Science of Synthesis Knowledge Updates 2010 Vol. 2 (eBook)
546 Seiten
Thieme (Verlag)
978-3-13-178641-8 (ISBN)
The Science of Synthesis Editorial Board,together with the volume editors and authors, is constantly reviewing the whole field of synthetic organic chemistry as presented in Science of Synthesis and evaluating significant developments in synthetic methodology. Four annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.
Content of this volume: Indole and Its Derivatives, 1H-Indol-1-ols (1-Hydroxy-1H-indoles), 1,3-Dihydro-2H-indol-2-ones (1H-Indol-2-ols, 2-Hydroxy-1H-indoles, or Oxindoles), 1,2-Dihydro-3H-indol-3-ones (1H-Indol-3-ols, 3-Hydroxy-1H-indoles, or Indoxyls), 1H-Indole-2,3-diones (Isatins).
Science of Synthesis: Knowledge Updates 2010/2 1
Title page 5
Imprint 7
Preface 8
Abstracts 10
Overview 12
Table of Contents 14
Volume 10: Fused Five-Membered Hetarenes with One Heteroatom 24
10.13 Product Class 13: Indole and Its Derivatives 24
10.13.1 Product Subclass 1: Indoles 24
10.13.1.1 Synthesis by Ring-Closure Reactions 29
10.13.1.1.1 By Annulation to an Arene 29
10.13.1.1.1.1 By Formation of Two N--C Bonds and One C--C Bond 29
10.13.1.1.1.1.1 With Formation of 1--2, 1--7a, and 3--3a Bonds 29
10.13.1.1.1.1.1.1 Method 1: From 1,2-Dihaloarenes 29
10.13.1.1.1.2 By Formation of Two N--C Bonds 30
10.13.1.1.1.2.1 With Formation of 1--2 and 1--7a Bonds 30
10.13.1.1.1.2.1.1 Method 1: From 2-(2-Haloalkenyl)haloarenes 30
10.13.1.1.1.2.1.2 Method 2: From 2-(2-Haloaryl)oxiranes 32
10.13.1.1.1.2.1.3 Method 3: From (2-Haloaryl)alkynes 33
10.13.1.1.1.3 By Formation of One N--C and One C--C Bond 35
10.13.1.1.1.3.1 With Formation of 1--2 and 3--3a Bonds 35
10.13.1.1.1.3.1.1 Method 1: From Arylhydrazones Fischer Synthesis
10.13.1.1.1.3.1.1.1 Variation 1: From 4-Chlorobutanal and Arylhydrazines Grandberg Tryptamine Synthesis
10.13.1.1.1.3.1.1.2 Variation 2: From ß-Oxo Esters and Arenediazonium Ions Japp–Klingemann Synthesis
10.13.1.1.1.3.1.1.3 Variation 3: From Nb-Aryl Benzophenone Hydrazones and Ketones 58
10.13.1.1.1.3.1.1.4 Variation 4: From Alkynes and Arylhydrazines 60
10.13.1.1.1.3.1.1.5 Variation 5: From Alkenes via Hydroformylation 62
10.13.1.1.1.3.1.2 Method 2: From O-Alkenyl N-Arylhydroxylamines 64
10.13.1.1.1.3.1.3 Method 3: From ortho-Substituted Nitroarenes Bartoli Synthesis
10.13.1.1.1.3.1.4 Method 4: From Arylamines and Alkylsulfanylmethyl Ketones Gassman Indole Synthesis
10.13.1.1.1.3.1.5 Method 5: From Arylamines and Ketones 74
10.13.1.1.1.3.1.6 Method 6: From o-Haloarylamines and Ketones or Aldehydes 74
10.13.1.1.1.3.1.7 Method 7: From Arylamines and 1,2-Diols 77
10.13.1.1.1.3.1.8 Method 8: From Arylamines and a-Halo Ketones Bischler Synthesis
10.13.1.1.1.3.1.9 Method 9: From o-Haloarylamines and Alkynes 79
10.13.1.1.1.3.1.9.1 Variation 1: Larock Synthesis 79
10.13.1.1.1.3.1.9.2 Variation 2: With Concomitant Introduction of a 3-Substituent 86
10.13.1.1.1.3.1.9.3 Variation 3: Using a Copper Catalyst 87
10.13.1.1.1.3.1.9.4 Variation 4: Using Hydroamination 88
10.13.1.1.1.3.1.9.5 Variation 5: Using Allenes 89
10.13.1.1.1.3.1.10 Method 10: From N-Acyl-o-bromoarylamines and a-Halo Ketones 90
10.13.1.1.1.3.1.11 Method 11: From ortho-Thallated N-Acylarylamines and 3-Chloroprop-1-ene 91
10.13.1.1.1.3.1.12 Method 12: From N-Alkyl-N-arylhydroxylamines and Alkynes Carrying Electron-Withdrawing Groups 92
10.13.1.1.1.3.1.13 Method 13: From N-Sulfinylarylamines and Grignard Reagents 93
10.13.1.1.1.3.1.14 Method 14: From N-Arylarenesulfonamides and Phenyl(propynyl)iodonium Trifluoromethanesulfonate 93
10.13.1.1.1.3.1.15 Method 15: From Nitroarenes 94
10.13.1.1.1.3.1.16 Method 16: From N-Propargylanilines 94
10.13.1.1.1.3.1.17 Method 17: From o-Bromoiodoarenes 95
