Science of Synthesis Knowledge Updates: 2016/3 (eBook)
560 Seiten
Georg Thieme Verlag KG
978-3-13-220941-1 (ISBN)
Science of Synthesis Knowledge Updates 2016/3 1
Title Page 6
Copyright 8
Preface 9
Abstract 11
Science of Synthesis Knowledge Updates 2016/3 13
Table of Contents 15
10.22 Product Class 22: Azaindoles and Their Derivatives 23
10.22.1 Product Subclass 1: Azaindoles 23
10.22.1.1 Synthesis by Ring-Closure Reactions 34
10.22.1.1.1 By Annulation to a Pyridine 34
10.22.1.1.1.1 By Formation of One N—C and One C—C Bond 34
10.22.1.1.1.1.1 With Formation of 1—2 and 3—3a Bonds 34
10.22.1.1.1.1.1.1 Method 1: From Pyridylhydrazones (Fischer Synthesis) 34
10.22.1.1.1.1.1.1.1 Variation 1: Indolization with Pyridinium Hydrochloride 39
10.22.1.1.1.1.1.1.2 Variation 2: From (6-Methoxypyridin-3-yl)hydrazine or (2-Methoxypyridin- 3-yl)hydrazine 40
10.22.1.1.1.1.1.1.3 Variation 3: Using Microwave Activation 44
10.22.1.1.1.1.1.1.4 Variation 4: From a Pyridin-4-yldiazonium N-Oxide and a ?-Oxo Acid 45
10.22.1.1.1.1.1.1.5 Variation 5: From a Pyridylhydrazine and an Enamine 46
10.22.1.1.1.1.1.1.6 Variation 6: From a Pyridylhydrazine and a ?-Halo Ketone (Grandberg Synthesis) 47
10.22.1.1.1.1.1.1.7 Variation 7: From 4-Hydrazino-6-methylpyridin-2(1H)-one 48
10.22.1.1.1.1.1.1.8 Variation 8: From a Pyridylboronic Acid and Di-tert-butyl Azodicarboxylate 49
10.22.1.1.1.1.1.2 Method 2: From ortho-Substituted Nitropyridines (Bartoli Synthesis) 53
10.22.1.1.1.1.1.3 Method 3: From N-Chloropyridin-2-amines and ?-Alkylsulfanyl Ketones (Gassman Synthesis) 57
10.22.1.1.1.1.1.4 Method 4: From Pyridinamines and ?-Hydroxy Ketones (Bischler Synthesis) 58
10.22.1.1.1.1.1.5 Method 5: From Halopyridin-2-amines and Alkynes (Larock Synthesis) 62
10.22.1.1.1.1.1.6 Method 6: From Enamines of Pyridyl Ketones/Aldehydes 74
10.22.1.1.1.1.1.7 Method 7: From Iodopyridinamines and Allyl Acetate 78
10.22.1.1.1.1.1.8 Method 8: From Nitropyridines and Alkynes 80
10.22.1.1.1.1.2 With Formation of 1—2 and 2—3 Bonds 81
10.22.1.1.1.1.2.1 Method 1: From an Alkyl-N-(tert-Butoxycarbonyl)pyridinamine and an Amide 81
10.22.1.1.1.1.2.1.1 Variation 1: From an Unprotected Alkylpyridinamine and an Ester 89
10.22.1.1.1.1.2.2 Method 2: From a 2-Aminopyridine-3-carbaldehyde and a Diazo Ester 90
10.22.1.1.1.1.2.3 Method 3: From a Methylpyridinamine and the Vilsmeier Reagent 91
10.22.1.1.1.1.3 With Formation of 1—7a and 2—3 Bonds 92
10.22.1.1.1.1.3.1 Method 1: From an Alkylpyridine and a Nitrile 92
10.22.1.1.1.1.3.1.1 Variation 1: From a 2-Fluoro(alkyl)pyridine and a Nitrile 93
10.22.1.1.1.1.3.2 Method 2: From a 2-(2-Chloropyridin-3-yl)oxirane and an Amine 94
10.22.1.1.1.1.3.3 Method 3: From a 2-Halopyridyl Aldehyde and Ethyl Isocyanoacetate 96
10.22.1.1.1.1.4 With Formation of 1—2 and 1—7a Bonds 97
10.22.1.1.1.1.4.1 Method 1: From a 2-Chloro-3-(2-chloroethyl)pyridine and an Amine 97
10.22.1.1.1.1.4.1.1 Variation 1: From 3-(2-{[(Trifluoromethyl)sulfonyl]oxy}ethyl)pyridine- 2,6-diyl Bis(trifluoromethanesulfonate) and an Amine 99
