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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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Contents
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
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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
722
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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
xxv
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
xxxiii
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
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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
xxxvii
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
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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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Lossen Rearrangement 1 2 3 4 5 6 7 8 9 10 11 12
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Orton Rearrangement
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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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1 Rearrangement Reactions
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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2 Condensation Reaction
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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.
112
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
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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
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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
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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.
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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].
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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
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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
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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)
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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
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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.
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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
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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
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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.
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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.
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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).
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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
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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
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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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Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation 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 29 30
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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.
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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
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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
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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
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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
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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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Gattermann–Koch Aldehyde Synthesis
66 Evano, G. and Theunissen, C. (2019). Angew. Chem. Int. Ed. 58: 7558–7598.
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12 13 14 15 16 17 18
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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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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Lett. 29: 2079–2086. Silveira, A. Jr. and McWhorter, E.J. (1972). J. Org. Chem. 37: 3687–3691. Ovodov, Y.S. and Evtushenko, E.V. (1973). Carbohydr. Res. 27: 169–174. Agranat, I. and Shih, Y.-S. (1976). J. Chem. Educ. 53: 488. Menicagli, R. and Piccolo, O. (1980). J. Org. Chem. 45: 2581–2585. Wipf, P. and Jung, J.K. (2000). J. Org. Chem. 65: 6319. Mullins, R.J. and Merling, E.W. (2010). Name Reactions for Carbocyclic Ring Formations, 342–355. Wiley.
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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12 Cohen, S., Thom, E., and Bendich, A. (1963). J. Org. Chem. 28: 1379–1383. 13 Kemp, D.S. (1971). J. Org. Chem. 36: 202–204. 14 Hirao, K., Ikegame, M., and Yonemitsu, O. (1974). Tetrahedron 30:
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.,
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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.
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6 Pd-Catalyzed C—C Bond-Forming Reactions
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
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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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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:
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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
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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
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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.
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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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Strecker Amino Acid Synthesis
29 Wang, Q., Wang, D.X., Wang, M.X., and Zhu, J. (2018). Acc. Chem. Res. 51:
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(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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1970–2042. (review). 40 Gazzotti, S., Rainoldi, G., and Silvani, A. (2019). Expert Opin. Drug Discovery
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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
402
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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Clemmensen Reduction 1 2 3 4 5 6 7 8 9
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Org. Chem. 67: 1975–1981. 16 Nishide, K., Ozeki, M., Kunishige, H. et al. (2003). Angew. Chem. Int. Ed. 42:
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:
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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:
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3169–3176. 29 Fernández, I., Sierra, M.A., and Cossío, F.P. (2007). J. Org. Chem. 72:
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Lett. 9: 2791–2793. 31 Dilger, A.K., Gopalsamuthiram, V., and Burke, S.D. (2007). J. Am. Chem. Soc.
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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-
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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:
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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:
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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:
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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
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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
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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
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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.
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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%).
References Bartoli Indole Synthesis 1 Bartoli, G., Learrdini, R., Medici, A., and Rosini, G. (1978). J. Chem. Soc.,
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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, 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.
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Skraup Quinoline Synthesis
37 Piemontesi, C., Wang, Q., and Zhu, J. (2016). J. Am. Chem. Soc. 138:
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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:
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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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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 chemical to handle it. Solid-Phase Peptide Synthesis Fmoc Strategy Resin selection, if C-terminal amide, Rink amide resin, if C-terminal acid, then 2-chlorotrityl chloride resin or Wang resin is widely used, respectively. Deprotection of 9-Fluorenylmethoxycarbonyl (Fmoc) group: 20% piperidine in DMF (v/v)
529
530
12 Amino Acids and Peptides
Fmoc-AA-OH FmocHN R
O H2N
O
DIEA, DMF
Cl
20% piperidine in DMF
O
Deprotection
O R
Cl
Cl
Cl Fmoc-AA-OH Oxyma Pure DIC, DIEA, DMF
Coupling
20% piperidine in DMF
O
R1
HN R
O
O
R1
O
H2N
HN
O
FmocHN Cl
R
O
Cl
TFA Cleavage cocktail O
R1 HN
OH
H2N R
O
Peptide using 2-chlorotrityl resin
OMe
OMe
OMe O
Fmoc-AA-OH H2N
FmocHN
OMe
R
N H
OMe
20% piperidine in DMF
OMe
N H
R
O
O
O
H2N
O Rink a mide AM resin Boc-AA-OH OMe R1
H N
H2N O
TFA
O NH2 R
R1
Cleavage cocktail
O
H N
BocHN O
R
N H
Amino Acids with Side-Chain Protecting Groups for Fmoc Strategy General Considerations A. B. C. D.
Avoid undesired side reaction. Protecting groups must be easily introduced and safely removed. Stable in reaction conditions. Orthogonal (Table 12.2).
OMe
O
Table 12.2 Side-chain protecting groups and deprotection conditions.
Introduction
Removal
Stable
Orthogonal
Amino acid side chain
t-Butyl (acid and hydroxyl group)
Isobutene
90% TFA in DCM
Basic and hydrogenation
Fmoc, Z, Alloc
D, E, S, T, Y
Trt (Trityl)
Trt-Cl
2% TFA in DCM
Basic and hydrogenation
Fmoc, Alloc
C, N, Q, H, W
Benzyl (Bn)
Bn-Cl
H2 , HF
Basic conditions
Boc, Fmoc, Trt
S, T, D, E
Meb (4-methylbenzyl)
Meb-Br
HF, TMS-Cl
Basic conditions
Fmoc, Alloc
C
Bom (benzyloxymethyl)
Bom-Cl
HF, TFMSA-TFA
Basic conditions
Fmoc
H
Dmb (2,4-dimethoxybenzyl)
Dmb-Cl
5% TFA in DCM
Acidic and hydrogenation
Fmoc, Alloc
D, E
Z or Cbz (benzyloxycarbonyl)
Cbz-Cl
H2 /Pd
Basic and acidic conditions
Boc, Fmoc, Trt
K
Allyl
Allyl-Cl
Pd(Ph3 P)4
Acidic and basic conditions
Boc, Fmoc
S, T, Y
Alloc (allyloxycarbonyl)
Alloc-Cl (Alloc)2 O
Pd(Ph3 P)4 PhSiH3
Basic and acidic conditions
Boc, Fmoc, Trt
K, Org, Dap, Dab
Tosyl
Ts-Cl
HF
Basic conditions
Fmoc
H
Formyl
Paraformaldehyde
HF, piperidine
Mild acidic conditions
Alloc
W
Acm (acetamidomethyl)
Acm-OH
I2 in AcOH, Tl(III)
Acidic and basic conditions
Boc, Fmoc, Trt, Alloc
C
Side-chain protecting group
TBDMS (tert-butyldimethylsilane) hydroxyl protection
TBDMS-Cl
TBAF, TFA
Basic conditions
Fmoc
S, T, Y
ivDde
ivDde-OH
5% hydrazine monohydrate in DMF
Acidic and basic conditions
Boc, Fmoc
K, Dap, Orn
Dde
Dde-OH
5% hydrazine in DMF
Acidic and basic condition
Boc, Fmoc
K, Dap, Orn
Dmab
Dmab-OH
5% hydrazine in DMF
Acidic and basic conditions
ONB (ortho-nitrobenzyl)
ONB-Br
Photolytic (320 nm)
Acidic and mild basic conditions
Boc, Fmoc
S, T, Y
Pbf
Pbf-Cl
90% TFA in DCM
Basic and hydrogenation
Fmoc, Alloc
R
D, E
Cleavage Cocktail
9-Fluorenylmethoxycarbonyl (Fmoc)
tert-Butyloxycarbonyl (Boc)
Introduction
Fmoc-Cl, base or sodium bicarbonate
(Boc)2 O, base, DMAP, or NaHCO3
Deprotection
20% piperidine
50% TFA
Stable
Acidic conditions, hydrogenation
Basic conditions, hydrogenation
Orthogonal
Boc, Cbz, Trt, Alloc, IvDde
Fmoc, CBz, Alloc, IvDde
Standard Fmoc Strategy for SPPS Fmoc: α-NH Boc: Lysine, tryptophan, histidine (side chains) Pbf: Arginine (side chains) Trt: Cysteine, aspartic acid, glutamic acid, asparagine, glutamine, histidine (side chains) tBu: Serine, threonine, hydroxyproline, tyrosine, aspartic acid, glutamic acid (side chains) For regular amino acids with α-NH Fmoc and side-chain protecting groups are as follows (both L and D): Fmoc-Ala-OH; Fmoc-Arg(Pbf )-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(Otbu)-OH; Fmoc-Cys(Trt)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Glu(Otbu)-OH; Fmoc-GlyOH; Fmoc-His(Trt)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Met-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(Otbu)-OH; FmocVal-OH. For side-chain modification on Lys, Dap, Dab, and Orn, use ivDde group, while for-side chain modification on Asp and Glu, use Dmab group. If two modifications needed, use ivDde- and Alloc-protected amino acids, which selectively removes each group separately.
Cleavage Cocktail Triisopropylsilane (TIPS) is used in cleavage cocktail to scavenge cationic species. Phenol, thioanisole, 1,2-ethanedithiol, and dithiothreitol (DTT) are used to prevent oxidation of cysteine, methionine, tyrosine, serine, and threonine. DTT has low odor than other thiol reagents.
533
534
12 Amino Acids and Peptides
If there are no cysteine and methionine, cleavage cocktail A should be used.
Cleavage Cocktail A TFA = 94% (v/v) TIPS = 2% (v/v) Phenol = 2% (w/v) Water = 2% (v/v) If peptide contains cysteine or methionine or any groups that can be oxidized easily, then cleavage cocktail B should be used.
Cleavage Cocktail B TFA = 90% (v/v) TIPS = 2% (v/v) Phenol = 2% (w/v) DTT = 4% (w/v) Water = 2% (v/v) The final protected peptide was treated with cleavage cocktail (TFA/phenol/ H2 O/TIPS: 94 : 2 : 2 : 2) for three hours at room temperature. The volume of TFA was reduced by rotary evaporator and precipitated in cold diethyl ether. The precipitated construct was cooled for 15 minutes at 0 ∘ C to ensure complete precipitation. The solid was separated from the diethyl ether by centrifugation, and the top phase was decanted off, and pellet resuspended with another addition of dry diethyl ether. The cooling and centrifugation process was done three times. Upon completion, the residue was dried and dissolved in water or acetonitrile or dimethylsulfoxide (DMSO) in minimum volume for high-performance liquid chromatography (HPLC) reverse-phase purification. The peptide was purified on reverse-phase HPLC on Phenomenex Luna 5 μ Semi-preparative (10 × 250 mm) C-18 column using solvent system A: 0.1% TFA in H2 O; solvent B: 0.1% TFA in acetonitrile with a linear gradient method (0 minute, 10% B; 2 minutes, 10% B; 20 minutes, 45% B; 25 minutes, 95% B; 27 minutes, 95% B; 30 minutes, 100% B; 33 minutes, 10% B) with flow rate of 5 ml/min at a wavelength of 280 or 254 or 220 nm. The fractions were collected and analyzed by MALDI-TOF mass spectrometry. The correct fraction was concentrated in vacuo (to remove acetonitrile) and then lyophilized.
Reagents and conditions H N
a FmocHN
FmocHN
(S)
O
a
FmocHN
(S)
c
O
N (S) H O O
H N
O a, d
O FmocHN
(S)
N (S) H O
O H N (S)
N (S) H O O
H N
FmocHN
O
a e
O
O O P O OH
O H N (S)
(S)
N H O
H N
(S)
O
O
a, f, g
O
O O P OH OH
O H N (S)
N (S) H O
O H N (S)
N (S) H O O
NH2
HO
Reagents and conditions (a) 20% piperidine in DMF, r.t. 30 minutes, two times; (b) Fmoc-l-Ala-OH, Oxyma Pure, DIC, DIEA, DMF, r.t. two hours; (c) Fmoc-l-Glu(Otbu)-OH, Oxyma Pure, DIC, DIEA, DMF, r.t. two hours; (d) Fmoc-l-cyclopentylglycine, Oxyma Pure, DIC, DIEA, DMF, r.t. two hours; (e) Fmoc-l-Obenzylphosphotyrosine, Oxyma Pure, DIC, DIEA, DMF, r.t. two hours; (f ) acetic anhydride, DIEA, DMF, r.t. two hours; (g) TFA, phenol, TIPS, water, r.t. three hours.
535
536
12 Amino Acids and Peptides
Covalent Peptides Targeting cysteine residue of proteins, Michael acceptor such as acrylamide and chloroacetyl amide groups can be easily introduced on solid-phase peptide synthesis [4, 6]. Fully protected resin-bound peptide with Lys(ivDde) or Dab(ivDde) can be synthesized on peptide synthesizer. Manually selective removal of ivDde group from Lys side chain could be achieved using 5% hydrazine in DMF (v/v), washing resin with DMF and dichloromethane (DCM), and repeating it three times. Acryloyl chloride or 2-chloroacetyl chloride reacts with side-chain amino group of Lys or Dap or Dab or Orn to form acrylamide or 2-chloroacetyl amide. The N-terminal group should be Boc protected if Fmoc protected after formation of acrylamide or 2-chloroacetamide followed by deprotection of Fmoc group with 20% piperidine is problematic, since piperidine can react with acrylamide or chloroacetamide, so avoid keeping any Fmoc group on fully protected peptide on resin. This Michael acceptor can react with thiol of cysteine residue of the protein to form a covalent bond as shown in Scheme 12.1.
O Cl
N H
SH N H
a O H N
b
O R S N H
N R H
O
R
O HN R S N H
O
O
Scheme 12.1 Modification of cysteine with (a) chloroacetamides and (b) acrylamides.
Staple Peptides O HN O
O NH 1. 5% NH2NH2 in DMF O
H N
BocHN
O N H
O
N H
H N O
H N
H2N
2. Acryloyl chloride, DIEA, DMF
O
O N H
O
N H
NH2 O
OH
3. TFA, cleavage cocktail
O
1. 5% NH2NH2 in DMF 2. Chloroacetyl chloride, DIEA, DMF 3. TFA, cleavage cocktail O Cl
HN
H N
H2N
O
O N H
O
N H
NH2 O
OH
Example of covalent peptides: selective removal of ivDde group (5% hydrazine in DMF, three times) and introduction of Michael acceptor. Finally it cleavages the resin from peptide and removes all protecting groups during this process.
Staple Peptides
The red coloring describes a helix, and the green coloring indicates the hydrocarbon staple. Source: Adapted from Douse et al. 2014 [7]. By introducing a synthetic staple hydrocarbon could help to lock a peptide in a specific conformation reducing conformational entropy [4, 15]. This strategy can increase target affinity, increase cell penetration, and protect against proteolytic degradation of peptide in in vivo. The stapled peptides were synthesized using ring-closing metathesis method (see Chapter 3).
537
538
12 Amino Acids and Peptides
Building Blocks for Stapled Peptides (Both L and D Analogs of Amino Acids Are Available)
(S)
(S)
OH
FmocHN
OH
FmocHN
O
O
Hydrocarbon Stapled Peptide Examples
N
O
H N
H N
N H
O
O
N H
R = Cyclohexyl
Cl Ru Cl P R R Ph R
O
N H R H n
BocHN
N
CH2Cl2
O
O
H N
H N
N H
O
H N
O
H N
N H
O
O
1. Grubbs catalyst, DCM 2. TFA, cleavage cocktail NH2 O O HN
H N O
O N H
NH O
N H
NH2 O
O N H
H N O
O
N H R H n
O
Building Blocks for Stapled Peptides (Both L and D Analogs of Amino Acids Are Available)
Experimental Procedure Grubbs ring-closing metathesis (from patent WO2012061408A2)
N
N O
O Cl
Grubbs′ 2nd generation catalyst
O
O
O
H N
N H
O
O
Cl
O H N
CH2Cl2 O
O
O N H
O
The acyclic precursor (758 mg, 1.17 mmol) was dissolved in dry CH2 Cl2 (200 ml, c. ∼0.006 mol/l); the solution was degassed and flushed with N2 (three times). Grubbs’ second-generation catalyst (80.0 mg, 0.091 mmol) dissolved in dry DCM (20 ml) was added dropwise over a period of five minutes. Stirring was continued for eight hours at room temperature. The clear, peach-colored solution turned dark blackish within a couple of hours. Water (30 ml) was added to deactivate the catalyst; the organic layer was separated and filtered through a plug of MgSO4 . Solvents were removed under reduced pressure, and the crude product was purified by column chromatography eluting with chloroform/methanol (30/1). The product (dark oil, 644 mg, 89%) was obtained as a mixture of E/Z isomers in a ratio of 78 : 22 (determined by LC-MS). The geometric isomers were separated by preparative HPLC to allow spectroscopic characterization. The final compounds were obtained in form of white solids.
Stapled Peptide by Click Chemistry
N N
N3
N Cu(I) cat.
539
540
12 Amino Acids and Peptides
Building Blocks for Click Chemistry (Both L and D Analogs Are Available) N3 N3 N3
FmocHN
OH
(S)
N3
FmocHN
OH
(S)
(R)
OH
(S)
FmocHN
OH
(S)
O
O
OH
OH
N (S) O Fmoc
O
OH
(S)
O
O
FmocHN
FmocHN
(S)
N O Fmoc
Example of stapled peptide by click chemistry N
N3 H N
O
H N
N H
O
N
CuSO4, sodium ascorbate
O
N H R H n
O
H N
O
H N
N H
DMSO, H2O
O
N
O
N H R H n
O
Side-Chain Modification Introducing FITC or any other groups can be synthesized by solid-phase peptide synthesis strategy. HO O O
OH
O 1. 5% NH2NH2 in DMF
NH
2. FITC, DIEA, DMF
S HN
3. TFA, cleavage cocktail BocHN
O H N (S)
(S)
O O
O N (S) H
(R)
N (S) H O
H N
O N H
O H N (S)
H2N (S) O
O
O N (S) H
(R)
N (S) H O
NH2
OH
References 1 Barany, G. and Merrifield, R.B. (1977). J. Am. Chem. Soc. 99: 7363. 2 El-Faham, A. and Albericio, F. (2011). Chem. Rev. 111: 6557. 3 Bonner, A.G., Udell, L.M., Creasey, W.A. et al. (2001). J. Pept. Res. 57: 48–58.
References
Barile, E., Marconi, G.D., De, S.K. et al. (2017). ACS Chem. Biol. 12: 444. Wu, B., De, S.K., Abdalla, A.F. et al. (2017). Cell Chem. Biol. 24: 293. Stebbins, J.L., Santelli, E., Feng, Y. et al. (2013). Chem. Biol. 20: 973. Douse, C.H., Maas, S.J., Thomas, J.C. et al. (2014). ACS Chem. Biol. 9: 2204. Verdine, G.L. and Hilinski, G.J. (2012). Methods Enzymol. 503: 3. Walensky, L.D. and Bird, G.H. (2014). J. Med. Chem. 57: 6275. Merrifield, R.B. (1963). J. Am. Chem. Soc. 85: 2149. Mitchell, A.R. (2008). Biopolymers 90: 175. Jaradat, D.M.M. (2018). Amino Acids 50: 39. Behrendt, R., White, P., and Offer, J. (2016). J. Pept. Sci. 22: 4. Palomo, J.M. (2014). RSC Adv. 4: 32658. Phillips, C., Roberts, L.R., Schade, M. et al. (2011). J. Am. Chem. Soc. 133: 9696–9699. 16 Lau, J.L. and Dunb, M.K. (2018). Bioorg. Med. Chem. 26: 2700–2707. 17 Chandrudu, S., Simerska, P., and Toth, I. (2013). Molecules 18: 4373–4388. 4 5 6 7 8 9 10 11 12 13 14 15
541
543
13 Functional Group Transformation Transformation of one functional group to another is a common practice in organic synthesis [1–25].
Alcohol to Aldehyde Primary alcohols oxidize to the corresponding aldehydes, or carboxylic acids dependent on nature of oxidants and amount of oxidants are used. Secondary alcohols oxidize to the corresponding ketones using the same types of oxidants. Tertiary alcohols are resistant to oxidation. O R
OH R
Primary alcohol
H
Aldehyde
R = alkyl or aryl
OH
OH
H
MnO2, DCM O
r.t.
Dess–Martin periodinane
H O
DCM, r.t.
OH
H
(COCl)2, DMSO, DCM O
Et3N Swern oxidation SO3 ·Py OH
H
DCM O
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.
544
13 Functional Group Transformation
TPAP, NMO OH
H
DCM O
Ley–Griffith oxidation
DMSO, DCC OH
H
DCM
Pfitzner–Moffatt oxidation
O
TEMPO OH
H
NaOCl O 1. NCS, Me2S
OH
H
2. Et3N O
Corey–Kim oxidation PDC or PCC OH
H
DCM O O2
OH
R
OH
H
Redox-active copper complex
O O
Chloramine-T DABCO, dioxane, H2O
R
H
Secondary Alcohol to Ketone Oxidants useful for the conversion of primary alcohols to aldehydes are generally suitable for the oxidation of secondary alcohols to ketones. O
OH R
R1
Secondary alcohol
R
R1
Ketone
Dess–Martin periodinane DCM, r.t. OH
O
Secondary Alcohol to Ketone
IBX DCM OH
O MnO2, DCM r.t. O
OH PCC, DCM r.t.
O
OH
PDC DCM OH
O 1. Oxalylchloride, DMSO, DCM 2. Et3N
OH
O
(Swern oxidation)
SO3 ·Py DCM OH
O 1.NCS, Me2S 2. Et3N
OH
O Corey–Kim oxidation DMSO, DCC DCM
OH
O Pfitzner–Moffatt oxidation
NaOCl OH
OH R
R1
O
O
Urea·H2O2 R
R1
545
546
13 Functional Group Transformation
Primary Alcohol to Carboxylic Acid O R
OH
R
OH
CrO3, H2SO4 OH
OH
H2O, acetone, r.t. O
(Jones oxidation) TPAP, NMO OH
OH
CH3CN, r.t. O
Ley–Griffith oxidation
OH
KMnO4 OH
NaOH, H2O O
OH
CrO3, H5IO6 OH
CH3CN O
PDC OH
OH
DMF O
RuO4 OH
OH
TEMPO O
O2 OH
OH
Platinum O
OH
PCC OH
CH2Cl2 O
Alcohol to Chloride
1,2-Diol Oxidation O
O
OH OH R R R R
NaIO4
R
R
+
R
O
O
OH OH R R R R
Pb(OAc)4
R
R
R
+
R
R
Alcohol to Fluoride [11, 14, 15] R OH
R F
OH
Alkyl Fluor
R
F
R1
R1
R
Dioxane
DAST OH
F
DCM, r.t. Deoxo-Fluor
OH
F
DCM, r.t. XtalFluor-M
OH
F
3,3-Difluoro-1,2-diarylcyclopropenes (CpFluors) OH F
Alcohol to Chloride R OH
R Cl Cl
OH R1
Ph3P
R2
CCl4
R1
R2
Appel reaction SOCl2 OH
Reflux
Cl
547
548
13 Functional Group Transformation
SOCl2 OH
DCM, DMF (cat.) r.t.
Cl
Ph3P, Bu4NI OH
ClCH2CH2Cl
Cl
Triphosgene, pyridine OH
Cl
DCM
Alcohol to Bromide R OH
R Br PBr3 OH
Ether, r.t.
Br
CBr4, Ph3P OH
DCM, r.t.
Br
(Appel reaction)
SOBr2, DMF(cat.) OH
Br
DCM, r.t.
Ph3P, Bu4NI OH
BrCH2CH2Br
Br
[Et2NSF2]BF4, Et4NBr OH
Br
DCM
Alcohol to Iodide [13] R OH
R I
I2, Ph3P OH Imidazole, THF r.t.
I
Alcohol to Ether
Ph3P, Bu4NI OH
I
ICH2CH2I
SMe
Me2N
I OH
I
Toluene, 85 °C
Alcohol to Ester O R OH
+
R1
O
H2SO4 OH
Primary or secondary alcohol
R1
Heat
O
R
Fischer esterification O
O
OH
OH O DIAD, Ph3P
(S)
+
Mitsunobu reaction
NO2
O
O R OH +
(R)
THF
EDC, DMAP OH
R1
DCM or DMF
R1
Alcohol to Ether H 2 R
OH
R
Heat
O
R
Primary alcohol
R OH
R1 X
NaH
R O R1
THF
ONa Acetone + R–X
O R
Heat
O OH +
Br
K2CO3 Acetone, reflux
O
R
NO2
549
550
13 Functional Group Transformation
Alcohol to Sulfonic Ester R OH
O R1 S Cl O
+
DIEA DCM 0 °C to r.t.
O R O S R1 O
R1 = Me Mesylate R1 = CF3 Triflate
Alcohol to Methylene OH R
Et3SiH
R
TFA, r.t.
R1
R1
OH Et3SiH TFA, r.t.
Alcohol to Azide OH R
N3
DPPA, Ph3P
R1
DIAD, THF, r.t. (Mitsunobu reaction)
R
R1
Ph3P, I2, imidazole
OH
N3
NaN3, DMSO DPPA, DBU
OH
THF, r.t.
N3
NaN3
Ts-Cl OH
DIEA, THF
OTs
DMF, heat
Azide to Amine R N3
Ph3P
R NH2
THF, H2O Ph3P N3
THF, H2O Staudinger reaction
R N3
H2 Pd/C, EtOH
R NH2
NH2
N3
Ketone to Alcohol
Aldehyde to Alcohol O
NaBH4
R
MeOH, r.t.
H
R
OH
NaBH4
H
OH
THF, r.t.
O
H
LiAlH4 OH
THF
O
Aldehyde to Carboxylic Acid O
O R
Oxidation H
R
OH
CrO3, H2O H
OH
Acetone, r.t. O
O
Other suitable oxidizing agents are KMnO4 , Ag2 O, and H2 O2 (H2 O2 not suitable if double bonds are present, as epoxidation can occur).
Aldehyde to Difluoro [14, 15] H
DAST DCM, heat
CHF2
O O Deoxo-Fluor reagent R1
H
Aminodifluorosulfinium tetrafluoroborate salt
O R1
DCM
H
R1
Et3N, DCM
Ketone to Alcohol O R
OH
NaBH4 R1
MeOH, r.t.
F
R
R1
F
F
R1
H
F H
551
552
13 Functional Group Transformation
O
OH
CBS reagent
R1
R1
R2
R2
Corey–Bakshi–Shibata reduction
O R1
R2
R1
DCM
R2
OH
O R1
OH
Cl3SiH
Sm, I2 R2
R2
R1
iPrOH
NaBH4 MeOH, r.t. OH
O LiAlH4 THF O
OH
Ketone to Ester O R
O
H2O2 R1
R
or m-CPBA
O
R1
Baeyer–Villige roxidation O R1
Sodium percarbonate R2
O R1
TFA
R1 O
H2O2 R2
R1
BF3, ether
Ketone to Difluoro [14, 15] O R
DAST R1
O R
DCM, r.t. Deoxo-Fluor
R1
O
DCM, r.t.
F R
F R
F R1
F R1
O
R2
O
R2
Acid (Carboxylic) to Ester
Aminodifluorosulfinium tetrafluoroborate salts
O R1
R2
F
Et3N, DCM
O
R1
F
F R2
F
Deoxo-Fluor DCM, r.t.
Ketone to Methylene O R
Zn/Hg R1
R
HCl
R1
Clemmensen reduction
O R
NH2NH2 R1
KOH, heat
H
H
R
R1
Wolff–Kishner reduction
SH
O R
R1
SH
H2 S
Acid
S
R
R
Raney Ni
R1
Mozingo reduction NH2NH2 KOH, heat O Wolff–Kishner reduction
Ketone to Thioketone S
O
Lawesson′s reagent Toluene, reflux
Acid (Carboxylic) to Ester O R
O
H2SO4 OH
MeOH, reflux
R
O
R1
553
554
13 Functional Group Transformation
O R
O
H2SO4 OH
R
EtOH, reflux
O
Fischer esterification works well with simple primary or secondary alcohols, which is used both as solvent and as reactant. O R
O
t-BuOH OH
R
EDC, DMAP, DCM
O
Steglich esterification
O R
OH O
R
O
O O
R
DMF, r.t.
O
O
Me2SO4 OH
R
K2CO3, DMF
O O
O R
R
2. MeOH MeI, K2CO3
OH
R
O
1. SOCl2
TMS-CHN2 OH
R
Toluene/MeOH
O
O
O OH
TMS-CHN2
O
Toluene/MeOH OH
OH
This method is selectively methylated carboxylic acid in the presence of hydroxyl group. A small amount of MeOH is used to dissolve the carboxylic acid – otherwise no needed methanol.
Acid to Amide O R
OH
O R
O
SOCl2 Reflux
R
OH
DMF(cat.), DCM
Cl
O
(COCl)2 R
O
R1 NH2 DIEA, DMF
R
DIEA, DMF
R1
O
R1 NH2 Cl
N H
R
N H
R1
Ester to Alcohol
O
O R
EDC, HOBt + R1 NH2
OH
R
N H
DIEA, DMF
R1
Other coupling agents can be used such as N,N ′ -dicyclohexylcarbodiimide/ 1-hydroxybenzotriazole (DCC/HOBt), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), HATU, DIC/oxyma pure, etc.
Acid to Ketone First convert acid to acid chloride using thionyl chloride, and then use the Weinreb reaction. H N
O Cl
R1
+
Me
O
Pyridine OMe
N OMe
R1
CH2Cl2
Me
N,O-Dimethyl hydroxylamine
Weinreb amide
Ester to Acid O R
O
LiOH or NaOH O
THF/MeOH, H2O r.t.
R
OH
O O
LiOH, H2O O
OH
THF, r.t.
Ester to Aldehyde DIBAL-H
O O R1
R
R
H
O
O R
O
–78 °C,DCM
O
R1
LiAlH4 THF
R
H
Ester to Alcohol O R
DIBAL-H (excess) O R1
–78 °C, DCM
R
O
1. R2Li or R2MgX
OH
2. Acidic work-up
R1
R2
555
556
13 Functional Group Transformation
O
DIBAL-H (excess) O
–78 °C, DCM
O
LiAlH4 O R1
R
THF, 0 °C
O
MeOH, r.t.
O
R
OH
R
THF, 66 °C
O R
OH
BH3-SMe2 O R1
R
R
NaBH4 O R1
R
OH
OH
Na O
R1
R
EtOH
OH
Bouveault–Blanc reduction
Ester to Ketone O R1
OR3 + Me
H N
O
Me3Al OMe
CH2Cl2
N,O-Dimethyl hydroxylamine
Me Weinreb amide
Nitro to Amine Reduction R NH2
R NO2 H2, Pd/C R NO2
R NO2
R NH2
MeOH H2, PtO2 MeOH
R NH2
Raneynickel, hydrazine R NO2
EtOH
NO2
Fe, AcOH EtOH, reflux
N OMe
R1
R NH2
NH2
O
1. R2Li or R2MgX 2. Acidic work-up
R1
R2
Alkene to Alkane
NO2
NH2
Zn Formic acid
NO2
NH2
Sm, NH4Cl
Decaborane, NO2 Pd/C
NH2
AcOH
R NO2
Zn, AcOH
R NH2
EtOH, heat
SnCl2
R NO2
EtOH, heat
O2N
NO2
R NH2
O2N
Na2S
NH2
EtOH, H2O, r.t.
Selectively reduces one nitro group in the presence of other nitro group.
Alkene to Epoxide R
R
DCM, r.t.
O R1
m-CPBA (portionwise)
R1
DCM, r.t.
O
m-CPBA (portionwise)
Alkene to Alkane R
R
R1
H2, Pd/C MeOH, r.t.
R1
R
HCO2NH4, Pd/C R MeOH, r.t.
H2, Pd/C MeOH, r.t.
R1
R1
557
558
13 Functional Group Transformation
Alkyne to Alkane R
R1
H2, Pd/C
R1
R
MeOH, r.t.
H2, Pd/C MeOH, r.t.
Alkyne to Alkene R
H2, Pd-CaCO3
R1
R
Pb(OAc)2
R1
(Lindlar catalyst)
H3C C C CH3
H3C
H2, Pd-CaCO3 Pb(OAc)2
cis
Cyano to Carboxylic Acid O
KOH, H2O EtOH, 78 °C
R
H2O, 100 °C
OH O
HCl R CN
R
OH O
CN
10 N HCl
OH
100 °C, 6 h
O CN
1. NaOH, H2O
OH
2. Acidic work-up
Cyano to Amine [16] R CN
H2, Pd/C EtOH
H
H
(Lindlar catalyst)
R CN
CH3
R
NH2
Methyl Phenyl Ether to Phenol
LiAlH4
R CN
R
THF
NH2
LiBH4 R CN
R
NH2
R
NH2
R
NH2
R
NH2
R
NH2
Na R CN Alcohol
Diborane R CN DIBAL-H R CN
R CN
SmI2 Et3N
Cyano to Amide O Urea·H2O2
R
R CN
NH2
O
, H2SO4
1. R CN
R 2. H2O
N H
Ritter reaction O HCl R CN
40 °C
R
NH2
Methyl Phenyl Ether to Phenol [17, 18] OMe
OH BBr3 CH2Cl2, 0 °C to r.t.
OMe
HBr, H2O 100 °C
OH
559
560
13 Functional Group Transformation
OMe
NEt2 ·HCl
HS
OH
KOtBu, DMF
Toluene to Benzyl Halides O N X X
O AIBN, CCl4, heat or light X = Cl, Br, I
Alkylbenzene to Benzoic Acid O KMnO4
OH
Pyridine, H2O heat
O KMnO4
OH
Pyridine, H2O heat
(Extra carbon chains also oxidized to provide the same product.) O KMnO4
OH OH
Pyridine, H2O heat
KMnO4
O
No reaction
Pyridine, H2O heat
No hydrogens are present on benzylic carbon; therefore no reaction occurs.
Aromatic Amine to Azide NH2
t-BuONO, TMS-N3 CH3CN, 0 °C to r.t.
