 1

O

3

4

N2

5

Isoxazole

Oxazole

4 5 N H Pyrrolidine

Se

N3 2 O 1

1

Thiazole

2

6 S Tetrahydrothiophene Thiolane

N

3

5

N 2 N H 1

Pyrazole

4 N N 3 2 5 O 1 1,3,4-Oxadiazole

O Tetrahydrofuran

3

5

N2 1

6

Pyridazine

4

Selenophene

Pyrrole

4

Thietane

3

4

Thiophene

Furan

4

3 2

S

NH Azetidine

Oxetane

4 N

N3 2 1

Pyrimidine

4 5 N 3 6 N 2 1 Pyrazine

N H Piperidine

455

456

9 Nomenclature and Application of Heterocyclic Compounds H N 5 O

S

N H

Tetrahydropyran

Thiane

Piperazine

5

4

3

5

N2

6

N

6 O

6 7

4a

4

8

9

7

c b de a N 10

6 5

e a f

b

3

10 9 8

2 3

6

Benzo[h]-quinoline (quinoxaline)

7

4

Benzo[b]quinoline dibenzo[b,e]pyridine acridine

1

5

4 4a b a O 8a 8 1

2

9

3 2

8

O

Benzo[b]pyran-2-one coumarin

5

6

7

1

2 N a b 3 c d 4

h e g f

N2

Benzo[c]pyridine isoquinoline

1

Purine 1

8a 8

Benzo[b]pyridine quinoline

2

4 d

3

N H 1

N 7

O Chroman

c 7

N

N

6

4a

6

c d 3 b e a f 2 N 8a 8 1

1H-Benzo[b]pyrrole (indole)

5

Benzimidazole

4

6

3

5 5

2

3a 3 c b de 2 a 7a N 7 H 1

1

Morpholine

N H 1

7

Indazole

3

5

2

6

N H 1

7

4

4

4 H N

7 6

3 c b d a e 4 N H 5

Benzo[b]indole, dibenzo[b,d]pyrrole carbazole

The Replacement Nomenclature In replacement nomenclature, the heterocycle’s name is included of the carbocycle’s name and a prefix that indicates the heteroatom. H N

O Oxacyclopropane

O Oxacyclobutane

O Oxacyclopentane

Azacyclopropane

S Thiacyclopropane

Application of Heterocyclic Compounds Heterocyclic compounds are all of the nucleic acids, the majority of drugs, most biomass (cellulose and related materials), and many natural and synthetic dyes. Fifty-nine percent of US Food and Drug Administration (FDA)-approved drugs contain at least one nitrogen atom [9].

Drugs for Oxetane Derivatives

Drugs for Oxirane Derivatives Fosfomycin (antibiotic), troleandomycin (antibiotic), parthenolide (allergic contact dermatitis), methscopolamine (peptic ulcers), and other medicines contain oxirane ring.

H3C

O

O P OH OH

Fosfomycin

Drugs for Aziridine Derivatives Mitomycin (antibiotic) and other investigational drugs such as carboquone, triaziquone, thiotepa, apaziquone, and imexon have aziridine ring. N O

N

N S P N N

N

Thiotepa

Triaziquone

O

Drugs for Azetidine Derivatives Ezetimibe is used as an adjunctive therapy to diet to lower cholesterol levels. O

F

N F

OH

OH Ezetimibe

Drugs for Oxetane Derivatives Paclitaxel (Taxol) and its derivatives such as cabazitaxel and docetaxel are used for the treatment of cancer and other diseases. Other taxol derivatives such as larotaxel, tesetaxel, ortataxel, and milataxel are in clinical trials. All taxol derivatives contain oxetane ring.

457

458

9 Nomenclature and Application of Heterocyclic Compounds

O

O

OH

O

O

O

NH O O

H O O

OH

OH

O

Oxetane ring

O

Paclitaxel (Taxol)

Orlistat, an oxetane derivative, is a medicine for the treatment of obesity. O O

O O HN

H O

Orlistat

Drugs for Furan Derivatives Nitrofurazone, nitrofurantoin, furosemide, ranitidine, cefuroxime, etc.

O2N

N H

O

H N

NH2 O

Nitrofurazone (Furacin) Antimicrobial

O O

OH

H N

SO2NH2 Cl Furosemide (Lasix) For heart failure and high blood pressure

O

N N O2N

O

NH O

Nitrofurantoin (Macrobid) Antibiotic for bladder infection

Drugs for Pyrrole and Pyrrolidine Derivatives

Drugs for Thiophene Derivatives Articaine (dental anesthetic), canagliflozin (type 2 diabetes), clopidogrel (antiplatelet), duloxetine (depressive disorder), ketotifen (allergic conjunctivitis), lipoic acid, pizotifen (migraine headaches), prasugrel (prevent blood clots), pyrantel (antiparasitic), rivaroxaban (anticoagulant), ticlopidine (antiplatelet), tiletamine (anesthetic), and tinoridine (nonsteroidal anti-inflammatory drug [NSAID]). NH HN

H N

O

O N

OMe

S

S

O Articaine (dental anesthetic)

N

S

Duloxetine (depressive disorder)

Pyrantel (antiparasitic)

NH S O Tiletamine (anesthetic)

Drugs for Pyrrole and Pyrrolidine Derivatives Glimepiride (type 2 diabetes), ketorolac (NSAID), piracetam (myoclonus), ramipril (high blood pressure), sunitinib (anticancer), tolmetin (NSAID), zomepirac, etc. Cl

O HO

O

N

O

Tolmetin (NSAID)

O

N

HO

O

HO

Ketorolac (NSAID)

O N O NH2 Piracetam (for myoclonus)

N

O

Zomepirac (NSAID)

459

460

9 Nomenclature and Application of Heterocyclic Compounds

Drugs for Imidazole, Imidazoline, and Imidazolidine Derivatives Antibacterial

Metronidazole, tinidazole. 4 4

3 N

3 N

2

O2N 5 N 1

2

O2N 5 N 1

O S O OH

Tinidazole (antibiotic)

Metronidazole (antibiotic, bacterial vaginosis)

Antifungal Bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, etc. N

N

N

N

N

N

Cl O Cl

Cl

O Cl

Cl

Cl

O

Cl

Cl

Cl

Econazole (antifungal)

Miconazole (antifungal)

Cl

Cl

Isoconazole (antifungal)

Other Cimetidine (peptic ulcers and heartburn), clonidine (high blood pressure, menopausal flushing), oxymetazoline (topical decongestant), xylometazoline (nasal congestion, allergic rhinitis, and sinusitis), phenytoin (anti-seizure medication), and mephenytoin (anticonvulsant). Cl

H N

H N

H N

HO N

Cl N Clonidine (high blood pressure, menopausal flushing)

Oxymetazoline (topical decongestant)

Drugs for Triazole Derivatives Antifungal: Albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, etc.

Drugs for Pyridine Derivatives

N

N N

N

N

N N N

HO

F

F

N

HO

N

F Me

F

N

F

Voriconazole (antifungal, candidiasis)

Fluconazole (antifungal)

Drugs for Isoxazole Derivatives Cloxacillin, flucloxacillin, oxacillin F Cl H N

N O

H

O

H N

N O

S

O

N O

H S N

O

OH

OH

O

O

Oxacillin (antibiotic)

Flucloxacillin (antibiotic)

Drugs for Thiazole Derivatives Abafungin, thiamine (vitamin B1 ), cefotaxime (antibiotic, joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis).

O N

O

N

N N H

S

N H

N S

Abafungin (antifungal)

H N O

H

S O

N O

H2N

O O

OH

Cefotaxime

Drugs for Pyridine Derivatives Antihistamine: Chlorphenamine, betahistine (also used to alleviate vertigo symptoms), bisacodyl, pheniramine, dexchlorpheniramine, mepyramine, nifedipine, nalidixic acid, sorafenib (anticancer).

461

462

9 Nomenclature and Application of Heterocyclic Compounds

Cl NMe2 N

N H

N Chlorphenamine (allergic rhinitis)

Betahistine (anti-vertigo)

O

CF3 O

N H

Cl

O

N N H

N H

Sorafenib (anticancer)

Cetylpyridinium chloride (mouthwashes, toothpastes, lozenges, throat sprays, breath sprays, and nasal sprays).

N

Cl

Cetylpyridinium chloride

Drugs for Pyrimidine Derivatives Barbiturates, fluorouracil, idoxuridine, imatinib (anticancer), minoxidil, phenobarbital, pentobarbital, trimethoprim, thiamin, uracil, etc. O N

H2N

NH2

O

N

F

NH

N N H Minoxidil (treatment for male hair loss)

H N

NH O Imatinib (Gleevec)

Fluorouracil (anticancer)

N N

N N

O

N

Drugs for Oxazole/Isoxazole/Thiazole/Thiadiazole Derivatives

Drugs for Pyrazine Derivatives Amiloride (high blood pressure), buspirone, cinnarizine, diethylcarbamazine, flunarizine, glimepiride, hydroxyzine, trifluoperazine, and many more. NH2 O H2N

N H2N

N

Cl

N

NH2

Amiloride (high blood pressure)

Drugs for Piperidine Derivatives Mepivacaine, bupivacaine, droperidol, haloperidol, trifluperidol, alfentanil (pain medication), fentanyl (pain medication), diphenoxylate, pethidine, etc. O

O

O N

N N N

N

N N

N

O

Fentanyl (pain medication)

Alfentanil (pain medication)

Drugs for Quinoline/Isoquinoline Derivatives Chloroquine (antimalarial), hydroxychloroquine, isoquine, (antispasmodic and erectile dysfunction), praziquantel, etc.

papaverine

O O

HN

N

N O

Cl

N Chloroquine (antimalarial)

O Papaverine (antispasmodic)

Drugs for Oxazole/Isoxazole/Thiazole/Thiadiazole Derivatives Acetazolamide, cloxacillin, flucloxacillin, oxacillin, abafungin, thiamine, cefotaxime, timolol, etc.

463

464

9 Nomenclature and Application of Heterocyclic Compounds

Drugs for Chromane Derivatives Cromoglicic acid, warfarin O

O

O

O

O

OH HO

OH

O

OH

O

O

O

O

Cromoglycic acid (asthma)

O

Warfarin (anticoagulant, blood thinner)

Drugs for Indole Derivatives Indometacin, lurasidone, melatonin, molindone, sertindole, serotonin, sumatriptan, ondansetron, oxypertine, sunitinib (anticancer), vincristine, ziprasidone H N

O N

N H

HO N H

F

NH2

O N H

Serotonin (neurotransmitter)

Sunitinib (anticancer)

Drugs for Benzimidazole Derivatives Albendazole, mebendazole, ciclobendazole H N

N

H N

O

N

H N

H N

O

Albendazole (parasitic worm infestations) O

flubendazole, O

H N

S

thiabendazole,

O O

Mebendazole (parasitic infections)

fenbendazole,

H N

N

F

O O

Flubendazole (anthelmintic)

S

H N N

H N

O O

Fenbendazole (parasitic infections)

Drugs for Xanthine Derivatives

Drugs for Indazole Derivatives Bendazac (NSAID), benzydamine (NSAID), ibrutinib (anticancer), niraparib (anticancer, breast, ovarian), pazopanib (anticancer).