10.13.1.1.1.3.1.18 Method 18: From Anilines and Alkynes 95
10.13.1.1.1.3.1.19 Method 19: From Aniline and Epoxides 96
10.13.1.1.1.3.2 With Formation of 1--2 and 2--3 Bonds 96
10.13.1.1.1.3.2.1 Method 1: From o-Alkylarylamines 96
10.13.1.1.1.3.2.2 Method 2: From o-Acylarylamines 101
10.13.1.1.1.3.2.3 Method 3: From 1-(o-Aminoaryl)alkenes 103
10.13.1.1.1.3.2.4 Method 4: From o-(Benzoylamino)aryl Nitriles 104
10.13.1.1.1.3.3 With Formation of 1--7a and 3--3a Bonds 104
10.13.1.1.1.3.3.1 Method 1: From Benzo-1,4-quinones and Enamines Nenitzescu Synthesis
10.13.1.1.1.3.4 With Formation of 1--7a and 1--2 Bonds 108
10.13.1.1.1.3.4.1 Method 1: From 1-(m-Hydroxyaryl)alkenes 108
10.13.1.1.1.3.5 With Formation of 1--7a and 2--3 Bonds 108
10.13.1.1.1.3.5.1 Method 1: From o-Bromoaryl Ketones or Aldehydes 108
10.13.1.1.1.4 By Formation of One N--C Bond 109
10.13.1.1.1.4.1 With Formation of the 1--2 Bond 109
10.13.1.1.1.4.1.1 Method 1: From a-(o-Aminoaryl) Ketones, 2-(o-Aminoaryl)aldehydes, or Synthons Thereof 109
10.13.1.1.1.4.1.1.1 Variation 1: From (o-Aminoaryl)pyruvates [3-(o-Aminoaryl)-2-oxopropanoates] Reissert Synthesis
10.13.1.1.1.4.1.1.2 Variation 2: From a-(o-Aminoaryl) Ketones 112
10.13.1.1.1.4.1.1.3 Variation 3: From 2-(o-Aminoaryl)acetaldehydes 123
10.13.1.1.1.4.1.1.4 Variation 4: From 2-(o-Aminoaryl)acetaldehyde Acetals or Hemiacetals 125
10.13.1.1.1.4.1.1.5 Variation 5: From 2-(o-Amidoaryl)enol Ethers and 2-(o-Nitroaryl)enol Ethers 129
10.13.1.1.1.4.1.1.6 Variation 6: From 2-(o-Nitroaryl)enamines Leimgruber–Batcho Synthesis
10.13.1.1.1.4.1.1.7 Variation 7: From 1-Nitro-2-(o-nitroaryl)ethenes 137
10.13.1.1.1.4.1.2 Method 2: From o-Alkynylarylamines 139
10.13.1.1.1.4.1.2.1 Variation 1: Closure Using a Base 139
10.13.1.1.1.4.1.2.2 Variation 2: Closure in Water Alone 144
10.13.1.1.1.4.1.2.3 Variation 3: Closure Using an Acid, Lewis Acid, or Metal Cation 144
10.13.1.1.1.4.1.2.4 Variation 4: Closure Using Palladium Catalysis 147
10.13.1.1.1.4.1.2.5 Variation 5: Closure with Concomitant Introduction of a 3-Substituent 149
10.13.1.1.1.4.1.2.6 Variation 6: Closure with Concomitant Introduction of a 2-Substituent 155
10.13.1.1.1.4.1.2.7 Variation 7: Closure with Concomitant Introduction of a 1-Substituent 156
10.13.1.1.1.4.1.3 Method 3: From o-Alkenylnitroarenes and o-Alkenylaryl Azides 157
10.13.1.1.1.4.1.4 Method 4: From o-Alkenylarylamines and N-Acyl Derivatives Thereof 163
10.13.1.1.1.4.1.5 Method 5: From o-Acetamidoaryl Alkynyl Carbinols 166
10.13.1.1.1.4.1.6 Method 6: From (o-Nitroaryl)acetonitriles 167
10.13.1.1.1.4.1.7 Method 7: From 1-(2-Aminoaryl)alk-2-yn-1-ols 168
10.13.1.1.1.4.1.8 Method 8: From o-Acyl-N-tosylanilines 168
10.13.1.1.1.2.1.9 Method 9: From o-Aminoaryl Allenes 168
10.13.1.1.1.4.1.10 Method 10: From (o-Aminoaryl)methyl Sulfones 169
10.13.1.1.1.4.1.11 Method 11: From Anilines and Pyrrolidin-3-one 169
10.13.1.1.1.4.1.12 Method 12: From o-(Chloroacetyl)arylamines Sugasawa Synthesis
10.13.1.1.1.4.2 With Formation of the 1--7a Bond 171
10.13.1.1.1.4.2.1 Method 1: From 2-Arylalkenyl Azides Hemetsberger–Knittel Synthesis
10.13.1.1.1.4.2.2 Method 2: From 2-(o-Haloaryl)-2-hydroxyethanamines 173
10.13.1.1.1.4.2.3 Method 3: From 1-(m-Hydroxyaryl)alkan-2-amines 174
10.13.1.1.1.4.2.4 Method 4: From 2-(2-Chlorophenyl)ethanal N,N-Dimethylhydrazones 176
10.13.1.1.1.4.2.5 Method 5: From 2-Aryl-1-nitroethenes 177
10.13.1.1.1.4.2.6 Method 6: From (2-Arylvinyl)amines 177
10.13.1.1.1.5 By Formation of One C--C Bond 178
10.13.1.1.1.5.1 With Formation of the 2--3 Bond 178
10.13.1.1.1.5.1.1 Method 1: From N-(o-Methylaryl)amides Madelung Synthesis
10.13.1.1.1.5.1.1.1 Variation 1: From N-[o-(Acylmethyl)-, N-[o-(Cyanomethyl)-, N-[o-(Alkoxycarbonylmethyl)-, or N-[o-(Phenylsulfonylmethyl)aryl]amides 181