Mild conditions and one-pot reaction.
N3
Thioether to Sulfone
Aromatic Halide to Aldehyde [21] O
1. n-BuLi, THF, –78 °C
X
H
2. DMF X = Cl, Br, I
O I
CO, Pd(OAc)2
H
Et3SiH, Na2CO3
Aromatic Halide to Benzoic Acid [22] O
X
1. n-BuLi, THF, –78 °C
OH
2. CO2 X = Cl, Br, I O Cl
NiCl2(Ph3P)2
OH
CO2, Et4NI
Thioether to Sulfoxide R
R
S
S
m-CPBA R1
R1
S
CH2Cl2
O S R 1 R
Urea·H2O2 R
m-CPBA
O S
R1 O S
CH2Cl2
Thioether to Sulfone
R
S
m-CPBA (excess) R1
CH2Cl2
O S R 1 R O
561
562
13 Functional Group Transformation
R
S
O S R R O 1
Urea ·H2O2 R1
O S O
m-CPBA (excess)
S
CH2Cl2
Thiol to Disulfide [23–25]
R
R
R
R
S
S
S
S
Urea·H2O2
H
S
R
R
S
Organodiselenide catalyst H
R
NaI, H2O2
H
R I2
H
CH3CN
R
S
S
S
S
S
S
R
R
R
Unsymmetrical Disulfide 1. 1-Chlorobenzotriazole Ar
Ar
SH
S
R2
S
2. R2SH
Reductive Amination O H
+
NH2
1. THF or dioxane, AcOH (cat.) 2. NaBH(OAc)3 Add after 30 min, portion wise
Amine to Urea and Thiourea R─NH2 +
R1─N ═ C ═O
R DMF or DCM
H N
H N O
R1
N H
References
R─NH2
+
R─NH2 +
R1─N ═ C ═O
R1─N ═ C ═S
DIEA
R
DMF or DCM
H N
R1
O
DIEA
R
DMF or DCM
NH2
H N
H N
H N
R1
S
H N
DMF +
R─N ═ C ═O
H N
R
O
or DCM
Urea
NH2 +
R─N ═ C ═S
H N
DMF
H N
R
S
or DCM
Thiourea
Urea Formation from Two Amines Triphosgene R─ NH2
+
R─N H2 +
R1─ NH2
R1─N H2
R
H N
DIEA, DMF
CDI DIEA, DMF
H N
R1
O
R
H N
H N
R1
O
References 1 Carey, F.A. and Sundberg, R.J. (2007). Advanced Organic Chemistry. Springer. 2 Pearson, A.J. and Roush, W.R. (1999). Handbook of Reagents for Organic
Synthesis: Activating Agents and Protecting Groups. Wiley. Larock, R.A. Comprehensive Organic Transformations. Wiley-VCH, 1999. Taber, D.F. (2008). Organic Synthesis: State of the Art, 2015–2017. Wiley. Caron, S. (2011). Practical Synthetic Organic Chemistry. Wiley. Burke, S.D. and Danheiser, R.L. (1999). Handbook of Reagents for Organic Synthesis. Wiley. 7 Corey, E.J. and Link, J.O. (1992). J. Am. Chem. Soc. 114: 1906. 8 Ahammed, S., Saha, A., and Ranu, B.C. (2011). J. Org. Chem. 76: 7235. 9 Barral, K., Moorhouse, A.D., and Moses, J.E. (2007). Org. Lett. 9: 1809. (for aromatic amines to azides). 3 4 5 6
563
564
13 Functional Group Transformation
10 Stevens, R., Chapman, K.T., and Weller, H.N. (1980). J. Org. Chem. 45: 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
2030–2032. Li, L., Ni, C., Wang, F., and Hu, J. (2016). Nat. Commun. 7: 13320. Chen, J., Lin, J.-H., and Xiao, J.-C. (2018). Org. Lett. 20: 3061–3064. Ellwood, A.R. and Porter, M.J. (2009). J. Org. Chem. 74: 7982–7985. Lal, G.S., Pez, G.P., Pesaresi, R.J. et al. (1999). J. Org. Chem. 64: 7048–7054. Beaulieu, F., Beauregard, L.-P., Courchesne, G. et al. (2009). Org. Lett. 11: 5050–5053. Szostak, M., Sautier, B., Spain, M., and Procter, D.J. (2014). Org. Lett. 16: 1092–1095. Ryu, I., Matsubara, H., Yasuda, S. et al. (2002). J. Am. Chem. Soc. 124: 12946–12947. Magano, J., Chen, M.H., Clark, J.D., and Nussbaumer, T. (2006). J. Org. Chem. 71: 7103–7105. Commnorganicchemistry.com Organic Chemistry Portal. Han, W., Liu, B., Chen, J., and Zhou, Q. (2017). Synlett: 835–840. Fujihara, T., Nogi, K., Xu, T. et al. (2012). J. Am. Chem. Soc. 134: 9106–9109. Rathore, V., Upadhyay, A., and Kumar, S. (2018). Org. Lett. 20: 6274–6278. Kirihara, M., Asai, Y., Ogawa, S. et al. (2007). Synthesis: 3286–3289. Hunter, R., Caira, M., and Stellenboom, N. (2006). J. Org. Chem. 71: 8268–8271.
565
14 Synthesis of Some Drug Molecules Aspirin (acetylsalicylic acid) is used for the fever reducer and painkiller. O O
Acetic anhydride
OH
OH
O
H3PO4
OH
O Acetylsalicylic acid
Acetaminophen (paracetamol) is used for the fever reducer and painkiller. OH
OH Acetic anhydride H2SO4 (few drops)
NH2
HN
O
Acetaminophen (paracetamol)
Aceclidine is used for the treatment of glaucoma. O OH N
O Cl
O
DIEA, DCM
N Aceclidine
Dimethyl fumarate (Tecfidera) is used for the treatment of psoriasis and multiple sclerosis [1]. O
O HO
H2SO4
O
O
OH O
MeOH, reflux
O Dimethyl fumarate (Tecfidera, Fumaderm)
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.
566
14 Synthesis of Some Drug Molecules
Eletriptan is used for the treatment of depression [2]. O S O
+ N H
H Acid
NH2
N Me
O
O S O
N Me N H
Fischer indole synthesis conditions
Eletriptan
Tadalafil (Cialis) is a medicine used for the treatment of erectile dysfunction [3]. O OMe O
NH OMe
NH2
N H
CF3CO2H
O
+
H
O O
N H
CH2Cl2 Pictet–Spengler reaction
O
O
D-Tryptophan methyl ester
O Cl
Cl
NaHCO3 Me
O
O
N
OMe O
N N H
CH3OH O
N
CH3NH2
O
Cl N H
O
O
O
Tadalafil
Oxcarbazepine is a medicine for the treatment of epilepsy [4]. O OH
N R
Friedel–Crafts cyclization
O
N R
O
N H2N
O Oxcarbazepine
Synthesis of Some Drug Molecules
Fluconazole, an antifungal medication, is used for a number of fungal infections [5]. Cl
MgCl
Cl
Grignard
F + Cl
Cl O
N
OH
N N NH
F
N N
reaction
OH
N N N
F Base, solvent
F
F F Fluconazole
Lumefantrine (benflumetol), an antimalarial drug, was synthesized using Knoevenagel condensation reaction [6]. NBu2
NBu2
O
H
HO
HO NaOH
Cl
Cl
+ MeOH
Cl
Cl
Cl
Cl Lumefantrine
Pictilisib, a PI3K inhibitor, is used for the treatment of blood cancer [7]. O
O
N S N N O S O H3C
N N
N
THP N +
N
Cl B(OH)2
S
1. Suzuki coupling 2. Deprotection
N N O S O H3C Pictilisib
N N
N NH
567
568
14 Synthesis of Some Drug Molecules
Naratriptan is an antimigraine drug [8]. N N H O N S O
Heck
Br O
+
N H
reaction
S O HN
N H Pd/C H2 N H O N S O N H Naratriptan
GRN-529 is used for the treatment of autism [9]. O I OMe O F
+
Pd(PPh3)2Cl2, CuI, NH4OH, NMP
N
F
Sonogashira coupling
O
N
OMe F
O
F LiOH, THF, H2O Hydrolysis
O
N F
OH
O
F
O
N
HN
N
F
EDC, HOBt, DIEA, DMF Coupling reaction
GRN-529
O
F
Nifedipine: 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 [10].
CHO
O
O2N + 2
NO2
O OMe
+
NH3
MeO2C
CO2Me N H
Nifedipine
Synthesis of Some Drug Molecules
l-DOPA is a medicine for the treatment of Parkinson’s disease. OH
OH 1. Acid, water, heat
HO HO
+ NH4CN
H
OH
OH
Strecker
O
2. Chiral resolution reaction H2N
OH
H2N
CN
O L- DOPA
R-Lacosamide is a medication for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain [11].
(S)
OH
O
+
+ +
O
O
NC
N (R)
Ugi reaction
(S)
N H
O
H
Chiral separation
NH2
Chiral auxiliary removal O H N (R) O
N H
R-Lacosamide
Penicillin (antibiotic) derivative was synthesized using combination of Asinger + Ugi reaction [12].
O
S O R
CHO N H
+ NH3 + NaSH +
CO2Me
Br
CHO
reaction
N
O
S
Asinger
OMe
NaOH
R
THF, H2O
OH N
HN
HN
O
R O
C6H11NC R
H N
O O
S N NHC6H11 O Penicillin
569
570
14 Synthesis of Some Drug Molecules
Sildenafil (Viagra) is a medicine for the treatment of male dysfunction [13, 14].
O
O
.
O
OEt NH2NH2 H2O
EtO
H N N
O
2. NaOH H2O
O
O
1. Me2SO4
HNO3/H2SO4
N
HO
N
N
HO
N
O2N
H2O
SOCl2, NH4OH
OEt O
O N
OEt H N 2 O
O
O
Cl N
N
H2N
N H
SnCl2
N
N
O2N
H2N
Et3N, DMAP CH2Cl2
N
H2N
NaOH EtOH, H2O O O 1. ClSO3H
N
O HN
N
O HN
N N
N 2. N-Methylpiperazine EtOH
N
O S O N N Sildenafil
Aripiprazole lauroxil is used for the treatment of schizophrenia [15, 16].
Cl Cl
N
O HCHO, Et3N
N H
Cl Cl
O
N N
DMF, 80 °C
HO
N
O O
N
Lauric anhydride THF, 60 °C
Cl Cl
O
N N
O O Aripiprazole lauroxil
N O
Synthesis of Some Drug Molecules
Safinamide is used for the treatment of Parkinson’s disease [16, 17]. O H
O
F
Cl
K2CO3
H
+ HO
F
O
Tetradecyl trimethyl ammonium bromide, toluene
H2N
NH2
(S)
O Reductive amination conditions
N H
F
NH2
(S)
O
O Safinamide
Selexipag is a medicine for the treatment of pulmonary arterial hypertension [18]. O O
OH
NH2.HCl
H2N
Cl
N
N
POCl3
N
N
NaOH, MeOH
O
H2SO4 (cat)
OH
N H 190 °C O HO
O
O
N
N
O N
N
Br
N
O
N
Bu4NHSO4, KOH, benzene
NaOH, MeOH O HO
O
O S H2N O
N N N
O O S N O H
O
N N N
CDI, DBU, THF
Selexipag
571
572
14 Synthesis of Some Drug Molecules
References 1 Reddy Pullagurla, M., Rangisetty, J.B., Nandakumar, M.V., and Radha,
2 3 4
5 6 7 8 9
10 11 12 13 14 15 16 17 18
N. (2015). An improved process for the synthesis of dimethyl fumarate, WO2015140811A2. Ashcroft, C.P. (2005). Modified fischer indole synthesis of eletriptan, WO2005103035A1. Pirc, S. (2008). Conversion of tryptophan into beta-carboline derivatives, US20110105751A1. Fushimi, N., Isaji, M., and Fujikura, H. (2005). Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof, US20070197450A1. Kim, Y.F., Yoon, G.J., and Park, M.H. (1998). Process for manufacturing fluconazole, WO1998032744A1. Beutler, U., Fuenfschilling, P.C., and Steinkemper, A. (2007). Org. Process Res. Dev. 11: 341–345. Rothbaun, W. (2019). Methods of treating myeloproliferative neoplasms, WO2019224803A2. Rao, D.R., Kankan, R.N., Chikhalikar, S.V., and Ghagare, M. (2010). Process for the synthesis of naratriptan, US8735589B2. O’Nell, S.V., Zegarelli, B.M., Springer, D.M., and Li, D.Z. (2010). Bisaryl alkynylamides as negative allosteric modulators of metabotropic glutamate receptor 5 (MGLUR5), US20100273772A1. Berwe, M., Diehl, H., Rittner, K., et al. (1997). Process for preparing nifedipine, US6294673B1. Wehlan, H., Oehme, J., Schfer, A., and Rossen, K. (2015). Org. Process Res. Dev. 19: 1980–1986. Weigert, W.M., Offermanns, H., and Scherberich, P. (1975). Angew. Chem. 83: 372–378. Dunn, P.J. (2005). Org. Process Res. Dev. 9: 88–97. Terrett, N.K., Bell, A.S., Brown, D., and Ellis, P. (1996). Bioorg. Med. Chem. Lett. 6: 1819. Hsiao, T.-Y. and Huang, Y.H. (2018). Process for preparing aripiprazole lauroxil and intermediates thereof, WO2018169491A1. Flick, A.C., Ding, H.X., Leverett, C.A. et al. (2017). J. Med. Chem. 60: 6480–6515. Muthukrishna, M. and Mujahid, M. 2014. An improved synthesis of anti-parkinson agent, WO2014178083A1. Mathad, V.T., Doddappa, P.A., Kardile, P.B., et al. 2016. Process for the preparation of selexipag and intermediates thereof, WO2017042828A2.
573
15 Common Laboratory Methods Acetylation of Alcohol (patent WO2013040068A2) CO2Me
CO2Me Ac2O, DMAP
O
O
CH2Cl2
OH
OAc
A
B
A 1 l three-neck RBF equipped with a magnetic stirrer, a temperature probe, and an addition funnel was charged at room temperature, under nitrogen, with 62.88 g (0.2 mol) of A, 252 ml of dichloromethane (DCM), and 25.6 g (0.24 mol) of acetic anhydride (Ac2 O). To the stirring solution was then added dropwise at 0 ∘ C a premixed solution of 29.32 g (0.24 mol) of 4-dimethylaminopyridine (DMAP) and 252 ml of DCM over 30 minutes. The solution was stirred at 0 ∘ C for 30 minutes, and TLC analysis (hexane/EtOAc, 7 : 3) indicated complete reaction. The reaction mixture was further diluted with 252 ml of DCM and successively was washed with 300 ml of 1 N hydrochloric acid, 126 ml of 5% sodium bicarbonate, and 189 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by column chromatography to afford 66 g (92% yield) compound B.
Deacetylation (patent WO2013040068A2) CO2Me
CO2Me
Conc. H2SO4
O
O OH OAc A
MeOH, r.t.
OH OH B
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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15 Common Laboratory Methods
A 500 ml RBF equipped with a magnetic stirrer was charged at room temperature, under nitrogen, with 45.3 g (130 mmol) of A, and 136 ml of methanol was cooled to 0 ∘ C. To this stirring solution slowly was added via a pipette 0.7 ml (13 mmol) of concentrated sulfuric acid (98%) over five minutes. The mixture was allowed to stir at room temperature for 24 hours. TLC analysis (hexane/EA 3 : 7) indicated complete reaction. Followed by the addition of 25 ml 5% NaHCO3 , the mixture was concentrated to dryness. To the residue was then added 91 ml of water and 91 ml of methyl tert-butyl ether (MTBE). The mixture was allowed to stir at room temperature for 12 hours. The white suspension was collected by filtration and dried under vacuum. The white solid was further recrystallized from MTBE to afford 37.5 g (94% yield) of the diol B. Note: Alkaline medium such as LiOH or NaOH in water can remove acetyl group, but these conditions are not suitable when another methyl ester is present.
Tosylation of Alcohol (patent US9399645B2) TsCl, Et3N, DMAP O
OH
CH2Cl2, r.t.
O
O S O O
A B
To a solution of alcohol A (3.77 g, 29.0 mmol) in DCM (60 ml) Et3 N (5.65 ml, 40.5 mmol) was added followed by TsCl (6.63 g, 34.8 mmol) and DMAP (60 mg). The resulting mixture was stirred at room temperature overnight. The solution was washed with H2 O, brine, dried (Na2 SO4 ), and concentrated. Silica gel was added; then the mixture concentrated and purified by chromatography (0–30% EtOAc in hexane) to afford compound B.
Benzoylation of Alcohol (patent WO2019093776A1) O
MeO O
MeO HO HO
Benzoyl chloride, NMM, DMAP
BzO
O O A
Toluene
BzO
O O B
Toluene (168.8 l), N-methylmorpholine (20.63 kg), and dimethylaminopyridine (1.66 kg) were added to the compound A (16.9 kg) and cooled to 5 ∘ C or lower. Benzoyl chloride (23.7 l) was added dropwise while keeping the temperature at 25 ∘ C or lower. The reaction solution was heated to 75 ∘ C and stirred for six hours. After cooling to 0 ∘ C or lower, 1 N hydrochloric acid (84.4 l) was slowly added dropwise and stirred for 15 minutes. The organic layer was separated and washed successively with a 20% aqueous sodium chloride solution (50.64 l), a 5% aqueous sodium hydrogen carbonate solution (50.64 l), and water (50.64 l). Compound B (31.04 kg) was obtained by concentrating the organic layer under reduced pressure.
Desilylation (patent WO1998008849A1)
Pivaloylation of Alcohol (patent WO2019093776A1)
Pivaloyl chloride , pyridine
BzO
O
BzO
OH
MeO
OH
MeO
OH
CH2Cl2
BzO BzO
O
OPiv
B
A
Methylene chloride (102 l) and pyridine (3.72 l) were added to the compound A (10.22 kg) and dissolved therein and cooled to −5–0 ∘ C. Pivaloyl chloride (4.24 l) was added dropwise, and the mixture was stirred at 20–30 ∘ C for six hours or more. A 15% aqueous ammonium chloride solution (102 l) was added and stirred for 15 minutes or longer, and the organic layer was separated. The organic layer was washed with 1 N hydrochloric acid (51 l) and water (51 l). The organic layer was concentrate under reduced pressure and chromatographed (ethyl acetate/hexane= 1 : 4) to obtain compound B (8.39 kg, 69%).
Silylation of Alcohol (patent WO1998008849A1) (S)-1,3-Di-[(tert-butyl diethylsilyloxy)]-4-methyl-4-penten (S)
TBS-Cl, imidazole
(S)
OH
TBSO
DMF, r.t.
TBSO
A
OTBS B
To a solution of 1.11 g (4.83 mmol) of (S)-1-[(tert-butyldimethylsilyloxy)]-4methyl-4-penten-3-ol (compound A) and 855 mg (12 : 56 mmol, 2.6 equiv.) of imidazole in 15 ml of absolute DMF was added 946 mg (6.28 mmol, 1.3 equiv.) tert-butyldimethylchlorosilane. The mixture was stirred for 16 hours at room temperature. 50 ml of a 1 M aqueous solution of KHSO4 was added to the reaction mixture and extracted four times with 50 ml Et2 O. The combined ether layer was washed with brine and water and dried over anhydrous MgSO4 . After distilling off the solvent in vacuo, the residue was purified by a silica gel column with pentane/Et2 O (20 : 1) to afford compound B (98%).
Desilylation (patent WO1998008849A1) (S)-2-Methyl-1-(2-methyl-thiazol-4-yl)-hexa-1,5-dien-3-ol TBAF S
(E)
N A
S
(S)
OTBS
THF
(E)
N
(S)
OH B
575
576
15 Common Laboratory Methods
18 ml (18 mmol, 2.5 equiv.) of TBAF (1 M solution in tetrahydrofuran [THF]) in 10 ml of absolute THF stirred for 20 minutes at room temperature in order to bind the residual water TBAF solution with activated molecular sieve 4 Å. To the resulting anhydrous TBAF solution was added dropwise a solution of compound A (151 mg, 0.47 mmol) at −78 ∘ C. The mixture is allowed to warm to room temperature slowly with stirring and hydrolyzed with 50 ml of saturated NH4 Cl solution when the solution in the starting compound A was no longer detectable by thin layer chromatography. It was extracted three times with 50 ml diethyl ether. After drying over anhydrous MgSO4 , the solvent was removed in vacuo. The residue was purified with pentane/Et2 O (20 : 1) to obtain 97 mg (0.465 mmol, 99%) compound B.
Esterification (ester formation) MeOH, H2SO4
O
O OMe
OH 65 °C
Benzoic acid (610 mg) was dissolved in methanol (25 ml). Conc. H2 SO4 (0.1 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 (50 ml), and the organic layer was washed with saturated sodium bicarbonate solution (2 × 30 ml) and brine and dried (MgSO4 ). The organic layer was concentrated in vacuo to afford methyl benzoate (90% yield). Note: This method works only with simple alcohols such as MeOH, EtOH, and/or n-PrOH.
Ester Formation from Acid and Alcohol (patent US9399645B2) O MeO
O
O
OH O
DCC, DMAP
MeO
O
+ CH2Cl2 A
OH B
C
To a solution of compound A (150 g, 0.65 mol), DCC (208 g, 1 mol), DMAP (40.6 g, 0.33 mol), and 10-camphorsulfonic acid (16.3 g, 0.07 mol) in DCM (2 l) was added compound B (85 g, 0.65 mol). The mixture was stirred at room temperature overnight. Water (1 l) was added and stirring was continued for
Carboxylic Acid to Acid Chloride (patent US20070197544A1)
one hour. The mixture was filtered with celite, which was washed with EtOAc. The combined organic layers were evaporated under reduced pressure, and the residue was purified over silica gel column (7% EtOAc/petroleum ether) to afford compound C.
Carboxylic Acid to Benzyl Ester (patent WO2019134765A1) Benzyl 5-chlorovalerate (B)
Cl
O
Bn–Br
O OH A
Cl
OBn
Na2CO3, CH3CN
B
5-Chlorovaleric acid (compound A) (1 g, 7.3 mmol) and benzyl bromide (1.248 g, 7.3 mmol) were dissolved in acetonitrile. Sodium carbonate was added to the above solution. The mixture was heated to reflux under argon for 15 hours. The reaction solution was cooled and concentrated 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 compound B as a colorless oil (1.65 g, 100%).
Hydrolysis (saponification) of Ester O O
LiOH, H2O
OH
OMe THF, r.t.
A mixture of methyl benzoate (544 mg, 4 mmol), LiOH (960 mg, 40 mmol), and water (4 ml) in THF (20 ml) was stirred at room temperature until completion of the reaction (TLC monitored). The reaction mixture was acidified with 1 N HCl followed by extraction with DCM (2 × 60 ml). The combined organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to afford the pure benzoic acid (88%).
Carboxylic Acid to Acid Chloride (patent US20070197544A1) OBn O
OBn O
Thionyl chloride
Cl
OH DMF (cat) Reflux, 3 h
BnO A
BnO B
577
578
15 Common Laboratory Methods
Compound A (1 g, 3 mmol) was mixed with thionyl chloride (7.2 g, 60 mmol) and three drops of DMF. The reaction mixture was refluxed for three hours under nitrogen. After cooling down to room temperature, thionyl chloride was removed under reduced pressure. Toluene (5 ml) was then added, and the mixture was dried under reduced pressure again. This process was repeated twice to ensure all the excess of thionyl chloride was removed. Compound B was further dried under high vacuum for half an hour and was used directly in the next step without purification.
Acid Chloride to Amide (patent US20070197544A1) HO
NO2
OBn O Cl BnO
NO2
OBn O
H2N
N H K2CO3, THF, r.t.
OH
BnO
B
C
Compound B (1 g, 3 mmol) was dissolved in THF (100 ml). K2 CO3 (2 g, 15 mmol) was added followed by 2-amino-5-nitrophenol (693 mg, 4.5 mmol). The reaction mixture was allowed to stir at room temperature overnight. K2 CO3 was filtered off though filter paper. The solvent was removed under reduced pressure. Liquid–liquid extraction was performed using CHCl3 (100 ml) and H2 O (50 ml). The organic layer was dried over anhydrous MgSO4 . After MgSO4 was filtered off, the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give compound C (786 mg, 55.7% isolated yield). Note: This reaction can be performed using an organic base such as Et3 N or DIEA.
Amide Bond Formation Using Carboxylic Acid and PBr3 (patent US20070197544A1) NH2 Cl OH O OH Me2N A
NO2
OH O NO2 PBr3, xylene, reflux
N H Me2N
Cl
B
4-Dimethylamino-2-hydroxybenzoic acid (compound A, 55 mg, 300 μmol) and 2-chloro-4-nitroaniline (52 mg, 300 μmol) in xylene (4 ml) were heated to reflux. PBr3 (12 μl, 120 μmol) was added dropwise. The reaction mixture was refluxed
Ester to Carboxylic Acid (patent WO2019134765A1)
for another three hours and then cooled down to room temperature. The solvent was removed under reduced pressure. Liquid–liquid extraction with CHCl3 (4 ml) and H2 O (2 ml × 3) followed by flash chromatography purification gave compound B (71 mg, 70.6%) as a solid. Note: Aromatic amines are less reactive than aliphatic amines. Direct coupling of an aromatic amine with a carboxyl acid compound using coupling agent such as HATU, HBTU, or EDC/HOBt gives an amide compound in moderate yield. So via acid chloride or bromide to amide generally gives satisfactory yield.
Buchwald–Hartwig Amination (patent US20070197544A1) BocHN Br
Br
(S) (R)
+ NO2
N H
(S)
(R) (S)
BocHN
Toluene, 100 °C
NHBoc
NHBoc
NHBoc Pd2(dba)3, Xantphos, Cs2CO3
N
N
(R)
NHBoc
B
A
NO2 C
1,3-Dibromo-5-nitrobenzene (compound A, 140.5 mg, 0.5 mmol), (3R,5S)-3,5bis(tert-butoxycarbonylamino)-piperidine (compound B, 410 mg, 1.3 mmol), Cs2 CO3 (488.7 mg, 1.5 mmol), Xantphos (87 mg, 0.15 mmol), Pd2 (dba)3 (46 mg, 0.05 mmol), and 5 ml of anhydrous toluene were added into a 40 ml vial. N2 was purged and bubbled through the mixture for two minutes. The vial was capped with a piercing septa cap right away. A N2 balloon was then added on the cap through a needle. The reaction mixture was heated at 100 ∘ C with good stirring for 27 hours. The reaction mixture was checked by LC-MS. The mixture had 50% desired product, 45% of compound B, and 5% (by ELSD) of other undefined impurity. The reaction mixture was diluted by a mixture of CHCl3 , MeOH, and EtOAc (total 10 ml) first, and the solid was then filtered off through celite under vacuum. The majority of the excess (3R,5S)-3,5-bis(tert-butoxycarbonylamino)-piperidine (compound B) was removed by scavenger resin by adding isocyanate resin (800 mg) and heating at 80 ∘ C in THF (15 ml) overnight. After the resin was removed, the solution was concentrated down on rotary evaporator and was further purified by flash chromatography using neutral Al2 O3 (CHCl3 /MeOH/NH4 OH = 20 : 1 : 0.1). The final product (compound C) was confirmed by LC-MS with MS of 750.5 [M + 1]+ with HPLC purity of 90% by ELSD.
Ester to Carboxylic Acid (patent WO2019134765A1) O
O
NaOH, H2O HO
EtO F A
MeOH, r.t.
F B
579
580
15 Common Laboratory Methods
2-Fluoropentanoic acid (B). Compound A (350 mg, 2.3 mmol) was dissolved in a mixture of methanol (5 ml) and 1 M NaOH solution in water (5 ml). The mixture was stirred for five hours at room temperature. Then HCI (1 M) was added until acidic reaction, and the mixture was extracted with ethyl acetate (3 × 50 ml). The combined organic layers were washed with water and brine, dried over anhydrous Na2 SO4 , filtered, and evaporated to dryness in vacuo to give B (280 mg, 99%) as a colorless volatile oil. Note: Hydrolysis of some esters occurs at high temperature. Methanol or both THF and MeOH could be used as solvent.
Benzyl Ester to Carboxylic Acid (patent WO2019134765A1) 5-(Tosyloxy)pentanoic acid (B) O TsO
OBn A
O
H2, Pd/C EtOH, r. t.
TsO
OH B
To the solution of benzyl 5-(tosyloxy)pentanoate (compound A, 500 mg, 1.38 mmol) in ethanol (10 ml) was added palladium on charcoal (50 mg) under argon atmosphere. The flask was equipped with a hydrogen balloon. The gas in the flask was exchanged. After stirring vigorously for three hours at room temperature, the catalyst was filtered off through a pad of celite, and the filtrate was concentrated. The compound was obtained as a colorless oil B (360 mg, 96%).
Boc- Protection of Amino Group (patent US20090054548A1) O H N
(Boc)2O, Et3N, DMAP N
O
N N
CH3CN/MeOH r.t. B A
A mixture of amine (compound A, 970 mg, 5 mmol), (Boc)2 O (1.31 g, 6 mmol), Et3 N (1.04 ml, 7.5 mmol), and DMAP (61 mg, 0.5 mmol) was dissolved in CH3 CN (20 ml) and MeOH (5 ml). The reaction mixture was stirred at room temperature until completion of the reaction (TLC monitored). The solvents were removed
Sulfonation of Aromatic Compound (patent WO2002030878A1)
in vacuo. The residue was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to afford compound B in 85% yield.
Deprotection of Boc Group (patent US20090054548A1) O O
N
H N
TFA, CH2Cl2
N
N r.t.
B
C
Compound B (1.17 g, 4 mmol) was dissolved in CH2 Cl2 (4 ml) and TFA (4 ml) and stirred at room temperature until completion of the reaction (TLC monitored). TFA and CH2 Cl2 were removed in vacuo, and the residue was extracted with CH2 Cl2 (3 × 50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (2 × 50 ml) and brine (2 × 40 ml) and died over anhydrous MgSO4 . The organic layer was concentrated in vacuo to give compound C in 80% yield.
Sulfonation of Aromatic Compound (patent WO2002030878A1) CH3
CH3
CH3
SO3H
SO3
+
Ionic liquid, r.t. A
SO3H
C
B
In a round-bottom flask (25 ml) equipped with a magnetic stirrer flea and stopper, l-decyl-3-methylimidazolium trifluoromethanesulfonate (ionic liquid) (0.97 g, 2.5 mmol) and toluene (compound A, 0.46 g, 5.0 mmol) were added. Sulfur trioxide (0.44 g, 5.5 mmol) was cautiously added (carried out in a dry box), and the mixture was stirred for one hour. A crude sample was taken from the flask and analyzed by 1 H NMR (CDC13 , 300 MHz). This showed that the reaction was complete and gave 77% of p-toluenesulfonic acid (compound B) and 22% o-toluenesulfonic acid (compound C). The products were isolated from the ionic liquid by Kugelrohr distillation at 1 mmHg. This gave colorless solid (b.p. 200 ∘ C at 1 mmHg). The structures were confirmed by NMR analysis and were in accordance with authentic material.
581
582
15 Common Laboratory Methods
Nitration of Aromatic Compound (mild and noncorrosive conditions) (patent WO1994019310A1) OH
OH Claycop, acetic anhydride
NO2
CCl4, r.t. CH3
CH3 A
B
Freshly prepared claycop (copper(II) nitrate trihydrate in montmorillonite clay K-10, 2.4 g) was suspended in a mixture of carbon tetrachloride (30 ml) and Ac2 O (15 ml) and stirred at room temperature for about 45 minutes. p-Cresol (1.08 g, 10 mmol) was added and stirring was continued at room temperature for 15 minutes. The resulting mixture was filtered; then the filter cake was washed with organic solvent. The combined organic portions were washed with water and dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude product. The crude was crystallized in methanol–ether to obtain a pure product B in 80% yield.
Nitration of Aromatic Compound (regular method) Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate O
O MeO
OMe
HO
HNO3
MeO
OMe
HO
AcOH, r.t.
NO2
A
B
Fuming nitric acid (3.6 ml) was added slowly to a mixture of A (9 g, 49.4 mmol) and acetic acid (63 ml) at 0 ∘ C. After the addition, the reaction mixture was stirred at room temperature for six hours. The reaction mixture was quenched with ice-cold water, and the resulting solid was filtered, washed with water, and dried to obtain pure compound B (7 g, 62.5%) as a yellow solid.
Nitration of Aromatic Compound (regular method) (patent WO2016118450A1) OMe HNO3
OMe NO2
Acetic anhydride A
NO2 B
Reduction of Nitro Group by Hydrogenation (patent US6329380B1)
Concentrated nitric acid (2.96 g, 47 mmol, 2 ml) was added dropwise to Ac2 O (5 ml, 5.4 g, 53 mmol) at 0 ∘ C with stirring. After 10 minutes, a solution of compound A (1.08 g, 10 mmol) in Ac2 O (1 ml) was added dropwise. The reaction mixture was allowed to reach to room temperature. After stirring overnight, the reaction mixture was poured into water (50 ml) and stirred for one hour. The crude solid was filtered and crystallized from 20% EtOAc/hexane to afford compound B (1.62 g, 8.2 mmol) in 82% yield as colorless needles.
Reduction of Nitro Group (patent WO2018167800A1) Preparation of 4-bromo-N-2-(oxetan-3-yl)benzene-l,2-diamine (B) Br
Br O
NO2
N H
NH4Cl, Zn
O
THF/MeOH NH2
A
N H
B
To a solution of compound A (0.4 g, 1.47 mmol) and ammonium chloride (0.39 g, 7.35 mmol) in THF/MeOH (1 : 1, 8 ml) at 0∘ C, zinc dust (0.48 g, 7.35 mmol) was added. The reaction mixture was stirred at room temperature for three hours. After completion of the reaction, it was filtered through celite and washed with EtOAc (10 ml × 3). The combined organic layers were washed with water (30 ml × 2) and brine (30 ml), dried over anhydrous Na2 SO4 , filtered, and concentrated under reduced pressure to provide the desired product B (0.37 g, quantitative yield) as a brown oil.