O

NH2

H N

N

N

N

N N

N

N N

N N

O S O NH2 Pazopanib (kidney cancer)

O

O

Ibrutinib (anticancer)

NH2 NH

N N

Niraparib (ovarian cancer)

Drugs for Azepin/Diazepine Derivatives Carbamazepine, clomipramine (chronic pain), clonazepam, clobazam, etophylline, diazepam, nitrazepam, imipramine, carbamazepine. N N

Cl

O

N

Cl Me2N Clomipramine (chronic pain)

Diazepam (anxiety, trouble sleeping)

Drugs for Xanthine Derivatives Acyclovir (antiviral), aminophylline (asthma, COPD), azathioprine (rheumatoid arthritis, granulomatosis with polyangiitis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus), caffeine, diprophylline, etc.

465

466

9 Nomenclature and Application of Heterocyclic Compounds

HO O N

N O

N

OH

O

N

Caffeine (from coffee, stimulant of CNS)

N

N O

N

N

Diprophylline (asthma, bronchitis)

Drugs for Lactone Derivatives Spironolactone (Aldactone) (treatment for heart failure, high blood pressure, adult acne vulgaris, female hair loss, and others), erythromycin (antibacterial), ivermectin (antiparasitic), roxithromycin (antibiotic), natamycin (antibiotic), sirolimus (rapamycin) (prevents organ transplant rejection, treatment of a rare lung disease lymphangioleiomyomatosis), candicidin (treatment of vulvovaginal candidiasis), pimecrolimus (atopic dermatitis, eczema). O O H H

H

O

S O

Spironolactone (Aldactone)

Drugs for 𝛃-Lactam Derivatives Cefotiam (antibiotic), penicillin (antibiotic), flucloxacillin (antibiotic), ampicillin (antibiotic), amoxicillin (a broad-spectrum antibiotic used to treat middle ear infection, strep throat, pneumonia, skin infections, urinary tract infections, and others), piperacillin (antibiotic), nafcillin (antibiotic), oxacillin (antibiotic), hetacillin (antibiotic), cyclacillin (antibiotic), mezlocillin (antibiotic), benzylpenicillin (antibiotic), cefalotin (antibiotic), cefaclor (antibiotic), cefprozil (antibiotic), pivampicillin (antibiotic), and many more.

References

N N S

N

N

O

N

O

NH2

N

O

S

N H

H N

NH2 H N

S

OH

O

O

O

HO

O

Ampicillin

H N

O O

H N

Amoxicillin

H S

S N O

NH2

OH

H

N

O

N

Core structure of penicillin

H

O

S

O

Cefotiam NH2

H

O O

N

H N

R

HO

O OH

N O

OH

Benzylpenicillin

H S N O

O O

O

Pivampicillin (prodrug of ampicillin)

References 1 Robert, C.W. and Melvin, J.A. (1980). CRC Handbook of Chemistry and Physics.

CRC Press. 2 Quin, L.D. and Tyrell, J.A. (2010). Fundamental of Heterocyclic Chemistry.

Wiley. Kaushik, N.K., Kaushik, N., Attri, P. et al. (2013). Molecules 18: 6620. Zhang, S.-G., Liang, C.-G., and Zhang, W.-H. (2018). Molecules 23: 2783. Jena, S. (2015). Basic Study of Heterocyclic Chemistry. LP publisher. Dahm, R. (2008). Am. Sci. 96: 320. IUPAC (1979). Nomenclature of Organic Compounds. Oxford, UK: Pergamon Press. 8 Ashe, A. III, (1971). J. Am. Chem. Soc. 93: 3293. 9 Vitaku, E., Smith, D.T., and Njardarson, J.T. (2014). J. Med. Chem. 57: 10257–10274. 3 4 5 6 7

467

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions Bartoli Indole Synthesis The synthesis of indole derivatives from ortho-substituted nitroarenes or nitrosoarenes and excess vinyl Grignard reagents is known as the Bartoli indole synthesis or Bartoli reaction [1–3]. The substitution of ortho group on nitroarene is required, and bulkier substituents provide higher yields for this reaction. Possibly, the steric bulk helps in the [3,3]-sigmatropic rearrangement, which is an essential step for the product formation [4–21]. The reaction also performs on solid support [11, 18]. R2 1. R3

R3

MgBr (3 equiv.), THF

NO2 2. aq. NH4Cl

R1

1. NO2

R2

MgBr (3 equiv.), THF

2. aq. NH4Cl

1.

R1

N H

N H

MgBr (2 equiv.), THF

NO 2. aq. NH4Cl

N H

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Mechanism BrMg Step 1

O N O

R

MgBr

Step 2

R1

O

N O O MgBr

+

N

MgBr

R1 Step 3

BrMg H OMgBr

Step 5

O

N R1

R1

Step4

N MgBr

[3,3] Sigmatropic rearrangement

R1

O N MgBr

Step 6 H

H Step 8

Step 7 OMgBr N H

R1

H3O

R1

N H

OH2 R1

N H

Step 1: The Grignard reagent attacks on the nitroarene. Step 2: The intermediate spontaneously decomposes to a nitrosoarene. Step 3: Addition of second equivalent Grignard reagent on nitrosoarene forms an intermediate. Step 4: The Claisen-type [3,3]-sigmatropic rearrangement gives an aldehyde intermediate. Step 5: Intramolecular cyclization. Step 6: The third equivalent of Grignard reagent abstracts proton to restore aromaticity. Step 7: Acidic work-up gives a hydroxyl intermediate. Step 8: Protonation of hydroxyl group and subsequently elimination of water gives the desired product. Application See drugs for indole derivatives in Chapter 9. Total syntheses of (±)-cis-trikentrin A, (±)-herbindole A [12], (±)-herbindole A, (±)-herbindole B, and (±)-herbindole C [17] have been completed using this reaction. Experimental Procedure (from patent US9567339B2) Br

1.

NO2 O

OH A

Br

MgBr, THF, –50 °C

2. aq. NH4Cl

O

N H OH B

Bischler–Napieralski Reaction

To a solution of 4-bromo-2-nitrobenzoic acid (A, 30 g, 122 mmol) in anhydrous tetrahydrofuran (THF; 500 ml), a solution of vinylmagnesium bromide (51.2 ml, 512 mmol, 1 N) in THF was added dropwise at about −30 to −50 ∘ C. The reaction mixture was stirred at about −30 to −50 ∘ C for about two hours. Then the reaction mixture was poured into saturated aqueous NH4 Cl solution, and the mixture was extracted with EtOAc (200 ml × 2). The combined organic layers were washed with brine, dried over anhydrous Na2 SO4 , filtered, and concentrated under reduced pressure to provide 4-bromo-1H-indole-7-carboxylic acid (33 g crude). The crude residue was purified over silica gel chromatography (hexane/ethyl acetate) to afford a pure product (compound B).

Bischler–Napieralski Reaction The synthesis of 3,4-dihydroquinolines from β-phenylethylamides using P2 O5 or POCl3 or ZnCl2 is called the Bischler–Napieralski reaction [1]. This is an intramolecular aromatic substitution reaction discovered by August Bischler and Bernard Napieralski in 1893. This reaction is used to synthesize a variety of isoquinolines [2–36]. Pd–C

POCl3 HN

O

N

N Heat

Tolune, reflux

R

R

3,4-Dihydroisoquinoline

Isoquinoline

R

The Bischler–Napieralski reaction is generally carried out in refluxing acidic conditions and requires a dehydrating agent such as a phosphoryl chloride (POCl3 ) or P2 O5 . Other catalysts such as BF3 -etherate, SnCl4 , and polyphosphoric acid have been used for this reaction. Mechanism

HN ..

O R

O Cl P Cl Cl

Step 2

Step 1 NH – Cl

R

O O P Cl Cl

H Cl

N H O O R P Cl Cl Step 3

PO2Cl +

HCl

Step 4

+

N R

N H R O Cl

Cl

P O Cl

Step 1: Nucleophilic attacks by an amide oxygen on phosphorous atom of POCl3 and elimination of chloride. Step 2: An intramolecular electrophilic aromatic substitution reaction undergoes. Step 3: Deprotonation ensures the aromatization. Step 4: Abstraction of proton by chloride ion provides the desired isoquinoline.

471

472

10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Alternative Mechanism

N R

Cl

H

O O P Cl Cl

Step 1

Step 2

N

N

N

C R

R

H Cl

Nitrilium

R Step 3

N R

Step 1: Abstraction of proton and formation of a nitrilium. Step 2: An intramolecular aromatic electrophilic substitution reaction occurs. Step 3: Deprotonation ensures rearomatization and formation of the desired product. Application Syntheses of (−)-γ-lycorane [10], (−)-yohimbane [11], pyrimido[4,5-b][1,4] benzothiazepines [14], schulzeines B and C [15], protopine alkaloids [17], alkaloid clivonine [22], (S)-scoulerine [23], trigonoliimine B [24], (+)-antofinem, (−)-cryptopleurine [26], yohimbane [32], and Dysoxylum alkaloid [33] have been accomplished using this reaction. Experimental Procedure (from patent US6048868A) MeO HN N H

O

POCl3 Xylene, reflux

A

N

MeO N H B

To a solution of A (500 mg) in refluxing xylene was added POCl3 (1 ml) with stirring. After refluxing for five hours, the reaction medium was filtered. The solid was taken up in water, basified (KOH, 40%), and then extracted with ethyl acetate. After removal of the solvent, the residue was purified to give compound B.

Combes Quinoline Synthesis Acid-catalyzed condensation of primary aryl amines with β-diketones followed by ring closure reaction of the Schiff base intermediate leading to the formation

Combes Quinoline Synthesis

of quinoline derivatives is known as the Combes quinoline synthesis [1]. Both steric and electronic effects influence the regioselectivity on this reaction [2–11]. O + NH2

R2

O

R1

H2SO4 R2

O

Heat

N

R1

H2SO4

O

+ NH2

Heat

N

Mechanism .. O

H

H O

O

O

O

O

H

Step 3 .. NH2

Step 1

.. N

N H H O

Step 2

OH ..

H

Step 4 H

H H

OH

Step 7

O

O Step 5

Step 6 .. N H

N H

.. O

H

N

N H

Schiff base

Enamine

imine

Step 8 –H OH

N H

OH2 Step 10

Step 11

Step 9 H

.. N H

N H

N Quinoline

Step 1: Protonation of oxygen atom of the β-diketones. Step 2: Nucleophilic addition of aniline to the protonated carbonyl group. Step 3: Intramolecular proton transfer. Step 4: E2 mechanism, loss of water, deprotonation, and formation of imine (Schiff base). Step 5: The imine tautomerizes to an enamine. Step 6: Protonation via acid catalyst. Step 7: Annulation and aromatic electrophilic substitution-type reaction. Step 8: Deprotonation and rearomatization remove positive formal charge on the nitrogen atom. Step 9: Protonation of hydroxyl group.