10.13.1.1.1.5.1.1.2 Variation 2: From [(o-Acylaminoaryl)methyl]phosphonium Salts 182
10.13.1.1.1.5.1.1.3 Variation 3: From [(o-Acylaminoaryl)methyl]silanes 185
10.13.1.1.1.5.1.2 Method 2: From o-Acylarylamines 186
10.13.1.1.1.5.1.3 Method 3: From o-Alkylaryl Isocyanides and o-Alkenyl Isocyanides 188
10.13.1.1.1.5.1.4 Method 4: From o-Alkenylaryl Isocyanides Fukuyama Synthesis
10.13.1.1.1.5.1.5 Method 5: From N-(o-Acylaryl)amides Fürstner Synthesis
10.13.1.1.1.5.1.6 Method 6: From o-Aminobenzonitriles 198
10.13.1.1.1.5.1.7 Method 7: From N-(o-Alkylaryl)imidates and -imines 199
10.13.1.1.1.5.1.8 Method 8: From Anilides and Thioanilides via Radical Processes 204
10.13.1.1.1.5.1.9 Method 9: From o-Alkenylaniline Enol Phosphates 204
10.13.1.1.1.5.2 With Formation of the 3--3a Bond 205
10.13.1.1.1.5.2.1 Method 1: From 2-(Arylamino)aldehydes, a-(Arylamino) Ketones, or Synthons Thereof 205
10.13.1.1.1.5.2.2 Method 2: From 3-Arylamino-1-(trialkylsilyl)prop-1-ynes 208
10.13.1.1.1.5.2.3 Method 3: From (o-Haloarylamino)alkenes 209
10.13.1.1.1.5.2.4 Method 4: From Arylaminoalkenes 212
10.13.1.1.1.5.2.5 Method 5: From N-(o-Haloaryl)prop-2-ynylamines 213
10.13.1.1.1.5.2.6 Method 6: From N-(o-Haloaryl)allylamines 213
10.13.1.1.1.5.2.7 Method 7: From N-(m-Haloaryl)imines 215
10.13.1.1.1.5.2.8 Method 8: From 1-Aryl-1,2,3-triazoles 216
10.13.1.1.1.5.2.9 Method 9: From N-Arylethanolamines 216
10.13.1.1.1.5.2.10 Method 10: From N-Aryl-2-chloroprop-2-enylamines 218
10.13.1.1.1.5.2.11 Method 11: From N-(2-Aminoaryl)-2-bromo-N-mesylallylamines 218
10.13.1.1.1.5.2.12 Method 12: From N-Alkynyl-N-tosyl-2-iodoarylamines 219
10.13.1.1.1.5.2.13 Method 13: From N-Tosyl(2-iodoaryl)aminoallenes 219
10.13.1.1.2 By Annulation to a Pyrrole 220
10.13.1.1.2.1 By Formation of Three C--C Bonds 220
10.13.1.1.2.1.1 With Formation of 3a--4, 4--5, and 6--7 Bonds 220
10.13.1.1.2.1.1.1 Method 1: From Pyrrole Chromium Carbene Complexes 220
10.13.1.1.2.2 By Formation of Two C--C Bonds 221
10.13.1.1.2.2.1 With Formation of 3a--4 and 5--6 Bonds 222
10.13.1.1.2.2.1.1 Method 1: From 2-Alkenylpyrroles 222
10.13.1.1.2.2.2 With Formation of 5--6 and 7--7a Bonds 223
10.13.1.1.2.2.2.1 Method 1: From 3-Alkenylpyrroles 223
10.13.1.1.2.2.3 With Formation of 3a--4 and 7--7a Bonds 225
10.13.1.1.2.2.3.1 Method 1: From Pyrroles and 1,4-Diones 225
10.13.1.1.2.2.4 With Formation of 3a--4 and 4--5 Bonds 225
10.13.1.1.2.2.4.1 Method 1: From 2-(3-Acyloxyprop-1-enyl)pyrroles and Carbon Monoxide 225
10.13.1.1.2.3 By Formation of One C--C Bond 226
10.13.1.1.2.3.1 With Formation of the 3a--4 Bond 226
10.13.1.1.2.3.1.1 Method 1: From Pyrroles with a C4-Chain at C2 226
10.13.1.1.2.3.2 With Formation of the 7--7a Bond 230
10.13.1.1.2.3.2.1 Method 1: From Pyrroles with a C4-Chain at C3 230
10.13.1.1.2.3.3 With Formation of the 5--6 Bond 234
10.13.1.1.2.3.3.1 Method 1: From 2-Acyl-3-(2-haloaryl)pyrroles 234
10.13.1.1.2.3.3.2 Method 2: From 2-Alk-1-enyl-1-methyl-4-nitro-3-styrylpyrroles or 2-Alk-1-enyl-3-allenylpyrroles 235
10.13.1.2 Synthesis by Ring Transformation 236
10.13.1.2.1 Method 1: From Other Heterocyclic Systems 236
10.13.1.3 Aromatization 239
10.13.1.3.1 Method 1: Dehydrogenation of 2,3-Dihydro-1H-indoles 239
10.13.1.3.2 Method 2: Dehydrogenation of Benzene Ring Reduced Indoles 244
10.13.1.3.3 Method 3: Reduction and Other Transformations of 1H-Indole-2,3-diones (Isatins), 1,2-Dihydro-3H-indol-3-ones (Indoxyls), 1H-Indol-1-ols, and 1,3-Dihydro-2H-indol-2-ones (Oxindoles) 244
10.13.1.4 Synthesis by Substitution 245
10.13.1.4.1 Substitution of N-Hydrogen 245
10.13.1.4.1.1 Method 1: Giving N-Halogen Indoles 246
10.13.1.4.1.2 Method 2: Giving N-Nitrogen Indoles 246
10.13.1.4.1.3 Method 3: Giving N-Phosphorus Indoles 246
