Preview Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry (Surya K. De) (2020)

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
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v

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


vi

Contents

Claisen Rearrangement 11
Mechanism 11
Application 12
Experimental Procedure (from patent WO2016004632A1) 13
Eschenmoser–Claisen Rearrangement 13
Mechanism 13
Ireland–Claisen Rearrangement 14
Mechanism 14
Johnson–Claisen Rearrangement 15
Mechanism 15
Overman Rearrangement 15
Mechanism 16
Cope Rearrangement 16
Mechanism 17
Application 17
Experimental Procedure (from patent US 4421934A) 17
Curtius Rearrangement 17
Mechanism 18
Application 18
Experimental Procedure (from patent EP2787002A1) 19
Demjanov Rearrangement 19
Mechanism 20
Application 21
Experimental Procedure (from Reference [14], copyright 2008,
American Chemical Society) 21
Tiffeneau–Demjanov Rearrangement 22
Mechanism 22

Application 23
Experimental Procedure (from Reference [10], copyright, The Royal
Society of Chemistry) 23
Fries Rearrangement 23
Mechanism 24
Application 24
Experimental Procedure (from patent US9440940B2) 25
Favorskii Rearrangement 25
Mechanism 25
Application 26
Experimental Procedure (from patent EP3248959A2) 26
Fischer–Hepp Rearrangement 26
Mechanism 27
Experimental Procedure (general) 27
Hofmann Rearrangement (Hofmann degradation of amide) 28
Mechanism 28
Application 29
Experimental Procedure (from patent CN105153023B) 29
Hofmann–Martius Rearrangement 29
Mechanism 30


Contents

Experimental Procedure (from patent DD295338A5) 30
Lossen Rearrangement 31
Mechanism 31
Application 32
Experimental Procedure (from patent EP2615082B1) 32
Orton Rearrangement 32

Mechanism 33
Pinacol–Pinacolone Rearrangement 33
Mechanism 34
Application 34
Experimental Procedure (general) 34
Rupe Rearrangement/Meyer–Schuster Rearrangement 34
Rupe Rearrangement 35
Meyer–Schuster Rearrangement 35
Mechanism 35
Application 36
Experimental Procedure (from patent US4088681A) 36
Schmidt Rearrangement or Schmidt Reaction 36
Mechanism 37
Application 37
Experimental Procedure (from patent WO2009026444A1) 38
Wagner–Meerwein Rearrangement 38
Mechanism 38
Application 39
Wolff Rearrangement 39
Mechanism 39
Alternatively 40
Application 40
Experimental Procedure (from patent US9175041B2)
9175041B2 40
Arndt–Eistert Homologation or Synthesis 41
Mechanism 41
Application 42
Experimental Procedure (from patent US9399645B2) 42
Step 1 42
Step 2 42

Zinin Rearrangement or Benzidine and Semidine Rearrangements 42
Mechanism 43
Experimental Procedure (from patent US20090069602A1) 44
References 45
Baeyer-Villiger Oxidation or Rearrangement 45
Dakin Oxidation or Reaction 47
Bamberger Rearrangement 48
Beckmann Rearrangement 48
Benzilic Acid Rearrangement 50
Baker–Venkataraman Rearrangement 51

vii


viii

Contents

Claisen Rearrangement/Eschenmoser–Claisen
Rearrangement/Ireland–Claisen Rearrangement/Johnson–Claisen
Rearrangement/Overman Rearrangement 52
Cope Rearrangement 53
Curtius Rearrangement 54
Demjanov Rearrangement 56
Tiffeneau–Demjanov Rearrangement 56
Fries Rearrangement 56
Favorskii Rearrangement 58
Fischer–Hepp Rearrangement 58
Hofmann Rearrangement (Hofmann Degradation of Amide) 59
Hofmann–Martius Rearrangement 60

Lossen Rearrangement 60
Orton Rearrangement 61
Pinacol–Pinacolone Rearrangement 62
Rupe Rearrangement/Meyer–Schuster Rearrangement 62
Schmidt Rearrangement or Schmidt Reaction 63
Wagner–Meerwein Rearrangement 64
Wolff Rearrangement 65
Arndt–Eistert Homologation or Synthesis 66
Zinin Rearrangement or Benzidine and Semidine Rearrangements 67
2 Condensation Reaction 69