473

474

10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Step 10: Dehydration. Step 11: Deprotonation gives a 2,4-substituted quinoline derivative. Application Quinoline and its derivatives are used in antimalarial, anticancer, and anti-inflammatory drugs, antibiotics, dyes, and flavoring agents. Experimental Procedure (from patent WO2018234184A1) O O

O

H2SO4

Acetic acid

+

N

Reflux

NH2

N

CH3CN

A

B

A mixture of β-diketone (1 equiv.) and aniline (1 equiv.) was put under reflux in acetic acid (1 equiv.) for three hours. The reaction mixture was quenched by addition of saturated solution of sodium bicarbonate (NaHCO3 ), extracted with ether, dried over anhydrous sodium sulfate (Na2 SO4 ), and concentrated in vacuo. The crude was purified by column chromatography using a mixture of AcOEt in pentane (2–98%) to provide the compound A as a colorless oil. Compound A (1 mmol) was dissolved in CH3 CN (10 ml), and H2 SO4 (0.2 ml) was added to the reaction mixture. The reaction mixture was stirred at 82 ∘ C until completion of reaction (monitored by TLC or LC-MS). The solvent was removed under reduced pressure. The residue was extracted with dichloromethane (DCM), and the organic layer was washed with saturated solution of sodium bicarbonate solution and brine, respectively. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified over silica gel using 2–5% methanol in DCM to afford product B.

Conrad–Limpach Synthesis The condensation reaction between an aniline or a primary aryl amine and a β-keto ester followed by ring closure of Schiff base intermediate leading to 4-hydroxyquinoline is known as the Conrad–Limpach synthesis [1–3]. The reaction can undergo either under thermal conditions or in the presence of an acid [4–11]. OH O +

R NH2

O

R1

Heat OR3

R2

or acid

R2 R N

R1

Conrad–Limpach Synthesis

O

OH

O

260 °C

+

OEt

NH2

N

Mechanism O

O EtO

OEt

O

EtO Step 3

Step 2

Step 1

.. NH2

O

O

EtO .. N

N H H O

N

OH ..

H

Schiff base Step 4

OEt O Step 8

H

O

Step 7

H O

O Step 6 N

N H

N H

H

– HOEt

.. OEt

H

OH Step 5

EtO

N

N

Step 9 OH

N

Step 1: The amine attack to the keto group of β-keto ester. Step 2: Intramolecular proton transfer. Step 3: Elimination of water forms the Schiff base. Step 4: Keto–enol tautomerization. Step 5: An aromatic electrophilic substitution reaction (6-π-electron electrocyclization). Step 6: Elimination of EtOH. Step 7: Proton addition from EtOH. Step 8: Proton removal by EtO− . Step 9: Keto–enol tautomerization. Application Streptonigrone [8], ellipticine analogs as anticancer agents [9], and potential antitrypanosomal agent waltherione F [11] have been synthesized using this reaction. Experimental Procedure (from patent US20120010237A1) OH

O O

Cl

O

+

OEt

NH2

MeO A

1. TsOH, benzene

B

2. DowTherm A 250 °C

Cl

Cl MeO

N H C

MeO

N

475

476

10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

A solution of 5-amino-2-chloroanisole (A, 10.0 g, 63.5 mmol), ethyl acetoacetate (B, 8.1 ml, 63.5 mmol), and catalytic para-toluenesulfonic acid (302 mg, 1.59 mmol) in 65 ml benzene over 4 Å molecular sieves was stirred for six hours at 80 ∘ C. The reaction mixture was then filtered and concentrated in vacuo. A mixture of the resulting residue and 6.4 ml DOWTHERM A was heated to 250 ∘ C for 20 minutes. The reaction mixture was cooled to room temperature, and the precipitate was washed with hexane and ethyl acetate to give 6.43 g (45% yield) of 6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (C) as a light brown solid.

Doebner–Miller Reaction The condensation of primary aryl amines with α,β-unsaturated carbonyl compounds in the presence of an acid catalyst followed by the ring closure reaction and oxidation leading to formation of a quinoline derivative is known as the Doebner–Miller reaction [1–4]. This is a variant of the Skraup quinoline synthesis, and reaction works well with Brønsted acids such as HCl and p-TsOH and Lewis acids such as ZnCl2 , SnCl4 , Sc(OTf )3 , and iodine [5–22]. The German chemists Oscar Döbner (Doebner) and Wilhelm von Miller discovered this reaction in 1881. HCl

H + O

Air oxidation

R

N H

NH2

R

N

or oxidizing agent

R

Mechanism O

H

H R

.. NH2

H

Step 8 N H

R

Step 9 Air oxidation – 2H

N

O Step 2

Step 1

R

Quinoline

N H

H N H

R

N

R

N

R

Step 7 N H

R

H

R

H H

Step 6

O

H

Step 3

H

H .. OH

OH2

OH

H

H OH

N H

step 4 O H

H

R Step 5

.. N H

R

Feist–Benary Synthesis of Furan

Step 1: Conjugate addition Step 2: Proton transfer Step 3: Tautomerization Step 4: Protonation Step 5: Ring closure (aromatic electrophilic substitution reaction) Step 6: Deprotonation and rearomatization Step 7: Protonation Step 8: Deprotonation and elimination of water Step 9: Oxidation Application The classical and economical Doebner–Miller reaction has been used as a key step for the synthesis of actinophenathroline A [15, 20] and ammosamide B [22].

Feist–Benary Synthesis of Furan The synthesis of furans from α-haloketones and β-keto esters in the presence of pyridine is referred to as the Feist–Benary reaction [1, 2]. Asymmetric version of this reaction also known as interrupted Feist–Benary reaction has gained current interest [3–19].

O

O OEt

CO2Et

Pyridine

O Cl

+

O

Mechanism

..N O O

O

Step 1

O

O

H N

+

O

O

Step 2

OEt

O O

H

Cl

Cl

O OEt

OEt

OEt

H

Step 3

OH H N

Cl

.. N

Step 4 N H CO2Et O

Step 7

H 2O

.. N

H

.. HO

CO2Et

CO2Et O

Step 6

OH

Cl

CO2Et H

O

Step 5

O

477

478

10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Step 1: Deprotonation Step 2: Nucleophilic addition Step 3: Proton transfer Step 4: Enolate formation Step 5: Nucleophilic substitution reaction and ring closing Step 6: Protonation of hydroxyl group Step 7: Elimination of water and formation of furan derivative Application Total syntheses of (−)-variabilin [12] and tanshinone I [18] have been accomplished using this reaction. Experimental Procedure (from patent CN106243072A) O

O O O

Br

EtO

100 °C

+ O

O

O

O No catalyst

C

B

A

To a 50 ml round-bottom flask, 3-ethyl bromopyruvate (A, 10 mmol) and 1,3-pentanedione (B, 5 mmol) were added. It was heated with stirring at 100 ∘ C, and the mixture became a uniform liquid. The reaction was monitored by TLC. After completion of the reaction, the residue was purified by silica gel column chromatography to give a yellow oil furan derivative (compound C) in 81% yield.

Fischer Indole Synthesis The Fischer indole synthesis is a conversion of a phenylhydrazine and an aldehyde or ketone to an indole using an acid catalyst (acetic acid or sulfuric acid or Lewis acid such as ZnCl2 ) under thermal conditions [1, 2]. The reaction is named after its discoverer Emil Fischer in 1883. Several new catalysts have been employed on this reaction [3–34]. R2 N H

NH2

+

Phenylhydrazine

R1

R1

R2 O

Aldehyde or ketone

N H

R2 Acid

N

Phenylhydrazone

Heat

N H

R1

Indole

Fischer Indole Synthesis

Mechanism R2 Step 1

N H

N H

.. NH2

R2 R1 O

Step 2

NH H

N H

R1 .. OH

N H

R2

H

Step 3

Step 4

O

H

[3 + 3]

NH

N H

Step 7

NH2

H

R1

R1

R2

R2

R2 R2

N H

N H

R1

R2

R1 OH2

NH2

N H

Step 6

R1

Step 5

R1

N H

NH

N

H Step 8 R2 .. NH2

R1

H R2

R2

Step 9

Step 10

R1

NH2

N H H

NH .. 2

N H

R2 Step 11

R1 NH3

N H

– NH3

R1

Indole

Step 1: Nucleophilic attacks by the hydrazine to the electron-deficient carbonyl carbon atom. Step 2: Proton transfer. Step 3: Protonation of the hydroxyl group making a better leaving group. Step 4: Elimination of water forms a phenylhydrazine derivative. Step 5: Tautomerization or rearrangement. Step 6: Protonation. Step 7: [3+3]-Sigmatropic rearrangement. Step 8: Rearomatization. Step 9: Nucleophilic attacks by the amine to the imine and ring closing. Step 10: Proton transfer. Step 11: Elimination of ammonia and formation of indole derivative.

Application This type of reaction is used for the preparation of indomethacin (nonsteroidal anti-inflammatory drug), triptan, iprindole, eletriptan (treatment for the depression), and other medicines. O S O

+ N H

NH2

H N Me

O

Acid Fisher indole synthesis conditions

O S O

N Me N H Eletriptan

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Experimental Procedure (General) Synthesis of 2-phenylindole (step 2) H3C

EtOH N H

NH2

+ O

A

PPA

AcOH, heat CH3

N H

N N H

50 °C

C

D

2-Phenylindole

B

Polyphosphoric acid (2 g) was taken into a container and heated at 50 ∘ C. Acetophenone phenylhydrazone (compound C, 210 mg) was added to the solution in portion with constant stirring. After completion of the addition, the reaction mixture was stirred at 50 ∘ C for an additional 30 minutes. The reaction mixture was cooled down to room temperature, and ice was added with stirring. The precipitation formed was filtered and was washed with cold methanol. The crude solid was recrystallized from ethanol/water to give the pure product (compound D, 2-phenylindole).

Friedländer Synthesis or Annulation The Friedländer synthesis is a condensation reaction of 2-amino aryl carbonyl compounds with ketones in the presence of acid or base to form quinoline derivatives [1, 2]. It was discovered by German chemist Paul Friedländer. This reaction is one of the most simple and straightforward acid- or base-catalyzed methods for the preparation of the polysubstituted quinolines [3–32]. Several Lewis acids have been used for this reaction including ZnCl2 , Bi(OTF)3 , Sc(OTf )3 , and Y(OTf )3 as well as other catalysts such as NaF, molecular iodine, TFA, p-TsOH, etc. R

O R NH2

+ R 1

R2

OH

O R2

Ethanol

N

R1

Friedländer Synthesis or Annulation

Mechanism O O

O

Step 1 R2

R1

Step 2

R1

Step 3

O NH2 R1

R2

– H2O

H

HO R R 2

R R2 H O NH2 R1

O

OH

Step 4 R

OH

NH2

R2

R R2 N

R

R Step 6

R1

R2

Step 5

O .. NH2R1

OH N R1 H OH

Step 1: Proton abstraction by the hydroxide ion forms an enolate. Step 2: Enolate attacks to another carbonyl compound (aldol condensation). Step 3: Proton transfer. Step 4: Elimination of water. Step 5: Nucleophilic attacks by the lone pair of amine (ring closure). Step 6: Elimination of water gives the substituted quinoline. Application Camptothecin, an anticancer drug, has been synthesized using this reaction. Experimental Procedure (General) Synthesis of ethyl 2-methyl-4-phenylquinoline-3-carboxylate Ph O O

Catalyst

O

Ph +

O

CH3CN

O O

N

NH2

A mixture of 2-aminobenzophenone (1 mmol), ethyl acetoacetate (1.3 mmol), and a catalyst [Sc(OTf )3 or select other catalyst] in acetonitrile was stirred at room temperature or 60 ∘ C. After completion of reaction (TLC monitored),

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

solvent was removed; then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified over silica gel column chromatography (hexanes/ethyl acetate) to afford the desired product.