10.13.1.4.1.4 Method 4: Giving N-Silicon Indoles 246
10.13.1.4.1.5 Method 5: Giving N-Carbon Indoles 246
10.13.1.4.1.6 Method 6: Giving N-Metal Indoles 254
10.13.1.4.2 Substitution of C-Hydrogen 255
10.13.1.4.2.1 Electrophilic Substitution 255
10.13.1.4.2.1.1 On the Five-Membered Ring 255
10.13.1.4.2.1.1.1 Method 1: Giving C-Deuterium/Tritium Indoles 255
10.13.1.4.2.1.1.2 Method 2: Giving C-Halogen Indoles 256
10.13.1.4.2.1.1.3 Method 3: Giving C-Sulfur Indoles 259
10.13.1.4.2.1.1.4 Method 4: Giving C-Nitrogen Indoles 263
10.13.1.4.2.1.1.5 Method 5: Giving C-Carbon Indoles 266
10.13.1.4.2.1.1.5.1 Variation 1: Introduction of Carboxy and Cyano Groups 266
10.13.1.4.2.1.1.5.2 Variation 2: Introduction of Acyl Groups 267
10.13.1.4.2.1.1.5.3 Variation 3: Introduction of Hydroxyalkyl and Related Groups 274
10.13.1.4.2.1.1.5.4 Variation 4: Introduction of Aminoalkyl Groups 281
10.13.1.4.2.1.1.5.5 Variation 5: Introduction of Sulfanylalkyl Groups 292
10.13.1.4.2.1.1.5.6 Variation 6: Introduction of Alkyl Groups 293
10.13.1.4.2.1.1.6 Method 6: Giving C-Silicon Indoles 315
10.13.1.4.2.1.1.7 Method 7: Giving C-Mercury Indoles 315
10.13.1.4.2.1.1.8 Method 8: Giving C-Thallium Indoles 315
10.13.1.4.2.1.1.9 Method 9: Giving C-Palladium Indoles 315
10.13.1.4.2.1.2 On the Benzene Ring 316
10.13.1.4.2.1.2.1 Method 1: Substitution of Indoles 316
10.13.1.4.2.1.2.2 Method 2: Substitution of 2,3-Dihydro-1H-indoles (Indolines) 321
10.13.1.4.2.2 Nucleophilic Substitution 326
10.13.1.4.2.2.1 Method 1: Giving C-Oxygen Indoles 326
10.13.1.4.2.2.2 Method 2: Giving C-Nitrogen Indoles 329
10.13.1.4.2.2.3 Method 3: Giving C-Carbon Indoles 329
10.13.1.4.2.3 Radical and Carbene Substitution 333
10.13.1.4.2.3.1 Method 1: Giving C-Carbon Indoles 333
10.13.1.4.2.3.2 Method 2: Giving C-Heteroatom Indoles 337
10.13.1.4.2.4 Transition-Metal-Catalyzed Substitution 338
10.13.1.4.2.4.1 Method 1: Giving C-Carbon Indoles 338
10.13.1.4.2.4.1.1 Variation 1: Giving 3-Substituted Indoles 338
10.13.1.4.2.4.1.2 Variation 2: Giving 2-Substituted Indoles 342
10.13.1.4.2.4.2 Method 2: Giving C-Silicon Indoles 348
10.13.1.4.2.4.3 Method 3: Giving C-Boron Indoles 349
10.13.1.4.2.5 Metalation 350
10.13.1.4.2.5.1 Method 1: Giving C-Lithium Indoles 350
10.13.1.4.3 Substitution of N-Metal 357
10.13.1.4.3.1 Giving N-Substituted Products 357
10.13.1.4.3.1.1 Method 1: Giving N-Halogen Indoles 357
10.13.1.4.3.1.2 Method 2: Giving N-Sulfur Indoles 358
10.13.1.4.3.1.3 Method 3: Giving N-Nitrogen Indoles 359
10.13.1.4.3.1.4 Method 4: Giving N-Carbon Indoles 359
10.13.1.4.3.1.4.1 Variation 1: Introduction of Carboxy, Cyano, and Related Groups 359
10.13.1.4.3.1.4.2 Variation 2: Introduction of Acyl Groups 360
10.13.1.4.3.1.4.3 Variation 3: Introduction of Alkenyl Groups 362
10.13.1.4.3.1.4.4 Variation 4: Introduction of Aryl Groups 362
10.13.1.4.3.1.4.5 Variation 5: Introduction of Alkyl Groups 363
10.13.1.4.3.1.5 Method 5: Giving Other N-Metal Indoles 367
10.13.1.4.3.2 Giving C-Substituted Products 368
10.13.1.4.3.2.1 Method 1: Giving C-Halogen Indoles 368
10.13.1.4.3.2.2 Method 2: Giving C-Sulfur Indoles 369
10.13.1.4.3.2.3 Method 3: Giving C-Nitrogen Indoles 369
10.13.1.4.3.2.4 Method 4: Giving C-Carbon Indoles 369
10.13.1.4.4 Substitution of C-Metal 373
10.13.1.4.4.1 Method 1: Giving C-Halogen Indoles 373
10.13.1.4.4.2 Method 2: Giving C-Oxygen Indoles 374
10.13.1.4.4.3 Method 3: Giving C-Sulfur Indoles 374
10.13.1.4.4.4 Method 4: Giving C-Nitrogen Indoles 375
10.13.1.4.4.5 Method 5: Giving C-Phosphorus Indoles 375
10.13.1.4.4.6 Method 6: Giving C-Carbon Indoles 375
10.13.1.4.4.6.1 Variation 1: Reactions with Carbon Electrophiles 375
10.13.1.4.4.6.2 Variation 2: Via Reactions with Boron Electrophiles 376