Reduction of Nitro Group by Hydrogenation (patent US6329380B1) O2N
A
N
H2, Pd/C
N H
THF
H2N
N N H B
To a stirred solution of 5-nitrobenzimidazole A (1 g, 6.13 mmol, 1 equiv.) in THF (100 ml) was added 10% palladium on carbon (385 mg). The flask was purged with H2 , and the mixture was stirred under a balloon of H2 for several hours. The flask was purged with N2 . The catalyst was filtered through a pad of celite and washed with MeOH. The solution was concentrated under reduced pressure to afford 800 mg of the desired product B (98%).
583
584
15 Common Laboratory Methods
Reduction of Nitro Group Using Hydrazine Raney Nickel (patent US20070197544A1) O2 N
O
OH
OBn
Hydrazine monohydrate, Raney nickel
N H OBn
H2N
O
THF/MeOH, r.t.
OH
OBn
N H OBn B
A
Compound A (470 mg, 1 mmol) was dissolved in MeOH (15 ml) and THF (15 ml). Raney nickel (50% slurry in water) (2 ml) was added to the reaction mixture followed by hydrazine (1 ml). The reaction mixture was stirred at room temperature for 30 minutes until the bubbling was stopped. The solid was filtered off through celite under reduced pressure and washed with MeOH. The solvent was removed under reduced pressure. Liquid–liquid extraction was performed using CHCl3 (15 ml) and H2 O (8 ml × 2). The organic layer was dried over anhydrous MgSO4 , filtered, and concentrated to give compound B (263.8 mg, 59.9% crude yield). Note: Regular method H2 , Pd/C can remove benzyl group also, hard to control.
Reduction of Nitro Group Using Fe and NH4 Cl (patent US20070197544A1) O
N H
H N O A
O
OH
H N
Fe, NH4Cl NO2
EtOH, reflux
N H
O
OH
NH2 B
Compound A (1.36 g, 4.18 mmol), Fe powder (702.2 mg, 12.54 mmol), 25 ml of EtOH, and saturated NH4 Cl (15 ml) were mixed. The mixture was refluxed for 3.5 hours. TLC result confirmed the completion of the reaction. The reaction mixture was concentrated on a rotary evaporator without filtering off the iron powder. The residue was directly added on a silica gel column and was purified by flash chromatography using 100% EtOAc as eluting solvent to give 1.065 g (86.6% isolated yield) desired product (compound B) as a yellow solid with HPLC purity of 100% by ELSD.
Reduction of Ester to Alcohol (patent US9399645B2)
Reduction of Ketone with NaBH4 (patent WO2013040068A2) CO2Me
CO2Me NaBH4 O
O
MeOH, –10 °C
O
OH
A
B
A 3 l three-neck RBF equipped with a magnetic stirrer, a temperature probe, and an addition funnel was charged at room temperature, under nitrogen, with 157.2 g (0.5 mol) of compound A and 786 ml of methanol. The reaction solution was cooled to 0 ∘ C, and while stirring slowly, a total of 18.92 g (0.5 mol) of sodium borohydride was added in portions over 30 minutes. During the addition the temperature was maintained below −5 ∘ C. The reaction mixture was allowed at −10 ∘ C for another one hour, and TLC analysis (hexane/EtOAc, 7 : 3) indicated complete reaction. The mixture was quenched at −10 ∘ C with 157.2 ml of 3 N hydrochloric acid over 10 minutes and allowed to stir at room temperature for 10 additional minutes. The reaction mixture was concentrated by rotary evaporation and extracted with 2 × 755 ml (1570 ml total) of MTBE. The combined extracts were successively washed with 414.4 ml of 5% sodium bicarbonate and 314.4 ml of brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 134.5 g (85% yield) compound B.
Reduction of Ester to Alcohol (patent US9399645B2) O
LiAlH4 OMe
OH THF, 0 °C
O A
O B
A solution of ester (compound A, 22.0 g, 152.8 mmol) in THF (220 ml) at 0 ∘ C was treated portionwise with a solution of LiAIH4 (11.6 g, 305.6 mmol) in THF (260 ml) under a nitrogen atmosphere. The mixture was stirred at 0 ∘ C for 30 minutes, and then the cooling bath was removed. Stirring was continued for three hours, and the solution was recooled to 0 ∘ C and treated with 5 M NaOH (48.5 ml). The solid was filtered and washed with THF, and the combined filtrates were concentrated in vacuo to give compound B.
585
586
15 Common Laboratory Methods
Reduction of Ester to Alcohol with DIBAL-H (patent WO2016037566A1) OTBS
OTBS MeO
O
MeO
OEt
DIBAL-H
MeO
CH2Cl2, –78 °C
MeO
OH OMOM
OMOM A
B
DIBAL-H (2.15 ml, 2.37 mmol) was added in the solution of compound A (436 mg, 0.95 mmol) with 10 ml CH2 Cl2 at −78 ∘ C. After completion of the reaction, MeOH was added to quench the excess DIBAL-H, followed by 5 ml; 1.2 M sodium potassium tartrate was added and allowed to warm up to room temperature. The mixture was extracted with CH2 Cl2 (3 × 20 ml), and the combined layer was dried by anhydrous sodium sulfate and concentrated; then it was purified by column chromatography on silica gel (hexane/ethyl acetate, 4 : 1) to give alcohol compound B (346 mg, 87% yield).
Ester to Aldehyde (patent US20190337964A1) H
O O OEt
O
H
OTBS I
H DIBAL-H
OTBS H
OTBS
Toluene, –65 °C
O O
O
H
OTBS I OTBS
H
OTBS
H
Compound A (1 g) was dissolved in toluene (14 ml) and cooled to −65 ∘ C or lower. 1.2 M DIBAL-H (1.4 ml) was added dropwise thereto with maintaining the temperature of −65 ∘ C or lower and stirred for 30 minutes, followed by confirming the completion of the reaction (TLC). Methanol (0.15 ml) was added dropwise thereto, and 1 N hydrochloric acid (10 ml) and MTBE (4 ml) were added thereto, followed by stirring for 30 minutes. The organic layer was separated and washed with 1 N hydrochloric acid (10 ml), water (10 ml), saturated sodium bicarbonate (10 ml), and saturated sodium chloride solution (10 ml). Sodium sulfate was added to the organic layer, followed by filtration and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate/hexane= 1 : 8) to give compound B (890 mg, 94.6%). Note: If excess DIBAL-H is used, then ester converts to primary alcohol.
Oxidation of Primary Alcohol Using TEMPO (patent US10407378B2)
Selective Oxidation of Primary Alcohol (patent WO2013040068A2) CO2Me
CO2Me MnO2 O
O
CH2Cl2, r.t.
O
OH
H OH
OH A
B
A 500 ml three-neck RBF equipped with a mechanical stirrer and a temperature probe was charged at room temperature and under nitrogen with compound A (10 g, 30.1 mmol), MnO2 (13 g, 150 mmol), and 100 ml of DCM. The solution was stirred at 20 ∘ C for 20 hours, and TLC analysis (hexane/EtOAc 7 : 3) indicated complete reaction. The mixture was filtered and concentrated to dryness to afford 9.4 g of (95% yield) compound B.
Oxidation of Alcohol Using DMP OH
O DMP
H
CH2Cl2
To a solution of benzyl alcohol (540 mg, 5 mmol) in DCM was added Dess–Martin periodinane (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 (MgSO4 ), and concentrated in vacuo. The residue was chromatographed over silica gel to afford a pure product as a solid (88%).
Oxidation of Primary Alcohol Using TEMPO (patent US10407378B2) H O OH
KBr, TEMPO, NaOCl Toluene
A
B
587
588
15 Common Laboratory Methods
In a nitrogen atmosphere, [(1S*,2S*)-1-methyl-2-((R*)-1-phenylethyl)cyclopropyl] methanol (compound A, 1.02 g, 5.37 mmol), potassium bromide (0.36 g), 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) (0.085 g), and toluene (10 ml) were placed in a 100 ml flask equipped with a stirrer, a dropping funnel, and a thermometer and cooled to 0 ∘ C. An aqueous sodium hypochlorite solution (concentration: approximately 13.5%, 5.0 g, 0.0091 mol) was placed in the dropping funnel and added dropwise with the temperature at 0 ∘ C. After completion of the dropwise addition, the temperature was raised to 18 ∘ C for one hour. After that, the aqueous layer was separated, and the organic layer was washed with a 10% aqueous sodium thiosulfate solution and with water. The solvent was removed under reduced pressure to obtain a (1S*,2S*)-1-methyl-2-[(R*)-1-phenylethyl]cyclopropane-1-carbaldehyde (compound B, 0.91 g, 0.0048 mol, 89%).
Benzylation of Phenol OH +
O
K2CO3
I
Acetone, reflux A
C
B
A mixture of compound A (540 mg, 5 mmol), compound B (1.3 g, 6 mmol), and anhydrous K2 CO3 (1.03 g, 7.5 mmol) in acetone (25 ml) was stirred at 56 ∘ C for eight hours. Acetone was removed under reduced pressure. The residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified over silica gel column chromatography (5% ethyl acetate in hexane) to give a pure product C in 85% yield. Note: If benzyl chloride or benzyl bromide is used instead of benzyl iodide, then add 10 mol% of KI as these are less reactive than the corresponding iodides. The reactivity pattern is as follows: I > Br > Cl. This type of reaction can be performed in DMF at 80 ∘ C or higher temperature to shorten the reaction time.
Debenzylation by Hydrogenation (Patent WO1994028886A1) CO2Me
CO2Me H2, Pd/C
+
O
OH
Ethyl acetate A
B
H3C
Methylation of Phenol
The starting material (500 mg) was hydrogenated by catalytic reduction over 10% palladium–charcoal (130 mg) in ethyl acetate (50 ml) containing concentrated sulfuric acid (10 drops). The reaction mixture was stirred at room temperature under hydrogen for one day. The mixture was then filtered through a pad of celite, and solvent evaporated and purified by the column chromatographic method to give a pure product.
Iodination of Aromatic Compound (patent US7951832B2) H N
H N
KOH, I2 N
N DMF, r.t.
A
B
I
Compound A (indazole, 1.18 g, 10 mmol) was dissolved in DMF (10 ml). KOH (840 mg, 15 mmol) and iodine (2.52 g, 20 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for two hours. 1 N HCl was added to the reaction mixture followed by extraction with ethyl acetate (3 × 100 ml). The combined organic layer was washed with water (4 × 100 ml) and brine (4 × 100 ml). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give compound B in 90% yield.
Methylation of Phenol Methyl 3,4-dimethoxy-5-nitrobenzoate O
O MeO
OMe
HO NO2 A
(CH3)2SO4, K2CO3
MeO
Acetone, 60 °C
MeO
OMe
NO2 B
Dimethyl sulfate (13 g, 105.7 mmol) was added to a suspension of compound A (8 g, 35.2 mmol) and potassium carbonate (14.5 g, 105.7 mmol) in acetone (90 ml) at room temperature and stirred at 60 ∘ C for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. Separated organic layer was dried over anhydrous Na2 SO4 and concentrated under reduced pressure to give crude material. The crude was purified by silica gel column chromatography using 10% ethyl acetate in hexane as eluent to afford compound B (6.5 g, 77%) as a pale brown solid.
589
590
15 Common Laboratory Methods
Demethylation to Phenol (patent US6924310B2) HO
MeO BBr3
O
O CH2Cl2, r.t. NO2
NO2 B
A
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (compound A, 500 mg, 1.59 mmol) in CH2 Cl2 (12 ml) was added boron tribromide (1 M in CH2 Cl2 , 3.2 ml, 3.2 mmol). The resulting mixture was stirred one hour at room temperature and then quenched with water (15 ml) and 1 N HCl (10 ml). After stirring 30 minutes at room temperature, the solution was extracted with CH2 Cl2 (3 × 20 ml). Combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound B (75%).
Bromide to O-Benzyl (patent WO2019134765A1) O
O
Bn-OH, NaH
EtO DMF, 0 °C
Br
EtO OBn
A
B
Ethyl 2-(benzyloxy)pentanoate (B) Ethyl 2-bromopentanoate (A, 1.01 g, 4.83 mmol) was dissolved in dry DMF, and BnOH (522 mg, 4.83 mmol) was added. The resulting solution was cooled down to 0∘ C before NaH (60% suspension in paraffin oil, 232 mg, 5.80 mmol) was added portionwise. After complete addition the reaction mixture was stirred for one hour at 0∘ C and then for 23 hours at room temperature. After careful addition of water, the mixture was extracted with ethyl acetate (3 × 50 ml). The combined organic layers were washed with water, saturated NaHCO3 solution (2 × 50 ml), and brine, dried over anhydrous Na2 SO4 , filtered, and evaporated to dryness in vacuo to yield compound B (1.14 g, quantitative) as a colorless oil.
Tosylate to Fluoride (patent WO2019134765A1) O TsO
KF, 18-crown-6 OBn
A
O F
DMF, 110 °C
Benzyl 5-fluorovalerate (B)
OBn B
Ozonolysis of Alkene (patent WO2013040068A2)
A mixture of benzyl 5-(tosyloxy)pentanoate (compound A, 500 mg, 1.38 mmol), potassium fluoride (80 mg, 1.38 mmol), and 18-crown-6 (364 mg, 1.38 mmol) in dry DMF (10 ml) was stirred overnight at 110 ∘ C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine (4 × 50 ml) and water (4 × 50) in several times to remove DMF, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified via column chromatography (petroleum ether/ethyl acetate 10 : 1). The fluoride compound B was obtained as a colorless oil (40 mg, 14%).
Iodide to Tosylate (patent WO2019134765A1)
I
O
AgOTs
O
TsO
OBn
OBn
CH3CN, r.t. in darkness
A
B
Benzyl 5-(tosyloxy)pentanoate (B) To the cooled solution of benzyl 5-iodovalerate (compound A, 3.6 g, 11.3 mmol) in acetonitrile (10 ml) was added silver tosylate (3.46 g, 12.4 mmol). The resulting solution was protected from light (aluminum foil) and was stirred at room temperature overnight. The solid was filtered off. The solvent was removed under vacuum. The residue was diluted in ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified via column chromatography (petroleum ether/ethyl acetate, 3 : 1). The compound B was obtained as a colorless oil (2.03 g, 49.5%).
Ozonolysis of Alkene (patent WO2013040068A2) CO2Me
CO2Me 1. O3, –78 °C 2. Ph3P, –20 °C O
CH2Cl2
O O
OAc OAc A
OAc
H
B
A 2 l three-neck RBF equipped with a magnetic stirrer, a gas inlet, temperature probe, and a dry ice–acetone bath, charged with compound A (41.7 g, 100 mmol), 800 ml of DCM, and 200 ml of methanol was cooled to −78 ∘ C. The stirring solution was purged with ozone, generated by PCI-WEDECOTM ,
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15 Common Laboratory Methods
Model GLS-1 Ozonizer, at 10 psi pressure with 3 ft3 /h oxygen flow and 4% ozone (O3 ) in oxygen, over 40 minutes. During ozonolysis the temperature was maintained below−70 ∘ C. TLC analysis (hexane/EtOAc, 1 : 1) (a reaction sample was quenched with Ph3 P) indicated complete reaction. The mixture was purged with nitrogen gas for one hour while it was allowed to warm to −20 ∘ C. To the stirring solution, under nitrogen, slowly was added 12.5 g (220 mmol) of triphenylphosphine in portions over 30 minutes. The reaction mixture was stirred for 30 minutes while it was allowed to further warm to 0∘ C, and TLC analysis (hexane/EtOAc, 1 : 1) indicated complete reaction. The mixture was diluted with 400 ml of water and continued to stir for 30 minutes, followed by layer separation. The aqueous layer was back extracted with 400 ml of DCM. The combined organic extracts were concentrated to dryness. The residue was diluted in 500 ml of MTBE/hexane (1 : 4) and washed twice with 250 ml of water/methanol (1 : 2), and the layers were separated. The aqueous layer was checked for the absence of product. The organic layer was successively washed with 500 ml of brine/water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was further dried under vacuum to afford compound B (35 g. 100% yield).
Asymmetric Dihydroxylation of Alkene (Sharpless Method) (WO2019093776A1) O
MeO
O
potassium ferricyanide, potassium carbonate
HO
O A
HO
Butanol, 0 °C
O
MeO
(DHQ)2 AQN, potassium osmate dihydrate,
O O B
(DHQ)2 AQN (291.4 g), potassium ferricyanide (76.12 kg), and potassium carbonate (32 kg) were added after dissolving the compound A (14.6 kg) in 1-butanol (1 l). Potassium osmate dihydrate (75.2 g) was added so that the temperature did not exceed 0∘ C, and the mixture was stirred for 18 hours. Sodium thiosulfate (37.6 kg) was added to the reaction solution, and the mixture was heated to room temperature and stirred for 15 hours. Toluene (218.6 l) was added and stirred for 15 minutes, and then the organic layer was separated. 20% aqueous solution of sodium chloride (145.7 l) was added to the organic layer, and the mixture was stirred for 15 minutes. The organic layer was separated and concentrated under reduced pressure to obtain compound B (16.88 kg).
Alcohol to Fluoride (WO2019134765A1) O
O
DAST
EtO OH A
CH2Cl2, –78 °C
EtO F B
Alcohol to Bromide (patent WO2016037566A1)
Ethyl 2-fluoropentanoate (B) Compound A (1 g, 6.84 mmol) was dissolved in dry DCM and the solution was cooled to −78 ∘ C. Then diethylaminosulfur trifluoride (DAST) (1.22 g, 7.57 mmol) was added portionwise, and the reaction mixture was stirred at −78 ∘ C for two hours. Then the reaction mixture was allowed to reach room temperature, and it was stirred for 48 hours. Then ice water was added carefully, and the mixture was extracted with ethyl acetate (3 × 60 ml). The combined organic layers were washed with water, saturated NaHCO3 solution (2 × 70 ml) and brine, dried over anhydrous Na2 SO4 , filtered, and evaporated to dryness in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 98/2, Rf = 0.35) to yield compound B (380 mg, 37%) as a colorless oil.
Alcohol to Iodide (patent US9399645B2) Ph3P, Imidazole, I2
(S)
(S)
OH
O
THF/CH3CN
I
O B
A
To a stirring solution of compound A (20.0 g, 172.4 mmol) in THF (1 l) and CH3 CN (400 ml) were added Ph3 P (67.6 g, 258.0 mmol), imidazole (17.5 g, 258.0 mmol), and I2 (65.5 g, 258.0 mmol) at 25 ∘ C. The mixture was stirred at 25 ∘ C for two hours, and then the solvent was evaporated in vacuo. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (1–5% EtOAc in petroleum ether) to afford compound B.
Alcohol to Bromide (patent WO2016037566A1) OTBS OTBS MeO OH
MeO
CBr4, Ph3P,
MeO
CH2Cl2, 0 °C
MeO
Br OMOM
OMOM B
C
Ph3 P (240 mg, 0.9 mmol) and CBr4 (300 mg, 0.9 mmol) were added in the solution of alcohol B (346 mg, 0.83 mmol) with 8 ml CH2 Cl2 at 0 ∘ C and stirred for 10 minutes. The mixture was quenched with saturated aqueous NaHCO3 solution, and organic layer was separated. The solvent was concentrated under reduced pressure and then purified by column chromatography on silica gel (hexane/EtOAc, 9 : 1) to give bromo compound C ((E)-(5-(4-bromo-3-methylbut-2-enyl)-2,3-dimethoxy-4-(methoxymethoxy) cyclohexyloxy) (tert-butyl)dimethylsilane) (381 mg, 0.8 mmol), yield 96%.
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15 Common Laboratory Methods
Alcohol to Iodide via Tosylation (patent WO2016037566A1)
Ts-Cl, DIEA OH CH Cl 2 2
MeO
OTBS
OTBS
OTBS MeO
NaI
MeO OTs
MeO
OH
OH
A
B
MeO I
Acetone, reflux MeO OH C
The TsCl (0.69 g, 3.60 mmol) was added in a solution of compound A (0.95 g, 3.28 mmol) and DIEA (0.86 ml, 4.91 mmol) with 10 ml CH2 Cl2 at 0 ∘ C. The reaction mixture was stirred at room temperature for 12 hours. It was washed with 1 N HCl and saturated aqueous solution of sodium bicarbonate. The solvent was removed to give compound B. Compound B was dissolved in 15 ml acetone. NaI (1.23 g, 8.18 mmol) was added to the reaction mixture and refluxed for 15 hours. Acetone was removed under reduced pressure, and the residue was diluted with ether, washed with water, dried over anhydrous MgSO4 , and concentrated to give crude product that was purified with column chromatography to afford compound C (1.12 g, 86%).
Alkene to Aldehyde (patent WO1998008849A1) O
O
NaIO4, OsO4 THF
A
H
O
O
O B
To a solution of 286 mg (1.55 mmol) of the acetonide A in 18 ml THF, 14 ml of aqueous phosphate buffer pH 7 was added. To the vigorously stirred reaction mixture, 400 μl (0.031 mmol, 0.02 equiv.) OsO4 solution was added dropwise (in tert-butanol 2.5% strength). After 10 minutes, 996 mg (4.656 mmol, 3 equiv.) NaIO4 was added portionwise over a period of 20 minutes. The mixture was stirred vigorously at r.t., and after 24 and 48 hours, respectively, further 332 mg NalO4 was added. After 55 hours the phases were separated. The aqueous phase was extracted with ether; the combined organic phases was dried over anhydrous MgSO4 and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to give 221 mg (1.19 mmol) an aldehyde B in 76% yield.
Azide to Amine (patent US6329380B1)
Amine to Azide via Diazotization (patent WO20030135050A1) NH2
F
N3
1. HCl, NaNO2, H2O F
2. NaN3, H2O
A
F
F B
3,5-Difluoroaniline (64.5 g, 0.5 mol) (compound A) was added to a solution of water (206 ml) and concentrated hydrochloric acid (116 ml). The resulting solution was stirred for 10 minutes and cooled to 0 ∘ C. A solution of sodium nitrate (37.4 g, 0.54 mol) in water (125 ml) was added in a dropwise manner. After stirred for one hour, the mixture was filtered and the filtrate was cooled to 0 ∘ C. A solution of sodium azide (40.2 g, 0.62 mol) in water (125 ml) was added in a dropwise manner, and stirring was allowed to continue for 30 minutes. The reaction mixture was extracted with ether (3 × 250 ml), and the combined organic extracts were washed with saturated sodium bicarbonate solution (250 ml) and then brine (250 ml) and dried over anhydrous sodium sulfate. Removal of the volatiles in vacuo compound B was afforded as a yellow liquid (70 g, 90%).
Azide to Amine (patent US6329380B1) NH2
N3 NCbz
Ph3P
NCbz
THF, H2O A
B
To a solution of 3-(1-azidoethyl)-1-(benzyloxycarbonyl)piperidine (compound A, 1.95 g, 6.76 mmol) in THF (30.6 ml) was added Ph3 P (2.66 g, 10.14 mmol) followed by water (3.4 ml). The mixture was placed in an oil bath at 50 ∘ C for 2.5 hours. The reaction mixture was cooled and carefully poured into an Erlenmeyer flask containing 1 N HCl. The layers were separated, and the aqueous layer was washed once with EtOAc, and the organic extracts were discarded. The aqueous layer was then neutralized with saturated aqueous NaHCO3 carefully and was extracted with EtOAc (3 × 30 ml), and the organic extracts discarded. The aqueous layer was made strongly basic (>pH 12) with 5 N NaOH; then it was extracted with EtOAc (4 × 50 ml). The combined organic layer was washed with water (3 × 50 ml) and brine (2 × 50 ml) and dried over anhydrous MgSO4 . The organic layer was concentrated in vacuo, and the residue was purified over silica gel column (hexane/ethyl acetate solvent system) to afford compound B (80% yield).
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15 Common Laboratory Methods
Reductive Amination (patent WO2005118525A1) O O
ClH.HN O
H
Na(CH3COO)3BH
O
N
+
O
CH2Cl2
A
B
C
To a solution of 31.76 g (compound A, hydrochloride salt (150 mmol) in 600 ml DCM were added 15.94 g triethylamine (157.5 mmol) and 17.51 g benzaldehyde (B) (165 mmol), and the clear light orange solution was stirred at room temperature for one hour. 40.16 g sodium triacetoxyborohydride (180 mmol) was added under ice cooling, and the white suspension was stirred at room temperature for 24 hours. The reaction mixture was washed with 600 ml 10% Na2 CO3 and twice with 300 ml 10% brine. All three aqueous layers were extracted sequentially with 300 ml DCM, and the combined organic layers were dried over anhydrous Na2 SO4 . Filtration and removal of the solvent by rotary evaporation (45 ∘ C/>10 mbar) gave 41.3 g orange oily residue. Purification by vacuum distillation gave 38.4 g (96.5%) product C as a colorless oil, b.p. 85–87 ∘ C/0.05 mbar. Note: Triethylamine was used because amine was HCl salt – otherwise no needed triethylamine. If free amine, add few drops of acetic acid after addition of aldehyde to facilitate the imine formation.
Asymmetric C-Alkylation (patent WO2005118525A1) O
O N
(S)
Bn
O
O
(R) (E)
N
(E) (S)
then (E)
A
O
1. NaHMDS (1.1 equiv.), THF
O
Bn
(E)
Br (2 equiv.) B TBAI (0.1 equiv.)
C
To a THF solution (12.0 ml) containing (S)-4-benzyl-3-propionyloxalizolidin-2one (compound A, 1.12 g, 4.81 mmol), sodium bis(trimethylsilyl)amide in THF (1.0 M, 9.6 ml, 9.61 mmol) was added dropwise at −78 ∘ C. After the reaction mixture was stirred at −78 ∘ C for 15 minutes, (2E, 4E)-1-bromohexa-2,4-diene (compound B, 1.55 g, 9.61 mmol) and tetrabutylammonium iodide (TBAI) (177 mg, 0.481 mmol) were added, and the mixture was warmed to room temperature and stirred for one hour. Saturated aqueous ammonium chloride solution was added to the reaction system at 0 ∘ C to stop the reaction, ethyl acetate was added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography, and (S)-3-((R, 4E, 6E)-2-methylocta-4,6-dienoyl)-4-benzyloxazolidine-2-one (compound C) (1.31 g, 87%) was obtained.
Free Radical Reaction (patent WO2013040068A2)
Aldehyde to 1,1-Difluoroalkane (WO2018167800A1) MeO
MeO
O
O DAST O
O
O H
CH2Cl2, r.t.
F F
Br
Br B
A
Synthesis of methyl 2-[3-[4-bromo-2-(difluoromethyl)phenoxy]phenyl]acetate To a solution of compound A (1.5 g, 4.3 mmol) in anhydrous CH2 CI2 (15 ml) was added DAST (1.3 g, 8.3 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, volatiles were removed under reduced pressure, and it was diluted using water (30 ml). Extraction was carried out using EtOAc (30 ml × 3); the combined organic layers were washed with saturated NaHCO3 solution (50 ml) and brine (50 ml), dried over anhydrous Na2 SO4 , filtered, and concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography (0–20% EtOAc in hexane) to provide the desired product B (1.5 g, 94% yield).
Free Radical Reaction (patent WO2013040068A2) CO2Me
CO2Me n-Bu3SnH, AIBN O
Br
O A
Toluene, 100 °C
O
O B
A 12 l three-neck RBF equipped with a magnetic stirrer, a temperature probe, and a 2 l addition funnel was charged at room temperature, under nitrogen, with 200 g (0.51 mol) of compound A and 5 l of toluene. The stirring solution was degassed three times by introducing nitrogen each time before it was heated to 100∘ C. To this stirring solution slowly was added at 100∘ C, via the addition funnel, a solution made up with 205 g (0.76 mol) of tributyltin hydride and 1.8 g (11 mmol) of azobisisobutyronitrile (AIBN) in 1 l of toluene over 3.5 hours. The mixture was stirred at 100 ∘ C for additional three hours at which time TLC analysis (DCM/hexane/EtOAc, 5 : 4.5 : 0.5) indicated complete reaction. The mixture was concentrated to dryness and purified by silica gel column chromatography
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15 Common Laboratory Methods
to afford 103 g (64% yield) of the desired product B as well as 44.1 g (27.5% yield) of its epimer.
Umpolung Electrophilic carbon O
O R
R
H
H Nu
Nu Electrophilic carbon SH
O R
H
n-BuLi
SH
Lewis acid CH3CN
S R
S THF
H
1, 3-dithiane
R1 Br S R
S R
S
S R1
Nucleophilic carbon Reversal of polarity Umpolung
Silylation of 1,3-Dithiane (C-Silylation) (Model reactions for education purpose only)
n-BuLi, Ph2MeSiCl S
S
H
H A
THF, 0 °C
S Ph Ph Si Me
S H B
To a solution of compound A (601 mg, 5 mmol) in anhydrous THF (5 ml) was added n-BuLi (3.4 ml, 1.6 M in hexane) dropwise over 30 minutes at 0 ∘ C under argon. Diphenylmethylchlorosilane (Ph2 MeSiCl) (1.16 g) in THF (2 ml) was added dropwise to the reaction mixture at 0 ∘ C. The resulting reaction mixture was stirred for another one hour at the same temperature. The reaction mixture was quenched with water (100 ml) and was extracted with ether (3 × 50 ml). The combined ether layer was washed with water (2 × 50 ml) and brine (2 × 50 ml). The ether layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (5–10% ethyl acetate in hexane) to afford compound B (70% yield).
Preparation of Grignard Reagent and Reaction with an Aldehyde
Alkylation on 2-Diphenylmethyl-1,3-Dithiane Synthesis of 2-(3-(2,5-dioxacyclopentyl)propyl)-2-diphenylmethyl-1,3-dithiane (compound D) n-BuLi, HMPA
O S
S
Ph Ph Si Me
H
+
S
Br O
Ph Ph Si Me
THF, –78 °C
C
B
O
S
O D
To a solution of compound B (1.58 g, 5 mmol) in anhydrous THF (5 ml) was added n-BuLi (3.4 ml, 1.6 M in hexane) dropwise over 30 minutes at −78 ∘ C under argon. The resulting reaction mixture was stirred for another 30 minutes followed by addition of HMPA (5 equiv.). To the resulting reaction mixture, 2-(3-bromopropyl)-1,3-dioxolane (compound C, 0.81 ml) was added dropwise over 20 minutes. The reaction mixture was stirred at −78 ∘ C for another two hours and then let warming up to room temperature one hour further. The reaction mixture was poured into 100 ml water and followed by extraction with ether (3 × 50 ml). The combined organic layer was washed with water (2 × 50 ml) and brine (2 × 50 ml), dried over anhydrous MgSO4 , and concentrated in vacuo. The residual liquid was chromatographed over silica gel (5–10% ethyl acetate in hexane) to afford compound D in 85% yield.
Deprotection of 1,3-Dioxolane Synthesis of (1-diphenylmethylsilyl-2,6-dithiacyclohexyl)butanal (compound E) S Ph Ph Si Me
TsOH
O
S
S O
D
Acetone, H2O
Ph Ph Si Me
S
O H
E
A mixture of compound D (2.15 g, 5 mmol) and TsOH monohydrate (95 mg, 0.5 mmol) in acetone/H2 O (30 ml/15 ml) was stirred at 56 ∘ C for 20 hours, and then the reaction mixture was extracted with ether (3 × 50 ml). The combined ether layer was washed with water (50 ml), saturated NaHCO3 solution (50 ml), and brine (50 ml), respectively. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to afford compound E (colorless solid, 90%).
Preparation of Grignard Reagent and Reaction with an Aldehyde Synthesis of 1-(1-diphenylmethylsilyl-2,6-dithiacyclohexyl)-8-trimethylsilyl-oct7-yn-4-ol (compound G)
599
600
15 Common Laboratory Methods SiMe3
S Ph Ph Si Me
O
S
Br H
+
Mg, I2 (cat), HMPA
Me3Si THF, –78 °C F
E
S Ph Ph Si Me
OH
S
G
To a mixture of Mg turnings (150 mg, 6.25 mmol) and iodine (one small bead, cat.) was added 4-bromo-1-trimethylsilylbut-1-yne (compound F, 1.02 g, 5 mmol) in THF (5 ml) dropwise over a period of 30 minutes at room temperature under argon. The reaction mixture was stirred for 30 minutes further followed by addition of HMPA (2.5 mmol). The reaction mixture was then cooled at −78 ∘ C (dry ice–acetone bath). Aldehyde (compound E, 965 mg, 2.5 mmol) in THF (3 ml) was added to the reaction mixture dropwise over 30 minutes, and the reaction mixture was stirred for two hours at the same temperature. The reaction mixture was poured into 100 ml saturated NH4 Cl solution and extracted with ether (3 × 50 ml). The combined organic layer was washed with water (50 ml) and brine (50 ml), respectively. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give a liquid. The residue was chromatographed over silica gel (10–15% ethyl acetate in hexane) to afford the desired product G in 75% yield.
Alcohol to Bromide Synthesis of 5-bromo-1-trimethylsilyl-8-(1-diphenylmethylsilyl 0-2,6-dithiacyclohexyl)-oct-1-yne (compound H) SiMe3
SiMe3
Ph
S
OH
S
CBr4, Ph3P CH2Cl2, 0 °C
Si Ph Me G
Ph
S
Br
S
Si Ph Me H
To a mixture of compound G (2.56 g, 5 mmol) and CBr4 (4.97 g, 15 mmol) in CH2 Cl2 (5 ml) was added a solution of Ph3 P (3.93 g, 15 mmol) in CH2 Cl2 (15 ml) dropwise over 35 minutes at 0 ∘ C under argon atmosphere. The reaction mixture was stirred for two hours further. The solvent was removed under reduced pressure, and the resulting residue was chromatographed over silica gel (20–30% ethyl acetate in hexane) to obtain compound H (80%).