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

Mechanism 77
Application 77
Experimental Procedure (from patent DE3019500C2) 78
Claisen Condensation 78
Mechanism 78


Contents

Application 79
Experimental Procedure (from patent US9884836B2) 79
Darzens Glycidic Ester Condensation 80
Mechanism 80
Application 81
Experimental Procedure (from patent JP2009512630A) 81
Dieckmann Condensation 81
Mechanism 82
Application 82
Experimental Procedure (from patent US 7132564 B2) 82
Knoevenagel Condensation 83
Mechanism 83
Application 84
Lumefantrine 84
Experimental Procedure (from patent WO2010136360A2) 84
Pechmann Condensation (synthesis of coumarin) (also called von
Pechmann condensation) 85
Mechanism 85
Application 86
Experimental Procedure (from patent US7202272B2) 86
Perkin Condensation or Reaction 86

Mechanism 87
Application 88
Experimental Procedure (from patent US4933001A) 88
Stobbe Condensation 88
Mechanism 89
Application 89
Experimental Procedure (from patent US20160137682A1) 90
References 90
Aldol Condensation Reaction 90
Mukaiyama Aldol Reaction 93
Evans Aldol Reaction 96
Henry Reaction 98
Benzoin Condensation 99
Claisen Condensation 101
Darzens Glycidic Ester Condensation 102
Dieckmann Condensation 103
Knoevenagel Condensation 105
Pechmann Condensation 106
Perkin Condensation or Reaction 107
Stobbe Condensation 108
3 Olefination, Metathesis, and Epoxidation Reactions 111

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

ix

x

Contents

Experimental Procedure (from patent US5807866A) 112
Horner–Wadsworth–Emmons Reaction 113
Mechanism 113
Application 113
Experimental Procedure (from patent JPWO2015046403A1) 114
Julia–Lythgoe Olefination 114
Mechanism 115
Modified Julia Olefination 115
Mechanism 115
Application 116
Experimental Procedure (from patent CN103313983A) 116
Julia–Kocienski Olefination 117
Application 117
Experimental Procedure (from patent WO2016125086A1) 118
Kauffmann Olefination 118
Mechanism 119
Application 119
Experimental Procedure (from patent WO2014183211A1) 119
Peterson Olefination 119
Mechanism 120
Application 121
Experimental Procedure (from patent WO2017149091A1) 121
Petasis Olefination 122
Mechanism 122
Application 123
Experimental Procedure (from patent US5087790A) 123

Tebbe Olefination 123
Mechanism 123
Application 124
Experimental Procedure (from patent US8809558B1) 124
Wittig Reaction or Olefination 124
Mechanism 125
Application 126
Experimental Procedure (from patent WO2006045010A2) 126
Metathesis 127
Olefin Metathesis 127
Ring-Closing Metathesis 127
Mechanism 128
Experimental Procedure (from patent
US20022018351A1) 128
Cross Metathesis 128
Ring-Opening Metathesis 128
Ring-Opening Metathesis Polymerization (ROMP) 129
Asymmetric Epoxidation 129
Sharpless Asymmetric Epoxidation 129
Mechanism 129
Application 130


Contents

Experimental Procedure (from patent DE102014107132A1)
(For more experimental procedures see Chapter 15) 130
Jacobsen–Katsuki Asymmetric Epoxidation 130
Mechanism 131
Application 131