Knorr Pyrrole Synthesis Condensation between α-aminoketones and β-keto esters in the presence of an acid leading to pyrrole derivatives is known as the Knorr pyrrole synthesis [1–3]. Several new types of catalysts have been employed on this reaction [4–54]. O R1

O

R2

NH2

+ O

CO2Et

R1

OET

R2

R3

N H

R3

Mechanism CO2Et

CO2Et O ..

R3

O H

Step 1

R3

R1

EtO2C

O

.. H2N

Step 2

R2

R3 HO ..

R1 N H H

O Step 3

EtO2C R3 H2O

R2

H

R1 .. N H

O R2

Step 4 EtO2C H R1 R3

N H

OH R2

R3

Step 8 EtO2C R3

R2

N H

Step 6

EtO2C R3

R1 .. N H

O R2

Step 5

EtO2C R3

R1

EtO2C H R2

O

Enamine

R1 N H

R1

Step 7 EtO C 2

Step 9 R3

N H

R2

Step 1: Protonation Step 2: Nucleophilic addition Step 3: Proton transfer Step 4: Elimination of water and formation of imine after deprotonation Step 5: Tautomerization to enamine Step 6: Ring closing Step 7: Proton transfer Step 8: Elimination of water Step 9: Deprotonation and formation of pyrrole derivative

R1 N Imine

O R2

Madelung Indole Synthesis

Application Roseophilin [12, 20], (±)-funebrine, (±)-funebral [14], streptorubin B [29], marinopyrrole B [35], marineosin A [38, 45], and atorvastatin derivatives [49] have been synthesized utilizing this reaction.

Madelung Indole Synthesis The intramolecular cyclization (condensation) of 2-(acylamino)-toluenes using strong base such as NaNH2 , or EtONa, or n-BuLi to the corresponding indole derivatives is called the Madelung indole synthesis [1] named after Walter Madelung who discovered this reaction in 1912. Several modifications on this reaction have been investigated [2–14]. NaNH2 or EtONa

O N H

R

N H

n-BuLi

O N H

R

>250 °C

R

R

r.t.

N H

EtONa

O

Ph N H

Ph 360 °C

N H

2-Phenyl-1 H-indole

Mechanism n-Bu H

H Step 1

O N H

R

Step 2

O N

R

O N

R

Acidic work-up Step 3

n-Bu

Step 1: Deprotonation with n-BuLi Step 2: Intramolecular cyclization Step 3: Proton transfer from acid Step 4: Protonation and elimination of water

OH H N H

R Step 4

R N H

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Application Total syntheses of (−)-scholarisine G, (+)-melodinine E, and (−)-leuconoxine [13] have been accomplished using this reaction. Experimental Procedure (General) NaOEt

O N H

N H

360 °C

A

B

A mixture of A (1 equiv.) and NaOEt (3 equiv.) was heated at 360 ∘ C. After cooling to room temperature, 1 N HCl was added to the reaction mixture followed by extraction with DCM. The organic layer was washed with brine and water. The organic layer was dried (MgSO4 ) and concentrated. The residue was purified over silica gel using 20–40% ethyl acetate in hexane to afford a pure product B. This method requires harsh condition and high temperature. The modified Madelung method used butyllithium as a base, and it worked at low temperature.

Paal–Knorr Furan Synthesis The acid-catalyzed cyclization of 1,4-dicarbonyl compounds to furans is called the Paal–Knorr furan synthesis [1, 2]. In 1884 the Austrian chemist Carl Paal and the German chemist Ludwig Knorr independently reported this reaction. This is a versatile reaction, and all dicarbonyls can be converted to the corresponding heterocycles [3–17].

R4

R1 O

O

R3

R2

R3

R2

Acid catalyst

R1

O

or dehydrating agent

H2SO4

Ph

O

O R

– H2O

O

O

P4S10

O

Ph

R

S

R

R Thiophene derivative

R4

Paal–Knorr Pyrrole Synthesis

Mechanism H H O

O ..

H

Step 2

Step 1

O H

Step 3

O OH ..

O

+H

.. O O H H

Step 4 O – H2O Step 5

H

H

–H

O

Step 1: Protonation. Step 2: Ring closure with mono enol. Step 3: Proton transfer. Step 4: Elimination of water. Step 5: Deprotonation ensures aromatization. Experimental Procedure (General) p-TsOH O

O Benzene, reflux

O B

A

A mixture of A (5 mmol) and p-TsOH (1 mmol) in benzene (25 ml) was stirred at 80 ∘ C until completion of the reaction (TLC). Benzene was removed under reduced pressure. The residue was extracted with ethyl acetate (100 ml), and the organic layer was washed with sodium bicarbonate solution, water, and brine, respectively. The organic layer was dried (MgSO4 ) and concentrated in vacuo. The residue was purified over silica gel (hexane/ethyl acetate) to afford compound B.

Paal–Knorr Pyrrole Synthesis The Paal–Knorr pyrrole synthesis is the condensation reaction between 1,4-diketones and primary amines or ammonia in the presence of an acid catalyst to give pyrroles [1, 2]. Several substituted pyrrole derivatives have been synthesized using this reaction [3–31]. R2

R1 O

O

or NH4OAc/AcOH R2

R1 O

O

Ammonia R1

N H

R1

N R

R2

R-NH2 Acid

R2

485

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Ammonia

Ph O

O

Ph

N H

Mechanism Step 4

O

O

O

Step 3

Step 2

Step 1

R

.. R NH2

HO

O

NH2

R

NH ..

.. NH

O N

O

O

R

R

Enamine

Imine

step5 H

Step 8 N R

N R

H O H

+H Step 7

N R

H .. OH

Step 6 H

N R

O

Step 1: Nucleophilic attacks by the lone pair electrons of primary amine to the carbonyl carbon atom. Step 2: Proton transfer. Step 3: Elimination of water forms an imine. Step 4: Imine–enamine tautomerization. Step 5: Ring closing. Step 6: Proton transfer. Step 7: Protonation. Step 8: Elimination of water gives the desired pyrrole derivative. Application Atorvastatin (Lipitor), a statin medication used to prevent cardiovascular disease and treat abnormal lipid levels, has been synthesized using this reaction. F

OH OH O N

H N O

(R)

(R)

OH

Atorvastatin (Lipitor)

Total syntheses of (±)-funebrine, (±)-funebral [8], roseophilin [18], and marinopyrroles A–F [21] have been completed using this reaction conditions.

Pictet–Gams Isoquinoline Synthesis

Experimental Procedure (an intermediate for Atorvastatin, from patent WO2009023260A2) F

O

H N

O O

O

+

O

O

H2N

O B

A

Pivalic acid Toluene, 100 °C F

O N

H N O

O

O O

C

A four-neck flask equipped with a condenser, thermometer pocket, drying tube, and mechanical stirrer was charged with toluene (250 ml), 4-fluoro-α-[2-methyl-l-oxopropyl]-γ-oxo-N,β-diphenylbenzene butanamide (1,4-diketone A) (25 g, 0.0599 mol), and compound B (21.29 g, 0.0779 mol). The mass was refluxed for 60–90 minutes, followed by stirring at mass temperature of about 90–100 ∘ C. Pivalic acid (2.45 g, 0.0239 mol) was added, and the reaction mixture was refluxed, and the water generated in the reaction was removed azeotropically. Reaction mass was maintained at its reflux for 30 hours. Then after mass temperature was brought down to 25–30 ∘ C, this was followed by washing with sufficient amount of aqueous sodium chloride, aqueous sodium bicarbonate, and aqueous sodium chloride solution. The solvent was stripped off under reduced pressure, and the residue obtained was crystallized from an ethanol–water mixture, filtered, and dried to get 18 g (45.92% yield) of a solid C, with high-performance liquid chromatography (HPLC) purity of 98.38%.

Pictet–Gams Isoquinoline Synthesis The synthesis of isoquinoline from a β-hydroxy-β-phenethylamide with a strong dehydrating agent such as P2 O5 or POCl3 is referred to as the Pictet–Gams

487

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

isoquinoline synthesis [1]. Several modifications on this reaction have been reported [2–8]. OH P2O5 HN

N

O R

R

Mechanism

.. NH R

OH

OH

OH

O

Step 1

Step 2 N

O O P O P O O

R

H O

H

O P O O

O

OPO2 H

Step 6

H .. O

N

N R

O P O

R

O O P O P O O Step 4 N

Step 5 R

NH O O R P O O

P O

Step 3

OH .. NH O O R P O

Step 1: Nucleophilic addition-type reaction. Step 2: Aromatic electrophilic ring closure reaction. Step 3: Deprotonation restores aromaticity. Step 4: Elimination of PO3 − . Step 5: Formation of a better leaving group. Step 6: Deprotonation, elimination of PO3 − , and formation of an isoquinoline. Application Isoquinolines have many applications such as anesthetic agent dimethisoquin; antihypertension agents such as quinapril, quinapirilat, and debrisoquine; and antifungal agents such as 2,2′ -hexadecamethylenediisoquinolinium dichloride. Isoquinolines are used in dyes, paints, insecticides, and others.

Pictet–Spengler Reaction The condensation of β-arylethylamines and carbonyl compounds followed by ring closure in the presence of an acid catalyst to form 1,2,3,4-tetrahydroquinolines

Pictet–Spengler Reaction

is known as Pictet–Spengler tetrahydroquinoline synthesis [1]. Aldehydes react with amines faster than ketones to form the imines. Brønsted acids, Lewis acids, chiral catalyst, and enzyme catalysts have been employed on this reaction [2–59].

O +

NH2

HCl NH

R2

R1

R 1 R2

O NH2

+

R1

HCl NH

H R1

Mechanism .. O R1

O H

H H

R1 O H

..NH2

H

Step 1

R1

Cl Step 2

H

H H

N

Step 4 OH

Step 3 HN

R1

HN ..

OH .. R1

OH2

R1 H Step 5

Step 7

Step 6

NH

NH H

R1

R1

N H R1

Cl

Step 1: Protonation of a carbonyl oxygen atom. Step 2: Amine attacks to the electron-deficient carbonyl carbon atom. Step 3: Deprotonation. Step 4: Protonation of hydroxyl group. Step 5: Elimination of water and formation of iminium ion. Step 6: Ring closure by aromatic electrophilic substitution reaction with the loss of aromaticity. Step 7: Deprotonation restores aromaticity and provides the desired product.