Deprotection of 1,3-Dithiane Synthesis of 5-bromo-1-(diphenylmethylsilyl)-9-(trimethylsilyl)-non-8-yn-1-one (compound I)
Deprotection of 1,3-Dithiane
SiMe3
SiMe3 CAN, NaHCO3 Ph
S
Br
S
Celite, CH3CN, –15 °C
Si Ph Me
Br
O Ph Si Ph Me I
H
To a mixture of compound H (2.87 g, 5 mmol), NaHCO3 (2.52 g, 30 mmol), and celite (500 mg) in CH3 CN (5 ml) was added CAN (6.85 g, 12.5 mmol) in CH3 CN/H2 O (18 ml/6 ml) at −15 ∘ C. The reaction mixture was stirred at the same temperature for two hours and then diluted with ether (250 ml) and filtered. The ether layer was washed with water (2 × 50 ml) and brine (2 × 50 ml), dried over anhydrous MgSO4 , and concentrated under reduced pressure. The residue was chromatographed over silica gel (5–10% ethyl acetate in hexane) to give compound I (60%) as a liquid.
601
603
16 Common Reagents in Organic Synthesis Here we describe some reagents which are frequently used in organic synthesis [1–69].
Acetic Acid (CH3 CO2 H) Colorless liquid; b.p. 118 ∘ C; M.W. 60.05 Uses Solvent in nitration reaction of aromatic compounds NO2
HNO3, AcOH
OH
OH r.t.
Catalyst in reductive amination reaction AcOH (cat.), EtOH +
H
NH2
Na(OAc)3BH
N H
Solvent in 𝛼-bromination of ketone AcOH, Br2 Br O
O
Acetic Anhydride O
O O
Colorless liquid; b.p. 140 ∘ C; M.W. 102.09; density 1.08 g/ml 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.
604
16 Common Reagents in Organic Synthesis
Uses Acetylation of amines Ac2O
O N H
NH2
Acetylation of phenols and alcohols Ac2O
O
OH
O
Ac2O O
OH
O
Preparation of aspirin O
O Ac2O
OH
OH
Phosphoric acid
OH
O O Aspirin
Preparation of cinnamic acid O
O O H
+
O
NaOAc, NaOH
OH
O Acidic work-up Cinnamic acid Perkin condensation
It is also used for the conversion of cellulose to cellulose acetate, which is an important component of photographic film.
Acetyl Chloride O Cl
Colorless liquid; b.p. 52 ∘ C; M.W. 78.49; density 1.104 g/ml Uses Acetylation of alcohols and amines (similar to acetic anhydride).
Ammonium Chloride (NH4 Cl)
AlkylFluor
BF4
N
N F
Uses Reagent for the conversion of primary and secondary alcohols to the corresponding fluorides OH R1
R2
F
AlkylFluor Dioxane
R1
R2
Aluminum Chloride (Aluminium Chloride; AlCl3 ) Colorless solid; m.p. 190 ∘ C (anhydrous); M.W. 133.34 Uses It is a Lewis acid catalyst and used in a wide range of organic reactions. This catalyst is the choice of Friedel–Crafts reaction, Fries rearrangement, Gattermann–Koch aldehyde synthesis, and other reactions.
Aluminum Isopropoxide (Aluminium Isopropoxide) O O Al O
White solid; m.p. 128–133 ∘ C; M.W. 204.25 Uses Mostly it is used in the Oppenauer oxidation and the Meerwein–Ponndorf–Verley (MPV) reduction.
Ammonium Chloride (NH4 Cl) White solid; m.p. 338 ∘ C; M.W. 53.49
605
606
16 Common Reagents in Organic Synthesis
Uses It is used as a source of ammonia to form a carboxamide from a carboxylic acid. O
O NH4Cl, EDC, HOBt
OH
NH2
DMF
Nitro group reduction NO2
NH2
Zn, NH4Cl Dioxane, H2O
It is used as an expectorant in cough medicine. It is also used as a nitrogen source in fertilizers.
Ammonium Formate O H
NH4
O
White solid; m.p. 116 ∘ C; M.W. 63.06 Uses It is used as a hydrogen source in the presence of Pd/C. HCO2NH4 Pd/C, THF
Reductive amination of aldehydes and ketones O R1
HCO2NH4 R2
NH2 R1
R2
Deprotection of benzyl group O
Ph
Pd/C, HCO2NH4
OH
Reduction of nitro group NO2
Pd/C, HCO2NH4
NH2
Azobisisobutyronitrile (AIBN)
Ascorbic Acid (Vitamin C) Sodium Salt (Sodium L-Ascorbate) HO H
O
O
HO NaO
OH
White solid; m.p. 218 ∘ C; M.W. 198.10 Uses In click chemistry, it converts Cu(II) to Cu(I) in situ.
N3
CuSO4 +
N
N N
Sodium ascorbate t-BuOH/H2O
9-Azabicyclo[3.3.1]nonane N-Oxyl, (2-Azaadamantane-N-oxyl) (AZADO)
N
·
O
Solid; m.p. 182–189 ∘ C; M.W. 152.12 Uses It is less hindered radical and it works better than 2,2,6,6-tetramethylpiperidin1-yl)oxyl (TEMPO) when oxidation of alcohols is carried out to the corresponding aldehydes or ketones.
Azobisisobutyronitrile (AIBN) NC
N N
CN
White solid; m.p. 104 ∘ C; M.W. 164.21
607
608
16 Common Reagents in Organic Synthesis
Uses It is a radical initiator. AIBN (cat.), NBS
Br
CCl4, reflux
[1,1′ -(Azodicarbonyl)dipiperidine] (ADDP) O N
N N
N
O
Yellow powder; m.p. 134 ∘ C; M.W. 252.31 Uses It is widely used as a reagent for the Mitsunobu reaction.
Benzoyl Peroxide O O O O
White solid; m.p. 105 ∘ C; M.W. 242.23 Uses It is used as a radical initiator (PhCO2)2 (cat.), NBS
Br
CCl4, reflux
It is used in the treatment of acne lesions. It is also used in bleaching hair and tooth whitening.
[1,1′ -Bis(diphenylphosphino)ferrocene] palladium(II) dichloride, Pd(dppf)Cl2 Ph Ph PH Pd Fe
Cl Cl
P
Ph Ph
Red solid; m.p. 266–283 ∘ C; M.W. 731.70
Bismuth Chloride (BiCl3 )
Uses This catalyst is used in Suzuki and Negishi coupling reactions and provides better yield compared with other Pd catalysts.
[Bis(triphenylphosphine)palladium(II) dichloride], Pd(Ph3 P)2 Cl2
Cl P Pd P Cl
Yellow solid; M.W. 701.90 Uses This catalyst is used in Suzuki and Sonogashira coupling reactions.
I
CuI, DIEA, CH3CN r.t.
Bismuth Chloride (BiCl3 ) White solid; m.p. 227 ∘ C; M.W. 315.34 Uses It is used as a Lewis acid in the Michael addition, the Mukaiyama aldol reaction, and other organic reactions. Direct deoxygenative allylation [15]
OH
+
SiMe3
BiCl3 (cat.) CH2Cl2, r.t.
609
610
16 Common Reagents in Organic Synthesis
(Bis(trifluoroacetoxy)iodo)benzene Phenyliodine bis(trifluoroacetate) (PIFA) F3C O
O O I
CF3 O
White solid; m.p. 121–125 ∘ C; M.W. 430.04 Uses Conversion of thiacetals to the corresponding carbonyl compounds [42] R3S SR3 R1
R2
O
PhI(OCOCF3)2 CH3CN
R1
R2
Fluorination of styrene [43] PhI(OCOCF3)2, Py·HF CH2Cl2
F F
9-Borabicyclo[3.3.1]nonane (9-BBN)
H B
White solid; m.p. 154 ∘ C; M.W. 122.02 [44] Uses It is used for hydroboration–oxidation of alkene (Brown reaction). 1. 9-BBN, THF 2. H2O2, KOH
Boron Tribromide (BBr3 ) Colorless liquid; b.p. 91 ∘ C; M.W. 250.52
OH
N-Bromosaccharin (NBSa)
Uses For demethylation O
OH
BBr3 DCM
It is also used in pharmaceutical manufacturing, image processing, semiconductor doping, and photovoltaic manufacturing [45].
Boron Trifluoride Diethyl Etherate (BF3 -OEt2 ) Yellow liquid; b.p. 126–129 ∘ C; M.W. 141.93 Uses It is used as a Lewis acid in a variety of organic reactions.
Bromine (Br2 ) Brown fuming liquid; b.p. 59 ∘ C; M.W. 159.81 Uses It is used for the bromination reaction. It is harmful and not easy to handle. O R
Br2, NaOH R–NH2
NH2
H2O Hofmann rearrangement
N-Bromosaccharin (NBSa) O N Br S O
O
White solid; M.W. 262.08 Uses It is used for the oxidative cleavage of oximes to the corresponding aldehydes and ketones. N R
OH R1
O
NBSa R Acetone, H2O Microwave 200 W
R1
611
612
16 Common Reagents in Organic Synthesis
N-Bromosuccinimide (NBS) O N Br O
White solid; m.p. 175–180 ∘ C; M.W. 177.98 Uses It is safe and alternative to bromine for bromination and other reactions [34–37]. Benzylic and allylic bromination (PhCO2)2 (cat.), NBS
Br
CCl4, reflux NBS, (PhCO2)2 Br
CCl4, reflux
Bromination of phenol OH
OH NBS DMF Br
Addition to alkene OH
NBS R
R
Br
THF : H2O (1 : 1)
𝛼-Bromination of 1,3-dicarbonyl compounds. O R1
O
O
NBS, MoO2Cl2 R2 CH2Cl2
O
R1
R2 Br
Burgess Reagent [Methyl N-(triethylammoniosulfonyl)carbamate] O O
O S N N O
Solid; m.p. 76–79 ∘ C; M.W. 238.30
tert-Butyl Hydroperoxide (TBHP)
Uses It is a powerful dehydration agent. It is used to dehydrate secondary and tertiary alcohols with an adjacent H atom into alkenes. H
Burgess reagent R1
R
R1
R2
OH
tert-Butyldimethylsilyl Chloride (TBDMS-Cl) Si Cl
Colorless hygroscopic solid; m.p. 86–89 ∘ C; M.W. 150.72 OH
TBDMS-Cl
O Si
Imidazole, DCM
Uses It is used for the protection of an alcohol group.
tert-Butyldimethylsilyl Trifluoromethanesulfonate (TBS-OTf) Si
O S CF3 O O
b.p. 65–67 ∘ C/12 mmHg; M.W. 264.34 Uses It is a strong reactive silylating agent and Lewis acid capable of converting primary, secondary, and tertiary alcohols to the corresponding tert-Butyldimethylsilyl (TBDMS) ethers [46]. It is expensive and has stability problem that is why it is not used widely in organic reactions.
tert-Butyl Hydroperoxide (TBHP) O O H
613
614
16 Common Reagents in Organic Synthesis
It is normally available in water. A dry solution of this in toluene can be prepared by azeotropic removal of water. Uses It is used for the oxidation of alcohols to the corresponding aldehydes or ketones. It is also used in Sharpless epoxidation reaction.
n-Butyllithium (n-BuLi) Li
Typically it is available with hexane (1.6 or 2.5 M) or in THF. Uses It is a strong base and pyrophoric (handle carefully). Formylation through Li–halogen exchange reaction. O
1. n-BuLi, THF, –78 °C
X
H 2. DMF X = Cl, Br, I
Preparation of benzoic acid derivatives from aryl halides X
O
n-BuLi
OH
CO2
Alkylation n-BuLi, THF, –78 °C S
S
S
S
Br
Silylation of alkyne OH n-BuLi, TMS-Cl THF
tert-Butyllithium Li
OTMS Me3Si
OH
1 N HCl Me3Si
Carbon Tetrabromide (CBr4 )
It is available in pentane (1.5 M). It is a stronger base than n-BuLi. It is capable of deprotonating many weak carbon acidic H including benzene where n-BuLi fails.
tert-Butyl Nitrite (TBN) O N O
Yellow color liquid; b.p. 61–63 ∘ C; M.W. 103.12 Uses Reagent for diazotization of aromatic amines NH2
t-BuONO
Br
CuBr2, CH3CN
Aromatic amine to azide via diazotization [47] NH2
t-BuONO, TMS-N3
N3
CH3CN, 0 °C to r.t.
Nitration of alkene [48] R2
tBuONO, TEMPO
R1
Dioxane
R2
NO2
R1
Carbon Tetrabromide (CBr4 ) Yellow color solid; m.p. 88–90 ∘ C; M.W. 331.63 Uses Alcohol to bromide CBr4 , Ph3P OH
Br
DCM, r.t. (Appel reaction)
S Me3Si
S
OH
CBr4, Ph3P SiMe3 CH2Cl2
S Me3Si
S
Br
SiMe3
615
616
16 Common Reagents in Organic Synthesis
Aldehyde to alkyne O R1
CBr4, Ph3P H
Br
Br
1. nBuLi
R1
H
2. H2O
H
R1
Corey–Fuchs reaction
Carbonyldiimidazole (CDI) O N
N
N
N
White solid; m.p. 116–118 ∘ C; M.W. 162.15 Uses Coupling agent for amide, carbamate, and urea formation O OH
+
O
O
CDI N
N H
DCM, r.t.
O
Reagent for urea formation CDI, DIEA NH2
+
N H
H N
N
DMF, r.t. O
Ceric Ammonium Nitrate (CAN; (NH4 )2 Ce(NO3 )6 ) Orange solid; m.p. 108 ∘ C; M.W. 548.26 Uses As a deprotection reagent S Me3Si
S
Br
O
CAN SiMe3
Me3Si
Br SiMe3
CH3CN, H2O
Oxidation of benzylic and allylic alcohol to the corresponding carbonyl compound O OH CAN, TEMPO O2, CH3CN
H
Chloramine-T, N-chloro Tosylamide Sodium Salt
Cesium Carbonate (Cs2 CO3 ) O Cs
O
O
Cs
White powder; m.p. 610 ∘ C (decompose); M.W. 325.82 Uses As a base for alkylation of phenol, it is better soluble in organic solvents than K2 CO3 . OH
Cs2CO3 +
Br
O
Acetone, reflux
It is used as a base for the Suzuki coupling reaction.
Cesium Fluoride (CsF) White solid; m.p. 682 ∘ C; M.W. 151.90 Uses As a base in Suzuki and Stille coupling reactions Removal of silyl group [49] O
O SiMe3
CsF THF
Chloramine-T, N-chloro Tosylamide Sodium Salt O S N Cl O Na
White powder; M.W. 227.64 Uses It is a biocide and disinfectant. It is also a source of electrophilic chlorine. Oxidation of primary alcohol to aldehyde Chloramine-T R
O
OH DABCO, dioxane, H2O
R
H
617
618
16 Common Reagents in Organic Synthesis
m-Chloroperbenzoic Acid (m-CPBA) O Cl
O OH
White powder; m.p. 92–94 ∘ C; M.W. 172.57 Uses Reagent for the Baeyer–Villiger oxidation reaction m-CPBA
O R
R1
O R
DCM
R1
O
Oxidation of thioether to sulfoxide or sulfone S
O S
m-CPBA CH2Cl2
O S O
m-CPBA (excess)
S
CH2Cl2
Formation of epoxide DCM, r.t.
O
m-CPBA (portionwise)
Oxidation of cyclic tertiary N [50] m-CPBA N O
DCM
N
Formation of alkene R
m-CPBA N
Heat R
N
CH2Cl2
O
Cope elimination
As an oxidant in Rubottom oxidation OSiMe3 R3
R1 R2
m-CPBA H2O
R1
Rubottom oxidation
R3 OH R2
R
Chromium Trioxide
𝛼-Hydroxylation
O
O
O
m-CPBA
R
O
R
OR2
OR2 OH
Toluene, 60 °C
N-Chlorosuccinimide (NCS) O N Cl O
Solid; m.p. 148–150 ∘ C; M.W. 133.53 Uses It is a chlorinating and oxidizing agent. NCS, AIBN
Cl
CCl4, heat
Chlorination of aromatic compounds [51] Ar
H
NCS, BF3, H2O
Ar Cl
In Hunsdiecker reactions [52] CO2H
Cl
NCS, Et3N CH2Cl2
Chromium Trioxide O O Cr O
Red solid; m.p. 196 ∘ C; M.W. 99.99 Uses Oxidation of primary alcohol to acid CrO3, H2SO4 OH
OH H2O, acetone, r.t. (Jones oxidation)
O
619
620
16 Common Reagents in Organic Synthesis
Oxidation of secondary alcohol to ketone OH R1
O
CrO3
R2
R1
CH3CN
R2
Cobalt Chloride CoCl2 ; blue crystals; m.p. 726 ∘ C; M.W. 129.84 Uses Chemoselective protection of aldehydes [25] O R
+
H
CoCl2 SH
SH CH3CN
S
S
R
H
In Strecker reaction [69] CoCl2 R CHO +
R1 NH2 + TMS-CN
CH3CN
HN R1 R
CN
Strecker reaction
Copper Iodide (CuI) White powder; m.p. 605 ∘ C; M.W. 190.45 Uses Reagent for the Sonogashira coupling reaction R I
CuI, Pd(Ph3P)2Cl2 R
+
Et3N, CH3CN, r.t.
In Ullmann reaction CuI Ar1 OH
+
Ar2 X CH3CN
Ar1 X
+
R OH
Ar1
CuI CH3CN
Ar1
O
O
Ar2
R
(Diacetoxyiodo)benzene (DAIB)
Dess–Martin Periodinane (DMP) 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one O O
O O I O O
O
O
White powder; m.p. 130–133 ∘ C; M.W. 424.14 Uses Oxidation of alcohols OH
O
DMP R1
R2
R2
R1
CH2Cl2 R1 = alkyl, aryl R2 = H, alkyl, aryl
Dess–Martin periodinane DCM, r.t. O
OH
(Diacetoxyiodo)benzene (DAIB) O O I O O
White powder; m.p. 161–163 ∘ C; M.W. 322.10 Uses It is used in a variety of organic reactions. Oxidation of alcohols OH R1
R2
O DAIB CH2Cl2
R1 = alkyl, aryl R2 = H, alkyl, aryl
R1
R2
621
622
16 Common Reagents in Organic Synthesis
Dimethoxylation [11]
R2
O
R1 O
N H
DAIB
R2
Dry MeOH
R1
O
O
OMe OMe HN
Diacetoxylation [53, 54] R2
R1
DAIB, BF3· OEt2
AcO
AcOH
R1
R2 OAc
1,4-Diazabicyclo[2.2.2]octane (DABCO) N N
White solid; b.p. 174 ∘ C; M.W. 112.18 Uses It is used as an organic base in variety of organic reactions. O
O R1
H
R2
+
OH O
DABCO R1
R2
Morita–Baylis–Hillman reaction
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) N N
Colorless liquid; b.p. 80 ∘ C; M.W. 152.24 Uses It is used as an organic base in several types of organic reactions.
Diazomethane H 2C N N
2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ)
It is available as a solution in diethyl ether. Uses It is used for the methylation of acid and other groups. It can be selectively methylated carboxylic group in the presence of hydroxyl group. O
O OH
CH2N2
O
Toluene
OH
OH
In Arndt–Eistert reaction 1. CH2N2
O
OH
R Cl
R1
2. Ag2O, H2O
O
Di-tert-butyl Azodicarboxylate (DBAD) O
O N N
O
O
Solid; m.p. 89–92 ∘ C; M.W. 230.26 Uses It is a reagent for the Mitsunobu reaction.
2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) O Cl
CN CN
Cl O
Yellow to orange powder; m.p. 210–215 ∘ C; M.W. 227 Uses Dehydrogenation DDQ O
O
623
624
16 Common Reagents in Organic Synthesis
Aromatization DDQ
Deprotection of PMB (p-methoxybenzyl) group [38] OMe R
DDQ R OH
O
Deprotection of PMBM (p-methoxybenzyloxymethyl) group [39] OMe R
O
DDQ R OH
O H2O
N,N′ -Dicyclohexylcarbodiimide (DCC) N C N
White solid; m.p. 34–35 ∘ C; M.W. 206.33 Uses It is used as a coupling agent for the amide bond formation between acid and amine. In ester formation O R1
O
DCC, DMAP OH
+
R2 OH
R1
CH2Cl2
O
Oxidation of alcohols to aldehydes or ketones OH R1
R2
O
DCC, DMSO R1
R2
Et3N, CH2Cl2 Pfitzner–Moffatt oxidation
Diethylaminosulfur Trifluoride (DAST) F F S N F
Colorless oil; M.W. 161.19
R2
Diiodomethane (CH2 I2 )
Uses Alcohol to fluoride DAST OH
F
DCM, r.t.
Aldehydes and ketones to geminal difluorides O
F
F
DAST
R
R
DCM
Diethyl Azodicarboxylate (DEAD) O O
N
N
O O
Orange liquid; M.W. 174.15 It is available in toluene. Uses This reagent is used for the Mitsunobu reaction. O OH R1
O
R3CO2H R1
R2
R3 R2
DEAD, Ph3P
Diiodomethane (CH2 I2 ) Colorless liquid; b.p. 67–69 ∘ C; M.W. 267.84 Uses Formation of cyclopropane (Simmons–Smith reaction) CH2I2, Zn-Cu OH
OH CH2Cl2 CH2I2, Et2Zn CH2Cl2
625
626
16 Common Reagents in Organic Synthesis
Diisobutylaluminum Hydride (DIBAL-H) H Al
Uses It is available in DCM, hexane, or THF. Reduction of ester to alcohol O
DIBAL-H (excess)
OH
O –78 °C, DCM
Reduction of cyano to amine DIBAL-H R1 CN
R1
NH2
CH2Cl2
Diisopropylaminoborane N BH 2
Preparation of aryl boronic acid Br
Pd(Ph3P)2Cl2 N BH 2
+
Et3N, H2O
Diisopropyl Azodicarboxylate (DIAD) O
O N N
O
O
Uses This reagent is used in Mitsunobu reaction. This is safer than diethyl azodicarboxylate (DEAD). O OH R1
O
R3CO2H R1
R2 DIAD, Ph3P
R3 R2
OH B OH
Diphenylphosphoryl Azide (DPPA)
N,N-Diisopropylethylamine (DIEA) (Hünig’s Base) N
Colorless liquid; b.p. 127 ∘ C; M.W. 129.24; density 0.742 Uses It is widely used as an organic base in numerous organic reactions.
4-Dimethylaminopyridine (N,N′ -Dimethylaminopyridine) (DMAP) NMe2
White solid; m.p. 108–110 ∘ C; M.W. 122.17 Uses It is used in numerous organic reaction as an organic base.
R
O
t-BuOH
O OH
EDC, DMAP, DCM
R
O
Steglich esterification
Diphenylphosphoryl Azide (DPPA) O O P O N3
Light yellow liquid; b.p. 157 ∘ C; M.W. 275.20 Uses Alcohol to azide (Mitsunobu reaction) OH
N3 DPPA, Ph3P DIAD, THF, r.t.
627
628
16 Common Reagents in Organic Synthesis
Di-tert-butyl Peroxide (DTBP) O
O
Colorless liquid; b.p. 109–110 ∘ C; M.W. 146.23 Uses It is very stable organic peroxide due to the bulky tert-butyl groups. It is used as a radical initiator in polymer chemistry and organic synthesis. Oxidative C–H amination [55] O +
CuCl, DTBP
O
AcOH
N
R NH2
N
N H
R
Ethyl Chloroformate O Cl
O
Colorless liquid; b.p. 95 ∘ C; M.W. 108.52 Uses It is used for the formation of amides via mixed anhydrides.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDC⋅HCl) NMe2 HCl
N C N
White powder; m.p. 110–115 ∘ C (HCl salt); M.W. 191.70 (HCl salt) Uses Coupling agent for amide bond formation from acid and amine O R
OH
+ R1 NH2
R DIEA, DMF
For ester formation O
t-BuOH
O R
O
EDC, HOBt
OH
EDC, DMAP, DCM
R
Steglich esterification
O
N H
R1
Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU)
Formic Acid HCO2 H; colorless fuming liquid; b.p. 100 ∘ C; M.W. 46.02 Uses It is used as an acid catalyst in organic synthesis. O
OMe OH
Cl
O Formic acid Reflux
OMe O
Cl
O-(7-Azabenzotriazol-1-yl)-N,N,N′ ,N′ -tetramethyluronium hexafluorophosphate (HATU) O N N N
N
NMe2
Me2N
PF6
White powder; m.p. 183–185 ∘ C; M.W. 380.23 Uses It is used for the peptide synthesis as a coupling agent.
Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU) O N N N Me2N
NMe2 PF6
White powder; m.p. 200 ∘ C; M.W. 379.24 Uses It is used for the peptide synthesis as a coupling agent.
629
630
16 Common Reagents in Organic Synthesis
Hexamethylphosphoramide (HMPA) N N P N O
Colorless liquid; b.p. 232 ∘ C; M.W. 179.20 Uses It is used as a polar solvent and additive in organic synthesis. It improves the selectivity of lithiation reactions using lithium bases such as n-butyllithium. It selectively solvates cations, thereby freeing up the n-butyl anion and increasing the basicity significantly. The basic nitrogen centers of hexamethylphosphoramide (HMPA) coordinate strongly to Li+ and reduce any unwanted side reactions. n-BuLi, THF, –78 °C; HMPA S
S
S O
Me3Si
Me3Si
Br
S
O O
O
Hydrazine (NH2 NH2 ⋅H2 O) It is available as a monohydrate. Uses It is used as a hydrogen source. NH2NH2 NO2
Raney Ni EtOH
NH2
This reagent is also selectively deprotect Dde and IvDde groups in the presence of Boc, Fmoc, and other groups.
1-Hydroxybenzotriazole (HOBt) N N N OH
White powder; m.p. 156–159 ∘ C; M.W. 135.12 Uses It is another coupling agent for peptide synthesis.
[Hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s Reagent)
Hydrogen Peroxide H2 O2 . It is available in water (30% w/w). It is an oxidizing agent. S
O S O
H2O2 EtOH
[Hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s Reagent) OH I
O
S O
O
CH3
White solid; m.p. 131–137 ∘ C; M.W. 392.21 Uses It is widely used as an oxidant in various organic reactions [57]. Ph R2
O
R2
O Ph
HTIB R1 O
N
R1
N H
CH3CN , r.t.
O
Construction of tricyclic compounds [30] O CH3 N
O
HTIB CH3CN, r.t.
N
OH
Tosyloxylation of ketone O R
R1
O
O
O
HTIB CH3CN
R
R1 OTs
+ O
CH3 O
631
632
16 Common Reagents in Organic Synthesis
Imidazole N N H
White solid; m.p. 88–91 ∘ C; M.W. 68.08 Uses As an organic base OH
O SiMe3
TMS-Cl, imidazole DMF
Iodine (I2 ) Purple-black solid; m.p. 113 ∘ C; M.W. 253.81 Uses Iodination H N
H N
I2, KOH
N
N DMF, r.t. I
It is also used as a catalyst for the Strecker reaction [16]. In Prévost trans-dihydroxylation reaction O
Ph R
R1
OH O
I2, PhCO2Ag
R1
R
Benzene
KOH, H2O R
O
OH trans (anti) Diols
O
Alkene E or Z
R1
Ph
In Woodward cis-dihydroxylation
R Alkene E or Z
I2, AgOAc
R
AcOH, H2O
HO
R1
R1 O O
KOH, H2O or acid, H2O
R
R1 OH OH
cis (syn) Diols
2-Iodoxybenzoic Acid (IBX)
Iodobenzene Dichloride Cl I Cl
Yellow solid; m.p. 115–120 ∘ C; M.W. 274.91 Uses Oxidation of alcohols to aldehydes or ketones [58] OH R1
O
PhICl2, TEMPO
R2
R1
CHCl3
R2
N-Iodosuccinimide (NIS) O N I O
White to slightly yellow solid; m.p. 202–206 ∘ C; M.W. 224.98 Uses Iodination of aromatic ring [51] NIS, BF3·OEt2 Ar H
Ar
I
2-Iodoxybenzoic Acid (IBX) O
I OH O O
White solid; m.p. 233∘ C; M.W. 280.02 Uses Oxidation of primary alcohols to aldehydes and secondary alcohols to ketones OH
O
IBX R1
R2
Acetone, H2O
R1
R2
633
634
16 Common Reagents in Organic Synthesis
Iron(III) Nitrate Nonahydrate Fe(NO3 )3 ⋅9H2 O Pale violet crystal; m.p. 47 ∘ C; M.W. 403.99 Uses It is used as an oxidant. Oxidation of alcohols to aldehydes or ketones [56]
R1
O
Fe(NO3)3 ·9 H2O
OH R2
R1
R2
Thiols to disulfides Fe(NO3)3 ·9 H2O 2 R SH
R
S
S
R
Isoamyl Nitrite (Also Called Amyl Nitrite)
O
N O
Yellowish liquid; b.p. 99 ∘ C; M.W. 117.15 Uses It is used for diazotization of aromatic amines. Br
NH2 Isoamyl nitrite, CH3CN CuBr Sandmeyer reaction
Isobutyl Chloroformate O Cl
O
Colorless liquid; b.p. 128 ∘ C; M.W. 136.58 Uses It is used for the formation of amides via mixed anhydrides.
Lead Tetraacetate (Pd(OAc)4 )
Jones Reagent CrO3 in H2 SO4 Uses Oxidation of secondary alcohols to ketones OH R1
O
Jones reagent
R2
Acetone, H2O
R1
R2
Oxidation of primary alcohols to carboxylic acid O
Jones reagent R1
OH Acetone, H2O
R1
OH
Lawesson’s Reagent 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphos phetane-2,4-disulfide MeO
OMe
S S P P S S
Slightly yellow powder; m.p. 228–231 ∘ C; M.W. 404.45 Uses It is used for the conversion of ketone to thioketone or other carbonyls to thiocarbonyl compounds. O
O Lawesson's reagent R1
R2
R1
Toluene, reflux
Lead Tetraacetate (Pd(OAc)4 ) Colorless solid; m.p. 175 ∘ C; M.W. 443.37 Uses Oxidative cleavage of 1,2-diols to aldehydes OH R
R1 OH
O
O
Pd(OAc)4 R
H + R1
H
R2
635
636
16 Common Reagents in Organic Synthesis
Lithium Aluminum Hydride (LiAlH4 ) White solid; m.p. 150∘ C; M.W. 37.95 Uses It is a strong reducing agent that reduces a vast number of different functional groups. Reduction of ketones to secondary alcohol O R2
R1
OH
LAH THF
R1
R2
Aldehydes to primary alcohol O R1
LAH H
THF
R1
OH
Acids to primary alcohols O R1
LAH OH
THF
R1
OH
Esters to primary alcohols O
LAH OR2
R1
THF
R1
OH
Nitro to amine R1 NO2
LAH THF
R1 NH2
Organic halides to alkanes LAH
R1 X
R1 H THF
Acid chlorides to alcohols O R1
OH
LAH Cl
THF
R1
H
Manganese Dioxide (MnO2 )
Azides to amines LAH R1 N3
R1 NH2 THF, H2O
Lithium Diisopropylamide (LDA) Li N
Colorless solid; M.W. 107.12 Uses It is used as a strong base in organic reactions.
2,6-Lutidine (2,6-Dimethylpyridine)
N
Colorless oily liquid; b.p. 143–145 ∘ C; M.W. 107.15 Uses It is used as an organic base in a variety of organic reactions. OH
TMS-Cl, 2,6-lutidine
O
SiMe3
CH2Cl2
Manganese Dioxide (MnO2 ) Black solid; m.p. 535 ∘ C; M.W. 86.93 Uses For oxidation of primary alcohols to aldehydes MnO2, DCM OH
r.t.
O H
637
638
16 Common Reagents in Organic Synthesis
Methanesulfonyl Chloride (Mesyl Chloride) O S Cl O
Colorless liquid; b.p. 161 ∘ C; M.W. 114.54 Uses Alcohols to mesylates
OH
O O S O
MeSO2Cl DIEA, CH2Cl2
N-Methylmorpholine N-oxide (NMO) O N O
Colorless solid; m.p. 180–184 ∘ C; M.W. 117.15 Uses It is used for the oxidation of primary alcohols to carboxylic acids using tetrapropylammonium perruthenate (TPAP) and N-Methylmorpholine N-oxide (NMO) as a co-oxidant. TPAP, NMO OH
OH CH3CN, r.t.