10.13.1.4.4.6.3 Variation 3: Via Ipso Displacement of Silicon 377
10.13.1.4.4.6.4 Variation 4: Via Organopalladium Intermediates Using Metalated Indoles 378
10.13.1.4.4.6.5 Variation 5: Via Organopalladium Intermediates Using Indole Halides and Trifluoromethanesulfonates 389
10.13.1.4.4.6.6 Variation 6: Synthetic Applications of Hapto Metal Complexes of Indoles 394
10.13.1.4.4.7 Method 7: Giving Other C-Metal Indoles 396
10.13.1.5 Synthesis by Substituent Modification 396
10.13.1.5.1 Modification of N-Carbon Functionalities 396
10.13.1.5.1.1 Method 1: Giving N-Hydrogen Indoles 396
10.13.1.5.1.2 Method 2: Giving N-Carbon Indoles 397
10.13.1.5.2 Modification of C-Carbon Functionalities 399
10.13.1.5.2.1 Method 1: Giving C-Hydrogen Indoles 399
10.13.1.5.2.2 Method 2: Giving C-Oxygen Indoles 400
10.13.1.5.2.3 Method 3: Giving C-Nitrogen Indoles 400
10.13.1.5.2.4 Method 4: Giving C-Carbon Indoles 400
10.13.1.5.3 Modification of N-Heteroatom Functionality 413
10.13.1.5.3.1 Method 1: Modification of N-Sulfur Functionality 413
10.13.1.5.3.2 Method 2: Modification of N-Silicon Functionality 415
10.13.1.5.4 Modification of C-Heteroatom Functionality 415
10.13.1.5.4.1 Method 1: Of C-Halogen Indoles 415
10.13.1.5.4.2 Method 2: Of C-Oxygen Indoles 416
10.13.1.5.4.3 Method 3: Of C-Sulfur Indoles. 417
10.13.1.5.4.4 Method 4: Of C-Nitrogen Indoles 417
10.13.1.5.4.5 Method 5: Of C-Silicon Indoles 417
10.13.1.5.5 Rearrangement of N-Substituents 417
10.13.1.5.5.1 Method 1: Giving C-Halogen Indoles 417
10.13.1.5.5.2 Method 2: Giving C-Carbon Indoles 417
10.13.1.5.6 Rearrangement of C-Substituents 418
10.13.1.5.6.1 Method 1: Giving C-Nitrogen Indoles 418
10.13.1.5.6.2 Method 2: Giving C-Carbon Indoles 418
10.13.2 Product Subclass 2: 1H-Indol-1-ols (1-Hydroxy-1H-indoles) 419
10.13.2.1 Synthesis by Ring-Closure Reactions 422
10.13.2.1.1 By Annulation to an Arene 422
10.13.2.1.1.1 By Formation of One N--C and One C--C Bond 422
10.13.2.1.1.1.1 With Formation of 1--2 and 3--3a Bonds 422
10.13.2.1.1.1.1.1 Method 1: From Nitrosoarenes and Alkynes 422
10.13.2.1.1.2 By Formation of One N--C Bond 422
10.13.2.1.1.2.1 With Formation of the 1--2 Bond 422
10.13.2.1.1.2.1.1 Method 1: From (Arylmethyl)(o-nitroaryl)acetonitriles 422
10.13.2.1.1.2.1.2 Method 2: From 2-(o-Nitroaryl)enamines 423
10.13.2.1.1.2.1.3 Method 3: From 2-(o-Nitroaryl)acetic Acids and Esters 424
10.13.2.1.1.2.1.4 Method 4: From o-Nitrobenzyl Ketones/Aldehydes 425
10.13.2.1.1.2.1.5 Method 5: From Dimethyl 2-Alkyl-2-(o-nitrophenyl)malonates 425
10.13.2.1.1.2.1.6 Method 6: From 3-(2-Bromo-6-nitrophenyl)-2-oxobut-3-enoates 426
10.13.2.1.1.2.2 With Formation of the 1--7a Bond 427
10.13.2.1.1.2.2.1 Method 1: From 1-Aryl-2-nitroalkenes 427
10.13.2.2 Aromatization 428
10.13.2.2.1 Method 1: Oxidation of 2,3-Dihydro-1H-indoles (Indolines) 428
10.13.2.2.2 Method 2: Reduction of 1-Hydroxy-1,3-dihydro-2H-indol-2-ones 428
10.13.3 Product Subclass 3: 1,3-Dihydro-2H-indol-2-ones (1H-Indol-2-ols, 2-Hydroxy-1H-indoles, or Oxindoles) 429
10.13.3.1 Synthesis by Ring-Closure Reactions 433
10.13.3.1.1 By Annulation to an Arene 433
10.13.3.1.1.1 By Formation of One N--C and One C--C Bond 433
10.13.3.1.1.1.1 With Formation of 1--2 and 3--3a Bonds 433
10.13.3.1.1.1.1.1 Method 1: From Arylamines and an a-(Alkylsulfanyl) Ester 433
10.13.3.1.1.1.1.1.1 Variation 1: From Arylamines and (Methylsulfinyl)acetates 434
10.13.3.1.1.1.1.2 Method 2: From Arylhydrazides Brunner Synthesis
10.13.3.1.1.1.1.3 Method 3: From [(Arylamino)sulfanyl]alkynes 436
10.13.3.1.1.1.2 With Formation of 1--2 and 2--3 Bonds 437
10.13.3.1.1.1.2.1 Method 1: From N-Protected o-Alkylanilines 437
10.13.3.1.1.1.2.2 Method 2: From o-Alkynylanilines 438
10.13.3.1.1.2 By Formation of One N--C Bond 438
10.13.3.1.1.2.1 With Formation of the 1--2 Bond 438