Experimental Procedure (from patent US7501535B2) 132
Shi Asymmetric Epoxidation 132
Mechanism 133
Application 133
Experimental Procedure (from patent EP1770095A1) 133
Sharpless Asymmetric Dihydroxylation 134
Mechanism 135
Application 135
Experimental Procedure (from patent US7472570B1) 136
Sharpless Asymmetric Aminohydroxylation 136
Mechanism 137
Application 137
Experimental Procedure (from patent US8987504B2) 137
Woodward cis-Dihydroxylation 138
Mechanism 138
Application 139
Experimental Procedure (from patent WO1997013780A1) 139
Prévost trans-Dihydroxylation Reaction 140
Mechanism 140
Application 141
References 141
Corey–Winter Olefin Synthesis 141
Horner–Wadsworth–Emmons Reaction 141
Julia–Lythgoe Olefination 143
Julia–Kocienski Olefination 144
Kauffmann Olefination 146
Peterson Olefination 146
Petasis Olefination 148
Tebbe Olefination 148
Wittig Reaction or Olefination 149

Metathesis 150
Sharpless Asymmetric Epoxidation 150
Jacobsen–Katsuki Asymmetric Epoxidation 152
Shi Asymmetric Epoxidation 153
Sharpless Asymmetric Dihydroxylation 155
Sharpless Asymmetric Aminohydroxylation 156
Woodward cis-Dihydroxylation 158
Prévost trans-Dihydroxylation Reaction 158
4 Miscellaneous Reactions 161

Alder-Ene Reaction 161
Mechanism 161

xi


xii

Contents

Application 162
Experimental Procedure (from patent WO2015149068A1) 162
Appel Reaction 162
Mechanism 163
Application 163
Experimental Procedure (from patent WO2015134973A1) 163
Barton Decarboxylation 164
Mechanism 164
Application 165
Experimental Procedure (from patent US6080563A) 165

Barton Nitrite Photolysis (Barton nitrite ester reaction) 166
Mechanism 166
Application 167
Experimental Procedure (from patent US3214427A) 167
Brown Hydroboration 167
Mechanism 168
Application 168
Experimental Procedure (from patent WO1995013284A1) 168
Bucherer Reaction 169
Mechanism 169
Application 170
Experimental Procedure (from Reference [7], copyright 2020,
American Chemical Society) 170
Chichibabin Reaction 170
Mechanism 171
Application 171
Experimental Procedure Amination of 3-Picoline (from patent
EP0098684B1) 171
Chugaev Elimination Reaction 172
Mechanism 173
Application 173
Experimental Procedure (from Reference [10], copyright 2008,
American Chemical Society) 173
Cannizzaro Reaction 173
Mechanism 174
Application 175
Experimental Procedure (general) 175
Cope Elimination Reaction 175
Mechanism 175
Application 176

Experimental Procedure (from Reference [3], copyright, Organic
Syntheses) 176
Corey–Fuchs Reaction 176
Mechanism 177
Application 177
Experimental Procedure (from patent JP2015500210A) 178
Formation of Compound B 178


Contents

Formation of Compound C 178
Corey–Nicolaou Macrolactonization 178
Mechanism 179
Application 179
Experimental Procedure (patent US20060004107A1) 179
Danheiser Annulation 180
Mechanism 181
Danheiser Benzannulation 181
Mechanism 182
Application 182
Experimental Procedure (from Reference [22], Copyright 2013,
American Chemical Society) 182
Diels–Alder Reaction 183
Normal Electron Demand Diels–Alder Reaction 183
Inverse electron Demand Diels–Alder Reaction 183
Hetero–Diels–Alder Reaction 183
Mechanism 184
Application 184
Experimental Procedure (from patent CA 2361682A1) 184

Dutt–Wormall Reaction 185
Mechanism 185
Étard Reaction 185
Mechanism 186
Application 186
Experimental Procedure (US8957255B2) 186
Finkelstein Reaction 187
Mechanism 187
Application 188
Experimental Procedure (from patent WO2019134765A1) 188
Fischer–Speier Esterification 188
Mechanism 188
Experimental Procedure (general) 189
Mukaiyama Esterification 189
Mechanism 190
Application 190
Experimental Procedure (from patent US4206310A) 190
Yamaguchi Esterification 191
Mechanism 191
Application 192
Experimental Procedure (from patent WO 2019033219A1) 192
Grignard Reaction 193
Mechanism 193
Application 194
Experimental Procedure (general) 194
Experimental Procedure (from patent WO1994028886A1) 195
Gabriel Synthesis 195
Mechanism 196