489

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Application Tadalafil (Cialis), a medicine for the treatment of erectile dysfunction, was synthesized using this reaction. O OMe O OMe N H

NH2

+

NH

CF3CO2H

O H

O

N H

CH2Cl2

O Pictet–Spengler reaction

D-Tryptophan methyl ester

O

O O Cl

Cl

NaHCO3 Me

O

O

N

OMe N

O

CH3NH2

O

N Cl

N H

CH3OH O

N H

O O

O

Tadalafil

Several natural products including (±)-lycopodine [3], (−)-(S)-brevicolline [4], (+)-vellosimine [318], (−)-eburnamonine, (+)-epi-eburnamonine [327], (−)-lemonomycin [332], (−)-jorumycin [335], (−)-eudistomin C [336], (+)-peganumine A [347], and (−)-jorunnamycin A [351] have been synthesized using this reaction as a key step. Experimental Procedure (from patent CN107552089A) O

F3C

O

HN

F3C

N

MeO N H N H A

H

Ph

O

+

N Chiral catalyst Toluene, 100 °C

B

C N N H D

Skraup Quinoline Synthesis

A mixture of the amide derivative cinchona alkaloid catalyst (compound C, 0.5 mmol), benzyltryptamine (compound A, 1.25 g, 5 mmol), and benzaldehyde (B, 0.8 g, 7.5 mmol) in toluene (5 ml) was stirred at 100 ∘ C for six hours. The reaction mixture was concentrated under reduced pressure. The residue was purified over silica gel column chromatography using 2–10% methanol in DCM to afford (S)-2-benzyl1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (compound D) 1.58 g as a white solid, yield 94%, ee 89%.

Skraup Quinoline Synthesis The synthesis of quinoline from a mixture of aniline, glycerol, sulfuric acid, nitrobenzene, and ferrous sulfate under thermal conditions is called the Skraup quinoline synthesis [1]. Nitrobenzene serves as a solvent and an oxidizing agent. The presence of ferrous sulfate makes this reaction less violent. The reaction is named after the Czech chemist Zdenko Hans Skraup. Several substituted quinoline derivatives have been synthesized using this reaction [2–30].

+

HO

NH2

OH

H2SO4, FeSO4

OH

N

PhNO2, heat

Mechanism H

H H HO

OH ..OH

HO Step 1

OH OH2

HO

OH

.. HO

O H

Step 2 Step 3 H

H

O Step 4 H O

H2O

H H

Formation of acraldehyde (acrolein) by protonation and dehydration of glycerol

491

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10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

H .. O

O .. NH2

O

H

H

HO Step 6

Step 5 N H

N H

H

N H H

Step 7 H .. OH

OH2

H Step 9

H Step 10 N H

OH

N H

N H

H

OH Step 8

.. N H

Step 11

Step 12 N H

N

PhNO2 – H2

Step 1: Protonation. Step 2: Dehydration. Step 3: Protonation. Step 4: Dehydration and formation of an acraldehyde (acrolein). Step 5: Conjugate addition, i.e. Michael-type addition reaction. Step 6: Proton transfer. Step 7: Protonation. Step 8: Intramolecular electrophilic addition (Friedel–Crafts-type ring closing reaction). Step 9: Rearomatization. Step 10: Protonation of the alcohol. Step 11: Elimination of water. Step 12: Oxidation by PhNO2 gives the final product. Experimental Procedure (from patent WO2011022928A1) NO2

NO2 + HO F3C

NH2 A

OH OH

H2SO4 As2O5, 180 °C

B

N

F3C C

Preparation of 7-Trifluoromethyl-5-nitroquinoline

3-Nitro-5-aminobenzotrifluoride (compound A, 7.5 g), glycerol (B, 1.3 g), and arsenic pentoxide (6.8 g) were added to the reaction flask. After stirring

Bartoli Indole Synthesis

until evenly mixed, concentrated sulfuric acid (8 g) was slowly added, and the reaction was carried out at 130 ∘ C for one hour, and then the temperature was raised to 180 ∘ C for four hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then made alkaline with 4 mol/l sodium hydroxide solution. The solid was filtered off, mixed into ethanol, and decolorized with activated carbon, and the solvent was distilled off to yield the final product 7-trifluoromethyl-5-nitroquinoline (compound C, 1.7 g, 15%).

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6034–6038. Polossek, T., Ambros, R., von Angerer, S. et al. (1992). J. Med. Chem. 35: 3537–3547. Sotomayor, N., Domínguez, E., and Lete, E. (1996). J. Org. Chem. 61: 4062–4072. Banwell, M.G., Harvey, J.E., Hockless, D.C., and Wu, A.W. (2000). J. Org. Chem. 65: 4241–4250. Bergmeier, S.C. and Seth, P.P. (1999). J. Org. Chem. 64: 3237–3243. Ishikawa, T., Shimooka, K., Narioka, T. et al. (2000). J. Org. Chem. 65: 9143. Bungard, C.J. and Morris, J.C. (2002). Org. Lett. 4: 631–633. Fu, R., Xu, X., Dang, Q., and Bai, X. (2005). J. Org. Chem. 70: 10810–10816. Gurjar, M.K., Pramanik, C., Bhattasali, D. et al. (2007). J. Org. Chem. 72: 6591–6594. Xu, X., Guo, S., Dang, Q. et al. (2007). J. Comb. Chem. 9: 773–782. Wada, Y., Kaga, H., Uchiito, S. et al. (2007). J. Org. Chem. 72: 7301–7306. Liermann, J.C. and Opatz, T. (2008). J. Org. Chem. 73: 4526–4531. Kuo, C.Y., Wu, M.J., and Lin, C.C. (2010). Eur. J. Med. Chem. 45: 55–62. Awuah, E. and Capretta, A. (2010). J. Org. Chem. 75: 5627–5634. Movassaghi, M. and Hill, M.D. (2008). Org. Lett. 10: 3485–3488. Haning, H., Giró-Mañas, C., Paddock, V.L. et al. (2011). Org. Biomol. Chem. 9: 2809–2820. Schrittwieser, J.H., Resch, V., Wallner, S. et al. (2011). J. Org. Chem. 76: 6703–6714. Buyck, T., Wang, Q., and Zhu, J. (2012). Org. Lett. 14: 1338–1341. Medley, J.W. and Movassaghi, M. (2013). Org. Lett. 15: 3614–3617. Ying, W. and Herndon, J.W. (2013). Eur. J. Org. Chem. 3112–3122. White, K.L., Mewald, M., and Movassaghi, M. (2015). J. Org. Chem. 80: 7403–7411. Huang, P.Q., Huang, Y.H., and Xiao, K.J. (2016). J. Org. Chem. 81: 9020–9027. Amer, M.M., Carrasco, A.C., Leonard, D.J. et al. (2018). Org. Lett. 20: 7977–7981. Han, Y., Hu, Z., Liu, M. et al. (2019). J. Org. Chem. 84: 3953–3959.

Conrad–Limpach Synthesis

31 Abas, H., Amer, M.M., Olaizola, O., and Clayden, J. (2019). Org. Lett. 21:

1908–1911. 32 Kao, H.K., Lin, X.J., Hong, B.C. et al. (2019). J. Org. Chem. 84: 12138–12147. 33 Puerto Galvis, C.E. and Kouznetsov, V.V. (2019). J. Org. Chem. 84:

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Paal, C. (1884). Ber. Dtsch. Chem. Ges. 17: 2756. Knorr, L. (1884). Ber. Dtsch. Chem. Ges. 17: 2863. Amarnath, V. and Amarnath, K. (1995). J. Org. Chem. 60: 301. Amarnath, V., Amarnath, K., Valentine, W.M. et al. (1995). Chem. Res. Toxicol. 2: 234. Khanna, I.K., Weier, R.M., Yu, Y. et al. (1997). J. Med. Chem. 40: 1619–1633. Haubmann, C., Hübner, H., and Gmeiner, P. (1999). Bioorg. Med. Chem. Lett. 9: 3143–3146. Braun, R.U., Zeitler, K., and Müller, T.J. (2001). Org. Lett. 3: 3297–3300. Dong, Y., Niranjan, N., Pai, N. et al. (1999). J. Org. Chem. 64: 2657–2666. Görlitzer, K., Fabian, J., Frohberg, P., and Drutkowski, G. (2002). Pharmazie 57: 243–249. Banik, B.K., Samajdar, S., and Banik, I. (2004). J. Org. Chem. 69: 213–236. Bharadwaj, A.R. and Scheidt, K.A. (2004). Org. Lett. 6: 2465–2468. Demirayak, S., Karaburun, A.C., and Beis, R. (2004). Eur. J. Med. Chem. 39: 1089–1095. Veitch, G.E., Bridgwood, K.L., Rands-Trevor, K., and Ley, S.V. (2008). Synlett 2597. Rao, H.S.P., Jothilingam, S., and Scheeren, H.W. (2004). Tetrahedron 60: 1625. Minetto, G., Raveglia, L.F., and Taddei, M. (2004). Org. Lett. 6: 389–392.

Pictet–Spengler Reaction

16 Bharadwaj, A.R. and Scheidt, K.A. (2004). Org. Lett. 6: 2465. 17 Brummond, K.M., Curran, D.P., Mitasev, B., and Fischer, S. (2005). J. Org. 18 19 20 21 22 23 24 25 26 27 28 29 30 31

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Pictet–Gams Isoquinoline Synthesis 1 2 3 4 5 6 7 8

Pictet, A. and Gams, A. (1910). Ber. Dtsch. Chem. Ges. 43: 2384. Herz, W. and Tsai, L. (1955). J. Am. Chem. Soc. 77: 3529. Whaley, W.M. and Govindachari, T.R. (1951). Org. React. 6: 151. Fitton, A.O., Frost, J.R., Zakaria, M.M., and Andrew, G. (1973). J. Chem. Soc., Chem. Commun. 889–890. Kulkarni, S.N. and Nargund, K.S. (1967). Indian J. Chem., Sect B 5: 294. Poszavacz, L. and Simig, G. (2001). Tetrahedron 57: 8573. Blair, A., Stevenson, L., and Sutherland, A. (2012). Tetrahedron Lett. 53: 4084–4086. Li, J.J. (2014). Pictet–Gams isoquinoline synthesis. In: Name Reactions. Springer.

Pictet–Spengler Reaction 1 Pictet, A. and Spengler, T. (1911). Ber. Dtsch. Chem. Ges. 44: 2030–2036. 2 Whaley, W.M. and Govindachari, T.R. (1951). Org. React. 6: 151–190. 3 Padwa, A., Brodney, M.A., Marino, J.P. Jr.,, and Sheehan, S.M. (1997). J. Org.

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Skraup Quinoline Synthesis

37 Piemontesi, C., Wang, Q., and Zhu, J. (2016). J. Am. Chem. Soc. 138:

11148–11151. 38 Gao, K., Fukui, N., Jung, S.I. et al. (2016). Angew. Chem. Int. Ed. 55:

13038–13042. 39 Lichman, B.R., Zhao, J., Hailes, H.C., and Ward, J.M. (2017). Nat. Commun. 8:

14883. 40 Wani, I.A., Das, S., Mondal, S., and Ghorai, M.K. (2018). J. Org. Chem. 83:

14553–14567. 41 Welin, E.R., Ngamnithiporn, A., Klatte, M. et al. (2019). Science 363: 270–275. 42 Sheng, X. and Himo, F. (2019). J. Am. Chem. Soc. 141: 11230–11238. 43 Glinsky-Olivier, N., Yang, S., Retailleau, P. et al. (2019). Org. Lett. 21:

9446–9451. 44 Baumann, M. (2011). Beilstein J. Org. Chem. 7: 442–495. 45 Stockigt, J., Antonchick, A.P., Wu, F., and Waldmann, H. (2011). Angew.