10.13.3.1.1.2.1.1 Method 1: From (o-Nitroaryl)acetic Acids and Esters 438
10.13.3.1.1.2.1.2 Method 2: From N,O-Diacylarylhydroxylamines 439
10.13.3.1.1.2.1.3 Method 3: From Nitroarenes 440
10.13.3.1.1.2.1.4 Method 4: From (o-Nitroaryl)pyruvates [3-(o-Nitroaryl)-2-oxopropanoates] 441
10.13.3.1.1.2.1.5 Method 5: From (o-Nitroaryl)acetonitriles 441
10.13.3.1.1.2.2 With Formation of the 1--7a Bond 443
10.13.3.1.1.2.2.1 Method 1: From (o-Haloaryl)acetamides 443
10.13.3.1.1.2.2.2 Method 2: From N-Methoxyarylacetamides 443
10.13.3.1.1.3 By Formation of One C--C Bond 444
10.13.3.1.1.3.1 With Formation of the 3--3a Bond 444
10.13.3.1.1.3.1.1 Method 1: From N-Arylchloroacetamides and Related Amides 444
10.13.3.1.1.3.1.2 Method 2: From 2-(Alkoxycarbonyl)- or 2-Acyl-N-aryl-2-diazoacetamides 447
10.13.3.1.1.3.1.3 Method 3: From N-Aryltrichloroacetamides 448
10.13.3.1.1.3.1.4 Method 4: From N-(o-Haloaryl)alkanamides 449
10.13.3.1.1.3.1.5 Method 5: From a,ß-Unsaturated N-(o-Haloaryl)alkanamides 449
10.13.3.1.1.3.1.6 Method 6: 1,3-Dihydro-2H-indol-2-ones via Copper(II)-Mediated C--H, Aryl--H Coupling 451
10.13.3.2 Synthesis by Substituent Modification 452
10.13.3.2.1 Method 1: Oxidation of Indoles 452
10.13.3.2.2 Method 2: Reduction of 1H-Indole-2,3-diones (Isatins) 455
10.13.3.2.3 Method 3: Reaction of 1H-Indole-2,3-diones (Isatins) with 4-Hydroxyproline 456
10.13.3.2.4 Method 4: Nucleophilic Displacements of Halogen/Alkoxy Groups from 3-Halo- or 3-Alkoxy-1,3-dihydro-2H-indol-2-ones 456
10.13.3.2.5 Method 5: Cyclization of 2-Chloro-3-(2-aminoethyl)indoles (2-Chlorotryptamines) 457
10.13.3.2.6 Method 6: From Methyl 1H-Indole-3-carboxylate by Chlorination Then Reaction with an Allylic Alcohol 458
10.13.4 Product Subclass 4: 1,2-Dihydro-3H-indol-3-ones (1H-Indol-3-ols, 3-Hydroxy-1H-indoles, or Indoxyls) 459
10.13.4.1 Synthesis by Ring-Closure Reactions 460
10.13.4.1.1 By Annulation to an Arene 460
10.13.4.1.1.1 By Formation of One N--C and One C--C Bond 460
10.13.4.1.1.1.1 With Formation of 1--2 and 3--3a Bonds 460
10.13.4.1.1.1.1.1 Method 1: From Arylamines and Glyoxal Derivatives 460
10.13.4.1.1.1.1.2 Method 2: From Arylamines, Aldehydes/Ketones, and Isocyanides 460
10.13.4.1.1.2 By Formation of One N--C Bond 462
10.13.4.1.1.2.1 With Formation of the 1--2 Bond 462
10.13.4.1.1.2.1.1 Method 1: From 1-(o-Aminoaryl)allyl Silyl Ethers 462
10.13.4.1.1.2.1.2 Method 2: From o-Aminoaryl Halomethyl Ketones Sugasawa Indoxyl Synthesis
10.13.4.1.1.3 By Formation of One C--C Bond 463
10.13.4.1.1.3.1 With Formation of the 2--3 Bond 463
10.13.4.1.1.3.1.1 Method 1: From [(o-Carboxyaryl)amino]acetic Acids and {[o-(Alkoxycarbonyl)aryl]amino}acetic Acid Esters 463
10.13.4.1.1.3.2 With Formation of the 3--3a Bond 465
10.13.4.1.1.3.2.1 Method 1: From N-Arylglycines 465
10.13.4.2 Synthesis by Substituent Modification 465
10.13.4.2.1 Method 1: Oxidation of Indoles 465
10.13.5 Product Subclass 5: 1H-Indole-2,3-diones (Isatins) 469
10.13.5.1 Synthesis by Ring-Closure Reactions 469
10.13.5.1.1 By Annulation to an Arene 469
10.13.5.1.1.1 By Formation of One N--C and One C--C Bond 469
10.13.5.1.1.1.1 With Formation of the 1--2 Bond and the 3--3a Bond 469
10.13.5.1.1.1.1.1 Method 1: From Anilines and Chloral 469
Author Index 510
Abbreviations 544
List of All Volumes 550
10.13 Product Class 13: Indole and Its Derivatives
J. A. Joule
10.13.1 Product Subclass 1: Indoles