O
Dihydroxylation of alkenes R2
R1
OH
HO
OsO4, NMO Acetone, H2O
R1
R2
Oxidation of primary alcohols to aldehydes and secondary alcohols to ketones OH R1
R2
O NMO, TPAP CH3CN
R1
R2
Osmium Tetroxide
Nitrosobenzene N O
White powder; m.p. 65–69 ∘ C; M.W. 107.11 Uses Preparation of 3-aminophenylflavone [11] OH
Ph
N O
KOH
+
O
Ph
O
N H
MeOH O
In
hetero-Diels–Alder derivatives [59]
reaction,
after
rearrangement
formed
R4
R4
Ph
R3
pyrrole
R4
R3
R3
+
N O
N O
O O
O
R2
R2
R2
R1
R1
Osmium Tetroxide O O Os O O
Yellow solid; m.p. 39–41 ∘ C; M.W. 254.23 Uses Alkene to diols OsO4, NMO Acetone, H 2O
N
OH OH
R1
639
640
16 Common Reagents in Organic Synthesis
Alkenes to aldehydes
R1
OH
OsO4
R2
NaIO4
R2
R1
H + R2
R1
OH
Oxalyl Chloride O Cl
Cl O
Colorless liquid; b.p. 64 ∘ C; M.W. 126.93 Uses Conversion of carboxylic acid to acid chloride O R
O
(COCl)2, DMF (cat.) OH
R
DCM, 40 °C
Cl
Alcohol to aldehyde (Swern oxidation) (COCl)2, DMSO, DCM OH
O
Et3N
H
Oxone (Potassium Peroxymonosulfate) O O S K O O OH
White powder; M.W. 152.2 g/mol (614.76 as triple salt) Uses Oxidation of thioether to sulfone S
O S O
Oxone MeOH, H2O
Oxidation of N-heterocyclic to N-oxide Oxone N
NaHCO3, MeOH
N O
O
O
H
Ozone (O3 )
In Shi epoxidation O
Chiral catalyst, oxone
R2
R1
R2
R1
K2CO3, CH3CN, H2O
Phosphines to phosphine oxides Oxone
Ph3P═O
Ph3P
Ozone (O3 ) Pale blue gas; M.W. 47.99 Uses For ozonolysis and after cleavage CHO CHO
1. O3, DCM 2. Ni/H2
Alkenes to carbonyl compounds (aldehydes or ketones depend on substrate) R1 R2
O3
R3
R1
CH2Cl2
R4
O O
R2
O
R3 R4
O
Ph3P or Me2S
O R2
R1
+
R4
R3
Alkenes to alcohols and carbonyl compounds H R2
R3
O3
R4
CH2Cl2
H
O O
R3
O
R4
O O
R3
R2
O
NaBH4 R2
OH
+
OH
+
R4
R3
Alkenes to carboxylic acids H R2
R3
O3
R4
CH2Cl2
H
R2
O
R4
Alkynes to 1,2-diketones [60]
R1
R2
O
O3 CH2Cl2
R1
O R2
O
H2O2 R2
O R3
R4
641
642
16 Common Reagents in Organic Synthesis
Alkynes can give two carboxylic acids [60]. O
O
R1
R2
R1
CH2Cl2
O
R1
R2
O
O
H2O
O3
OH
+
R2
OH
Acid anhydride
PhenoFluor Mix Cl
N
N
x CsF
Cl
Uses Reagent for the conversion of phenols to fluoro compounds OH
PhenoFluor mix
F
Toluene, reflux
Palladium on Calcium Carbonate (Pd/CaCO3 ) It is known as the Lindlar catalyst. Uses It is used for the partial hydrogenation (alkynes to alkenes, without further hydrogenation into alkanes) [61, 62]. H2, Pd-CaCO3 R
R1
R Pb(OAc)2
R1
(Lindlar catalyst)
H3C C C CH3
H2, Pd-CaCO3 Pb(OAc)2 (Lindlar catalyst)
H3C
CH3 H
H cis
Phenyltrimethylammonium Perbromide (PTAB)
Palladium on Carbon Pd/C; black powder Uses It is used as a catalyst of hydrogenation of a variety of reactions. Nitro to amine NO2
H2, Pd/C
NH2
MeOH
Alkene to alkane H2, Pd/C MeOH
In debenzylation
R1
O
Ph
H2, Pd/C R1 OH MeOH
Phenyltrimethylammonium Perbromide (PTAB) or Phenyltrimethylammonium Tribromide (PTT) N
Br Br Br
Solid; m.p. 110–115 ∘ C; M.W. 375.93 Uses It is used as a brominating agent. PTT
Br
DCM
Br
Selective bromination [63] O
O
Br
PTT MeO
THF
MeO
643
644
16 Common Reagents in Organic Synthesis
Phosphorus Oxychloride O Cl P Cl Cl
Colorless liquid; b.p. 106 ∘ C; M.W. 153.33 Uses Conversion of hydroxyl to chloro in heterocyclic compounds POCl3
N N
N N
Reflux
OH
Cl
In dehydration of primary amides to nitriles O R
POCl3 NH2
R CN
It is used also as a catalyst for the Vilsmeier–Haack reaction and Bischler–Napieralski reaction.
Phosphorus Tribromide (PBr3 ) Colorless liquid; b.p. 175 ∘ C; M.W. 270.69 Uses Alcohol to bromide PBr3 OH
Br
Ether, r.t.
𝛼-Bromination of carboxylic acids O
O R
PBr3, Br2 OH
R
OH Br
Hell–Volhard–Zelinsky reaction
Piperidine
N H
Colorless liquid; b.p. 106 ∘ C; M.W. 85.15
Potassium tert-Butoxide
Uses Removal of Fmoc group from amines
Platinum on Carbon Pt/C Uses It is used as a catalyst for hydrogenation similar to Pd/C.
Platinum(IV) Oxide PtO2 Uses It is used as a catalyst for hydrogenation with hydrogen. H2, PtO2 MeOH
Potassium bis(trimethylsilyl)amide (KHMDS) (Potassium Hexamethyldisilazide) Si N Si K
It is similar to lithium bis(trimethylsilyl)amide (LiHMDS) and sodium bis(trimethylsilyl)amide (NaHMDS). These are strong bases that deprotonate several types of organic compounds.
Potassium tert-Butoxide O K
White solid; m.p. 256 ∘ C; M.W. 112.21 Uses It is used in Wittig reaction as a base. In C-silylation [64] KOtBu N Me
Et3SiH
N Me
SiEt3
645
646
16 Common Reagents in Organic Synthesis
In dehydrohalogenation H
KOtBu X
Potassium Carbonate O K
O
O
K
White powder; m.p. 891 ∘ C; M.W. 138.21 Uses As a base OH Br
+
R1
O
K2CO3 R1
Acetone, reflux
Deprotection of trimethylsilyl (TMS) group from alkyne Si
K2CO3 Dry MeOH
R1
R1
Potassium Iodide KI; white solid; m.p. 681 ∘ C; M.W. 166.00 Uses In Sandmeyer reaction NH2
I
NaNO2 KI, H2O
As a cocatalyst to accelerate the reaction OH Cl
+
K2CO3, KI
O
Acetone, reflux O
OMe OH
O
OMe
Cl O K2CO3, KI, DMF, 80 °C
Potassium Sodium Tartrate Tetrahydrate (Rochelle’s Salt)
Potassium Permanganate O K O Mn O O
Purple solid; m.p. 240 ∘ C; M.W. 158.03 Uses As an oxidant O KMnO4
OH
Pyridine, H2O 80 °C
Oxidation of primary alcohols to carboxylic acids O
KMnO4 R
OH
OH
R
H2O
Aldehydes to carboxylic acid O R
O
KMnO4 H
R
OH
Acetone, H2O
Thioethers to sulfones
R
S
KMnO4 R1 Acetone, H2O
O S R R1 O
Potassium Sodium Tartrate Tetrahydrate (Rochelle’s Salt) O
OH O Na
K O OH O
White solid; m.p. 75 ∘ C; M.W. 282.1 Uses It is used in aqueous work-ups to break up emulsions, especially for reactions in which an aluminum-based hydride reagent was used (e.g. diisobutylaluminum hydride [DIBAL-H]).
647
648
16 Common Reagents in Organic Synthesis
Propylphosphonic Anhydride (T3P) O P
O O P P O O O
M.W. 318.18 Uses It is used as a coupling agent to form amide bond. O
O OH +
NH2
T3P, DIEA
N H
DMF
PyAOP N N
N N O N P N N
PF6
PyAOP
Uses This is a coupling agent for the peptide synthesis.
(Benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphate (PyBOP) N N N O N P N N
PyBOP
PF6
Pyridinium Dichromate (PDC)
Uses This is a coupling agent for the peptide synthesis.
Pyridine
N
Colorless liquid; b.p. 115 ∘ C; M.W. 79.01 Uses It is an organic base and used in several organic reactions. It is used as an organic solvent also.
Pyridinium Chlorochromate (PCC)
N H
O Cl
Cr
O O
Red solid; m.p. 205–208 ∘ C; M.W. 215.56 Uses Oxidation of secondary alcohols to ketones PCC, DCM r.t. OH OH
R1
R2
O O
PCC CH3CN
R1
R2
Oxidation of primary alcohols to carboxylic acid O
PCC R1
OH CH3CN
R1
OH
Pyridinium Dichromate (PDC) NH
O O O Cr O Cr O HN O O
Orange to brown solid; m.p. 152–153 ∘ C; M.W. 376.20
649
650
16 Common Reagents in Organic Synthesis
Uses Oxidation of primary alcohols to carboxylic acids O
PDC R1
OH
CH3CN
R1
OH
Oxidation of secondary alcohols to ketone OH
O
PDC R1
R2
CH3CN
R1
R2
Pyridinium p-Toluenesulfonate (PPTS) O S O HN O
White solid; m.p. 120∘ C; M.W. 251.30 Uses Pyridinium p-toluenesulfonate (PPTS) is used as a weakly acidic catalyst, providing an organic soluble source of pyridinium (C5 H5 NH+ ) ions. It deprotects silyl ether in mild conditions where substrate is unstable in stronger acidic conditions. Formation of acetals and ketals O R
R2–OH, Py·p-TsOH
R2O OR2 R
R1
Deprotection of silyl ethers Py·p-TsOH R–OSiMe3
R OH CH2Cl2
Deprotection of THP group Py·p-TsOH R O
R OH O
CH2Cl2
R1
Ruthenium(III) Chloride (RuCl3 )
Raney Nickel Uses It is used as a catalyst for the hydrogenation reactions. Raney nickel is pyrophoric and must be handled with proper care. NH2NH2 NO2
NH2
Raney Ni EtOH
In desulfurization S
S
R1
R2
H2, Raney nickel R1
Mozingo reduction
R2
Reduction of nitriles to amines H2, Raney nickel R CN
R
NH2
Alkenes to alkanes H2, Raney nickel R
R
Alkynes to alkanes H2, Raney nickel R
R
Ruthenium(III) Chloride (RuCl3 ) Black solid; M.W. 207.43 Uses Selective protection of aldehydes [14] O
S H
RuCl3
S H
+ SH
SH
CH3CN, r.t.
651
652
16 Common Reagents in Organic Synthesis
Acetylation of alcohols and phenols [23] Ac2O, RuCl3 R OH
R
O
CH3CN
O
Selective protection of aldehydes [22] O R
R2O OR2
R2 OH, RuCl3 H
R
CH3CN
H
Oxidative cleavage of olefins to carbonyl compounds [66] R1 R2
R3 R4
CH3CN, H2O
O
O
RuCl3, NaIO4 R1
R2
+
R4
R3
In Strecker reaction [68] RuCl3 R CHO + R1 NH2 + TMS-CN
HN R1 R
CN
CH3CN Strecker reaction
Scandium(III) Trifluoromethanesulfonate (Scandium Triflate) Sc(OTf )3 ; M.W. 492.16 Uses It is a Lewis acid and used in several organic reactions [17, 20].
Selectfluor N-Chloromethyl-N ′ -fluorotriethylenediammonium bis(tetrafluoroborate) or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) Cl N
BF4
N F
BF4
White solid; m.p. 260 ∘ C; M.W. 354.26
Sodium Borohydride
Uses It is a reagent for fluorinations and a source of electrophilic F+ [66].
Sodium Azide Na N N N
White solid; m.p. 275 ∘ C; M.W. 65.01 Uses NaN3
I
N3
DMF, 80 °C
OMs
NaN3
N3
DMF
Sodium Bis(trimethylsilyl)amide (NaHMDS) Si
Si N Na
It is similar to LiHMDS and potassium bis(trimethylsilyl)amide (KHMDS). These are strong bases and deprotonate several types of organic compounds.
Sodium Borohydride Na
H B H H H
White solid; m.p. 400 ∘ C; M.W. 37.83 Uses Reduction of aldehyde to alcohol O H
NaBH4 THF
OH
653
654
16 Common Reagents in Organic Synthesis
Reagent for reductive amination O H
NH2
1. AcOH (cat.), MeOH
+ 2. NaBH4
N H
This reagent is used for the synthesis of antibiotics such as chloramphenicol, dihydrostreptomycin, and thiophenicol.
Sodium Cyanoborohydride H Na B H NC H
Uses It is milder reducing agent than NaBH4 . O H +
NH2
1. AcOH (cat.), MeOH
N H
2. Na(CN)BH3
Sodium Hydride (NaH) Uses It is available 60% in mineral oil. Sodium hydride (NaH) is a strong base. It is used to deprotonate alcohols, amine, amides, and other acidic protons.
Sodium Hypochlorite (Bleach) NaOCl; colorless liquid Uses It is an oxidizing agent. Sodium hypochlorite in aqueous solution has broad-spectrum antimicrobial activity. It is used in healthcare facilities in a variety of settings.
Sodium Triacetoxyborohydride (STAB)
Sodium Nitrite Na O N O
White/slightly yellowish; m.p. 271 ∘ C; M.W. 68.99 Uses In Sandmeyer reaction NH2
NaNO2, H2O
Br
CuBr2
It is used with sodium thiosulfate as an efficient drug in case of cyanide poisoning.
Sodium Periodate O Na O I O O
White solid; m.p. 300 ∘ C; M.W. 213.89 Uses Alkenes to aldehydes O OsO4, NaIO4 R1
THF, H2O
H R1
Sodium Sulfide (Na2 S) Colorless solid; M.W. 78.04 Uses Reduction of nitro to amine
Sodium Triacetoxyborohydride (STAB) O H Na
O B O O
O
O
White powder; m.p. 116–120 ∘ C; M.W. 211.94
655
656
16 Common Reagents in Organic Synthesis
Uses It is mild reducing agent. It is used for the reductive amination reaction. O H
NH2
1. AcOH (cat.), dioxane
+
N H
2. Na(OAc)3BH
Tetra-n-butylammonium Fluoride (TBAF)
N F
It is available in THF. Uses Deprotection of silyl ether group to a free alcohol R1 R O Si R1 R1
TBAF R OH THF
O SiMe3
TBAF
OH
THF
Tetra-n-butylammonium Iodide (TBAI)
N I
Uses It is used as a phase transfer catalyst. It can accelerate the reaction for the synthesis of ether using alkyl bromides or alkyl chlorides. OH
Br
O
Cs2CO3, TBAI CH3CN
Thionyl Chloride
Tetrakis(triphenylphosphine)palladium(0) (Pd(Ph3 P)4 ) Yellow solid; M.W. 1155.56 Uses It is used as a catalyst in Suzuki and Negishi coupling reactions.
2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) N O
Uses It is used as a catalyst for the oxidation of primary alcohol to aldehydes.
Tetrapropylammonium Perruthenate (TPAP)
N O O Ru O O
Green solid; m.p. 160 ∘ C; M.W. 351.43 Uses Oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones OH R1
R2
O
TPAP, NMO R1
CH3CN OH
R2
H
TPAP, NMO CH3CN
O
Thionyl Chloride O S Cl Cl
Colorless liquid (yellow on aging); b.p. 79 ∘ C; M.W. 118.97
657
658
16 Common Reagents in Organic Synthesis
Uses Alcohols to chlorides SOCl2 Cl
OH
Reflux
Carboxylic acids to acid chlorides O
O SOCl2
OH
Cl
Reflux
R1
R1
Acids to esters O R
O
1. SOCl2 OH
2. MeOH
R
O
Titanium(IV) Chloride Cl Cl Ti Cl Cl
Colorless liquid; b.p. 135–136 ∘ C; M.W. 189.68 Uses It is used as a Lewis acid catalyst in organic synthesis.
Titanium Isopropoxide
O O Ti O O
Colorless liquid; b.p. 232 ∘ C; M.W. 284.22 Uses It is used as a catalyst for the Sharpless asymmetric epoxidation.
Triethylamine (TEA)
p-Toluenesulfonic Acid O S OH O
White solid; m.p. 103–106 ∘ C (monohydrate); M.W. 172.20 (190.22 for monohydrate) Uses It is used as an acid catalyst in a variety of organic reactions.
Tributyltin Hydride
Sn
H
Bu3 SnH; colorless liquid; b.p. 80 ∘ C; M.W. 291.06 Uses Conversion of halides to the corresponding hydrocarbons Br
Tributyltin hydride AIBN, heat
In free radical reaction (author’s unpublished work) Me3Si SiMe3 O
Br
n-Bu3SnH
+
Triethylamine (TEA) N
Colorless liquid; b.p. 88–89 ∘ C; M.W. 101.19 Uses It is used as a base in organic reactions.
H
SiMe3 Me
Me3SiO
Me3SiO
AIBN, benzene, 80 oC
Me3Si
H
H
+ H
SiMe3
Si Me O H
659
660
16 Common Reagents in Organic Synthesis
Triethyl Orthoformate
O O
O H
Colorless liquid; b.p. 146 ∘ C; M.W. 148.20 Uses It is used in Bodroux–Chichibabin aldehyde synthesis to prepare an aldehyde with one carbon higher by reacting with Grignard reagent. It can be used in the electrophilic formylation of activated aromatic species such as phenol.
Trifluoroacetic Acid (TFA) O F
OH
F F
Colorless liquid; b.p. 72 ∘ C; 114.02 Uses It is used to deprotect Boc group from amine, tert-butyl from ester, and others. It is also used to cleave the resin for the solid-phase peptide synthesis.
Trimethylsilyl Chloride (TMS-Cl) Si
Cl
Colorless liquid; b.p. 57 ∘ C; M.W. 108.64 Uses It is used as protection of alcohols and amines. Desulfurization of thiocarbonyls to carbonyls S R1
O
TMS-Cl, H2O2 R2 EtOH
R1
R2
Trimethylsilyl Cyanide (TMS-CN)
It is used in Mukaiyama aldol reaction as masked enolate equivalents.
R1
OH O
OSiMe3
O
R1
R2
+
H
R2
Mukaiyama aldol reaction
2-(Trimethylsilyl)ethoxymethyl Chloride (SEM-Cl) Cl
SiMe3
O
Colorless liquid; b.p. 170–172 ∘ C; M.W. 166.72 Uses It is used to protect amino and hydroxyl groups. H N
O
SEM-Cl
N
N
SiMe3
N NaH, DMF
Trimethylsilyl Cyanide (TMS-CN) Si CN
Colorless liquid; b.p. 114–117 ∘ C; M.W. 99.20 Uses It is a reagent for the source of cyanide. I
TMS-CN
CN
CH3CN
It is also used in Strecker reaction [26, 67]. HN R1 Catalyst R CHO
+ R1 NH2
R
+ TMS-CN CH3CN Strecker reaction
CN
661
662
16 Common Reagents in Organic Synthesis
Trimethylsilyl Diazomethane Si N
N
Greenish yellow liquid; b.p. 96 ∘ C; M.W. 114.22 Uses Preparation of methyl ester from carboxylic acid O
O OH TMS-CHN 2
O
Toluene/MeOH
OH
OH
Trimethylsilyl Iodide Si
I
Colorless liquid; b.p. 106–109 ∘ C; M.W. 200.09 Uses Protection of alcohol group OH
TMS-I, imidazole
O Si
DCM
Deprotection of Boc-group O O N
TMS-I
N
H N N
CH2Cl2
Triphenylphosphine (Ph3 P)
P
White solid; m.p. 80 ∘ C; M.W. 262.29
Triphosgene [bis(trichloromethyl) carbonate (BTC)]
Uses It is used as a ligand for Pd-catalyzed C—C bond-forming reactions. Alcohol to azide (Mitsunobu reaction) OH
N3 DPPA, Ph3P DIAD, THF, r.t.
Ether formation (Mitsunobu reaction) Ph3P, DEAD
+
THF
O
OH
OH
Azide to amine Ph3P N3
NH2
THF, H2O Staudinger reaction
Triphosgene [bis(trichloromethyl) carbonate (BTC)] Cl Cl Cl O Cl Cl O O Cl
White solid; m.p. 80 ∘ C; M.W. 296.74 Uses It is used as a reagent in organic synthesis. This reagent is a less hazardous substitute for phosgene for a variety of chemical transformations including to bond one carbonyl group to two alcohols. It is used to convert an amine group into isocyanate to urea with another amine. Formation of urea with two amines
NH2
Triphosgene
N H
+ CH3CN, Et3N
R1 R2
R2
O
NH2
0 oC to r. t.
R1
N H
663
664
16 Common Reagents in Organic Synthesis
Tris(dibenzylideneacetone)dipalladium(0) This is a catalyst for the Suzuki, Negishi, and other Pd-catalyzed organic reactions.
Trityl Chloride (Triphenylmethyl Chloride)
Cl
White to yellow solid; m.p. 109–112 ∘ C; M.W. 278.77 Uses It protects amino groups and it is widely used in peptide synthesis.
Urea Hydrogen Peroxide (UHP) O H2N
NH2 . H2O2
White solid; m.p. 75–91 ∘ C; M.W. 94.07 Uses Conversion of cyano to amide O CN
UHP, KOH EtOH, H2O
R1
NH2 R1
Secondary alcohol to ketone O
OH UHP R1
EtOH
R1
Zinc Chloride
Thioether to sulfoxide and sulfone O S
UHP
S
+
EtOH
Thiol to disulfides S S
UHP
SH
Zinc (Zn) Silver–gray solid; m.p. 419 ∘ C; M.W. 65.38 Uses Reduction of nitro group NO2
NH2
Zn, NH4Cl Dioxirane
Reduction of conjugated double bonds O
O
Zn, NH4Cl
Dioxirane
Zinc Chloride White solid; m.p. 732 ∘ C; M.W. 136.31 Uses It is used as a Lewis acid in variety of organic reactions. Catalyst in the Fischer indole synthesis Ph N N H
ZnCl2 Heat
Ph N H
O S O
665
666
16 Common Reagents in Organic Synthesis
References 1 Burke, S.D. and Danheiser, R.L. (1999). Handbook of Reagents for Organic
Synthesis: Oxidizing and Reducing Agents. Wiley. 2 Pearson, A.J. and Roush, W.R. (1999). Handbook of Reagents for Organic
Synthesis: Activating Agents and Protecting Groups. Wiley. 3 Larock, R.C. (1999). Comprehensive Organic Transformations. Wiley-VCH. 4 Patrick, G.L. (2013). An Introduction to Medicinal Chemistry. Oxford Univer5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
sity Press. Molander, G.A. (2013). Handbook of Reagents for Organic Synthesis: Catalyst Components for Coupling Reactions. Wiley. Fuchs, P.L. (2013). Handbook of Reagents for Organic Synthesis: Catalytic Oxidation Reagents. Wiley. Kurti, L. and Czako, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis. Academic Press. Reich, H.J. and Rigby, J.H. (1999). Handbook of Reagents for Organic Synthesis: Acidic and Basic Reagents. Wiley. Tojo, G. and Fernandez, M. (2006). Oxidation of Alcohols to Aldehydes and Ketones. Springer. Clayden, J. (2002). Organolithiums: Selectivity for Synthesis. Pergamon. De, S.K., Dhara, M.G., and Mallik, A.K. (1998). Can. J. Chem. 76: 199. Fujimoto, T. and Ritter, T. (2015). Org. Lett. 17: 544. Wikipedia. De, S.K. (2005). Adv. Synth. Catal. 347: 673. De, S.K. (2005). Tetrahedron Lett. 46: 8345. Royer, L., De, S.K., and Gibbs, R.A. (2005). Tetrahedron Lett. 46: 4595. De, S.K. and Gibbs, R.A. (2005). Tetrahedron Lett. 46: 1811. De, S.K. and Gibbs, R.A. (2005). Tetrahedron Lett. 46: 1647. De, S.K. and Gibbs, R.A. (2005). Synthesis 1748. Placzek, A.T., Donelson, J.L., Trivedi, R. et al. (2005). Tetrahedron Lett. 46: 9029. De, S.K. and Gibbs, R.A. (2005). Synthesis 1231. De, S.K. and Gibbs, R.A. (2004). Tetrahedron Lett. 45: 8141. De, S.K. (2004). Tetrahedron Lett. 45: 2919. De, S.K. (2004). Tetrahedron Lett. 45: 2339. De, S.K. (2004). Tetrahedron Lett. 45: 1035. De, S.K. and Gibbs, R.A. (2004). Tetrahedron Lett. 45: 7407. De, S.K. (2004). Synthesis 2837. De, S.K. (2004). Synthesis 828. De, S.K. (2003). Tetrahedron Lett. 44: 9055. De, S.K. and Mallik, A.K. (1998). Tetrahedron Lett. 39: 2389. Dhara, M.G., De, S.K., and Mallik, A.K. (1996). Tetrahedron Lett. 37: 8001. Organic Chemistry Portal. Commonorganicchemistry.com Amat, M., Hadida, S., Sathyanarayana, S., and Bosc, J. (1998). Org. Synth. 9: 417.
References
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Gilow, H.W. and Burton, D.E. (1981). J. Org. Chem. 46: 221. Mitchell, R.H., Lai, Y.H., and Williams, R.V. (1979). J. Org. Chem. 44: 4733. Corey, E.J. and Ishiguro, M. (1979). Tetrahedron Lett. 20: 2745. Kozikowsski, A.P. and Wu, J.-P. (1987). Tetrahedron Lett. 32: 6943. Horita, K., Abe, R., and Yonemitsu, O. (1988). Tetrahedron Lett. 29: 4139. Synarchive.com Pubchem. Fleming, F.F., Funk, L., Altundas, R., and Tu, Y. (2001). J. Org. Chem. 66: 6502–6504. Kitamura, T., Muta, K., and Oyamada, J. (2015). J. Org. Chem. 80: 10431–10436. Soderquist, J.A. and Brown, H.C. (1981). J. Org. Chem. 46 (22): 4599–4600. Suzuki, A., Hara, S., and Huang, X. (2001). Boron Tribromide. E-EROS Encyclopedia of Reagents for Organic Synthesis. Wiley. Hua, D., Chen, J., Grainger, R.S., and Arico, C.S. (2001). Encyclopedia of Reagents for Organic Synthesis. Wiley. Barral, K., Moorhouse, A.J., and Moses, J.E. (2007). Org. Lett. 9: 1809–1811. Maity, S., Naveen, T., Sharma, U., and Maiti, D. (2013). Org. Lett. 15: 3384–3387. Smith, A.P., Lamba, J.J.S., and Fraser, C.L. (2002). Org. Synth. 78: 82. Jana, N.K. and Verkade, J.V. (2003). Org. Lett. 5: 3787–3790. Surya Prakash, G.K., Mathew, G.T., Hoole, D. et al. (2004). J. Am. Chem. Soc. 126: 15770–15776. Prakash, J. and Roy, S. (2002). J. Org. Chem. 67: 7861–7864. Zhong, W., Yang, J., Meng, X., and Li, Z. (2011). J. Org. Chem. 76: 9997–10004. Zhdankin, V.V. (2013). Hypervalent Iodine Reagents in Organic Synthesis. Wiley. Gu, J. and Cai, C. (2015). Synlett 26: 639–642. Cornélis, A., Laszlo, P., and Zettler, M.W. (2004). Iron(III) nitrate – K10 montmorillonite clay. In: Encyclopedia of Reagents for Organic Synthesis (ed. L. Paquette). New York, NY: Wiley. De, S.K. and Mallik, A.K. (1997). Indian J. Chem., Sect B 36B: 536. Zhao, X.-F. and Zhang, C. (2007). Synthesis 551–557. Mallik, A.K., De, S.K., and Chattopadhyay, F. (2004). Indian J. Chem. 43B: 2032. Bailey, P.S. (1982). Ozonation in Organic Chemistry, vol. 2. New York, NY: Academic Press. Lindlar, H. and Dubuis, R. (1966). Org. Synth. 46: 89. Overman, L.E., Brown, M.J., and McCann, S.F. (1993, Collective volume ). Org. Synth. 8: 609. Jacques, J. and Marquet, A. (1973). Org. Synth. 53: 111. Toutov, A.A., Liu, W.-B., Stoltz, B.M., and Grubbs, R.H. (2016). Org. Synth. 93: 263. Yang, D. and Zhang, C. (2001). J. Org. Chem. 66: 4814–4818. Singh, R.P. and Shreeve, J.M. (2004). Acc. Chem. Res. 37: 31. De, S.K. (2005). J. Mol. Catal. A: Chemical 225: 169.
667
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16 Common Reagents in Organic Synthesis
68 De, S.K. (2005). Synth. Commun. 35: 653. 69 De, S.K. (2005). Beilstien J. Org. Chem. 1: 8.
Further Reading Organic and Medicinal Chemistry Books Consulted Ghosh, S.K. (2009). Advanced General Organic Chemistry, vol. 1, 2. New Central Book Agency. Finar, I.L. (2012). Organic Chemistry, vol. 1. Pearson India. Smith, M.B. and March, J. (2020). Advanced Organic Chemistry. Wiley. Carey, F.A. and Sundberg, R.A. (2008). Advanced Organic Chemistry. Springer. Morrison, R.T. and Boyd, R.N. (1992). Organic Chemistry. Prentice Hall. Li, J.J. (2003). Name Reactions. Springer. Larock, R.A. (1999). Comprehensive Organic Transformations. Wiley. Organic Chemistry Portal. Bansal, B.K. (2012). Organic Reaction Mechanism. New Age Science. Kurti, L. and Czako, B. (2005). Strategic Applications of Name Reactions in Organic Synthesis. Academic Press. Name-reaction.com Commonorganicchemistry.com Organic-reaction.com Wikipedia.org Synarchive.com Nasipuri, D. (2012). Stereochemistry of Organic Compounds. New Academic Science. Eliel, E.L. (1994). Stereochemistry of Carbon Compounds. McGraw-Hill Inc. McMurry, J. and Begley, T. (2015). The Organic Chemistry of Biological Pathways. W. H. Freeman. Wang, Z. (2009). Comprehensive Organic Name Reactions and Reagents. Wiley-Inter science. Bhal, B.S. and Bhal, A. (2014). Advanced Organic Chemistry. S. Chand & Company Ltd. Carruthers, W. (2004). Modern Method of Organic Synthesis. Cambridge University Press. Mann, F.G. and Saunders, B.C. (1965). Practical Organic Chemistry. Pearson Higher Education. Agarwal, O.P. (2006). Text Book of Organic Chemistry. Goel Publishing House. House, H.O. (1972). Modern Synthetic Reactions. W. A. Benjamin. Kemp, W. (2019). Organic Spectroscopy. Macmillan. Mukherji, S.M. and Sing, S.P. (2006). Reaction Mechanism in Organic Chemistry. Laxmi Publications. Kocienski, P.J. (2003). Protecting Groups. Thieme Publishing Group. Pearson, A.J. and Roush, W.R. (1999). Handbook of Reagents for Organic Synthesis: Activating Agents and Protecting Groups. Wiley-Blackwell. (2001). Organic Name Reactions. Merck & Co., Inc.
Organic and Medicinal Chemistry Books Consulted
Laue, T. and Plagens, A. (2007). Named Organic Reactions. Wiley-Interscience. Mundy, B.R., Ellerd, M.G., and Favaloro, F.G. (2005). Name Reactions and Reagents in Organic Synthesis. Wiley. Hassner, A. and Stumer, C. (2007). Organic Synthesis Based on Name Reactions. Wiley. Lednicer, D. (2013). The Organic Chemistry of Drug Synthesis. Oxford. Patrick, G.L. (2009). An introduction to Medicinal Chemistry. Springer. Pretsch, E., Bühlmann, P., and Badertscher, M. (2006). Analytical Chemistry. Wiley. Francotte, E. and Lindner, W. (2006). Chirality in Drug Research. Wiley. Quin, L.D. and Tyrell, J. (2010). Fundamental of Heterocyclic Chemistry. Wiley-Blackwell. Zweifel, G.S. and Nantz, M.H. (2017). An introduction – Modern Organic Synthesis. Wiley-Blackwell. Bruice, P.Y. (2017). Organic Chemistry. Pearson. Clayden, J., Geeves, N., and Warren, S. (2014). Organic Chemistry. Oxford University Press. Sankaraman, S. (2005). A Textbook – Pericyclic Reactions. Wiley-VCH. Moloney, M.G. (2008). Structure and Reactivity in Organic Chemistry. Blackwell Publishing. Grossman, R.B. (2002). The Art of Writing Reasonable Organic Reaction Mechanism. Springer. Nicolau, K.C. and Montagnon, T. (2008). Molecules That Changed the World. Wiley. Nicolau, K.C. and Sorensen, E.J. (1996). Classics in Total Synthesis. Wiley. Olah, G.A. and Klumpp, D.A. (2007). Superelectrophiles and Their Chemistry. Wiley. Li, J.J. and Corey, E.J. (2013). Total Synthesis of Natural Products. Springer. Corey, E.J., Kurti, L., and Czako, B. (2007). Molecules and Medicine. Wiley. Silverman, R. (2012). The Organic Chemistry of Drug Design and Drug Action. Elsevier. Thomas, G. (2003). Fundamental of Medicinal Chemistry. Wiley-Blackwell. Fisher, J. and Ganellin, C.R. (2006). Analogue-based Drug Discovery. Wiley-VCH. Li, J.J., Johnson, D.S., Sliskovic, D.R., and Roth, B.D. (2004). Contemporary Drug Synthesis. Wiley-Interscience. Nelson, D.L. and Cox, M.M. (2012). Lehninger Principle of Biochemistry. W.H. Freeman. Greim, H. and Snyder, R. (2008). Toxicology and Risk Assessment. Wiley.
669
671
Appendix A List of Medicines (Partial) and Nutrients Antibiotic (antibacterial agent) Medicine
Chemical structure
Amoxicillin
Use
NH2 H N
H
O
N
HO
S
O
O
Ampicillin
NH2
H N
H S
O
N
O
OH
O
Benzylpenicillin (penicillin G)
H N O O
H S N O
Cefalexin (cephalexin)
OH
NH2 H N O
H
OH
Middle ear infection, strep throat, pneumonia, skin infections, urinary tract infections, and others Respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis Pneumonia, strep throat, syphilis, necrotizing enterocolitis, diphtheria, gas gangrene, leptospirosis, cellulitis, and tetanus Middle ear, bone and joint, skin, and urinary tract
S
N O O
OH
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.