10.22.1.1.1.1.4.2 Method 2: From a 2-Bromo-3-(2-bromoalkenyl)pyridine and an Amine 101
10.22.1.1.1.1.4.3 Method 3: From a 2-Alkynyl-3-bromopyridine and a Carbamate 103
10.22.1.1.1.2 By Formation of One N—C Bond 103
10.22.1.1.1.2.1 With Formation of the 1—2 Bond 103
10.22.1.1.1.2.1.1 Method 1: From (3-Nitropyridin-2-yl)pyruvates (Reissert Synthesis) 103
10.22.1.1.1.2.1.2 Method 2: From a Halopyridinamine and an Enolate 111
10.22.1.1.1.2.1.3 Method 3: From Alkynylpyridinamines 114
10.22.1.1.1.2.1.3.1 Variation 1: Base-Mediated Cyclization 114
10.22.1.1.1.2.1.3.2 Variation 2: Using Microwave Activation 125
10.22.1.1.1.2.1.3.3 Variation 3: Copper(I) Iodide Mediated Cyclization 128
10.22.1.1.1.2.1.3.4 Variation 4: Copper(II) Acetate Mediated Cyclization 133
10.22.1.1.1.2.1.3.5 Variation 5: Indium(III) Bromide Mediated Cyclization 133
10.22.1.1.1.2.1.3.6 Variation 6: Gold(III) Chloride Mediated Cyclization 134
10.22.1.1.1.2.1.3.7 Variation 7: Acid-Mediated Cyclization 135
10.22.1.1.1.2.1.3.8 Variation 8: Palladium(0)-Mediated Cyclization with Concomitant Introduction of a 3-Aryl Substituent 135
10.22.1.1.1.2.1.3.9 Variation 9: Iodine-Mediated Cyclization with Concomitant Introduction of a 3-Iodo Substituent 137
10.22.1.1.1.2.1.3.10 Variation 10: Copper(I)-Mediated Cyclization with Concomitant Introduction of a 2-Dialkylamino Substituent 137
10.22.1.1.1.2.1.4 Method 4: From Allenylpyridinamines 139
10.22.1.1.1.2.1.5 Method 5: From Nitropyridyl Enamines (Leimgruber–Batcho Synthesis) 140
10.22.1.1.1.2.1.6 Method 6: From 2-(2-Nitropyridyl)enol Ethers 147
10.22.1.1.1.2.1.7 Method 7: From Nitro(vinyl)pyridines 150
10.22.1.1.1.2.1.8 Method 8: From Nitro(2-nitrovinyl)pyridines 154
10.22.1.1.1.2.1.9 Method 9: From Alkenylnitropyridines or Alkenylazidopyridine N-Oxides via Nitrenes 156
10.22.1.1.1.2.1.10 Method 10: From 2-(Arylamino)-3-(1-hydroxyalkyl)pyridines or 2-(Arylamino)- 3-alkenylpyridines 157
10.22.1.1.1.2.1.11 Method 11: From (2,2-Dihalovinyl)pyridinamines 158
10.22.1.1.1.2.1.12 Method 12: From N-(Styrylpyridyl)hydroxylamines 162
10.22.1.1.1.2.1.13 Method 13: From a 2-(Nitropyridyl)acetonitrile 163
10.22.1.1.1.2.1.14 Method 14: From (2-Aminopyridyl) Aldehydes and Ketones Derived by Carbolithiation of a 3-Vinylpyridin-2-amine 168
10.22.1.1.1.2.2 With Formation of the 1—7a Bond 170
10.22.1.1.1.2.2.1 Method 1: From a (2-Aminoethyl)halopyridine 170
10.22.1.1.1.2.2.2 Method 2: From a Pyridylacetic Acid Hydrazide 171
10.22.1.1.1.2.2.3 Method 3: From a 2-Azido-3-pyridylacrylate (Hemetsberger–Knittel Synthesis) 171
10.22.1.1.1.2.2.4 Method 4: From a 2-Amino-3-(3-bromopyridin-4-yl)acrylate 177
10.22.1.1.1.3 By Formation of One C—C Bond 177
10.22.1.1.1.3.1 With Formation of the 2—3 Bond 177
10.22.1.1.1.3.1.1 Method 1: From an Acylaminopyridyl Ketone (Fürstner Synthesis) 177
10.22.1.1.1.3.1.2 Method 2: From an Acylamino(methyl)pyridine (Madelung Synthesis) 178