xiii

xiv

Contents

Application 196
Experimental Procedure (from patent US9540358B2) 197
Hell–Volhard–Zelinsky Reaction 197
Mechanism 198
Application 198
Experimental Procedure (from patent WO199101199A1) 199
Hofmann Elimination or Exhaustive Methylation 199
Mechanism 199
Application 200
Hosomi–Sakurai Reaction 200
Mechanism 201
Application 201
Experimental Procedure (from patent WO2019093776A1) 201
Huisgen Cycloaddition Reaction 202
Click Chemistry 202
Mechanism 203
Experimental Procedure (from patent WO2008124703A2) 203
Hunsdiecker Reaction 203
Mechanism 204
Application 204
Experimental Procedure (from patent WO2017060906A1) 204
Keck Asymmetric Allylation 204
Mechanism 205
Application 205

Experimental Procedure (from patent US6603023B2) 205
Thionation Reaction (Lawesson’s Reagent) 206
Mechanism 207
Application 207
Experimental Procedure (general) 207
Michael Addition or Reaction 208
Mechanism 208
Application 209
Experimental Procedure (Aza-Michael Addition) (from patent
CN102348693B) 209
Mitsunobu Reaction 209
Mechanism 210
Application 211
Experimental Procedure (from patent US20170145017A1) 211
Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction) 211
Mechanism 212
Application 213
Experimental Procedure (from patent US20060094739A1) 213
Nozaki–Hiyama–Kishi Reaction 213
Mechanism 214
Application 214
Experimental Procedure (from patent US20190337964A1) 214
Paterno–Büchi Reaction 215


Contents

Mechanism 215
Application 215
Experimental Procedure (from Reference [29], copyright 2019,

American Chemical Society) 216
Pauson–Khand Reaction 216
Mechanism 217
Application 217
Experimental Procedure (from patent WO2003080552A2) 217
Reformatsky Reaction 218
Mechanism 218
Application 219
Experimental Procedure (from patent US6924386B2) 219
Ritter Reaction 220
Mechanism 220
Application 221
Experimental Procedure (from patent WO1996036629A1) 221
Robinson Annulation 221
Mechanism 222
Application 222
Experimental Procedure (from patent WO2018226102A1) 223
Sandmeyer Reaction 223
Mechanism 224
Application 224
Experimental Procedure (from patent WO20100234652A1) 224
Schotten–Baumann Reaction 225
Mechanism 225
Amide Formation 225
Ester Formation 225
Application 226
Simmons–Smith Reaction 226
Mechanism 227
Application 227
Experimental Procedure (from patent US7019172B2) 228

Stork Enamine Synthesis 228
Mechanism 229
Application 230
Experimental Procedure (from patent US2773099A) 230
Tishchenko Reaction 230
Mechanism 231
Application 231
Experimental Procedure (from Reference [38], copyright 2012,
American Chemical Society) 231
Ullmann Coupling or Biaryl Synthesis 232
Mechanism 232
Application 233
Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman
Condensation 233

xv


xvi

Contents

Ullmann Biaryl Ether Synthesis 233
Goldberg Reaction (biaryl amines) 233
Ullmann-Type Reaction/Ullmann Condensation 234
Mechanism 234
Application 234
Experimental Procedure (from Patent
WO1999018057A1) 234
Weinreb Ketone Synthesis 235

Mechanism 236
Application 237
Experimental Procedure (from patent US9399645B2) 237
Step 1 237
Step 2 237
Williamson Ether Synthesis 238
Mechanism 238
Application 238
Experimental Procedure (from patent WO1994028886A1) 239
Wurtz Coupling or Reaction 239
Mechanism 239
Application 240
Wurtz–Fittig Reaction 240
Mechanism 240
References 240
Alder-Ene Reaction 240
Appel Reaction 242
Barton Decarboxylation 242
Barton Nitrite Photolysis (Barton Nitrite Ester Reaction) 244
Brown Hydroboration 244
Bucherer Reaction 246
Chichibabin Reaction 246
Chugaev Elimination Reaction 247
Cannizzaro Reaction 247
Cope Elimination Reaction 249
Corey–Fuchs Reaction 250
Corey–Nicolaou Macrolactonization 250
Danheiser Annulation/Danheiser Benzannulation 251
Diels–Alder Reaction 252
Dutt–Wormall Reaction 253