The word indole is derived from the word India: indigo (3), the blue dye, was first exported from India to Europe in the 16th century. Indoles are generally crystalline colorless solids, the simpler ones having characteristic odors: pure 1H-indole itself has a jasmine-like odor while that of 3-methyl-1H-indole (skatole) is notorious for its fecal character. The electron-rich character of indoles brings a tendency to light-catalyzed autoxidation; indoles should be stored away from oxygen and light. Simple indoles are also sensitive to strong acids, a point that must be taken into account in designing synthetic manipulations. Electron-withdrawing substituents have a stabilizing effect on each of these sensitivities.
1H-Indole (1) is the only tautomer detectable under normal circumstances; 3H-indole (2, indolenine in older literature) can be generated, but tautomerizes rapidly to 1H-indole at temperatures above –50°C (▶ Scheme 1).[1]
▶ Scheme 1 The Tautomeric Structures of Indole
The indole system occurs in the essential amino acid tryptophan (4; ▶ Scheme 2), and thence in proteins and in thousands of indole and 2,3-dihydro-1H-indole (trivially known as indoline) containing natural products[2] biosynthetically derived therefrom, e.g. the alkaloids reserpine (tranquilizer) and vincristine (cancer chemotherapeutic), in the neurotransmitter substance serotonin (5-hydroxytryptamine), in the plant growth-regulating hormone 1H-indole-3-acetic acid, in lysergic acid diethylamide (LSD), and in several significant modern synthetic drugs, such as indomethacin, ondansetron, pindolol, alosetron, ropinirole, tadalafil, and sumatriptan. As a consequence, the rich chemistry of indoles has been extensively studied, many routes for the ring synthesis of indoles have been developed and some frequently exemplified, as have substitutions and other manipulations of preformed indoles.
Functional group transformations of both ring and side-chain substituents (▶ Section 10.13.1.5) generally proceed normally, with emphasis given at appropriate points in this section to situations where this is not the case; reference should be made to other volumes in this series for particular functional group chemistry; however, many of these transformations are of great importance in the synthesis of indole-containing compounds and consequently are either exemplified in this section and/or reference is made to typical examples. Perhaps most significant to modern indole transformations are: (1) the use of organometallic, particularly organolithium, derivatives as nucleophiles; and (2) cross coupling processes, most often using palladium(0) as catalyst, with halogen, tin, zinc, mercury, thallium, boron, and trifluoromethanesulfonate derivatives of indoles. Enormous use has been made of cross-coupling processes involving both indole halides and trifluoromethanesulfonates and indole boronates and stannanes. There are examples of boronic acids or boronates at all of the carbon positions of the indole ring and there are examples of stannanes at all of the carbon positions of the indole ring (see ▶ Sections 10.13.1.4.2.4.3 and 10.13.1.4.4.6.4).
Several excellent general and specific reviews of indole chemistry are available.[3–6] Reviews on the synthesis of 3-substituted indoles via reactive alkylidene-3H-indole intermediates;[7] the control of enantio- and regioselectivity in asymmetric Friedel–Crafts alkylations;[8] the asymmetric Pictet–Spengler[9] and Bartoli[10] reactions; cross-coupling reactions;[11] the synthesis of indoles from indol-2-ylacyl radicals;[12] the catalytic synthesis of indoles from alkynes,[13] by rhodium[14] or palladium-catalyzed reactions[15–17] or other transition metal reagents;[18] the alkylation of indoles;[19,20] the synthesis of indoles via isocyanides;[21] the solid-phase synthesis of indoles;[22] halogen-,[23] sulfur-,[24] oxygen-containing indoles;[25] the nucleophilic substitution of indoles;[26,27] on methods and applications of indole ring synthesis;[28] and on indoles in general[29,30] are also available.