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Skraup Quinoline Synthesis 1 2 3 4 5

Skraup, Z.H. (1880). Ber. Dtsch. Chem. Ges. 13: 2086–2087. Manske, R.H.F. (1942). Chem. Rev. 30: 113–144. Bradford, L., Elliott, T.J., and Rowe, F.M. (1947). J. Chem. Soc. 437–445. Yale, H.L. (1947). J. Am. Chem. Soc. 69: 1230. Yale, H.L. and Bernstein, J. (1948). J. Am. Chem. Soc. 70: 254.

505

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6 Hamaguchi, F., Kato, T., and Oiwa, T. (1956). Pharm. Bull. 4: 178–181. 7 Dufour, M., Buu-Hoi, N.P., and Jacquignon, P. (1967). J. Chem. Soc., Perkin

Trans. 1 1415–1416. 8 Manske, R.H.F. and Kulka, M. (1953). Org. React. 7: 59–98. 9 Buu-Hoi, N.P. and Jacquignon, P. (1968). J. Chem. Soc., Perkin Trans. 1

2070–2072. 10 Warner, V.D., Musto, J.D., Turesky, S.S., and Soloway, B. (1975). J. Pharm. Sci. 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

64: 1563. Eisch, J.J. and Dluzniewski, T. (1989). J. Org. Chem. 54: 1269–1274. Sami, I., Kar, G., and Ray, J. (1992). Tetrahedron 48: 5199–5208. Fujiwara, H. and Kitagawa, K. (2000). Heterocycles 53: 409. Boger, D.L. and Boyce, C.W. (2000). J. Org. Chem. 65: 4088–4100. Pomeranc, D., Heitz, V., Chambron, J.C., and Sauvage, J.P. (2001). J. Am. Chem. Soc. 123: 12215–12221. Choi, H.Y., Kim, D.W., Chi, D.Y. et al. (2002). J. Org. Chem. 67: 5390–5393. Theoclitou, M.-E. and Robinson, L.A. (2002). Tetrahedron Lett. 43: 3907–3910. Ku, Y.Y., Grieme, T., Raje, P. et al. (2003). J. Org. Chem. 68: 3238–3240. Denmark, S.E. and Venkatraman, S. (2006). J. Org. Chem. 71: 1668. Qi, S., Shi, K., Gao, H. et al. (2007). Molecules 12: 988–996. Wu, Y.C., Liu, L., Li, H.J. et al. (2006). J. Org. Chem. 71: 6592–6595. Horn, J., Marsden, S.P., Nelson, A. et al. (2008). Org. Lett. 10: 4117–4120. Milbank, J.B., Stevenson, R.J., Ware, D.C. et al. (2009). J. Med. Chem. 52: 6822. Fotie, J., Kemami Wangun, H.V., Fronczek, F.R. et al. (2012). J. Org. Chem. 77: 2784–2790. Fotie, J., Kemami Wangun, H.V., Dreux, K. et al. (2012). Magn. Reson. Chem. 50: 68–73. Praveena, K.S., Durgadas, S., Suresh Babu, N. et al. (2014). Bioorg. Chem. 53: 8–14. Ullah, M.A., Adeel, M., Tahir, M.N. et al. (2017). Med. Chem. 13: 780–786. Yang, G., Li, G., Huang, J. et al. (2017). Org. Biomol. Chem. 15: 10167–10171. AlMarzouq, D.S. and Elnagdi, N.M.H. (2019). Molecules 24: E1806. Ramann, G.A. and Cowen, B.J. (2016). Molecules 21: E986. (review).

507

11 Protection and Deprotection of Common Functional Groups Each reaction first step is the protection and second step is the deprotection as shown below.

Amines Protection and deprotection of amino functional group are key steps in organic synthesis [1–5]. tert-Butyloxycarbonyl (Boc) O

TFA

(Boc)2O, DMAP, DIEA

R NH2

R N H

CH3CN

O

CH2Cl2

R NH2

O

H N

TFA

H N

CH2Cl2 (1 : 1)

I

O

(Boc)2O

N

N

N

N

DIEA, CH3CN I

I

2-(Trimethylsilyl)ethoxymethyl (SEM) O H N

NaH, SEM-Cl

SiMe3

N N

N

TBAF

H N N

THF, reflux

DMF

I

I

Carbobenzyloxy/Carboxybenzyl/Benzyloxycarbonyl (Cbz or Z) O O Ph R NH2

O

Cl

Na2CO3, dioxane

R N H

O

Ph

H2, Pd/C, MeOH or Et3SiH

R NH2

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

508

11 Protection and Deprotection of Common Functional Groups

9-Fluorenylmethyloxycarbonyl (Fmoc) O O

Cl

O R NH2

R N H

NaHCO3, dioxane

20% piperidine in DMF

O

R NH2

Allyloxycarbonyl (Alloc) O

Cl O

R NH2

R

H N

Pd(Ph3P)4

O O

Pyridine

R NH2

AcOH

Benzyl (Bn) Br R

R NH2

H2,Pd/C

H N

MeOH

R NH2

K2CO3, DMF

p-Methoxybenzyl (PMB) Br MeO R NH2

OMe

K2CO3, DMF

R

(CH3CO)2O

H N

H N

H2,Pd/C MeOH

R NH2

Acetyl (Ac) R NH2

R

HCl Reflux

DIEA, THF, or DMF

R NH2

O

O Cl R NH2

R

H N

HCl Reflux

DIEA, DMF

R NH2

O

Trifluoroacetyl (CF3CO)2O R NH2

Pyridine, DCM

R

H N

CF3 O

NaOMe, MeOH or K2CO3, MeOH, H2O

R NH2

Alcohols

Tosyl (Ts) H O N R S O

Ts-Cl

R NH2

DIEA,DCM

HBr

R NH2

AcOH, heat

Trityl (Trt) R NH2

Ph

Trt-Cl

R

DIEA, DCM

N H

5% TFA

Ph

R NH2

DCM

Ph

2,2,2-Tricholoethoxycarbonyl (Troc) Cl Cl

Cl O

Cl O

R NH2

R

Pyridine or aqueous NaOH

Cl

H N

O

Cl Cl

Zn

R NH2

O

Methyl Carbamate O Cl R NH2

O R

DIEA, DMAP, CH2Cl2

H N

O

TMSI, CH2Cl2

R NH2

or HBr, acetic acid

O

Formamide O H R NH2

O R

DIEA

H N

H O

HCl, MeOH, H2O

R NH2

or NaOH, MeOH

Alcohols Selective protection and deprotection of hydroxyl group are the essential steps for the synthesis of complex molecules [1–7]. Methyl Ether NaH, MeI, THF R1 OH

or Me2SO4, NaOH, THF

R1

O

TMS-I, CH2Cl2 or BBr3, CH2Cl2

R1 OH

509

510

11 Protection and Deprotection of Common Functional Groups

Methoxymethyl (MOM) Ether O

Cl R1

R1 OH

O

O

HCl, MeOH

R1 OH

or TFA, DCM

NaH, THF or DIEA, THF

2-Methoxyethoxymethyl (MEM) Ether O R1 OH

O

Cl R1 O

NaH, THF or DIEA, DCM

ZnBr2, DCM

O

O

or FeCl3 or TFA, DCM

R1 OH

Benzyloxymethyl (BOM) Ether R1 OH

Ph

O

Cl

R1

DIEA, Bu4NI

O

O

Na, NH3, EtOH

Ph

R1 OH

or PhSH, BF3·Et2O DCM

Tetrahydropyranyl (THP) Ether AcOH, THF R1 OH

O O

TsOH, DCM or Ph3P, DEAD, THF

O

R1 OH

R1 or PPTS, EtOH

Benzyl (Bn) Ether I R1 OH

K2CO3, THF or NaH, THF

R1

O

H2, Pd/C

R1 OH

EtOH

tert-Butyl (t-Bu) Ether This group is stable in basic conditions and frequently used in peptide synthesis.

R1 O

R1 OH

TFA or HBr, AcOH

BF3·OEt2, H3PO4

R1 OH

Silyl Ether Trimethylsilyl (TMS) Ether R1 OH

Me3SiCl DIEA, THF

R1

O

Bu4NF, THF SiMe3

or K2CO3, dry MeOH

R1 OH

Alcohols

Triisopropylsilyl (TIPS) Ether

Si Cl

R1 OH

R1 Imidazole, DCM, or DMF

O

Bu4NF, THF

Si

R1 OH

or HCl, EtOH

tert-Butyldimethylsilyl (TBS or TBDMS) Si Cl Bu4NF, THF

R1 O Si

R1 OH

R1 OH

or AcOH, THF, H2O

Imidazole, DCM, or DMF

tert-Butyldiphenylsilyl (TBDPS) Ph Si Cl Ph R1 OH

Imidazole, DCM, or DMF

Ph R1 O Si Ph

Bu4NF THF

R1 OH

2-(Trimethylsilyl)ethoxymethyl (SEM) Ether Si R1 OH

O

Cl

DIEA, DCM

R1

O

O

SiMe3

Bu4NF

R1 OH

THF, reflux

Ester Formation Acetate or Acetyl (Ac) Ester R1 OH

Ac2O, pyridine

R1

LiOH, THF, H2O

O

or AcCl, pyridine DMAF or Ac2O, Lewis acid, CH3CN

O

or K2CO3, MeOH, H2O

Methanesulfonate (Mesylate) R1 OH

MsCl, Et3N, DMAP

NaNH2 R1

OMs

CH2Cl2

R1 OH

DMF

Tosylation R1 OH

TsCl, Et3N, DMAP CH2Cl2

R1

OTs

Pyr·BH3

R1 OH

R1 OH

511

512

11 Protection and Deprotection of Common Functional Groups

Benzoate (Bz) Ester O

Cl O , pyridine

R1 OH

R1

NaOH, MeOH, H2O

R1 OH

O

CH2Cl2

Pivaloate (piv) Ester O

Cl , pyridine

R1 OH

aq. MeNH2

O

R1

R1 OH

O

For 1,2-Diols Acetonide (Isopropylidene Ketal) O R

, TsOH

OH

R

OH

O

O

or Me2C(OMe)2, TsOH, DMF

HCl, THF

R

OH OH

Carbonate R1 HO

R2

HO

R2 OH

R2

O

DMF

O

R1

NaOH MeOH

R2 OH

HO

O R1

NaH, CDI

R2

O

or triphosgene pyridine

OH

R1

R1

Phosgene, pyridine

R1

NaOH

O

MeOH

HO

R2 OH

O

Benzylidene Acetal R1 HO

R2

R1

PhCHO, Lewis acid Benzene

OH

R2

O

or PhCH(OMe)2 TsOH, benzene

O Ph

R1

H2, Pd/C, AcOH or Na/NH3 or BCl3

HO

For 1,3-Diols O R1

R2 OH

OH

,

TsOH

or Me2C(OMe)2, TsOH,DMF

R1

R2 O

O

HCl, THF

R1

R2 OH

OH

R2 OH

For Phenols

R1 OH

R1

PhCHO, Lewis acid

R2

O

Benzene

OH

R2

or PhCH (OMe)2 TsOH, benzene

O Ph

H2, Pd/C, EtOH

or Na/NH3 or BCl3

R1

R2 OH

OH

For Phenols OH

O

Me OH BBr3, DCM

MeI, K2CO3, acetone, reflux or Me2SO4, NaOH, EtOH R

R

R

Cl OH

OH

OBn H2, Pd/C

, K2CO3 Acetone, reflux O OH

OH

O LiOH, THF

AcCl, NaOH, dioxane

H2O

or Ac2O, Lewis acid, CH3CN OTMS

OH TMS-Cl, pyridine DMF

R1

OH TBAF THF

R1

OH

R2

OTBDMS TBDMS-Cl, imidazole DMF

R1 R2

R1

R2

R2

OH

KF, HBr DMF

R1 R2

R1 R2

513

514

11 Protection and Deprotection of Common Functional Groups

OH

OTIPS TIPS-Cl, imidazole DMF

R1

THF

R1 R2

R2

OH

OTBDPS TBDPS-Cl, imidazole

R1 R2 OH TBAF

DMF

R1

OH TBAF

THF

R1 R2

R1

R2

R2

Protection and Deprotection for the Carboxylic Acid Group Protection and deprotection for the carboxylic acid group are common practice in organic synthesis [1–8]. Methyl ester (first step called esterification and second step called hydrolysis or saponification) O