Étard Reaction 253
Finkelstein Reaction 254
Fischer–Speier Esterification 255
Mukaiyama Esterification 255
Yamaguchi Esterification 256
Grignard Reaction 257
Gabriel Synthesis 258
Hell–Volhard–Zelinsky Reaction 259
Hofmann Elimination or Exhaustive Methylation 259


Contents

Hosomi–Sakurai Reaction 260
Huisgen Cycloaddition Reaction/Click Chemistry 262
Hunsdiecker Reaction 262
Keck Asymmetric Allylation 263
Thionation Reaction (Lawesson’s Reagent) 264
Michael Addition or Reaction 265
Mitsunobu Reaction 266
Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction) 268
Nozaki–Hiyama–Kishi Reaction 270
Paterno–Büchi Reaction 271
Pauson–Khand Reaction 272
Reformatsky Reaction 274
Ritter Reaction 276
Robinson Annulation 277
Sandmeyer Reaction 279
Schotten–Baumann Reaction 280
Simmons–Smith Reaction 281

Stork Enamine Synthesis 282
Tishchenko Reaction 283
Ullmann Coupling or Biaryl Synthesis 285
Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman
Condensation 286
Weinreb Ketone Synthesis 287
Williamson Ether Synthesis 289
Wurtz Coupling or Reaction 290
Wurtz–Fittig Reaction 290
5 Aromatic Electrophilic Substitution Reactions 293

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

xvii


xviii

Contents

Experimental Procedure (from patent CN106977377A) 304
Houben–Hoesch Reaction 304
Mechanism 305
Application 306
Experimental Procedure (from patent EP0431871A2) 306
Kolbe–Schmitt Reaction 306
Mechanism 307
Application 307
Experimental Procedure (from patent US7582787B2) 307
Reimer–Tiemann Reaction 308
Mechanism 308
Application 310
Experimental Procedure (from patent US4324922A) 310
Vilsmeier–Haack Reaction 311
Mechanism 312
Application 313
Experimental Procedure (from patent US5599966A) 313
References 313
Bardhan–Sengupta Synthesis 313
Bogert–Cook Reaction or Synthesis of Phenanthrene 314
Friedel–Crafts Reaction 314
Gattermann Aldehyde Synthesis 317

Gattermann–Koch Aldehyde Synthesis 317
Haworth Reaction 318
Houben–Hoesch Reaction 318
Kolbe–Schmitt Reaction 319
Reimer–Tiemann Reaction 319
Vilsmeier–Haack Reaction 320
6 Pd-Catalyzed C—C Bond-Forming Reactions 323

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


Contents

Sonogashira Coupling Reaction 331

Mechanism 332
Application 332
Experimental Procedure (General) 333
Kumada Cross-Coupling 333
Mechanism 334
Application 335
Experimental Procedure (from patent WO2015144799) 335
Hiyama Coupling Reaction 335
Mechanism 336
Application 336
Experimental Procedure (from patent US20022018351A1) 336
Liebeskind–Srogl Coupling Reaction 337
Mechanism 337
Application 338
Experimental Procedure (from patent WO2008030840A2) 338
Fukuyama Coupling Reaction 338
Mechanism 339
Application 339
Experimental Procedure (from patent US20150336915A1) 339
Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig
Amination) 340
Mechanism 340
Buchwald–Hartwig Amination 340
Application 341
Experimental Procedure (from patent US7442800B2) 341
Tsuji–Trost Allylation 341
Mechanism 342
Application 343
Experimental Procedure (from patent US20190270700A1) 343
References 343