672
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Cefazolin
Chemical structure N N
N
H N
N
H
O
Use
S
N
N
S
O O
OH
OH OH
Chloramphenicol
Cl HN
O2N
Cl
S
N
Cellulitis, urinary tract infections, pneumonia, endocarditis, joint infection, and biliary tract infections Meningitis, plague, cholera, typhoid fever, conjunctivitis
O
Clindamycin
Cl
S
Joint infections, pelvic inflammatory disease, strep throat, pneumonia, middle ear infections, and endocarditis
O
HO
HN OH
HO
O N
Cl
Cloxacillin
Impetigo, cellulitis, pneumonia, septic arthritis, and otitis externa
N O
H N
H
O
S
N O OH
O
Doxycycline
OH
O
OH O OH
O NH2
H
H OH NMe2
N
Metronidazole O2N
N
OH
Nitrofurantoin
O
N N O2N
O
NH O
Bacterial pneumonia, acne, chlamydia infections, early Lyme disease, cholera, typhus, and syphilis Pelvic inflammatory disease, endocarditis, and bacterial vaginosis Bladder infections
Antiviral Medicines
Medicine
Chemical structure
Phenoxymethylpenicillin (penicillin V)
H N
O
H
O
673
Use
Strep throat, otitis media, and cellulitis S
N O OH
O NH H
Spectinomycin HO N H
H OH
O O
Gonorrhea infections
O OH
H
O
NH2
Trimethoprim
OMe
N H2N
N
OMe
Middle ear infections and travelers’ diarrhea
OMe O N O S N O H
Sulfamethoxazole H2N
Urinary tract infections, bronchitis, and prostatitis
Antiviral Medicines Medicine
Chemical structure O
Aciclovir N N O
OH
NH N
NH2
Use
Herpes simplex virus infections, chickenpox, and shingles
674
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Abacavir
HIV/AIDS NH N N
HO
Daclatasvir
N N
NH2
Hepatitis C virus
O O
NH O N N
N N H
N H
Dasabuvir
N
O
Sofosbuvir
NH O O P O NH O
N
HO
N N
OH
Hepatitis C virus
O
O F
O
Entecavir HO
O N
O S N H O
O
O
O
Hepatitis C virus
O
O HN
HN
O
NH N
NH2
Hepatitis B virus
Antiviral Medicines
Medicine
Chemical structure
Use
O
Lamivudine
675
HIV/AIDS NH O
N
HO
O S
Ombitasvir
O
O
NH
HN
O H N N
O NH2 N
O
N
O
O
O
N
H N
O
O
O
O
N
Tenofovir disoproxil
Hepatitis C virus
O
O O P O
N
Hepatitis B, HIV/AIDS
N
O
O O
Nevirapine
HIV/AIDS NH
N
N
N
O
Zidovudine
HIV/AIDS NH
HO
N O
N3
O
676
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure H N
Efavirenz
Use
HIV/AIDS
O O
Cl
CF3
Atazanavir
HIV/AIDS N
HN
N OH HN
O
O HN O
HN O O
O
N
Ritonavir
HIV/AIDS
S S N
O HN
O
N
OH H HN N
O
O
NH2
Darunavir
HIV/AIDS
O S O N HO NH
H
O O O
O H
Antiviral Medicines
Medicine
Chemical structure
677
Use
Lopinavir
HIV/AIDS O O
HN
NH
OH H N
N
O
O
O
Dolutegravir
OH O
N O
F
HIV/AIDS
F
H N
N H
O O
Raltegravir N N
H N
O
OH H N
N N
O
HIV/AIDS
O O
Ribavirin N HO
F
Hepatitis C
NH2
N ON
OH OH O
Valganciclovir N NH2
O
O
HIV/AIDS NH
N
N O OH
Oseltamivir
O O
O
HN O
NH2
Influenza A and B
678
Appendix A List of Medicines (Partial) and Nutrients
Antifungal Medicines Medicine
Chemical structure
Use OH
Amphotericin B
O HO
O
OH
OH
OH
Fungal infections and leishmaniasis
OH OH
OH O O O
O HO H2N N
Clotrimazole
Vaginal yeast infections, oral thrush, diaper rash, pityriasis versicolor, and types of ringworm such as athlete’s foot and jock itch Candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor Candida infections and cryptococcosis
N
Cl
N
Fluconazole N
F
Flucytosine
N N N N
HO
F
NH2 F
N N H
O
OMe
Griseofulvin
OH
O
MeO OMe
Ringworm
O OMe
O
Antifungal Medicines
679
Medicine
Chemical structure
Use
Itraconazole
Cl
Aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis
Cl O O
O
N N
N
N N
O N
N N
OH
Nystatin
OH
O HO
O
OH
OH OH OH
OH
OH O
OH O O O HO H2N
OH
Candida infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections
N
Miconazole N
Antifungal, ringworm, pityriasis, yeast infection of the skin or vagina Onychomycosis
O Cl
Cl
Cl
Cl
N
Bifonazole
N
Butoconazole
N
Vaginal cream N
Cl S
Cl
Cl
680
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
N
Econazole
Athlete’s foot, tinea, pityriasis, ringworm, jock itch
N
Cl
O Cl
Cl N
Fenticonazole
Vulvovaginal candidiasis
N O S
Cl
Cl
N
Isoconazole
Foot and vaginal infections
N
Cl O Cl
Luliconazole Cl
Cl
Cl
Cl CN
S
N
S N
Oxiconazole
Athlete’s foot, jock itch, ringworm
N Cl
Athlete’s foot, jock itch, ringworm
N O Cl
Cl
Cl N
Sertaconazole
Foot and vaginal infections
N S Cl
O Cl
Cl
Antifungal Medicines
Medicine
Chemical structure
Use
N
Sulconazole
Athlete’s foot, jock itch, ringworm, sun fungus
N S Cl
Cl
Cl
N
Tioconazole
Athlete’s foot, jock itch, ringworm, sun fungus
N Cl O
S
Cl
Cl
N
Voriconazole N
Aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis
N N
HO
F
681
N
F
F N
Efinaconazole N
Fungal infection of the nail
N
HO
N F
F N
Epoxiconazole
Antifungal
N N
Cl
H
O F
Terconazole
N N O
Cl
O O N N N
Vulvovaginal candidiasis (vaginal thrush)
682
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Abafungin
Dermatomycoses
O
H N
N
NH
N S
Butenafine
Candida albicans, tinea, ringworm N
Naftifine N
Tinea pedis, tinea crusis, tinea corporis
N
Pityriasis versicolor, ringworm, nail infection, jock itch
Terbinafine
Ciclopirox
Flucytosine
Tinea versicolor
OH N
O
NH2 F
Candida infections, cryptococcosis
N O
N H O
Griseofulvin
O O O O
O Cl
Ringworm, fungal infections of the nails and scalp
Antimalarial Medicines
Medicine
Chemical structure
Tolnaftate
Use
Ringworm, jock itch, athlete’s foot
S N
O
Undecylenic acid
Fungal infections of the skins; other uses such as cosmetics, perfumes, and production of nylon-11 Tinea, Candida albicans; other uses such as textile dye, paper dye, ballpoint pens, and inkjet printers Skin sporotrichosis and phycomycosis
HO O
NMe2
Crystal violet
Me2N
Potassium iodide
N
Cl
KI
Antimalarial Medicines Medicine
683
Chemical structure
Use
OH
Amodiaquine
N
HN
Cl
Plasmodium falciparum malaria
N
Artemether
Severe malaria
H O O O HO
H O
684
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Artesunate
Use
Severe malaria
H O O O HO
H O O
OH O
Dihydroartemisinin
H
Antimalarial
O O O HO
H OH
Chloroquine
Antimalarial N
HN
Cl
Mefloquine
N CF3
Antimalarial N
CF3
HO H HN
Lumefantrine
Antimalarial
N
OH Cl
Cl
Cl
Medicine
Chemical structure
Primaquine
NH2
HN
Use
Plasmodium vivax and Plasmodium ovale
N O
Quinine
Malaria and babesiosis HO H
O N
N
Antituberculosis Medicines
685
Antituberculosis Medicines Medicine
Chemical structure OH
Ethambutol
H N
N H
HO H N NH 2
Isoniazid O
Use
Tuberculosis, Mycobacterium avium complex, and Mycobacterium kansasii Antibiotic and antituberculosis
N O
Pyrazinamide N
Antituberculosis NH2
N
Bedaquiline
Br
Antituberculosis NMe2 OH
N O
686
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
O
Cycloserine HN O
Antibiotic and antituberculosis
NH2 O
Delamanid
Antituberculosis N
F3CO O
O
N
N NO2
S
Ethionamide
Antibiotic and antituberculosis
NH2 N
Linezolid
Antibiotic and antituberculosis
O N
O
F
N
O
O N H
H
Moxifloxacin
Pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis
OMe N H H
N
N OH
F O
O
O
4-Aminosalicylic acid
Antituberculosis OH
H2N
OH OH
Streptomycin HO HO
O HN
O
HO O O
OHC OH
OH N
N OH
NH2 NH2
NH2 NH2
Antibiotic and antituberculosis
Medicines for Pain
Medicines for Pain Medicine
Chemical structure
Use
O
Aspirin
Pain, fever, and inflammation
O OH O
Ibuprofen
Pain, fever, inflammation, painful menstrual periods, migraines, and rheumatoid arthritis
OH O H N
Paracetamol (acetaminophen)
Pain, fever, and inflammation O
HO
Codeine
O
Pain, coughing, and diarrhea
O
H
H
N
HO
Fentanyl
O
Opioid pain medication
N N
Morphine
HO
Acute pain and chronic pain H
O H
N
HO
Methadone
O
N
Acute pain and chronic pain
687
688
Appendix A List of Medicines (Partial) and Nutrients
Anticonvulsants Medication (antiepileptic drugs or as antiseizure drugs) Medicine
Chemical structure
Carbamazepine
Use
Epilepsy and neuropathic pain N O
NH2
Diazepam
N
Cl
Lamotrigine
Anxiety, seizures, alcohol withdrawal, syndrome, , muscle spasms, trouble sleeping, and restless legs syndrome
O
N
H2N
N N
NH2
Epilepsy and bipolar disorder
N Cl Cl H N
Lorazepam
Anxiety disorders, trouble sleeping
O OH N
Cl
Cl
N
Midazolam
Anesthesia, procedural sedation, trouble sleeping, and severe agitation
N OH Cl
N F
Magnesium sulfate
MgSO4 ⋅7H2 O
Treat and prevent low blood magnesium and seizures in women with eclampsia
Anti-infective Medicines (anthelminthics and antifilarials)
Medicine
Chemical structure
689
Use
Phenobarbital
Epilepsy O
O
HN
NH O O
Phenytoin HN
Antiseizure medication
NH
O
O
Valproate sodium valproate
Epilepsy, bipolar disorder, prevent migraine headaches
HO
Ethosuximide O
H N
Antiseizure medications O
Anti-infective Medicines (anthelminthics and antifilarials) Medicine
Chemical structure
Use O
Albendazole
S
N N H
N H
Ivermectin
O
O
Parasitic worm infestations giardiasis, trichuriasis, filariasis, neurocysticercosis, hydatid disease, pinworm disease, and ascariasis
O
O
O
HO
O O
O
O
O
O
HO O
H
OH
H
Head lice, scabies, river blindness, strongyloidiasis, trichuriasis, ascariasis, and lymphatic filariasis
690
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Levamisole
Ascariasis and hookworm infections
N N
S
O
Mebendazole
Ascariasis, pinworm disease, hookworm infections, guinea worm infections, hydatid disease, giardia
O N N H
Niclosamide
NO2
O Cl
N H
O
N H OH
Diphyllobothriasis, hymenolepiasis, and taeniasis
Cl
O
Praziquantel
Schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, hydatid disease
N N O
Pyrantel
Ascariasis, hookworm infections, enterobiasis, trichostrongyliasis, and trichinellosis
N N S
O
Diethylcarbamazine
N
Lymphatic filariasis, tropical pulmonary eosinophilia, loiasis
N
N
Medicines for Migraine Medicine
Chemical structure O
Aspirin O
OH O
Use
Migraine and pain
Antileprosy Medicines
Medicine
Chemical structure
Ibuprofen
Use
Migraine and pain
OH O H N
Paracetamol (acetaminophen)
Migraine and pain O
HO
Propranolol
OH O
High blood pressure, migraine
H N
Amitriptyline
Mental illnesses, anxiety disorders, migraine N
Antileprosy Medicines Medicine
Chemical structure
Use
Cl
Clofazimine
Antileprosy
N
N
N
N H
Cl
O S O
Dapsone
Antibiotic, antileprosy
NH2
H2N
Rifampicin OH OH O
OH
OH
O
O
N O
O O
Antibiotic, antileprosy
NH
OH O
N N
691
692
Appendix A List of Medicines (Partial) and Nutrients
Disinfectant and Antiseptics Antiseptic
Chemical structure
Chlorhexidine
H N
H N NH
Cl
Use NH
H N
N H
NH
NH
N H
Cl
Skin disinfection, leaning wounds, preventing dental plaque, treating yeast infections of the mouth, sterilize surgical instruments
N H
Ethanol
CH3 CH2 OH
Antiseptic, disinfectant, and antidote, hand and mouth wash
Povidoneiodine
Poly(vinylpyrrolidinone) iodide polymer
An antiseptic used for skin disinfection before and after surgery
OH
Isopropanol
Glutaraldehyde (Cidex)
O H
Rubbing alcohol, hand sanitizer, and disinfecting pads O
Disinfectant, medication, preservative, and fixative, sterilize surgical instruments and other areas of medical center
H
Antidiabetic Medicines (diabetes medications) Medicine
Chemical structure
Use
Insulin
Peptide hormone
Type 1 diabetes treatment
NH
Metformin N
Gliclazide
N H
NH NH2
O O S N N N O H H
Treatment of type 2 diabetes Type 2 diabetes mellitus
Antidiabetic Medicines (diabetes medications)
Medicine
Chemical structure
Use
Glucagon
Peptide
Low blood sugar, beta blocker overdose, calcium channel blocker overdose
H N
Diazoxide
Hypoglycemia
N S O O
Cl
Nateglinide
O
O
Type 2 diabetes OH
N H
Repaglinide
OH
Type 2 diabetes mellitus
CF3
Type 2 diabetes
O N
O O
N H
Sitagliptin N
F N
N N
NH2 O
F F
Teneligliptin
Type 2 diabetes mellitus
O N N N
N
N
S
NH
Linagliptin
Type 2 diabetes mellitus
O N
N
N N
O
N N
N NH2
693
694
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Saxagliptin
O
Use
Type 2 diabetes
H N
HO
NH2
H
N
Vildagliptin
Type 2 diabetes HO
N
N H
O O
Alogliptin
Type 2 diabetes N
H2N
N
N
O
N
Gliclazide
O O S N N N O H H
Type 2 diabetes
Tolazamide
O O S N N N O H H
Type 2 diabetes
Glyclopyramide
Type 2 diabetes
O O N S N N O H H Cl
Gliquidone
O O S N N O H H
O O
Type 2 diabetes
O
O O S N N O H H
Tolbutamide
O O S N N O H H
Chlorpropamide Cl
Type 2 diabetes
Type 2 diabetes
Medicines for Anesthetics (anesthetics)
Medicine
Chemical structure
Acetohexamide
Use
Type 2 diabetes
O O S N N O H H O
Glipizide
O O S N N O H H
O N N
N H
O
O
Glimepiride N
Miglitol
O O S N N O H H
OH
Type 2 diabetes mellitus, greater glycemic control
OH OH
Voglibose
Type 2 diabetes
N H
OH N
HO HO
Type 2 diabetes
Lowering postprandial blood glucose levels in diabetes mellitus
HO HO HO OH NH
OH OH
Medicines for Anesthetics (anesthetics) Medicine
Chemical structure F
Halothane
Br
F Cl
Isoflurane F3C
Nitrous oxide
Inhalational, general anesthetic
Cl
F
Use
N2 O
F O
General anesthetic F
Inhalational, general anesthetic
695
696
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Ketamine
Injectable anesthetic pain relief, sedation HN O
Cl
OH
Propofol
Bupivacaine
Injectable general anesthetic
Local anesthetic
H N
N O
H N
Lidocaine
Local anesthetic N O N
Midazolam
Anesthetic, procedural sedation, trouble sleeping, and severe agitation
N N
Cl
F
Antiallergics and Medicines for Anaphylaxis Medicine
Chemical structure
Dexamethasone
O HO
OH H F
H
O
Epinephrine
OH HO HO
OH
H N
Use
Rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, and along with antibiotics in tuberculosis Anaphylaxis, cardiac arrest
Cardiovascular Medicines
Medicine
Chemical structure
Hydrocortisone
Use
OH
O HO
Adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD
OH H H
H
O
Loratadine
Cl
Allergic rhinitis (hay fever) and hives N N O
O
Prednisolone
OH
O HO
Allergies, inflammatory conditions, autoimmune disorders, and cancers
OH H H
H
O
Cardiovascular Medicines Medicine
Chemical structure
Use OH
Bisoprolol O O
O
Nitroglycerin
O O2N
O
O
O NO2
Isosorbide dinitrate
H O O H O NO2
NO2 NO2
H N
High blood pressure, chest pain, and heart failure Heart failure, high blood pressure, anal fissures, painful periods Heart failure, esophageal spasms
697
698
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Verapamil
O
Use
N
O
O
N
H N
Lidocaine
High blood pressure, angina
O
Numb tissue in a specific area
N O
Amiodarone
I
O
N
O I
O
O
Enalapril
O
H N
O
OH
O N
HN NH2
Hydralazine
H N
Cl O H2N S O
NH S O O
Furosemide
H N
O HO
O
Cl O S NH2 O
HO
Losartan Cl N
N
High blood pressure, diabetic kidney disease, and heart failure
High blood pressure and heart failure
N N
Hydrochlorothiazide
Irregular heartbeats, ventricular tachycardia
HN N N N
High blood pressure and swelling due to fluid build up Fluid buildup due to heart failure, liver scarring, or kidney disease High blood pressure, diabetic kidney disease, heart failure
Cardiovascular Medicines
Medicine
Chemical structure
Use O
Spironolactone
Fluid buildup due to heart failure, liver scarring, or kidney disease
O H H
H
O
S O
Dopamine
HO
NH2
Very low blood pressure, a slow heart rate
HO
Clopidogrel
O
Heart disease and stroke
O N S
Cl
HO
Simvastatin
O
Lipid-lowering medication, heart problems
O O O
Atorvastatin (Lipitor)
H
O N H
OH OH O N
OH
Lipid-lowering medication, prevent cardiovascular disease
F
Fluvastatin
OH OH O N
OH
Lipid-lowering medication, prevent cardiovascular disease
F
Pitavastatin
OH OH O N
OH
F
Lipid-lowering medication, prevent cardiovascular disease
699
700
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Rosuvastatin
Use
OH
OH
Lipid-lowering medication, prevent cardiovascular disease
O
N O S N N O
OH
F
HO
Lovastatin
O
Reduce high blood cholesterol, prevent cardiovascular disease
OH
Reduce high blood cholesterol, prevent cardiovascular disease
O
O O
H
Pravastatin
O HO HO
O O
H
HO
Medicines for Gastrointestinal Medicine
Omeprazole
Chemical structure O
Use
O S
N
Gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome
N
N H O
H N
Ranitidine N
S
H N
O NO2
O
Metoclopramide Cl H2N
N H O
N
Decreases stomach acid production, peptic ulcer disease, gastroesophageal reflux disease Stomach and esophageal problems, prevent nausea and vomiting
Medicines for Mental and Behavioral Disorders
Medicine
Chemical structure
Ondansetron
Use
Prevent nausea and vomiting
N N
O
N
Aprepitant HN
O F3C
N
O
H N O
Prevent nausea and vomiting
N
CF3 F
Sulfasalazine
N
Rheumatoid arthritis, ulcerative colitis, and Crohn’s disease
O N S H O N N OH O
OH
Medicines for Mental and Behavioral Disorders Medicine
Chemical structure
Use
S
Chlorpromazine Cl
Psychotic disorders such as schizophrenia, bipolar disorder
N
N S
Fluphenazine F3C
Psychotic disorders such as schizophrenia
N
N N OH
701
702
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use Cl
Haloperidol O
Schizophrenia, mania in bipolar disorder
OH
N F N
Risperidone
N
N
Schizophrenia, bipolar disorder, autism
O
N O
F
Clozapine
Schizophrenia
N
N
Cl
N
N H
Major depressive disorder, anxiety disorders, and insomnia
Amitriptyline
N
Fluoxetine
H N
O CF3
Carbamazepine
Epilepsy, neuropathic pain, bipolar disorder
N O
NH2
O
Lithium compounds Li O
Major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder
O
Li
Bipolar disorder, major depressive disorder
Medicine for Joint Paints
Medicine
Chemical structure O
Valproate
Use
Epilepsy, bipolar disorder and to prevent migraine headaches
HO
Diazepam
O
N N
Cl
Clomipramine N Cl
Anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, trouble sleeping
Obsessive–compulsive disorder, panic disorder, major depressive disorder, and chronic pain
N
Methadone
Chronic pain
N
O
Medicine for Joint Paints Medicine
Chemical structure O
Allopurinol
Use
Gout pain
N
NH N H
N
NO2
Azathioprine N
S
N N
N
H N N
Rheumatoid arthritis, granulomatosis with polyangiitis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, and kidney transplants to prevent rejection
703
704
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use O
Methotrexate
CO2H
Cancer, psoriasis, rheumatoid arthritis, Crohn’s disease, ectopic pregnancy, and medical abortions
N H HO2C
NH2 N H2N
O
Penicillamine HS
Rheumatoid arthritis OH
NH2
Sulfasalazine
O S O
F3C
Rheumatoid arthritis, ulcerative colitis, and Crohn’s disease
N N
CF3
OH O
OH
Medicines Affecting the Blood Medicine
Chemical structure
Use
Iron salts
FeSO4
Iron deficiency anemia NH2
Dabigatran O
O
O
N N
Heparin Phytomenadione
Glycosaminoglycan O
O
Anticoagulant
N N N
N H
O
O
Anticoagulant Bleeding disorders
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Tranexamic acid
H2N
Use
O
Blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation
OH
O
Warfarin
Anticoagulant (blood thinner)
OH
O
Deferoxamine
O
OH N
H2N O
O N OH
N H
O
O NH
O N OH
O
Hydroxycarbamide H2N
N H
Iron overdose, hemochromatosis
Sickle-cell disease, chronic myelogenous leukemia, cervical cancer, and polycythemia vera
OH
Medicines for Cancer (antineoplastics) Medicine
Chemical structure
Use
Arsenic trioxide
As2 O3
Acute promyelocytic leukemia N
Anastrozole N N
N
N
Abemaciclib
Breast cancer
N N
F
N N
N H
Breast cancer N
N
N F
705
706
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Acalabrutinib
Mantle cell lymphoma O
N
N
O
N
N H
N
Afatinib
N
NH2 O
O
N
HN Me2N
Non-small cell lung carcinoma
N HN
O
F Cl
Alectinib
Non-small cell lung cancer
O N H N
N
CN O
Axitinib
H2N
O
Renal cell carcinoma
H N
S
N
N
Bendamustine
Cl
N
N N
Cl
Bicalutamide
F3C NC
OH
H HO N O
O
O S O
Chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin’s lymphoma Prostate cancer
F
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Use
Br
Binimetinib
Melanoma F
F HO
HN H N
O
N N
O
Bosutinib
N
N
O
N
Chronic myelogenous leukemia
CN
O HN
O
Cl
Cl
Bortezomib O N
OH B OH
H N
N H
Multiple myeloma and mantle cell lymphoma
O
N
Brigatinib
O
Lung cancer
H N
N N
N
Cl
HN
N
O
N
P
O
Capecitabine HN F
Breast cancer, gastric cancer, and colorectal cancer
O N
O
N
O
OH OH H N
Cabozantinib
H N O
O O O
N
O
Renal cell carcinoma F
707
708
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure O
Carboplatin
Use
Ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma
NH3 O
Pt
O NH3
O
Chlorambucil
OH Cl
O
N
Cl
Cisplatin
Cl NH3 Cl Pt NH 3
Cobimetinib
Testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors, and neuroblastoma Melanoma
OH O
N
N H
Chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma
F
H N F
I
F
Crizotinib
HN
Cl
N N
O N
Cl
Cyclophosphamide O O
N P
Cl
NH2 N HO
O
N
OH OH
F
Lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma
NH
Cytarabine
Cl NH2
Non-small cell lung carcinoma
O
Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin’s lymphoma
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Use
O
Dacarbazine
Melanoma and Hodgkin’s lymphoma
NH2 N N N N
N H
Dacomitinib
O
N
HN N
Lung cancer
N
HN
O
F Cl
Dabrafenib
F
Melanoma
F
O H S N O F
N S N N
Dasatinib
HO
N
H N
M N
N
NH2
S
H N
N
Cl
O
O
Daunorubicin
OH
O
Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi’s sarcoma
OH H O
O
OH
O H
O OH NH2
O
Docetaxel
O
O O
O
O OH
OH
O
NH O OH
H O O O
Chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL)
O
Breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small cell lung cancer
709
710
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure O
Doxorubicin
OH
Use O
Breast cancer, bladder cancer, Kaposi’s sarcoma, lymphoma, and acute lymphocytic leukemia
OH OH H O
O
OH
O
O OH NH2
N
Duvelisib
Chronic lymphocytic leukemia
HN N HN
N
N Cl
Encorafenib
O
Colorectal cancer
O O
N
H N
N H
N
N
F
N Cl
Erlotinib
O
O O
N H
N
Non-small cell lung cancer (NSCLC) and pancreatic cancer
N
O HN
OH
Etoposide
MeO
OMe
O O O O H O O
H
O
OH
O H OH
O S O
Testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Use O
Folinic acid
NH O
N
N H2N
Colorectal cancer
O
O
N H
N H
OH
N H
O
OH
NH2
Fludarabine O HO P O OH
O
N
Chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia
N
N N
OH OH
Fluorouracil
O F N H
Gefitinib
Colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer
NH O
N
O O N
Lung cancer N
O HN
Cl F
NH2
Gemcitabine
Breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer
N HO
O F
N
O
OH F
Gilteritinib
N
O
N
N N N O
N
N H O
NH2
Acute myeloid leukemia
711
712
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
O
Hydroxycarbamide H2N
Ibrutinib
Sickle-cell disease, chronic myelogenous leukemia, cervical cancer, and polycythemia vera
OH
N H
Mantle cell lymphoma, chronic lymphocytic leukemia
O
N N
H2N N
N
O
N N
Idelalisib
Chronic lymphocytic leukemia
HN N HN
N
N N F
O
Imatinib (Gleevec)
H N
N
N
N
N N
NH O
Irinotecan
Colon cancer and small cell lung cancer
N N
O N
O
Chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL)
O
N O OH O
O
Lenalidomide
O NH
N NH2
O
Multiple myeloma (MM) and myelodysplastic syndromes (MDS)
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Use N
Lapatinib H N
O S O
Breast cancer
N
O HN
O Cl F Cl
Lenvatinib
H N
H N
Thyroid cancer
O O
O
O
N
H2N
Lorlatinib
Non-small cell lung cancer
NH2 N
O O
N NC N
Larotrectinib
N
N N
HO N
Solid tumors N
N
NH O F F
O
Melphalan
OH Cl N
NH2
Multiple myeloma, ovarian cancer, melanoma, and amyloidosis
Cl
Mercaptopurine
H N N
S N N H
Acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), Crohn’s disease, and ulcerative colitis
713
714
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use O
Methotrexate
CO2H
Breast cancer, leukemia, lung cancer, lymphoma, and osteosarcoma
N H HO2C
NH2 N H2N
Neratinib
O
Breast cancer
N CN
HN Me2N
HN
O
N O Cl
Nilotinib
H N
CF3
N
N
N N H
N N
O
O
Nintedanib N
Nivolumab
NH
NH2 NH2
NMe2
Lung cancer
N
Whole antibody
Oxaliplatin
Osimertinib
H N
O N
Chronic myelogenous leukemia
N
Melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, colon cancer, and liver cancer O
O Pt O
Colorectal cancer
O
Non-small cell lung cancer
O N
HN O
N H
N N
Medicines for Cancer (antineoplastics)
Medicine
Chemical structure
Use
Palbociclib Breast cancer
H N
N
N
N
O
N
N
O
HN
O
Paclitaxel (Taxol)
O
O O
O
NH O O
OH
OH
Pazopanib
H2N
Ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer
OH
H O O O
O S
H N
O
O
Renal cell carcinoma
N N N
N N
O
Ponatinib F3C
Chronic myeloid leukemia
N H
N N
N
N
N O
Procarbazine N H
Regorafenib
Hodgkin’s lymphoma and brain cancers
N H
H N
CF3
O N H
O
Cl
O
N F
N H
N H
Colorectal cancer
715
716
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Ribociclib H N N
N
Breast cancer
N
N
N NMe2
HN
Rituximab
O
Whole antibody
Ruxolitinib
Non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis, and Epstein–Barr virus-positive mucocutaneous ulcers Bone marrow
CN N N
N N
N H
O
Sorafenib
Cl
O
N N H
Sunitinib
Kidney cancer
CF3 O
N H
N H
Renal cell carcinoma
O N
N H N H O
F N H
Medicines for Cancer (antineoplastics)
Medicine
Tioguanine
Chemical structure S
H N
Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML)
N
N
Trametinib
N H
NH2
O
Melanoma
O N H
I
N N O
N H N
Tamoxifen
Trastuzumab
Use
F
O
O
Breast cancer
N
Whole antibody Breast cancer and stomach cancer O S NH F O
Vemurafenib
O
F
Vandetanib
Cl
N H
N
Thyroid cancer
N N
O
Skin cancer (melanoma)
N
O HN F
Vinblastine
Br
OH N N N H O O
O H
O
N HO
O O O
Hodgkin’s lymphoma, non-small cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer
717
718
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
OH
Vincristine
N N
H N H O O
O H
N HO
O O
O O O
Acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin’s disease, neuroblastoma, and small cell lung cancer
Medicines for Parkinson’s Disease Medicine
Chemical structure OH
Levodopa (l-DOPA)
Use
Parkinson’s disease
OH OH
H2N O
O
Carbidopa HO
Parkinson’s disease
OH NH NH2
HO
O
Tolcapone
Parkinson’s disease
HO HO NO2
O
Entacapone HO
Parkinson’s disease N
CN
HO NO2
Medicines for Parkinson’s Disease
Medicine
Chemical structure
Use O
Pimavanserin N H
Parkinson’s disease N
O
F N
Safinamide N H
F
NH2
Parkinson’s disease
O
O
H N
Pramipexole
Parkinson’s disease S NH2 N
Rotigotine
Parkinson’s disease N
S
OH
Profenamine
Parkinson’s disease N
N S
Rasagiline HN
Parkinson’s disease and relieve pain from muscle spasm
719
720
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Orphenadrine
Use
Parkinson’s disease
N O
SH
Acetylcysteine (N-acetylcysteine) O N H
Parkinson’s disease, paracetamol (acetaminophen) overdose, chronic obstructive pulmonary disease
OH O
Medicines for Ear, Nose, and Throat Medicine
Chemical structure
Use
Acetic acid
CH3 CO2 H
Infection of the ear canal, ear wick, urinary catheter, adjust pH of the vagina, and among others HO
Budesonide
O
O
HO
O
H H
Allergic rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease (COPD)
H
H
O O
Ciprofloxacin F N
O OH
N
HN
H N
Xylometazoline N
Endocarditis, malignant otitis externa, cellulitis, urinary tract infection, respiratory tract infection, anthrax, chancroid Nasal congestion, allergic rhinitis, sinusitis
Medicines for the Respiratory Tract
Medicines for the Respiratory Tract Medicine
Chemical structure
Use
Beclometasone O
O
O
Asthma, ulcerative colitis
O
HO
O
H H
Cl O
HO
Budesonide
O
O
HO
O
H H
H
H
Allergic rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease (COPD)
O
OH
Epinephrine
H N
HO
Asthma, anaphylaxis, cardiac arrest
HO
Ipratropium bromide
Br N OH
Asthma, open up airways in the lungs, COPD
O O OH
Salbutamol HO
H N
HO
Tiotropium bromide
Asthma, COPD
Br N O
Asthma, open up airways in the lungs, COPD
S OH
O O
S
721
722
Appendix A List of Medicines (Partial) and Nutrients
Reproductive Health and Perinatal Care Medicines Medicine
Chemical structure
Use
Ethynylestradiol
Birth control pills OH H H
H
HO
Levonorgestrel
Birth control pills OH H
H H
O
Norethisterone
Birth control pills OH H
H H
O
Ulipristal acetate
Me2N
O O H
Emergency birth control use within 120 hours of sex, uterine fibroids
O
O
Medroxyprogesterone acetate
O O
H H
H O
Estradiol cypionate
Injectable birth control, menopausal hormone therapy, endometriosis, abnormal uterine bleeding, abnormal sexuality in males Injectable birth control
O O H H HO
H
Reproductive Health and Perinatal Care Medicines
Medicine
Chemical structure
Norethisterone enanthate
Use
Injectable birth control, miscarriage, or abortion
O H
O
H H
H O