▶ Scheme 2 The Structures of Indigo, Tryptophan, and Tryptamine
1H-Indole is an electron-rich 10 π-electron aromatic system and as such undergoes electrophilic substitution reactions rapidly in the heterocyclic ring; a protodetritiation study showed the indole 3-position to be 5.5 × 1013 more reactive to electrophilic attack than a benzene position.[31] There is a strong preference for electrophilic attack at C3 (the β-position) though substitution at C2 (the α-position) of 3-substituted indoles 5 also takes place readily (▶ Scheme 3). In at least some instances, the observed α-substituted product 8 arises via initial β-attack producing a 3,3-disubstituted 3H-indolium intermediate 6 and then 1,2-rearrangement of 6 to 7,[32] though direct α-attack (to give 7) has also been demonstrated.[33,34]
In an elegant experiment (▶ Scheme 4) the intervention of a 3,3-disubstituted 3H-indolium intermediate in an indole overall α-substitution was shown by cyclization of the methanesulfonate of optically active 9 to give an optically inactive product 11, via the achiral, spirocyclic intermediate 10 arising from initial attack at the β-position.[35]
▶ Scheme 4 Demonstration of α-Electrophilic Substitution via Initial Attack at C3[35]
Indoles are weak bases[36,37] with pKa values of about –3, protonation taking place at C3[38,39] to generate 3H-indolium cations (indoleninium ions) 12 (▶ Scheme 5). It is the formation of such species and their further oligomerization and polymerization which is responsible for the acid sensitivity of indoles.[40]
Electrophilic substitution in the benzene ring only occurs in special cases, e.g. where the medium is strongly acidic and attack occurs on a pyrrole-ring-protonated species. Addition of a proton (at C3) then a nucleophile (at C2) can generate 2,3-dihydro-1H-indoles, arylamines in reactivity terms, which can undergo electrophilic substitution in the benzene ring, subsequent reversal of the earlier addition leading overall to benzene-ring-substituted indoles. Selective reduction of the pyrrole ring (best with triethylsilane in trifluoroacetic acid[41]) to produce 2,3-dihydro-1H-indoles (or the use of 2,3-dihydro-1H-indoles from other sources) then benzene ring substitution of these arylamines, and finally dehydrogenation of the five-membered ring, which is easy, can give the same result. However, most benzene-ring-substituted indoles are constructed by ring synthesis, and/or by functional group transpositions.
Indoles with an N-hydrogen have pKa values around 16 (in water)[37] or 21 (in DMSO)[42]for the loss of this proton; the acidity is increased by electron-withdrawing groups, in particular when located at C3.[43,44] Thus, N-deprotonation of indoles is readily achieved using strong bases. The resulting indolyl anions 13, which are ambident (▶ Scheme 6), react with electrophiles to give N-substituted products 14 or 3-substituted products 16 via 15, or mixtures of these depending on the counterion, the reactivity of the electrophile, and the solvent.[45–47] Reaction at nitrogen is favored by polar solvents and by more ionic metal—nitrogen bond character, sodium or potassium counterions; the use especially of zinc and magnesium intermediates can result in a greater proportion of C3 substitution. More reactive alkylating agents favor 3-alkylation.
Deprotonation of N-substituted indoles 17 with a strong base, such as butyllithium or lithium diisopropylamide, takes place...
| Erscheint lt. Verlag | 14.5.2014 |
|---|---|
| Reihe/Serie | Science of Synthesis |
| Verlagsort | Stuttgart |
| Sprache | englisch |
| Themenwelt | Naturwissenschaften ► Chemie ► Organische Chemie |
| Technik | |
| Schlagworte | Chemical Synthesis • Chemie • Chemische Synthese • chemistry of organic compound • chemistry organic reaction • chemistry reference work • chemistry synthetic methods • compound functional group • compound organic synthesis • Fischer Synthese • Fischer synthesis • functional groups • Indole • indole compounds • indole synthesis • Indoline • Indolsynthese • Indolverbindungen • Indoxyle • indoxyls • Isatin • Mechanism • methods in organic synthesis • methods peptide synthesis • N-Arylation • Organic Chemistry • organic chemistry functional groups • organic chemistry reactions • organic chemistry review • organic chemistry synthesis • ORGANIC CHEM ISTRY SYNTHESIS • organic chemisty • organic method • organic reaction • organic reaction mechanism • ORGANI C REACTION MECHANISM • Organic Syntheses • organic synthesis • organic synthesis reference work • Organisch-chemische Synthese • Organische Chemie • Oxindole • Palladium • Palladium Catalysis • Palladium-Katalyse • Peptide synthesis • Practical • practical organic chemistry • Reactions • reference work • Review • review organic synthesis • review synthetic methods • REVIEW SYNTHE TIC METHODS • Synthese • Synthetic Methods • Synthetic Organic Chemistry • synthetic transformation • Updates |
| ISBN-10 | 3-13-178641-8 / 3131786418 |
| ISBN-13 | 978-3-13-178641-8 / 9783131786418 |
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