Suzuki Coupling Reaction 343
Heck Coupling Reaction (Mizoroki–Heck Reaction) 345
Negishi Coupling Reaction 347
Stille Coupling Reaction (Migita–Kosugi–Stille Coupling
Reaction) 349
Sonogashira Coupling Reaction 351
Kumada Cross-Coupling 353
Hiyama Coupling Reaction 355
Liebeskind–Srogl Coupling Reaction 356
Fukuyama Coupling Reaction 357
Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig
Amination) 358
Tsuji–Trost Allylation 360

xix


xx

Contents

363
Biginelli Reaction (3-Component Reaction [3-CR]) 363
One of Plausible Mechanisms 364
Application 364
Experimental Procedure (from patent US810606062B1) 364
Gewald Reaction (3-Component Reaction [3-CR]) 365
Mechanism 365
Application 366
Experimental Procedure (from patent US20100081823A1) 366

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

Hantzsch Pyridine Synthesis 381
Mannich Reaction 382
Passerini Reaction 384
Strecker Amino Acid Synthesis 385
Ugi Reaction 386
Asinger Reaction 388

7 Multicomponent Reaction


Contents

Volume 2
Preface

xxi

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

507

xxi


v

Contents

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

363

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


vi

Contents

Application 390
Experimental Procedure (from patent US9212136B2) 390
Dess–Martin Oxidation 391
Mechanism 392
Application 392
Experimental Procedure (General) 392
Experimental Procedure (from patent US9212136B2) 393
Jones Oxidation 393
Mechanism 394
Application 395
Experimental Procedure (General) 395
Swern Oxidation 395
Mechanism 396
Experimental Procedure (from patent US9212136B2) 397
Pfitzner–Moffatt Oxidation 397

Mechanism 398
Application 398
Experimental Procedure (from patent WO2019202345A2) 399
Tamao–Fleming Oxidation 400
Fleming Oxidation 400
Tamao Oxidation 400
Mechanism 400
Application 401
Experimental Procedure (from patent WO2005113558A2) 402
Tamao–Kumada Oxidation 402
Mechanism 402
Oppenauer Oxidation 403
Mechanism 403
Application 404
Experimental Procedure (from patent US3506692A) 404
Riley Oxidation 404
Mechanism 405
Application 405
Experimental Procedure (from patent US20140341799A1) 405
Ley–Griffith Oxidation 406
Mechanism 406
Application 407
Experimental Procedure (from patent WO1998008849A1) 407
Criegee Oxidation (Criegee Glycol Cleavage) 407
Mechanism 408
Application 408
Experimental Procedure (from patent US5208036) 409
Criegee Ozonolysis 409
Mechanism 411
Application 411

Experimental Procedure (from patent US20030232989A1) 411
Reduction Reactions 412


Contents

Birch Reduction 412
Mechanism 412
Application 413
Experimental Procedure (from patent
US20090247756A1) 413
Bouveault–Blanc Reduction 414
Mechanism 414
Application 415
Experimental Procedure (from patent US2883424A) 415
Clemmensen Reduction 415
Mechanism 415
Carbanionic Mechanism 416
Carbenoid/Radical Mechanism 416
Application 417
Experimental Procedure (from patent WO1994028886A1) 417
Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey
reduction) 417
Mechanism 418
Application 418
Experimental Procedure (from patent WO2013040068A2) 419
Noyori Asymmetric Hydrogenation 419
Mechanism 420
Application 421
Experimental Procedure (from patent US20020173683A1) 421

Luche Reduction 422
Mechanism 422
Application 423
Experimental Procedure (from patent US20180134650A1) 423
Meerwein–Ponndorf–Verley Reduction 423
Mechanism 424
Application 424
Experimental Procedure (from patent US8674120B2) 424
Mozingo Reduction 425
Application 425
Rosenmund Reduction 425
Mechanism 425
Experimental Procedure (from patent US3517066A) 426
Preparation of 3,4,5-Trimethoxybenzaldehyde 426
Wolff–Kishner Reduction 426
Mechanism 427
Application 427
Experimental Procedure (from Patent US20060128691A1) 427
References 428
Corey–Kim Oxidation 428
Dess–Martin Oxidation 428
Jones Oxidation 430
Swern Oxidation 431

vii


viii

Contents

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