Copper IUDs
Intrauterine device contains copper
Birth control and emergency contraception
IUD with progestogen
Intrauterine device
Birth control, heavy menstrual periods
Etonogestrel birth control implant
Medical device
Birth control
Levonorgestrelreleasing implant
Medical device
Birth control
Progesterone vaginal ring
Device
Birth control when breastfeeding
Clomifene Cl N
Treatment of infertility in women who do not ovulate
O
Ergometrine O
Heavy vaginal bleeding after childbirth
NH
H
N
HN
Mifepristone
Me2N OH
Abortion within 63 days of pregnancy
H
O
O
Misoprostol O
OH OH
O
Labor induction, postpartum bleeding
723
724
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Nifedipine O2N
Premature labor, angina, high blood pressure
O
O
O
O N H
O
Caffeine citrate O
Lack of breathing in premature babies
N
N
N
N O
OH
O
HO
OH O
OH O
Prostaglandin E1
Babies with congenital heart defects
OH
O
OH
OH
O
Prostaglandin E2
Labor induction, bleeding after delivery, termination of pregnancy, ductus arteriosus open in newborn babies
OH O
OH
OH
O
Sildenafil (Viagra) O S N O
N
Erectile dysfunction in men
N
HN
N N
O O
Vardenafil (Levitra, Staxyn, Vivanza) N
O S N O
HN N O
N
N
Erectile dysfunction in men
Medicines for Dermatological (topical)
Medicine
Chemical structure
Tadalafil (Cialis)
Use
O
H
Erectile dysfunction in men, benign prostatic hyperplasia
N N
N H
O
O O
Flibanserin (Addyi)
Hypoactive sexual desire disorder in women
O N
HN N
CF3
N
Medicines for Dermatological (topical) Medicine
Chemical structure
Use N
Miconazole N
Antifungal, ringworm, pityriasis, yeast infection of the skin or vagina
O Cl
Cl
Cl
Cl
Selenium disulfide
S2 Se
Pityriasis versicolor, seborrheic dermatitis, dandruff
Sodium thiosulfate
Na2 S2 O3
Cyanide poisoning, pityriasis versicolor
Terbinafine
Pityriasis versicolor, fungal nail infection, ringworm, athlete’s foot
N
Mupirocin
OH O
HO OH O H
O
O H
HO O
Skin infections such as impetigo and folliculitis
725
726
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
Potassium permanganate
KMnO4
Fungal infections of the foot, impetigo, pemphigus, wounds, eczema, tropical ulcers
Silver sulfadiazine
N O S N N O H2N
Burns to prevent infection
Ag OH
Betamethasone
O OH
HO H F
Dermatitis, psoriasis, other uses such as Crohn’s disease, preterm labor, and leukemia
H
O OH
Hydrocortisone
O OH
HO H H
H
Dermatitis, other uses such as thyroiditis, asthma, COPD, high blood calcium, and rheumatoid arthritis
O
Benzoyl peroxide
O O
O O
Coal tar
Fluorouracil
From coal
Psoriasis, seborrheic dermatitis, dandruff, other uses such as shampoo, soap, and ointment
O
O
Actinic keratosis, skin warts, other uses such as stomach cancer, pancreatic cancer, breast cancer, cervical cancer, basal cell carcinoma, colon cancer
OH
Warts, calluses, acne, ringworm, ichthyosis, and psoriasis
F
NH N H
Salicylic acid
Acne, other uses such as hair bleaching, teeth whitening, textile bleaching, and bleaching flour
O
OH
Antidotes in Poisonings
Medicine
Chemical structure
Use
O
Urea H 2N
Dermatitis, ichthyosis, dry skin, eczema, keratosis, calluses, corns
NH2
O
Benzyl benzoate
Scabies, lice, other uses such as asthma and whooping cough
O
Permethrin
Scabies, lice
Cl O
O
Cl O OH
Tropicamide
Dilation of pupil, cycloplegia
N
N O
Diatrizoate O
Barium sulfate
OH
O I
I
N H
N H
I
Contrast agent in X-rays visualizing veins, urinary system, spleen, and joints
O
BaSO4
Contrast agent in X-rays visualizing stomach and intestines
Iohexol
HO OH
OH
H N
O
OH
I
I
N
N H
O
I
O
OH OH
Contrast agent in X-rays and computer tomography (CT scan) visualizing arteries, veins, urinary systems, and ventricles of the brain
Antidotes in Poisonings Agent
Chemical structure
Use
Activated charcoal
Carbon
Oral poisoning such as phenobarbital and carbamazepine; it does not work for poisoning by cyanide or other corrosive agents
727
728
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure
Use
OH OH
Calcium gluconate
Overdose of magnesium sulfate, black widow spider bites, other uses such as low blood calcium and high blood potassium
O
HO OH OH O
Ca2+
OH OH O
HO OH OH O
Methylene blue Me2N
S
Potassium cyanide poisoning, other uses such as methemoglobinemia, urinary tract infections, dye, or stain
NMe2 Cl
Naloxone
HO
Opioid overdose, clonidine overdose
O
O N
O
O
Penicillamine HS
Heavy metals poisoning, arsenic poisoning, kidney stones
OH NH2
Prussian blue
Fe4 [Fe(CN)6 ]3
Thallium poisoning, radioactive cesium poisoning
Sodium nitrite
NaNO2
Cyanide poisoning
Sodium thiosulfate
Na2 S2 O3
Cyanide poisoning
Deferoxamine
OH N
H2N O
O N OH
Dimercaprol
N H
SH HO
SH
O
O N OH
O NH
Acute iron poisoning (overdose)
Acute poisoning by arsenic, mercury, gold, lead
Antidotes in Poisonings
Medicine
Chemical structure
Use
Fomepizole
Methanol and ethylene glycol poisoning
N N H
O
Sodium calcium Edetate (Na Ca EDTA)
O
N
N O O
Ca2+
Lead poisoning O Na
O
O
Na
O
Succimer (dimercaptosuccinic acid)
O
SH
Lead, mercury, arsenic poisoning
OH
HO SH
O
O
Folinic acid (leucovorin)
O
O
N H
H2N
O
N
N
NH N H
OH
N H
Flumazenil
O
N
OH
O O
N
Methotrexate and trimethoprim overdose
Benzodiazepine overdose
N
F O
Acetylcysteine (N-acetylcysteine)
Pralidoxime
Protamine sulfate
SH
O N H
N
OH
Paracetamol (acetaminophen) overdose
OH
Organophosphate poisoning
O
N
Cationic polypeptide, molecular weight 5 kDa, isolated from salmon sperm
Heparin overdose
729
730
Appendix A List of Medicines (Partial) and Nutrients
Medicine
Chemical structure H N
Physostigmine
Use
Anticholinergic poisoning, other uses such as glaucoma and delayed gastric emptying
H
O
N O
N H
HO
Pyridoxine (vitamin B6 )
Certain types of mushroom poisoning
OH HO N
O
Phytomenadione (vitamin K1 )
Warfarin overdose and some rodenticide poisoning
O
Vitamins Vitamin
Chemical structure
Vitamin A (retinol, one of the major forms)
OH
NH2
B1 (thiamine) N
N
S
N OH
Deficiency diseases
Major food sources
Immune system, night blindness, hyperkeratosis, poor bone, hair and skin growth
Cod liver oil, broccoli, butter, spinach, orange, pumpkin, egg, carrot, sweet potato, chicken liver, and breast milk
Beriberi, Wernicke–Korsakoff syndrome, neuritis, edema, cardiac failure, fatigue, weak muscles, anorexia, weight loss, mental changes such as confusion or irritability, cracks in the lips
Whole grains, cereals, legumes, most fish, nuts, seeds, banana, breast milk
Vitamins
Vitamin
Chemical structure O
B2 (riboflavin)
N
NH
N
N
O
OH HO
O
731
Deficiency diseases
Major food sources
Corneal ectasia, photophobia, glossitis, itching and irritation of lips, eyes and skins, poor growth
Egg, milk, cheese, legumes, mushrooms, green vegetables, kiwifruit, almonds, breast milk
Pellagra, dermatitis, diarrhea, dementia, depression, dizziness, headaches, indigestion, insomnia. Limb pains, loss of appetite, low blood sugar, muscular weakness, skin eruptions, inflammation
Meat, fish, nuts, mushrooms
Irritability, fatigue, apathy, paresthesia, muscle cramps, insomnia, loss of antibody production
Mushrooms, sunflower seeds, egg, breast milk, legumes, fish, chicken, cereals, whole-grain breads
Skin disorder, abnormal nervous system, poor coordination and insomnia, anemia, irritability
Banana, potato, chickpeas, watermelon, wheat bran, walnuts, brown rice, whole-grain breads, cereals, soy, legumes, breast milk
Genetic disorder, hair thinning, skin rash, seborrheic dermatitis, glossitis, nausea, insomnia
Chicken liver, egg, salmon fish, avocado, peanuts, grapefruit, watermelon, strawberries
OH O
B3 (niacin, nicotinamide)
NH2 N
H OH H N
B5 (pantothenic acid) HO
OH
O
B6 (pyridoxal phosphate)
O O
O
O
O P OH OH
N
B7 (biotin, also called vitamin H)
O HN H
NH H OH S O
732
Appendix A List of Medicines (Partial) and Nutrients
Vitamin
Chemical structure CO2H
O
B9 (folate/folic acid)
N H
O N
HN H2N
N
N H
N
B12 (cobalamin)
Porphyrin-cobalt complex
Vitamin C (ascorbic acid)
HO
HO
H
O
HO
O OH
Vitamin D2 ergocalciferol H
H
HO
CO2H
Deficiency diseases
Major food sources
Neural tube defects, feeling tired, shortness of breath, anemia, digestive disorder, loss of appetite, weight loss, weakness, sore tongue, heart palpitation, forgetfulness, irritability, behavioral disorder, cancer
Peanuts, lentils, chickpeas, asparagus, spinach, lettuce, broccoli, bean, chicken liver, salmon, orange, whole-grain bread, cantaloupe, breast milk
Anemia, neurologic deteriorations include numbness or tingling of the extremities, abnormal gait
Meat, fish, egg, milk, soy, cereals, breast milk
Scurvy, bleeding and inflamed gums, loose teeth, poor wound healing, anemia, osmotic diarrhea
Orange, lemon, grape, guava, Indian gooseberry, bell pepper (capsicum), pineapple, papaya, kiwifruit, broccoli, tomato, mango, cabbage, cauliflower, strawberry
Weak, soft bones, skeletal deformities (rickets)
Lichen, egg, breast milk, fatty fish, sunlight
Vitamins
Vitamin
Chemical structure
Vitamin D3 Cholecalciferol
733
Deficiency diseases
Major food sources
Rickets, osteomalacia
Lichen, egg, breast milk, fatty fish, sunlight
H
H
HO
Vitamin E
R1 HO O
R2 R3
H
R1 , R2 , R3 = H or Me
Vitamin K1 Phytomenadione
O
O
Vitamin K3 Menadione
O
O
Hemolytic anemia in newborn infants, low weight babies, hyporeflexia, spinocerebellar, retinal degeneration
Breast milk, vegetable oils, egg, nuts, wheat germ, whole grains, cereals
Prolonged bleeding, hemorrhagic manifestations
Vegetable oils, spinach, cabbage, egg, breast milk, broccoli, sprouts, kale, collards, pork liver
Prolonged bleeding, internal hemorrhaging
Vegetable oils, spinach, cabbage, egg, milk, broccoli, sprouts, kale, collards, pork liver
Fat-soluble vitamins including A, D, E, and K can be stored in the human body and not need be consumed daily. Water-soluble vitamins B and C are not stored in the human body. Hence these can be consumed daily.
734
Appendix A List of Medicines (Partial) and Nutrients
Other Nutrients Nutrient
Deficiency symptoms
Major food sources
Protein
Edema, reddish pigmentation of hair and skin, fatty liver, retardation of growth, diarrhea, dermatosis, infections
Breast milk, seafood, meat, fish, beans, soy, egg, almond, oat, yogurt, broccoli, tuna fish, whey protein, lentils, pumpkin seeds, unsalted nuts and seeds
Fat
Eczema, low growth rate, hair loss, resistance in infections
Breast milk, meat, egg, dairy products, chocolate, avocado, nuts, seeds, olive oil, coconut
Carbohydrate
ketosis
Breast milk, whole-grain breads, rice, cereals, potatoes, wheat, corn, legumes
Calcium
Abnormal development of bones, muscle cramps, brain function, osteoporosis
Breast milk, tofu, salmon, broccoli, kale, collard, cinnamon, egg, nuts, seeds
Copper
Anemia, hair problems, dry skin, pallor, retarded growth, edema, loss of appetite
Seafood, nuts, seeds, beans, legumes, whole-grain breads, cereals, poultry
Chromium
Glucose intolerance, retarded growth, peripheral neuropathy
Meat, fish, whole-grain breads, cereals, broccoli, grape
Chloride
Nausea, cramps, vomiting, apathy
Table salt (sodium chloride), breast milk
Fluoride
Weak teeth and bones
Fluoridated water, marine fish
Iodine
Enlargement of the thyroid gland, endemic goiter, cretinism
Iodized salt, breast milk, seafood, edible seaweed, dairy products
Iron
Fatigue, lethargy, weakness, insomnia, headaches, shortness of breath, cracked lips, brittle nails, anorexia, irritability, pallor
Breast milk, egg, seafood, nuts, beans, meat, legumes, whole-grain breads, cereals, dark green vegetables
Magnesium
Fatigue, diarrhea, numbness, poor memory, irritability, tingling, rapid heartbeat
Breast milk, spinach, legumes, nuts, seeds, whole grains, avocado, broccoli
Manganese
Abnormal growth, dermatitis, poor memory, nervous irritability, fatigue, heavy menstrual periods, blood sugar problems, fragile bones
Whole-grain breads, cereals, legumes, seeds, nuts, tea, coffee, leafy vegetables
Molybdenum
High levels of sulfite and urate in blood, neurological damage
Legume, whole grain, meat, nuts, breads, cereals
Phosphorus
Weakness, bone pain, anorexia,
Chicken, breast milk, egg, fish, legumes, nuts, breads, rice, oats, cereals
Potassium
Muscle weakness, nausea, anorexia, cardiac arrhythmias, respiratory failure, irritability, depression
Potato, tomato, beans, breast milk, egg, meat, fish, lentils, seafood, banana, prune, carrot, orange, mushrooms, broccoli, sunflower seed, soy, green leafy vegetables
Sodium
Fatigue, apathy, nausea, muscle cramp, vomiting, dizziness, respiratory failure
Table salt (sodium chloride), soy, spinach, milk
Selenium
Myalgia, muscle cramp, cardiac myopathy, pancreas problems, fragility of red blood cells
Whole-grain bread, cereal, seafood, meat, egg, onion
Zinc
Slow healing of wounds, loss of taste, hair loss, diarrhea, slow growth, delayed sexual development in children, skin changes
Breast milk, seafood, poultry, egg, whole grain, bean, nut, cereal, legume
Further Reading
Medical Advice Disclaimer The information is provided here for educational purpose only and is not intended for medical advice, diagnosis, or treatment. Medical information changes constantly; hence, the information in this book or on the referenced websites should not be considered current, complete, or exhaustive. Do not rely on this information to select a course of treatment for you or any other individual. Reliance on any information in this book or on any referenced website is solely at the reader’s risk. Readers of this book assume full responsibility for how they choose to use the information presented. Readers who believe they are having a medical emergency should immediately call their doctor, go to the nearest emergency room, or call 911. Readers of this book understand and acknowledge that they are responsible for their own medical care, treatment, and supervision. All content of this book, including text, treatments, dosages, outcomes, charts, profiles, graphics, photographs, images, and advice, were created for informational purposes only and do not constitute provision of specific medical advice. Information is for educational purposes only. Readers of this book understand and acknowledge that they should always seek the advice of their physician or other qualified health provider with any questions or concerns regarding their health. Readers further understand and acknowledge that the contents of this book should never cause them to disregard or delay seeking professional medical advice related to treatment or standard of care, inasmuch as the information presented is not intended to be a substitute for professional medical opinions.
Further Reading 1 World Health Organization (WHO), essential medicines, retrieved 19 January 2 3 4 5 6 7 8
2017, 26 June 2016, 21st list 2019. WHO, healthy diet, nutrients, global target. National Institute of Health (NIH), USA, drug information portal. NIH, dietary supplement fact sheet. U.S. Department of Agriculture, nutrition.gov. U. S. Food & Drug Administration, nutrition facts label. FDA approved medicines. American Society for Nutrition.
735
737
Index a abafungin 461, 463, 682 abyssomicin C 79 acceptor 77 aceclidine 565 acetal 200, 650 acetaminophen 7, 565, 687, 691, 720, 729 acetanilide 7 acetazolamide 463 acetic acid 21, 27, 34, 69, 115, 138, 139, 221, 368, 406, 413, 417, 474, 478, 582, 596, 603, 720 acetic anhydride 87, 114, 536, 573, 582, 583, 603, 604 acetone 41, 86, 167, 187, 188, 216, 238, 239, 393, 395, 403, 419, 424, 588, 589, 591, 594, 599 acetonide protecting group 512, 594 acetonitrile 4, 7, 8, 137, 214, 238, 313, 333, 481, 534, 577, 591 acetophenone 69, 71, 79, 369, 421, 422 acetophenone oxime 7 acetyl (Ac) 508, 511 acetyl chloride 604 achalensolide 217 aciculatin 10 acidic work-up 9, 174, 176, 193, 401, 418, 424 acrolein 491, 492 actinophenathroline A 477 actinophyllic acid 17 actinoranone 211 active methylene compound 84, 208 aculeatins A, B, D 237
acutifolone A 423 acutiphycin 219 acutumine 17 acyclovir 465 acylation 228, 295, 301 acyl azide 17, 18 acylium ion 300, 303 acyl transfer 9, 87, 115, 372 adalat 368, 568 AD-mix 134 adunctin B 298 alanine 198, 520 albendazole 464, 689 alcohol 13–16, 19, 34, 36, 38, 39, 78, 81, 121, 129, 162, 163, 168, 169, 173, 188–193, 209, 210, 213, 214, 220–222, 225, 226, 235, 236, 338, 389–398, 401–404, 406, 407, 409, 410, 412–414, 417, 422–424, 427, 492, 509, 514, 543, 544, 546–551, 554, 555, 573–576, 585–588, 593, 594, 600, 604, 605, 607, 613–615, 617, 619–621, 624–627, 633–638, 640, 641, 644, 647, 649, 650, 652–654, 656–658, 660, 662–664, 688, 692, 703 aldactone 466 Alder Ene reaction 161 aldol 70–72, 74–76, 84, 89 aldol condensation 8, 69, 74, 83, 87, 222, 367, 481 aldosterone acetate 167 alfentanil 463 aliphatic 8, 173, 220, 235, 238, 520, 579 aliskiren 335
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.
738
Index
alkaloid 17, 19, 70, 188, 221, 472 alkylation 228, 295, 599, 614, 617 alkylfluor 605 alkyl migration 168 allene 181 allergic conjunctivitis 126, 459 allergic rhinitis 126, 460, 697, 720, 721 alliacol A 297 allosedridine 17 allylic alcohol 422, 616 allyloxycarbonyl (Alloc) 508, 531 allylstannane 204 α-amino ketones 482 α-diazoketone 39, 41 α-tocopherol 133 alstonerine 217 alstoscholarisine A 297 altinicline 332 aluminum chloride 25, 295, 296, 298, 299, 301, 304, 306, 605 aluminum ethoxide 230 aluminum isopropoxide 404, 423, 424, 605 alverine 327 amantadine 221 ambrisentan 133 amides 6, 7, 13, 28, 36, 39, 74, 189, 196, 206, 213, 220, 221, 225, 234, 235, 371, 471, 491, 526, 529, 554, 559, 578, 579, 616, 624, 628, 634, 644, 648, 654, 664 amiloride 463 amination 170, 171, 340, 562, 579, 596, 603, 606, 628, 654, 656 amine 1, 17, 19, 20, 22, 28, 29, 31, 32, 36, 39, 83, 84, 170, 171, 175, 176, 195, 196, 199, 200, 211, 223, 225, 305, 308, 311, 339–342, 364, 368, 369, 373–376, 475, 479, 481, 485, 486, 489, 507, 524, 525, 528, 550, 556, 558, 560, 562, 563, 579, 580, 595, 596, 604, 615, 624, 626, 628, 634, 636, 637, 643, 645, 651, 654, 655, 660, 663 amino acid 17, 69, 235, 373, 519–523, 526, 530, 533, 538 aminocyclitols 130
amino hydroxylation 136 4-aminophenol 5 aminophylline 465 amino thiophene 365 amipurimycin 71 ammonia 28, 69, 171, 172, 219, 305, 331, 366, 367, 375, 378, 412, 413, 479, 485, 606 ammonium chloride 114, 178, 228, 575, 583, 596, 605 ammonium formate 606 ammosamide B 477 amoxicillin 466, 671 amphidinolide 71 amphidinolide B 71 amphidinolide C 192 amphidinolide J 237 amphidinolide P 201 amphidinolide T3 123 amphidinolide W 136 amphidinolide X 192 amphilectane 17 amphirionin-4 214 ampicillin 466, 671 amyl nitrite 634 amythiamicin C 329, 330 angelmarin 133 anguinomycin C 329 anhydrous 17, 23, 28, 38, 72, 76, 79, 85, 90, 114, 119, 124, 132, 134, 136, 138, 140, 163, 167, 169, 170, 175, 178, 180, 188, 192, 193, 195, 199, 203, 204, 221, 224, 228, 230, 235, 237–239, 298, 299, 304, 325, 330, 331, 335, 338, 339, 341, 365, 391, 393, 395, 397, 402, 404, 406, 413, 415, 417, 419, 423, 425, 426, 428, 471, 474, 482, 525, 573, 575–586, 588–601, 605 aniline 29–31, 473, 474, 491 anmindenol A 230 antibacterial 123, 196, 238, 297, 363, 460, 466, 671 antibiotic 23, 24, 39, 70, 71, 74, 79, 113, 126, 130, 192, 227, 325, 330, 331, 370, 408, 421, 457, 461, 466, 474, 569, 654, 671, 685, 686, 691, 696
Index
anticancer 2, 79, 133, 135, 215, 224, 227, 237, 332, 459, 461, 462, 464, 465, 474, 475, 481 anticoagulant 459, 704, 705 anticonvulsant 460, 688 antifungal 121, 460, 488, 567, 678, 679, 681, 725 antihistamine 461 anti-inflammatory agent 42, 363 antimalarial 84, 211, 392, 463, 474, 567, 683, 684 anti-Markovnikov addition 168 antimicrobial 79, 192, 366, 368 antimitotic 70 antiparasitic 459, 466 antiplatelet 398, 459 antiproliferative 70 anti-seizure medication 460, 689 antispasmodic 463 anti-vertigo 461 antiviral 24, 118, 211, 221, 228, 230, 238, 363, 465, 673 antofinem 472 antroquinonol 12 antroquinonol D 12, 415 anxiety 421, 688, 691, 702, 703 AOP 526 apaziquone 457 apicularen A 214 apiosporic acid 118 aplysiasecosterol A 219 apoptolidin 330 Appel reaction 162–164 applanatumol B 213 aquatolide 73, 214 archazolid F 70 arginine 520, 533 aripiprazole lauroxil 570 aristeromycin 211 aristolactam gi 211 aristotelone 221 Arndt-Eistert homologation 41–42 aromatic 8, 9, 12, 24, 27, 30, 33, 76, 86, 161, 171, 173, 181, 184, 185, 190, 220, 223, 233, 238, 293–300, 303, 305, 307, 309, 311, 313, 338, 401, 411–413, 449, 471–473, 475, 477,
488, 489, 520, 528, 560, 561, 579, 581–583, 589, 603, 615, 619, 633, 634, 660 articaine 459 ascorbic acid 607, 732 asparagine 520, 533 aspartic acid 520, 533 asperazine 297 asperchalasines A, D, E, H 113 aspercyclides 214, 233 aspergillide B 118 aspergillide C 118 aspergillide D 192 aspeverin 19 aspidodasycarpine 71 aspidospermidine 201, 234, 427 aspinolide B 214 aspirin 306, 307, 565, 604, 687, 690 asymmetric epoxidation 129, 130, 132 atorvastatin 377, 483, 486, 487, 699 aurantioclavine 165 aurantoside G 82, 211 aureole 88 aurofusarin 82 australine 401 axamide-1 423 axenol 119 axial 12 axinellamines A, B 217 9-azabicyclo[3.3.1]nonane N-Oxyl 607 azacyclophanes 370 azadiradione 167 azaspiracid-1 73, 74, 162 azathioprine 465, 703 azetidine 215, 457 azides 36, 37, 202, 203, 342, 550, 560, 595, 615, 627, 637, 663 aziridine 457 azobisisobutyronitrile (AIBN) 164, 165, 597, 607 [1,1′ -(azodicarbonyl)dipiperidine] (ADDP) 608
b bacterial vaginosis 672 Baeyer-Villiger oxidation bafilomycin A 72
1–3, 618
739
740
Index
Baker-Venkataraman rearrangement 9 balanol 24 Bamberger rearrangement 5 barbiturates 462 Bardhan-Sengupta synthesis 293 Bartoli indole synthesis 469 Barton decarboxylation 164 Barton nitrite photolysis 166 basidalin 70 batatoside L 179 baulamycin A 113 Beckmann rearrangement 6, 7 bellenamine 42 benanomicin A 82 benazepril 7 bendazac 465 benflumetol 84, 567 benzalacetophenone 71 benzaldehyde 69, 71, 73, 77, 78, 186, 232, 369, 375, 491, 596 benzidine 42 benzidine rearrangement 42 benzil 8, 9, 406 benzilic acid rearrangement 8 benzimidazole 464 benzoate (Bz) ester 512 benzoin 76, 77 benzoin condensation 76 benzoyl peroxide 608, 726 benzydamine 18, 465 benzyl (Bn) 508, 510, 531 benzyl alcohol 191, 393, 395, 587, 590 benzylamine 375 benzyl chloride 239, 588 benzyl ester 515, 577, 580 benzyl ether 510 benzylidene acetal 512 benzyloxymethyl (BOM) ether 510, 531 benzylpenicillin 466, 671 beraprost 398, 419 berkeleyamide A 74 β-amino alcohols 22 β-diketones 9, 78, 472, 473 β-hydride 327 β-ketoesters 79, 474, 477, 482 β-naphthylamines 169
betahistine 461 biatractylolide 230 bifonazole 460, 679 Biginelli reaction 363, 364 bile acid 165 bimatoprost 116 binap 162, 419 biotin 339, 731 bipinnatin J 162, 214 birch reduction 412 bisacodyl 461 Bischler–Napieralski reaction 471, 644 [1,1′ -bis(diphenylphosphino)ferrocene] palladium(ii) dichloride, pd(dppf )cl2 608 biselyngbyolide A 331 biselyngbyolide B 331 bismuth chloride 609 (bis(trifluoroacetoxy)iodo)benzene 610 bitungolide F 113, 118 bleomycin A2 74 BMS-599793 329 BMS-955176 32 boesenoxide 112 Bogert–Cook synthesis 294 9-borabicyclo[3.3.1]nonane (9-BBN) 610 boronic acids 323, 325, 338 boronolide 130 boron tribromide 590, 610 boron trifluoride diethyl etherate 611 borrelidin 219 botryolide B 192 Bouveault–Blanc reduction 414 brassinosteroid 112 brazanquinones 24 breast cancer 705, 707–709, 711, 713–717, 726 brefeldin A 118, 188 bretonin B 121 brevenal 113, 126 brevetoxin A 201 brevetoxin-B 219 brevicolline 490 brevisamide 331, 427 bromadol 18
Index
bromination 223, 611, 612, 643 bromine 28, 29, 197–199, 204, 611, 612 broussonetine M 205 Brown hydroboration 167 bruceol 131 bryostatin 1 205 Bucherer reaction 169 Buchwald-Hartwig coupling reaction 340 bupivacaine 463, 696 Burgess dehydrating reagent 613 butoconazole 460, 679
c cabazitaxel 457 caffeine 465, 724 calanolide A 423 calcitriol 177 caldaphnidine 313 callipeltoside A 333 callyspongiolide 333 calyciphylline B 71 camptothecin 70, 135, 327, 481 canagliflozin 459 candesartan 18 candicidin 466 cannabisativine 226, 423 Cannizzaro reaction 173 cannogenol 209 capnellene 40 caprazamycin A 211 capreomycin ib 29 capsaicin 226 carbamazepine 465, 688, 702, 727 carbamic acid 29 carbapenem 421 carbene 77, 308, 309 carbobenzyloxy (Cbz) 507 carbocation 5, 7, 21, 22, 24, 34, 35, 39, 181, 220, 221, 294, 528 carbon–carbon bond 69, 75, 78, 127, 193, 326, 335 carbon dioxide 32, 165, 204, 306–308, 528 carbon electrophile 200, 211 carbon monoxide 216, 295, 300, 301 carbon tetrabromide 178, 615
carbonyl compounds 11, 33, 36, 37, 70, 78, 80, 120, 121, 193, 208, 211, 212, 228, 369, 370, 406, 407, 409, 411, 416, 425, 481, 488, 610, 616, 641, 652 carbonyldiimidazole (CDI) 616 carboquone 457 cassiarin F 306 cassine 168 casuarina 401 catecholamine 4 cefaclor 466 cefalotin 466 cefotaxime 461, 463 cefuroxime 458 cephalotaxus ester 73 cepharamine 29 ceric ammonium nitrate (CAN) 616 cesium carbonate 617 cesium fluoride 617 cetylpyridinium chloride 462 chalcone 71 chamuvarinin 118, 205 cheimonophyllal 73 cheimonophyllon E 72 Chichibabin reaction 170, 171 chlorizidine A 211, 219 chlorocatechelin A 226 chloroquine 463, 684 chlorphenamine 461 chromium trioxide 393, 394, 619 chromyl chloride 185, 186 Chugaev reaction 172 ciclobendazole 464 cinnamic acid 604 cis-solamin 162 cladospolide C 192 cladospolides A-C 118 Claisen condensation 78, 81 Claisen rearrangement 11, 12 clavicipitic acid 165 clavilactone B 130 clavosolide A 192 clavubicyclone 165 cleistenolide 192 clemmensen reduction 415 click chemistry 202, 539, 540, 607
741
742
Index
clivonine 472 clobazam 465 clomipramine 465, 703 clonazepam 465 clonidine 460, 728 clopidogrel 459, 699 clotrimazole 460, 678 cloxacillin 461, 463, 672 cobalt chloride 620 codeine 89, 222, 687 codeinone 404 combes quinoline synthesis 472, 473 combretastatin a-4 88 communiol E 26 concentricolide 24, 333 condensation reaction 69, 76, 370, 474, 480, 485 conduramines 130 conico 71 Conrad-Limpach reaction 474 Cope elimination 172, 175 copper iodide 620 Corey-Bakshi-Shibata reduction 417 Corey-Fuchs reaction 176 Corey-Kim reaction 389 Corey-Winter olefin synthesis 111 coriandrone A 133 coriolin 81 coronarin A 392 cortistatin 21 corylifolin 121 corymine 12 cosalane 297 coumarin 85, 86, 340 coumestrol 88 covalent peptides 536, 537 criegge oxidation 407 criegge ozonolysis 409 crixivan 221, 377 crocacin D 330 cromoglycic acid 464 crotepoxide 112 cruentaren A 237 cruentaren B 74, 126 cryptophycin 52 133 cryptopleurine 472 cryptosporin 200
curacin-A 227 Curtius rearrangement 17, 18 cyclacillin 466 cyclization 483, 484 cycloaddition 122, 180, 202, 203, 227 cycloheptanone 22 cyclohexane 301, 391, 397 cyclohexanone 7, 222, 230, 404 cyclohexyl 1, 377 cyclopentanone 83 cyclopentyl 535, 599 cyclopropane 22, 625 cyclopropyl 228 cycloviracin B 118 cylindramide 118 cylindrocyclophanes A 182 cyrneine A 427 cysteine 520, 533, 534, 536 cystothiazole A 74 cytospolide P 192
d dactylolide 113, 121, 205 dakin oxidation 3, 4 danheiser annulation 180 danheiser benzannulation 181 daphenylline 184, 223, 297, 298, 329, 333 daphlongamine H 217 darzens glycidic ester condensation 80 debrisoquine 488 decarboxylation 32, 164, 165, 203, 204 dehydration 69, 70, 294, 474, 491, 492, 613, 644 dehydrogenation 293, 295, 623 6,7-dehydrostipiamide 121, 177 3-demethoxyerythratidinone 19 Demjanov rearrangement 19, 22 dendrodolide-L 192 deoxygenation 609 2-deoxykealiiquinone 77 deoxymannojirimycin 401, 423 8-deoxyserratinine 82, 133 desferrisalmycin B 211 4′ -desmethoxykealiiquinone 77 7′ -desmethylkealiiquinone 77 desmycosin 399
Index