OH

O

O

H2SO4 (cat)

O LiOH, THF, MeOH

MeOH, reflux

O

OH

H2O

OH CH2N2

O

O

O

OH

LiOH, THF, MeOH

Ether

H2O

From Primary or Secondary Alcohol O

O

R1–OH

R

OH

EDC or DCC, DMAF, DCM

R

O

R1

O

LiOH, THF H2O

R

OH

For tert-Butyl Ester The tert-butyl ester is stable in basic conditions and cleavage under acidic conditions. O

O

O

TFA, DCM R

OH

O HO

H2SO4, ether

R

O

R

O

O OH

H2SO4, Et2O

O

O

OH

O

TFA O

DCM

HO

O OH

Protection and Deprotection of Carbonyl Group

Benzyl Ester OH

O R

O OH

R

TsOH

O

H2, Pd/C O

R

EtOH

OH

Silyl Ester O

O

R

OH Pyridine, DCM

R

O

TBAF, THF

TMS-Cl O

SiMe3

or K2CO3, MeOH

R

OH

2-(Trimethylsilyl)ethoxymethyl Ester (SEM Ester)

R

TBAF, THF Heat

O

O

SEM-Cl OH

R

DIEA, THF

O

SiMe3

O

O R

OH

Protection and Deprotection of Carbonyl Group The carbonyl functional group is the backbone in organic chemistry and frequently is required the protection and deprotection of this group [1–19]. Dimethyl Acetals and Ketals Aldehydes are more reactive than ketones. Aldehydes can be selectively protected using Lewis acid catalysts in the presence of ketones. O R

H

O R

MeO

MeOH, HCl Reflux or Lewis acid MeOH, reflux MeOH, HCl CH3

Reflux

R

O

TFA

OMe H

DCM

R

Acetal MeO

OMe

TFA

R

CH3

DCM

O R

CH3

Ketal

1,3-Dioxolane (Cyclic Acetals and Ketals) HO

O R

R1

OH

TsOH, benzene, reflux

O

O

R

R1

2 N HCl 80 °C

O R

R1

H

515

516

11 Protection and Deprotection of Common Functional Groups

1,3-Dioxane OH

O R1

R

OH

O

TsOH, benzene, reflux

O

O R1

R

PPTS Acetone, reflux

R

R1

1,3-Dithiolane (Cyclic Dithioacetals and Ketals) O R

HS-CH2-CH2-HS Lewis acid DCM or CH3CN

R1

S

S

AgNO3, EtOH

R

R1

or CAN, CH3CN

O R

R1

1,3-Dithiane O R

HSCH2CH2CH2SH R1

Lewis acid DCM or CH3CN

O

AgNO3, EtOH S R

S R1

or CAN, CH3CN

R

R1

Protection and Deprotection of Terminal Alkyne Protection and deprotection of the terminal alkynes are important steps in organic synthesis [1–5]. Si BuLi, THF

K2CO3, dry MeOH

TMS-Cl

or TBAF, THF

P Cl PPh2

CuI, Et3N, Toluene 80 °C

MeO

MeO H2O2

THF, 0 °C O PPh2

t-BuOK MeO

THF

MeO

Protection and Deprotection of Carbonyl Group

References Amines 1 Greene, T.W. and Wuts, P.G.M. (2007). Protection for the amino group. In: 2 3 4 5

Protective Groups in Organic Synthesis, 696. New York: Wiley. Vazquez, J., De, S.K., Chen, L.-H. et al. (2008). J. Med. Chem. 51: 3460. De, S.K., Stebbins, J.L., Pavlickova, P. et al. (2011). J. Med. Chem. 54: 6204. Kocienski, P.J. (2005). Protecting Groups. Thieme. Sartori, G., Ballini, R., Bigi, F. et al. (2004). Chem. Rev. 104: 199–250.

Alcohols 1 Greene, T.W. and Wuts, P.G.M. (2007). Protection for the hydroxyl group. In: 2 3 4 5 6 7

Protective Groups in Organic Synthesis, 24. New York: Wiley. Jung, M.E. and Kaas, S.M. (1989). Tetrahedron Lett. 30: 641. Niwa, H., Hida, T., and Yamada, K. (1981). Tetrahedron Lett. 22: 4239. Evans, D.A., Bender, L., and Morris, J. (1988). J. Am. Chem. Soc. 110: 2506. Lipshutz, B.H. and Pegram, J.J. (1980). Tetrahedron Lett. 21: 3343. De, S.K. (2004). Tetrahedron Lett. 45: 1035. Sartori, G., Ballini, R., Bigi, F. et al. (2004). Chem. Rev. 104: 199–250.

Protection and Deprotection for the Carboxylic Acid Group 1 Greene, T.W. and Wuts, P.G.M. (2007). Protection for the carboxyl group. In:

Protective Groups in Organic Synthesis, 533. New York: Wiley. Anderson, G.W. and Callahan, F.M. (1960). J. Am. Chem. Soc. 82: 3359. Alexakis, A., Gardette, M., and Colin, S. (1988). Tetrahedron Lett. 24: 2951. Holcombe, J.L. and Livinghouse, T. (1986). J. Org. Chem. 51: 111. Hassner, A. and Alexanian, V. (1978). Tetrahedron Lett. 19: 4475. Zhao, H., Pendri, A., and Greenwald, R.B. (1998). J. Org. Chem. 63: 7559. Chakraborti, A.K., Basak-Nandi, A., and Grover, V. (1999). J. Org. Chem. 64: 8014. 8 Motozaki, T., Sawmura, K., Suzuki, A. et al. (2005). Org. Lett. 7: 2261. 2 3 4 5 6 7

Protection and Deprotection of Carbonyl Group 1 Greene, T.W. and Wuts, P.G.M. (2007). Protection for the carbonyl group. In:

Protective Groups in Organic Synthesis, 431. New York: Wiley. 2 De, S.K. and Gibbs, R.A. (2004). Tetrahedron Lett. 45: 8141. 3 Ellison, R.A., Lukenbach, E.R., and Chiu, C.W. (1975). Tetrahedron Lett. 16:

499. 4 Trost, B.M. and Lee, C.B. (2001). J. Am. Chem. Soc. 123: 3671.

517

518

11 Protection and Deprotection of Common Functional Groups

Olah, G.A. and Mehrotra, A.M. (1982). Synthesis 962. Ranu, B.C., Jana, R., and Samanta, S. (2004). Adv. Synth. Catal. 346: 446. Mandal, P.K., Dutta, P., and Roy, S.C. (1997). Tetrahedron Lett. 38: 7271. De, S.K. (2005). Adv. Synth. Catal. 347: 673. De, S.K. (2004). Tetrahedron Lett. 45: 1035. De, S.K. (2004). Tetrahedron Lett. 45: 2339. De, S.K. (2004). Synthesis 828. Ranu, B.C., Das, A., and Samanta, S. (2002). Synlett 727. De, S.K. (2005). J. Mol. Catal. A: Chem. 226: 77. Yus, M., Najera, C., and Foubelo, F. (2003). Tetrahedron 59: 6147. Corey, E.J., Tius, M.A., and Das, J. (1980). J. Am. Chem. Soc. 102: 7612. Kamal, A., Chouhan, G., and Ahmed, K. (2002). Tetrahedron Lett. 43: 6947. Nicolaou, K.C., Ajito, K., Patron, A.P. et al. (1996). J. Am. Chem. Soc. 118: 3059. 18 Khan, A.T., Mondal, E., Ghosh, S., and Islam, S. (2004). Eur. J. Org. Chem. 2002. 19 Samajdar, S., Basu, M.K., Becker, F.F., and Banik, B.K. (2001). Tetrahedron Lett. 42: 4425. 5 6 7 8 9 10 11 12 13 14 15 16 17

Protection for the Terminal Alkyne CH 1 Greene, T.W. and Wuts, P.G.M. (2007). Protection for the alkyne -CH. In: 2 3 4 5

Protective Groups in Organic Synthesis, 927. New York: Wiley. Cai, C. and Vasella, A. (1995). Helv. Chim. Acta 78: 732. Nishikawa, T., Ino, A., and Isobe, M. (1994). Tetrahedron 50: 1449. Yang, X., Matsuo, D., Suzuma, Y. et al. (2011). Synlett 2402. Yang, X., Kajiyama, S., Fang, J.-K. et al. (2012). Bull. Chem. Soc. Jpn. 85: 687.

519

12 Amino Acids and Peptides Natural Amino Acids An amino acid has at least one amino and one carboxylic acid functional group. There are several types of amino acids such as α-amino acid, β-amino acid, γ-amino acid, δ-amino acid, and so on (see below examples). γ-C

α-C

α-C OH

H2N

H2N

OH

OH

H2N O

O

O

α-Amino acid

α-C

β-C β-Amino acid

β-C γ-Amino acid

H2N

OH O

δ-Amino acid

Here we describe α-amino acids only. Human bodies have almost 100 000 different proteins, which are built up of different arrangements of just 20 amino acids. So amino acid is a building block or a fundamental unit of all proteins. Twenty amino acids are essential to our bodies. Each amino acid has its own important functions for the human body. Peptides are used in drug discovery research extensively [1–17], and almost 60 peptide drugs are in market, over 150 peptides in clinical trials [16, 17]. The structure of an α-amino acid comprises, bound to a carbon (α-carbon) (Table 12.1), A. B. C. D. E. F.

A carboxyl group (–COOH). An amine group (–NH2 ). An atom of hydrogen (–H). A variable R, that is, the side chain. Except glycine (all are chiral). All natural chiral amino acids that are L (S), except l-cysteine, which is R.

Applied Organic Chemistry: Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry, First Edition. Surya K. De. © 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.

520

12 Amino Acids and Peptides

R H2N

R OH

H

H3N

O

α-Amino acid

O H

O

Neutral dipolar

Table 12.1 20 essential amino acids.