Dess-Martin oxidation 391, 392 Dess-Martin periodinane (DMP) 391, 393, 587, 621 diacerhein 24 (diacetoxyiodo)benzene (DAIB) 621 2,4-diaminobutyric acid (DAB) 531, 533, 536 2,3-diaminopropionic acid (DAP) 531–533, 536 1,4-diazabicyclo[2.2.2]octane (DABCO) 622 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) 75, 622 diazepam 465, 688, 703 diazo compounds 185 diazomethane 41, 42, 623 diazonium salts 185, 223, 224 diazotization 19, 595, 615, 634 dibromophakellstatin 29, 211 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) 623 dichloromethane (DCM) 75, 203, 237, 238, 331, 393, 484, 531, 532, 536, 539, 574, 576, 587, 626 didemnaketal B 214 diea 225, 525, 535, 578, 594, 627 Dieckmann condensation 81 Diels-Alder reaction 183, 184 diene 183 dienophile 183 diepoxin sigma 234 diethylaminosulfur trifluoride (DAST) 593, 624 diethyl azodicarboxylate (DEAD) 209, 210, 625, 626 diethylcarbamazine 463 dihydro-combretastatin D-2 234 dihydroxylation 134, 138, 140, 592, 638 diiodomethane 226, 228, 625 diisobutylaluminum hydride (DIBAL-H) 626 diisopropyl azodicarboxylate (DIAD) 211, 626 diisopropyl carbodiimide (DIC) 525, 526, 535, 555 1,2-diketones 8
4-dimethylaminopyridine (DMAP) 113, 165, 191, 192, 225, 533, 573, 574, 576, 580, 627 N,N-dimethylformamide (DMF) 195, 233, 238, 311–313, 323, 339, 376, 525, 529, 532, 535–537, 575, 578, 588–591 dimethyl fumarate 565 1,3-dioxane 516 1,3-dioxolane 515, 599 diphenylphosphoryl azide (DPPA) 627 diprophylline 465 diradical 204, 215 dirchromone-1 10 disorazoles a1 192 disproportion reaction 230 disulfide 562, 634, 665 diterpene 40, 42 di-tert-butyl azodicarboxylate (DBAD) 623 1,3-dithiane 516, 598, 600 1,3-dithiolane 516 diversonol 82 docetaxel 457, 709 Doebner reaction 476, 477 Doebner-Von-Miller reaction 476 dracaenones 71 dragmacidin D 42 duloxetine 459 Dutt-Wormall reaction 185 dysidiolide 418 dysoxylum alkaloid 421, 472
e eburnamonine 490 econazole 460 Ei 173, 176 elantrine 7 elanzeprine 7 electron-donating group 183, 412 electron-withdrawing group 8, 83, 183, 208, 233, 412 electrophile 212, 295, 296, 299, 300, 303, 305, 311 electrophilic addition 492
743
744
Index
electrophilic substitution 27, 30, 33, 293, 294, 296, 298, 303, 305, 307, 472, 473, 475, 477, 489 eletriptan 479, 566 elevenol 231 ellipticine 475 enamine 170, 228, 230, 367, 473, 482, 486 Ene reaction 161 enigmazole A 329 enophile 161 enprazepine 7 entecavir 211, 674 enyne 34, 35 epelsiban 377 ephedradine A 137 epiasarinin 81 1-epiaustraline 194, 401, 413 epibatidine 29 epicoccamide D 82 epiepiquinamide 19 epiquinamide 19 8-epi-swainsonine triacetate 205 epothilone A 71, 131 epothilone B, D 214 epoxidation 111, 129, 130, 134, 551 epoxide 81, 130, 133, 134, 200, 341, 557, 618 epoxyeujindole A 214 eremantholide A 74 erysotramidine 19, 37 erythromycin 466 Eschenmoser-Claisen rearrangement 13 esterification 189, 514, 576 estradiol methyl ether 298 Etard reaction 185 etazepine 7 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) 526, 579, 628 eudistomin 211 eudistomin C 490 eupalinilide E 423 eupomatilone-6 136 Evans Aldol reaction 73, 74
exiguolide 333, 336 ezetimibe 457
f Favorskii rearrangement 25 fawcettidine 82 fawcettimine 82 Feist-Benary furan synthesis 477 fenbendazole 464 fentanyl 463, 687 ferric chloride 295 ferrugine 173 ficuseptine 171 fidaxomicin 73, 325, 331 filibuvir 332 Finkelstein reaction 187 Fisher esterification 188, 554 Fisher-Hepp rearrangement 26 Fisher indole synthesis 478, 665 Fisher-Speier esterification 188 flavisiamine F 12 fleming oxidation 400 flubendazole 464 flucloxacillin 461, 463, 466 fluconazole 194, 460, 567, 678 9-fluorenylmethyloxycarbonyl (FMOC) 508 fluorouracil 462, 711, 726 fluoxetine 370, 702 fmoc group 529, 536, 645 folic acid 395, 732 formaldehyde 236, 369 formamide 220, 509 formic acid 36, 629 formylation 298, 300, 308, 311, 614, 660 Fosfomycin 457 fostriecin 70, 136, 330 FR66979 130 FR182877 74, 113 FR900482 130, 182 Friedel-Crafts reaction 295, 297, 298, 492, 605 Friedländer synthesis 480 Fries rearrangement 23, 24, 605 frondosin B 297 fumimycin 4
Index
fumiquinazoline G 226 funebrine 483, 486 furans 477, 484 furaquinocin A, B 113 furoclausine-B 133 furoscrobiculin B 34 fusarisetin A 82
g gabapentin 18 Gabriel synthesis 195 galantinic acid 137 Galbulimima alkaloid GB 13 413 Gattermann aldehyde synthesis 298 Gattermann-Koch reaction 300 gelsemine 84 Gewald reaction 365 gleenol 119 glucolipsin A 74 glutamic acid 520, 533 glutamine 520, 533 glyceollin ii 77 glycidic ester 80 glycine 519, 520, 526 glycinol 341 glycol 407 Goldberg reaction 233 goniothalamin 126 goniotrionin 73 gossypol 12 gracilioether A 3 gracilioether E 3 gracilioether F 3 granatumine A 84 grayanotoxin 124 Grignard reaction 193, 194 GRN-529 332, 568 Grubbs’ reagent 127, 539 guanacastepene A 39, 223 gymnodimine 73, 214 gymnothelignan N 74
h halichondrin B 411 halogen-metal exchange hamayne 162 hamigeran B 297
187
Hantzsch pyridine synthesis 366 haplophytine 297 hasubanonine 126 HATU 526, 555, 579, 629 Haworth reaction 301 HBTU 526, 555, 579, 629 HCTU 526 Heck reaction 325–327 heliespirone A 201 Hell-Volhard-Zelinsky reaction 197 hemigossypol 12 hemolytic cleavage 733 hennoxazole A 72 Henry reaction 75 herbindole A 470 heronapyrrole C 133, 136 hetacillin 466 Hetero-Diels-Alder reaction 183, 639 himandrine 413 hippodamine 370 hippolachnin A 2 hispanane 423 histidine 520, 533 Hiyama coupling reaction 335 HOAt 526 HOBt 525, 526, 555, 579, 630 Hofmann degradation 28 Hofmann elimination 199 Hofmann-Martius reaction 29 Hofmann rearrangement 28 hoiamide A 231 homologation 39, 41, 176 homospectinomycin 23 Hosomi-Sakurai reaction 200 Houben-Hoesch reaction 304 houttuynoid B 10 Huisgen cycloaddition reaction 202 Hunsdiecker reaction 203, 619 huperzine A 39, 341 huperzine B 207 huperzine-Q 217 hyacinthacine A 401 hybocarpone 79 hybridaphniphylline B 12 hydrastine 372 hydrazidomycins A-B 121
745
746
Index
hydrazines 426, 427, 479, 532, 536, 537, 584, 630 hydrazones 427 hydride transfer 404, 418, 421, 424 hydroboration 167, 168, 610 hydrogen peroxide 1, 3, 4, 75, 168, 176, 402, 631 hydroxamic acid 31 3-hydroxybakuchiol 121 10-hydroxycamptothecin 70, 135 hydroxylation 136 hydroxyproline 533
i ibrutinib 465, 712 ichthyothereol 330 idinavir 377 iejimalide B 331 igmesine 18 ileabethoxazole 217 illudinine 32, 84 imatinib 462, 712 imexon 457 imidazole 112, 454, 460, 575, 593, 632 imine 36, 170, 200, 299, 364, 370, 374, 376, 377, 406, 419, 473, 479, 482, 486, 489, 596 iminium ion 84, 369, 370, 374, 489 indazole 465, 589 indicanone 217 indolactam V 341 indole 181, 308, 340, 464, 469, 470, 478, 479, 483 indomethacin 479 indoxamycins A, B 217 ingenol 405 inthomycin C 73 iodine 34, 138–140, 194, 195, 197, 391, 392, 476, 480, 589, 600, 632, 692, 734 2-iodoxybenzoic acid (IBX) 633 iprindole 479 Ireland-Claisen rearrangement 14 iriomoteolide 118, 130 iriomoteolide-1a 192 iriomoteolide 3a 192 iriomoteolide-3a 192
isishippuric acid B 209 isoamyl nitrite 634 isobutyl chloroformate 634 isoconazole 460, 680 iso-crotepoxide 112 isocyanate 17, 18, 28, 29, 31, 32, 579, 663 isocyanide 308, 370, 372, 373, 375, 377 isodomoic acid 113 isofagomine 175 isolaulimalide 116 isoleucine 520 isolysergol 214 isomerization 22, 294, 329, 330, 334, 336, 406 isoprostane 116 isoquinoline 463, 471, 487, 488 isoschizogamine 39 isoxazole 461, 463 ivermectin 466, 689
j Jacobsen-Katsuki epoxidation 130 jasplakinolide 12 jerangolid A 118 jiadifenin 217 jiadifenolide 223 Johnson-Claisen rearrangement 15 Jones oxidation 393 jorumycin 490 jorunnamycin A 490 Julia–Kocienski olefination 117 Julia-Lythgoe olefination 114 Julia olefination 114, 115, 117 juliprosine 171 juliprosopine 171 justicidin B 79
k kainic acid 173, 209, 219 kaitocephalin 79 kanamycin A 238 kanmienamide 418 kauffmann olefination 118 Keck asymmetric allylation 204 kelsoene 26 kendomycin 24, 297, 325
Index
ketal 200, 512, 515, 516, 650 ketenes 14, 15, 39–41 ketones 1–3, 26, 35, 36, 69, 75, 80, 83, 84, 88, 89, 113, 114, 118, 119, 122–124, 200, 206, 211, 213, 217, 218, 221, 222, 226, 228, 235, 236, 303, 337, 338, 366, 370, 373, 375, 378, 389, 391, 393–395, 397, 398, 403, 404, 406, 407, 409, 410, 415, 417–419, 422–426, 478, 480, 489, 515, 543, 544, 551–553, 555, 556, 585, 603, 606, 607, 611, 614, 620, 624, 625, 631, 633–636, 638, 641, 649, 650, 657, 664 ketorolac 459 key step 82, 171, 186, 192, 194, 201, 209, 216, 222, 226, 234, 313, 327, 329, 341, 390, 401, 407, 423, 427, 477, 490 kibdelone C 133 Knoevenagel condensation 83, 84, 366, 567 Knorr pyrrole synthesis 482, 485 Kolbe-Schmitt reaction 306 Kumada coupling reaction 335
l lachnone C 82 lacosamide 377, 569 lactam 206, 235 lactonamycin 82 lactone 1, 73, 89, 178, 179, 189, 206, 235, 372, 466 lactonization 178 ladanein 24 laidlomycin 133 lanostane 167 larotaxel 457 laulimalide 118, 130 laurenditerpenol 118 Lawesson’s reagent (L.R.) 206, 207, 635 l-callipeltose 74 l-deoxymannojirimycin 423 l-DOPA 310, 375, 421, 569, 718 lemonomycin 201, 325, 490 lepadiformines A 37 lepadins A-E 121
leporin A 84 leucascandrolide A 72 leucine 520 leuconoxine 484 leucosceptroid K 71 leustroducsin B 214 levofloxacin 421 Lewis acid 23, 30, 32, 35, 72, 85, 180, 200, 201, 204, 220, 225, 230, 231, 295–298, 304, 363, 376, 402, 418, 476, 478, 480, 489, 515, 605, 609, 611, 613, 652, 658, 665 Liebeskind-Srogl coupling reaction 337 light 32, 42, 78, 86, 113, 166, 170, 204, 228, 328, 365, 476, 591, 596, 627 limonin 223 lintetralin 375 lipitor 377, 486, 699 liquid 128, 228, 365, 423, 478, 578, 579, 584, 595, 599–601, 603, 604, 610, 611, 615, 622, 625, 627–630, 634, 637, 638, 640, 644, 649, 654, 657–662 liquid ammonia 171, 172, 412 lithium aluminum hydride (LAH) 636 lithium bis(trimethylsilyl)amide (LIHMDS) 645, 653 loline 130 lonicerine 71 Lossen rearrangement 31, 32 luche reduction 422 lumefantrine 84, 567, 684 luminacin D 74, 231 2,6-lutidine 637 lycojaponicumin C 82 lyconadin C 19 lyconadins A 370 lycopodine 490 lycopodium alkaloid 19, 39, 71, 82, 341 lycoposerramine Z 223 lycorane 472 lycoricidine 392 lycospidine A 71 lyngbyaloside B 73 lyrica 421 lysergic acid 74, 214
747
748
Index
lysergol 214 lysine 520, 533
m macrolactin A 116 macrolactonization 178 macrostomine 335 macusine A 390 madelung indole synthesis 483 magellanine 217 magellaninone 217 malyngamide W 214 mandelalide A 118, 333 manganese dioxide 637 mangiferaelactone 425 Mannich reaction 369, 370 maresin 118 marineosin A 483 marinopyrrole B 483 martinellic acid 82, 209 mayurone 411 m-chloroperbenzoic acid (m-CPBA) 618 mebendazole 464, 690 Meerwein-Ponndorf-Verley reduction 423, 605 melleolide F 213 melodinine E 484 meloscine 217 merrifield resin 528 merrilactone A 216 mesembrine 71 metathesis 111, 127–129, 537, 539 methanesulfonate (Mesylate) 511 methanesulfonyl chloride 638 methionine 520, 533, 534 2-methoxyethoxymethyl (MEM) ether 510 methoxymethyl (MOM)-ether 510 methscopolamine 457 methyl atis-16-en-19-oate 427 methyl carbamate 509 methyl ether 298, 509 methynolide 214 metronidazole 460, 672 Meyer-Schuster rearrangement 34, 35 mezlocillin 466
Michael acceptor 208, 536, 537 Michael addition 208, 222, 609 Michael donor 208 miconazole 460, 679, 725 microcosamine A 423 migrastatin 71, 113 migration 1, 7, 9, 11, 27, 29, 32, 34, 37–41, 137, 161 milatxel 457 minifiensine 407 minoxidil 462 mitomycin 457 Mitsunobu reaction 209, 211, 608, 623, 625–627, 663 mniopetal E 130, 184 Morita-Baylis-Hillman reaction 211 morphine 211, 222, 687 mosin B 214 mozingo reduction 425 mucocin 118 Mukaiyama Aldol reaction 72, 609, 661 Mukaiyama esterification 189 mulinane 413 mulinane diterpenoid 298 munchiwarin 79 mupirocin H 118 muraymycin d1 375 muricadienin 24 murisolin 133 mycolactones A/B 192 mycophenolic acid 82, 182 mycothiazole 330 myrmicarin 297 myxalamide a 74, 325, 331 myxovirescin a1 329
n nadolol 139 nafcillin 466 naftifine 327, 682 nakadomarin A 217 nakijiquinones 188 nannocystin A 73, 211 naphthols 308 naratriptan 327, 568 narbonolide 214
Index
nardoaristolone B 223 natamycin 466 naucleofficine 370 n-bromoamide 28 n-bromosuccinimide 612 n-butyllithium 178, 237, 614, 630 n-chlorosuccinimide (NCS) 390, 619 negamycin 126 Negishi coupling reaction 328, 329, 609, 657 neocarzinostatin 130 neolaulimalide 116 neopeltolide 423 neovibsanin B 209 nhatrangin A 136, 192 nickel catalyzed 328, 334 nifedipine 368, 461, 568, 724 nigricanin 175, 233 ningalin D 19, 82, 325 n-iodosuccinimide (NIS) 633 niraparib 465 nitrilium ion 37, 221, 371 nitro aldol reaction 75, 76 nitrofurantoin 458, 672 nitrofurazone 458 nitrogen 3, 27, 29, 30, 36, 38–40, 113, 126, 136, 165, 167, 171, 172, 185, 211, 217, 219, 221, 224, 229, 236, 367, 377, 412, 418, 426, 450, 454, 456, 473, 573, 574, 578, 585, 587, 592, 597, 606, 630 nitrogen atmosphere 26, 162, 180, 228, 343, 375, 588 nitrosonium ion 20, 27 nivetetracyclate A 130, 421 N-methylmorpholine n-oxide (NMO) 638 N,N ′ -dicyclohexylcarbodiimide (DCC) 397–399, 576, 624 N,N-diisopropylethylamine (DIEA) 627 nonactin 74 norleucosceptroid A 71 norleucosceptroid B 71 norzoanthamine 223 noyori asymmetric hydrogenation 419
Nozaki-Hiyama-Kishi reaction nupharamine 209, 211, 370
213
o odorless 389 okadaic 418 okilactomycin 17 olefination 111, 114, 115, 117–119, 122–124 olefin metathesis 127 oligomycin 72 olopatadine 126 omaezakianol 133 omuralide 377 one pot 363, 560 onitin 34 ophiobolin A 201 Oppenauer oxidation 403, 423, 605 organoborane 324, 337 organostannanes 330 oridonin 201 orlistat 458 Orton rearrangement 32 oseltamivir 18, 677 oseltamivir phosphate 82 osmium tetroxide 134, 135, 137, 639 ouabain 223 Overman rearrangement 15 oxacarbazepine 297, 566 oxacillin 461, 463, 466 oxalyl chloride 395, 396, 640 oxazole 463 oxidation 1–4, 130, 168, 175, 185–187, 234, 366, 368, 389, 391–393, 395, 397, 398, 400, 402–404, 406, 407, 420, 423, 476, 477, 492, 533, 543, 544, 547, 587, 588, 605, 607, 610, 614, 616–621, 624, 633–635, 637, 638, 640, 647, 649, 650, 657 oxidative addition 214, 227, 232–234, 324, 326, 328, 330, 332, 334, 336, 337, 339, 340, 342, 426 oxime 6, 166, 611 9-oxoeuryopsin 71 21-oxogelsemine 124 oxone 132–134, 640 oxosilphiperfol-6-ene 216
749
750
Index
oxy-Cope rearrangement 16 oxyma pure 526, 535, 555 oxymetazoline 460 ozone 409, 411, 412, 591, 592, 641 ozonolysis 409, 412, 591, 592, 641
p Paal-Knor furan synthesis 484 Paal-Knor pyrrole synthesis 485 paclitaxel 457, 715 paecilomycin C 118 palladium on calcium carbonate 642 palladium on carbon 583, 643 pallambins C, D 223 palmarumycin cp17 427 palmerolide A 113, 192 palytoxin 141 pamamycin 621a 71 pamamycin-649b 192 papaverine 463 paracetamol 7, 565, 687, 691, 720, 729 paralemnolide a 219 parthenolide 457 Passerini reaction 370–372 Paterno-Buchi reaction 215 Pauson-Khand reaction 216 pazopanib 465, 715 Pechmann condensation or reaction 85 peganumine A 338, 490 peloruside A 74 penaresidin A 118 penicillin 378, 466, 569 penostatin E 201 pentalenene 217 peptides 42, 69, 192, 340, 370, 510, 519, 525, 526, 528, 529, 534, 536–540, 629, 630, 648, 649, 660, 664, 693 perhydrohistrionicotoxin 167 peribysin E 223 pericoannosin A 74 periconiasins A-E 70 Pericyclic reaction 161, 182, 184 peridinin 118, 130 periodinane 391 Perkin reaction 86
perylene dyes 204 pestalotiopsin A 214 Petasis olefination 122 Peterson olefination 119, 120 phakellstatin 29 phenanthrene 293–295, 301, 302 phenofluor mix 642 phenols 85, 86, 181, 182, 193, 300, 304, 306, 308, 311, 341, 513, 533, 534, 536, 559, 588–590, 604, 612, 617, 642, 652, 660 phenylalanine 520 phenyltrimethylammonium perbromide 643 phomactins 423 phomoidride B 339 phosphine 210, 211, 641 phosphorus oxychloride 644 phosphorus tribromide 644 phosphorus ylide 113 photochemical 39, 41, 215 PI-091 392 Pictet-Gams isoquinoline synthesis 487 Pictet-Spengler reaction 488 Pictet-Spengler tetrahydroquonoline synthesis 489 pictilisib 325, 567 pikromycin 192 pimecrolimus 466 piperacillin 466 piperidine 75, 83, 84, 208, 368, 463, 528, 531, 533, 535, 536, 644 pipoxide acetate 112 piracetam 459 pironetin 72, 74 pivaloate (piv) ester 512 pivampicillin 466 pladienolide B 133 platensimycin 113, 123, 223 platinum on carbon 645 platinum(IV) oxide 645 p-methoxybenzyl (PMB) 508 polycavernoside A 131, 231 polycitone B 211, 297 polyketide 39, 70, 118 polymer 189, 370–372, 628, 692
Index
polymerization 184 polyneuridine 390 polysphorin 136 ponatinib 332, 715 potassium carbonate 118, 140, 239, 325, 589, 592, 646 potassium hexamethyldisilazide (KHMDS) 645 potassium iodide 239, 646, 683 potassium permanganate 647 potassium sodium tartrate tetrahydrate 647 potassium tert-butoxide 88, 341, 645 prazepine 7 pregabalin 421 pregnanolone 223 prelactone-V 194 pre-schisanartanin C 136, 331 pretazettine 131 preuisolactone A 9 primary alcohol 169, 173, 188, 209, 220, 391, 393, 395, 397, 406, 414, 514, 543, 544, 546, 554, 586–588, 605, 613, 617, 619, 633, 635–638, 647, 649, 650, 657 primary alkyl 1, 187 primary amide 28, 644 primary amine 19, 20, 28, 31, 196, 225, 375, 485, 486 proline 222, 520 propylphosphonic anhydride (T3P) 648 prostaglandin e1 418, 724 prostaglandin F 190 protein 69, 519, 536, 734 protic acid 30, 35, 188, 220 protic solvent 238 protonation 5, 7, 10, 14, 15, 20–22, 27, 29, 30, 33–35, 37, 39, 44, 76, 82, 86, 88, 121, 139, 189, 198, 209, 219, 221, 222, 236, 294, 303, 305, 307, 309, 313, 369–371, 374, 377, 394, 416, 470, 473, 477–479, 482, 483, 485, 486, 489, 491, 492, 526528 proton transfer 4, 9, 14, 15, 26, 29, 32, 35, 40, 41, 70, 77, 84, 89, 121, 170,
171, 179, 189, 196, 210, 221, 229, 230, 305, 366–369, 375, 408, 413, 414, 427, 473, 475, 477–479, 481–483, 485, 486, 492 pseudodistomin B triacetate 82 pseudoguaianolides 141 pseudopteroxazole 223 PSI-352938 163 psiguadial-B 40 psilostachyin C 71 pteridic acid A 74, 339 p-toluenesulfonic acid 581, 659 purine 200 puromycin 423 purpuromycin 89 pyaop 526, 648 pybop 526, 648 pyranicin 113, 211 pyrantel 459, 690 pyrazine 454, 463 pyridindolol 136, 330 pyridine 124, 166, 170, 340, 366, 368, 373, 397, 454, 461, 477, 575, 649 pyridinium chlorochromate (PCC) 649 pyridinium dichromate (PDC) 649 pyridinium p-toluenesulfonate (PPTS) 650 pyrimidine 340, 454, 462 pyrrole 183, 309, 454, 459, 482, 485, 486, 639
q quadrone 39 quaternary 200 quinagolide 413 quinapirilat 488 quinapril 488 quinine 134, 211, 407, 684 quinocarcin 375 quinolines 170, 340, 454, 463, 472–474, 476, 480, 481, 491
r radical
131, 164–167, 203, 204, 215, 224, 232, 234, 239, 415, 416, 588, 597, 607, 608, 628, 659
751
752
Index
radiosumin 112 raney nickel 425, 584, 651 rapamycin 466 rasfonin 121 ratjadone 126 rearrangement 1, 5–9, 11–19, 21–26, 28–36, 38, 39, 41–44, 77, 116, 135, 183, 186, 376, 377, 390, 397, 401, 405, 469, 470, 479, 605, 639 redox 3, 173, 195 reduction 214, 301, 303, 412, 414, 417, 422, 423, 425, 426, 583–586, 589, 605, 606, 626, 636, 651, 653, 655, 665 reduction 414, 415 reductive amination 562, 596, 603, 606, 654, 656 Reformatsky reaction 218 Reimer-Tiemann reaction 308 resveratrol 88 retosiban 377 retrojusticidin B 79 reveromycin B 71, 184, 330 rhein 24 rhizoxin D 70, 74, 113, 231 rhodamine B 226 riley oxidation 404 ring closing metathesis 127, 537, 539 ring closure 179, 364, 472, 474, 476, 477, 481, 485, 488, 489 ring expansion 19, 22, 309 ripostatin B 192, 331 Ritter reaction 220 Robinson annulation 221, 222 Rochelle’s salt 647 roflamycoin 72 rofleponide 399 rolitetracycline 370 Rosenmund reduction 425 rosuvastatin 117, 700 roxithromycin 466 rubifolide 392 rubriflordilactone A 73 rubriflordilactone B 333 rucaparib 325 Rupe rearrangement 34, 35 rutamycin B 72
ruthenium (III) chloride ryanodol 405
651
s sacacarin 82 safinamide 571, 719 sagittacin E 133 salicylic acid 306, 308, 310, 726 salicylihalamide 211, 329 salicylihalamides A, B 74 salimabromide 3, 39, 298 salinosporamide A 213 salvilenone 40, 42 Sandmeyer reaction 223, 646, 655 sanggenons C 12 sanglifehrin A 74 santiagonamine 234 sapinofuranone B 126 sarcodictyin 84 saundersiosides A-H 168 11-saxitoxinethanoic acid 73 schiff base 472–475 schiglautone A 12 schindilactone A 82 Schmidt reaction 36 scholarisine G 484 Schotten-Baumann reaction 225 schulzeines B, C 136, 472 schweinfurthin B 71 schweinfurthins 89 scopadulin 71 scoulerine 472 secalonic acid E 82 secodaphniphylline 79 secokotomolide A 213 secondary alcohol 35, 169, 188, 192, 209, 220, 391, 393, 395, 397, 403, 406, 417, 514, 543, 544, 554, 605, 613, 620, 633, 635, 636, 638, 649, 650, 657, 664 secosyrin 1 413 sedridine 17 seimatopolide B 192 selectfluor 652 selenium dioxide 404, 406 selexipag 571 semidine rearrangement 42, 43
Index
senepoxide 112 serine 392, 520, 533 serotonin 464 serrulatane 17 sesaminone 74 Sharpless asymmetric amino hydroxylation 136 Sharpless asymmetric dihydroxylation 134 Sharpless asymmetric epoxidation 129, 658 sieboldine A 217 sildenafil 570, 724 silica gel 6, 7, 11, 28, 41, 72, 76, 90, 113, 114, 119, 128, 138, 140, 166, 169, 170, 178, 180, 183, 191, 199, 203, 204, 207, 211, 218, 228, 239, 325, 328, 330, 331, 333, 338, 339, 341, 370, 373, 391, 393, 395, 397, 400, 402, 412, 425, 426, 471, 474, 478, 482, 484, 485, 491, 525, 574, 575, 577, 584, 586–589, 593, 595, 597–601 silyl ester 515 simethisoquin 488 Simmons-Smith reaction 226, 227, 625 sinefungin 19 single electron transfer 115, 224, 413, 414, 416 sirolinus 466 sitagliptin 421, 693 Skraup quinoline synthesis 476, 491 sN 2 26, 81, 133, 139–141, 163, 187, 196, 210, 238, 239 sodium 171, 176, 239, 240, 306, 308, 412, 414, 415, 607, 617, 734 sodium azide 595, 653 sodium bis(trimethylsilyl)amide (NaHMDS) 645, 653 sodium borohydride 422, 585, 653 sodium cyanoborohydride 654 sodium hydride 79, 88, 114, 118, 654 sodium hypochlorite (bleach) 654 sodium methoxide 26, 81, 126 sodium nitrite 655, 728 sodium periodate 655
sodium triacetoxyborohydride 596, 655 sofosbuvir 73, 674 solandelactones E, F 214 solid phase peptide synthesis 528, 529, 536, 540, 660 solution phase peptide synthesis 525 Sonogashira coupling reaction 331, 332, 609, 620 sorafenib 461, 716 sorangicin A 118 sparteine 37, 219 spectinabilin 329 spectromycin 23 sphingofungin F 130 spinosyn A 213 spirangien A 121 spirocurcasone 73 spirofungin A 237 spirolactone 466 spirooliganones A,B 136 spirotryprostatin B 118 spliceostatin G 325 spongistatin 124 sporiolide A, B 192 sporiolide B 192 ST1535 335 stapled peptide 538–540 stemoamide 219, 329 stemonamine 37, 82 stenine 188 sterpurene 26 stigmatellin 211 stigmatellin A 10, 113 Stille coupling reaction 330, 617 stobbe condensation 88 stork enamine synthesis 228 Strecker reaction 374, 375, 620, 632, 652, 661 streptazolin 71 streptonigrone 475 streptorubin B 71, 483 stresgenin B 121 strongylophorines 2 9, 223 strychine 211, 405 subincanadine E 209 subincanadine F 82
753
754
Index
succinic anhydride 301, 303, 304 sulfonation 581 sulfone 114, 226, 341, 342, 561, 618, 640, 647, 665 sulfoxide 561, 618, 665 sulfur 165, 363, 365, 366, 378 sunitinib 459, 464, 716 Suzuki coupling reaction 323, 325, 617 swainsonine 130, 136, 423 Swern oxidation 395, 640 syn addition 167, 168, 327 syncarpamide 137 syringolin A 19
t tadalafil 490, 566, 725 tafluprost 116 taiwaniaquinol B 297 Talatisamine 39 Tamao-Kumada oxidation 402 TAN1251C 82 tandem 11 tanshinone I 478 taondiol 223, 298 tarchonanthuslactone 136, 205 tardioxopiperazine A 331 tashiromine 313 taurospongin A 130 tautomycetin 192 taxol 215, 457, 715 tebbe olefination 123 tecadenoson 18 tecfidera 565 tejedine 226 terguride 18 termicalcicolanone A 12 terminal alkyne 176, 177, 202, 331, 516 tert-butyldimethylsilyl (TBS or TBDMS) 511 tert-butyldimethylsilyl chloride (TBDMS-CL) 613 tert-butyldiphenyl silyl (TBDPS) 511 tert-butyl ester 514 tert-butyl (t-Bu) ether 510 tert-butyllithium 614 tert-butyl nitrite 615 tert-butyloxycarbonyl 507
tertiary alcohol 34, 36, 210, 220, 543, 613 tertiary alkyl 1 tesetaxel 457 testololactone 2 testudinariol A 71 tetrahydrocannabinol 182 tetrahydrofuran 11, 17, 73, 113, 114, 116, 118, 178, 219, 365, 413, 419, 576 tetrahydropyranyl (THP) ether 510 tetrakis(triphenylphosphine) palladium(0) 343, 657 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) 657 tetra-n-butylammonium fluoride 656 tetra-n-butylammonium iodide (TBAI) 656 tetrapropylammonium perruthenate (TPAP) 406, 407, 657 tetrasaccharide 423 tetrodotoxin 71 teucvidin 12 thailanstatin A methyl ester 121 thiamine 461, 463, 730 thiazole 461, 463 thielocin A1𝛽 417 thionyl chloride 199, 555, 578, 657 thiophene 365, 366, 454, 459 thiosegetalin A 207 threonine 520, 533 thuggacin A 113, 331 thujopsenes 411 tiacumicin A 73 tiacumicin B 121 Tiffeneu-Demjanov rearrangement 22 tiletamine 459 tingtanoxide 112 tinidazole 460 Tishchenko reaction 230 titanium(IV) chloride 658 titanium isopropoxide 129, 201, 658 tocotrienoloic acid 188 tolmetin 370, 459 tolpropamine 327 tosyl (Ts) 509 tramadol 370
Index
tranylcypromine 18 triazine 338 triazole 203, 460 1,2,3 triazole 202 tributyltin hydride 597, 659 trichodermamide B 17 2,2,2-tricholoethoxycarbonyl (Troc) 509 tricolorin A 179 tricycloclavulone 26 triethylamine 19, 192, 327, 333, 389, 395, 596, 659 triethyl orthoformate 660 trifarienol A 201 trifluoroacetic acid 3, 86, 660 trifluoroacetyl 508 trigonoliimine A 306 trigonoliimine B 472 triisopropylsilyl (TIPS) ether 511 trikentrin A 470 trimethylsilyl cyanide 375, 661 trimethylsilyl diazomethane 662 trimethylsilyl (TMS) ether 510 2-(trimethylsilyl)ethoxymethyl (SEM) 507 2-(trimethylsilyl)ethoxymethyl chloride (SEM-CL) 661 2-(trimethylsilyl)ethoxymethyl (SEM) ether 511 trimethylsilyl iodide 662 triphenylphosphine 162, 163, 178, 180, 209, 211, 592, 662 triphosgene 663 triptan 479 tris(dibenzylideneacetone) dipalladium(0) 664 trityl (Trt) 509, 531 trityl chloride 664 trocheliophorolide B 71, 162 troleandomycin 457 tryptophan 520, 533 tubingensin A 73 tubulysin B 126 tunicamycin 73 tunicamycin V 73 tyrosine 413, 520, 533
u Ugi reaction 375–378, 569 ulapualide A 192 Ullmann biaryl ether and biaryl amine synthesis 233 Ullmann coupling or biaryl synthesis 232 umpolung 77, 598 unsaturated 70, 180, 203, 208, 211, 409, 449–452 urea 17, 363, 364, 526, 562, 563, 616, 663, 727 urea hydrogen peroxide (UHP) 664
v valine 520 vallesamidine 209 vancomycin 325 variabili 341 variabilin 478 vedelianin 133 vellosimine 490 viagra 570, 724 vialinin B 234 vibsanin A 211, 214 vicinal diols 134, 407 Vilsmeier-Haack reaction 644 vincorine 70, 209, 327 virgatolide A 73 viridiofungin A 118 vitamin A 126, 730 vitamin d3 113, 733 voriconazole 460, 681
311, 312,
w Wagner-Meerwein rearrangement 38 warfarin 464, 705, 730 Weinreb amide 235, 236 Weinreb ketone synthesis 235 Williamson ether synthesis 238 Wittig reaction 124, 125 Wolff-Kishner reduction 425, 426 Wolff rearrangement 39 work-up 8, 74, 209, 311, 409, 411 Wurtz-Fittig reaction 240 Wurtz reaction 239, 240
755
756
Index
x X-206 408 xanthate 172 xanthate ester 172 xanthohumol 79 xantphos 579 xenematide 192
y yahazunol 165 yamaguchi esterification 191 yellow 19, 21, 86, 88, 113, 114, 119, 123, 163, 170, 173, 183, 206, 232, 301, 335, 365, 366, 393, 478, 582, 584, 595, 608, 609, 611, 615, 623, 627, 633, 635, 639, 657, 662, 664 yellowish 26, 391, 634, 655
ylide 113, 124–126, 177 yohimbine 81
z zapotin 10 zaragozic acid C 136 zearalenone 179, 424 zinc 218, 219, 416, 665, 734 zinc 239 zinc-amalgam 415, 417 zinc carbenoid 416 zinc chloride 665 zinc-copper 239 Zinin Benzidine rearrangement Zinin rearrangement 42 zoapatanol 2, 113, 237, 413 zomepirac 459 zwitterionic 210
42