Amino acids

Three letters

One letter

Hydropathy

Physiochemical

Charge

Polarity

Alanine

Ala

A

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Arginine

Arg

R

Hydrophilic

Aliphatic, basic

Positive

Polar

Asparagine

Asn

N

Hydrophilic

Aliphatic

Uncharged

Polar Polar

Aspartic acid

Asp

D

Hydrophilic

Aliphatic, acidic

Negative

Cysteine

Cys

C

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Glutamine

Gln

Q

Hydrophilic

Aliphatic, neutral

Uncharged

Polar

Glutamic acid

Glu

E

Hydrophilic

Aliphatic, acidic

Negative

Polar

Glycine

Gly

G

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Histidine

His

H

Hydrophilic

Aromatic, basic

Positive

Polar

Isoleucine

Ile

I

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Leucine

Leu

L

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Lysine

Lys

K

Hydrophilic

Aliphatic, basic

Positive

Polar

Methionine

Met

M

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Phenylalanine

Phe

F

Hydrophobic

Aromatic, neutral

Uncharged

Nonpolar

Proline

Pro

P

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Serine

Ser

S

Hydrophilic

Aliphatic, neutral

Uncharged

Polar

Threonine

Thr

T

Hydrophilic

Aliphatic, neutral

Uncharged

Polar

Tryptophan

Trp

W

Hydrophobic

Aromatic, neutral

Uncharged

Nonpolar

Tyrosine

Tyr

Y

Hydrophobic

Aromatic, neutral

Uncharged

Polar

Valine

Val

V

Hydrophobic

Aliphatic, neutral

Uncharged

Nonpolar

Natural Amino Acids

Amino Acids with Nonpolar Side Chain H H2N

OH H

OH

H2 N O

O

Glycine (not a chiral molecule) CH3

CH3

(R)

(S)

H2N

H

OH

H2N

H

H2N

O

O

L-Alanine

OH

D-Alanine

OH

(S)

H2N

O

O

L-Valine

D-Valine

(R)

H2N

OH

(S)

H2N

O

OH

(R)

H2N

D-Leucine

(R)

OH

(S)

H2N

O

O

L-Leucine

H2N

O

L-Isoleucine

D-Isoleucine

S

CH3

SH

OH

(R)

OH

(R)

S CH3 SH

OH

(R)

H2N

O

OH

(S)

OH H2N

O

l-Cysteine

(S)

H2N

O

O

L-Methionine

d-Cysteine

OH (R)

D-Methionine

NH NH OH H2N

(S)

O

H2N

O

L-Phenylalanine

D-Phenylalanine

(R)

OH N (S) H O L-Proline

OH

(R)

N H

OH O

D-Proline

H2N

OH

(S)

O

L-Tryptophan

H2N

OH

(R)

O D-Tryptophan

521

522

12 Amino Acids and Peptides

Amino Acids with Polar Side Chain

H2N

H2N

(R)

H2N

L-Serine

OH

(S)

O

O

(S)

(R)

OH

OH

(S)

OH

OH

OH

OH

H2N

(R)

O

O

OH

OH

D-Threonine

L-Threonine

D-Serine

OH

O

O NH2

H2N

OH

(S)

H2N

H2N

H2N

O

O L-Tyrosine O

OH

OH

(R)

O

H2N

O

OH

(R)

O

D-Asparagine

NH2

OH

(S)

(S)

L-Asparagine

D-Tyrosine

NH2

NH2

OH H2N

O

L-Glutamine

(R)

O D-Glutamine

Amino Acids with Positive Charged (Basic) Side Chain H2N

H2N

NH2

NH

NH

NH

OH (S)

H2N

OH H2N

O L-Lysine

(R)

O

D-Lysine

H N N

N

OH H2N

(S)

O

L-Histidine

OH H2N

OH H2N

(S)

O

L-Arginine

H N

(R)

O

D-Histidine

NH

H2N

H2N

OH

(R)

O

D-Arginine

Nonnatural Amino Acids

Amino Acids with Negatively Charged (Acidic) Side Chain O

O OH

H2N

H2N

O L-Aspartic

OH

O

O

OH

OH

(S)

OH

OH

(R)

H2N

H2N

O

O D-Aspartic acid

acid

OH

(S)

OH

(R)

O

L-Glutamic

D-Glutamic

acid

acid

Nonnatural Amino Acids OH

OH OH

OH

NH2

NH2

OH OH

(S)

H2N

H2N

L-Dap

D-DOPA

NH2

H2N

O

(2,4-diaminobutyric acid)

H2 N

O D-Dab

R1

OH

OH

(S)

H2N

O

L-Phenylalanine

(R)

O

D-Phenylalanine

derivatives R4

(Orn)

R2

R5

R1

O

R3

R4

R2

R5

(S)

L-Ornithine

R3

R4

OH

(R)

R5 R4

derivatives

R5

NH

R3

R1

R2

OH H2N

NH

R3

R1

R2

OH

(S)

L-Tryptophan

O derivatives

H2N

(R)

D-Tryptophan

D-Dap

H2N

H2N

OH

(S)

H2N

O

(2,3-diaminopropionic acid)

NH2

OH

L-Dab

(R)

O

L-DOPA

H2N

OH H2N

O

OH

H2N (R)

O

(S)

O derivatives

OH H2N

(R)

O D-Orn

523

524

12 Amino Acids and Peptides

Here from R1 , R2 , R3 , R4 , R5 , one group is hydroxyl or methyl or methoxy or fluoro or chloro or amine. HO

(R) (S)

OH H2N

N H

OH

(S)

O

H2N

OH

(R)

O

L-4-Hydroxyproline

O

L-Norvaline

D-Norvaline

SeH H2N

OH

(S)

H2N

O

OH

(R)

H2N

L-Homocysteine

OH

OH

(S)

O

O

D-Selenocysteine

OH

OH

H2N (R)

O

L-Selenocysteine

SH

OH

OH

H2N (S)

O

D-Norleucine

SH

(S)

H2N

O

L-Norleucine

H2N

OH

(R)

SeH

H2N

OH

(R)

O

O

D-Homocysteine

L-Homoserine

D-Homoserine

NH2 HN

H2N

OH

(S)

H2N

O

H2N

OH

(S)

OH H2N

O

L-Homophenylalanine

H2N

O

D-Homophenylalanine

OH

(S)

H2N

O

OH

(S)

NH

HN

OH

(R)

NH2

NH

OH

(S)

H2N

O

L-Homoarginine

H2N

OH

(S)

O

D-Homoarginine

H2N

OH

(S)

O

O

(R)

H2N

OH

(S)

O

O N3

N N N OH

H2N (S) O

H2N

OH

(S)

O

OH

H2N (S) O

H2N

OH

(S)

O

H2N

OH

(S)

O

Solution-Phase Peptide Synthesis

Solution-Phase Peptide Synthesis

Amide bond, peptide bond

O OH

BocHN O

+ H2N

BocHN O

DIEA, DMF

O

H N

DIC, HOBt

O

+ H2O

O 1. LiOH, THF, H2O 2. 50% TFA in DCM

H N

H2 N

O OH

O Small peptide

Experimental A mixture of acid (1 mmol), amine (1 mmol), diisopropyl carbodiimide (DIC; 1.2 mmol), 1-hydroxybenzotriazole (HOBt; 1.2 mmol), and diisopropylethylamine (DIEA; 2.5 mmol) in N,N-dimethylformamide (DMF; 3 ml) was stirred at room temperature for 12 hours. Water (50 ml) was added into the reaction mixture and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated NaHCO3 solution (4 × 50 ml), water (4 × 50 ml), and brine (4 × 50 ml), respectively, to remove by-products, remaining coupling agents, and DMF as these are soluble in water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (hexane/ethyl acetate solvent system) to afford a pure product.

525

526

12 Amino Acids and Peptides

Mechanism of DIC–HOBt Coupling Reaction N N N

HOBt

O

N

R1

N C N

O O

Step 1

R1

O O

N C N

H

R1

Step 2

O O

N C NH

Step 3

N N

N H O C NH

O

O-Acylisourea

DIC

O

R1

Step 4

N N N

H2N ..

O H N

R1

Step 7 R 1 R O

O

H N R 2 H

Step 6

R2 NH R1

O

H O

N N

N

R1 Step 5

R2 O

N N N

O

+

HN

O NH

Active ester +

By-product DIU

N N N HO HOBt

Step 1: Nucleophilic addition. Step 2: Protonation and formation of O-acylisourea. Step 3: Nucleophilic attacks by HOBt at electron-deficient carbonyl carbon atom of O-acylisourea. Step 4: Liberates by-product diisopropyl urea and forms an active ester. Step 5: Nucleophilic attacks by lone pair electrons of the amino compound. Step 6: Liberates HOBt. Step 7: Protonation gives the target amide. For amino acid coupling, HOBt reduces racemization, except that glycine other all amino acids are chiral (L or D). Other coupling agents are used in peptide synthesis as follows: EDC/HOBt, EDC/HOAt, DCC/HOBt, DIC/Oxyma pure, HBTU, HATU, BOP, PyBOP, AOP, PyAOP, HCTU, etc.

Solution-Phase Peptide Synthesis

N C N

N C N

N

N C N

HCl DIC

EDC

N

DCC N

N

N N O N P N N

PF6

N

N

N N O N P N N

N

PF6

BOP

N O N P N N

PF6

N

N N O N P N N

PF6

AOP PyBOP

PyAOP

N O

N

N

OH

N

CN O

O

P

O

N

O N N N

Cl

PF6

N

CN

PF6

N

O

Oxyma Pure

PyOxim

HCTU

O N

O N

N

N N NMe2

Me2N

N

N

NMe2

Me2N

PF6

PF6

HATU

HBTU

Mechanism of Boc Deprotection with TFA .. O O

H

OH Step 1

N R H

O

O H Step 2

O

N R H

O

Step 3 N R H

+

H

O

H O

CF3 Step 6

CF3

Step 4

O O

H3N R

N R H O

TFA excess

O

H O

CF3

.. H2N R

H HN R Step 5

+

+ CO2

527

528

12 Amino Acids and Peptides

Step 1: Protonation Step 2: Formation of carbocation Step 3: Elimination of t-butyl group, which liberates isobutene gas Step 4: Deprotonation by trifluoroacetic acid (TFA) and liberation of carbon dioxide gas Step 5: Protonation Step 6: Formation of zwitterion (dipolar) Mechanism of Fluorenyl-9-methoxycarbonyl (Fmoc) Deprotection with Piperidine .. N H

H O O H

O

N R H Step 1

O

+ N R H

H2N R + CO2

+ Step 2 N H H

H N

Step 3

H N

By-product

Step 1: Piperidine (base) abstracts fluorenyl proton; this proton is slightly acidic, as the negative charge is stabilized by the entire aromatic system. Step 2: Liberation of carbon dioxide gas and free amine. Step 3: By-product formation.

Solid-Phase Peptide Synthesis Merrifield Resin Merrifield resin (solid support) is a cross-linked polystyrene resin that carries a chloromethyl functional group. It is used for the synthesis of peptide acids by Boc-SPPS strategy.

Solid-Phase Peptide Synthesis

Merrifield resin is named after its inventor, Robert Bruce Merrifield, who received the Nobel Prize in Chemistry in 1984.

Cl

R

Heat, DMF Boc-AA-Cs salt KI

R

TFA O

BocHN O

O

H2N O

DCM Deprotection

Boc-AA-CO2H DIC, Oxyma Pure DIEA, DMF

R

O = Solid support (resin)

BocHN R1

N H

O O

AA is amino acid HF Cleavage cocktail O H2N R1

R N H

OH O

This method is used in the synthesis of small- to medium-sized peptides, since the benzyl ester resin linkage is not completely stable toward repetitive treatment with TFA. HF is not a good chemic