10.22.1.1.1.3.1.2.1 Variation 1: From a 2-[3-(Acylamino)pyridin-2-yl]acetonitrile 182
10.22.1.1.1.3.2 With Formation of the 3—3a Bond 183
10.22.1.1.1.3.2.1 Method 1: From a 2-(Pyridin-2-ylamino)ethyl Ethylxanthate 183
10.22.1.1.1.3.2.2 Method 2: From an N-Allyl-3-halopyridin-2-amine 184
10.22.1.1.1.3.2.3 Method 3: From an N-(2-Halopyridin-3-yl)cycloalkanimine 185
10.22.1.1.1.3.2.4 Method 4: From an N-Alkynylhalopyridinamine 186
10.22.1.1.2 By Annulation to a Pyrrole 188
10.22.1.1.2.1 By Formation of One N—C Bond and Two C—C Bonds 188
10.22.1.1.2.1.1 With Formation of 3a—4, 5—6, and 6—7 Bonds 188
10.22.1.1.2.1.1.1 Method 1: From a Pyrrol-2-amine, a Ketone, and an Aldehyde 188
10.22.1.1.2.2 By Formation of One N—C Bond and One C—C Bond 189
10.22.1.1.2.2.1 With Formation of the 3a—4 and 4—5 Bonds 189
10.22.1.1.2.2.1.1 Method 1: From 2-Aryl-2-(1H-pyrrol-2-yl)ethan-1-amines and an Aromatic Aldehyde 189
10.22.1.1.2.2.2 With Formation of 3a—4 and 6—7 Bonds 191
10.22.1.1.2.2.2.1 Method 1: From a Pyrrol-2-amine and a 1,3-Diketone 191
10.22.1.1.2.2.3 With Formation of 3a—4 and 7—7a Bonds 195
10.22.1.1.2.2.3.1 Method 1: From a 2,2-Dimethoxypyrrolidine and an Enaminone 195
10.22.1.1.2.3 By Formation of One N—C Bond 196
10.22.1.1.2.3.1 With Formation of the 1—7a Bond 196
10.22.1.1.2.3.1.1 Method 1: From Nicotine 196
10.22.1.1.2.3.2 With Formation of the 4—5 Bond 196
10.22.1.1.2.3.2.1 Method 1: From Ethyl 2-(2-Amino-1-hydroxyethyl)-1H-pyrrole-3-carboxylates 196
10.22.1.1.2.3.2.2 Method 2: From (Z)-2-(1-Amino-3-methoxy-3-oxoprop-1-en-2-yl)- 1-methyl-1H-pyrrole-3-carboxylate 198
10.22.1.1.2.3.2.3 Method 3: From 3-(Ethoxycarbonyl)pyrrole-2-acetamide 198
10.22.1.1.2.3.3 With Formation of the 5—6 Bond 199
10.22.1.1.2.3.3.1 Method 1: From 3-Alkynyl-2-(azidomethyl)pyrroles 199
10.22.1.1.2.4 By Formation of One C—C Bond 201
10.22.1.1.2.4.1 With Formation of the 3a—4 Bond 201
10.22.1.1.2.4.1.1 Method 1: From a Pyrrole with a C2N-Chain at C2 201
10.22.1.1.2.4.1.2 Method 2: From a Pyrrole with a 2,2-Diethoxyethylimino Chain at C2 202
10.22.1.1.2.4.1.3 Method 3: From a Pyrrole with a 2-(Azidocarbonyl)vinyl Chain at C2 203
10.22.1.1.2.4.1.4 Method 4: From 2-Cyano-2-(pyrrolidin-2-ylidene)acetamide and Dimethylformamide Dimethyl Acetal 205
10.22.1.1.2.4.2 With Formation of the 4—5 Bond 206
10.22.1.1.2.4.2.1 Method 1: From an Ethyl 2-{[N-(2-Methoxy-2-oxoethyl)tosylamino] methyl}-1H-pyrrole-3-carboxylate 206
10.22.1.1.2.4.2.2 Method 2: From a 2-Amino-1H-pyrrole-3-carbonitrile and a 3-Oxo Ester 207
10.22.1.1.2.4.3 With Formation of the 7—7a Bond 208
10.22.1.1.2.4.3.1 Method 1: From a 3-(1H-Pyrrol-3-yl)acryloyl Azide 208
10.22.1.1.2.4.3.2 Method 2: From N-Pyrrol-3-yl Enamines 209
10.22.1.1.2.4.3.3 Method 3: From 1-(Pyrrol-3-yl)-1-azaenynes 210
10.22.1.1.3 Without Annulation to an Existing Ring 211
10.22.1.1.3.1 By Formation of Two N—C and Three C—C Bonds 211
10.22.1.1.3.1.1 With Formation of the 2—3, 3a—4, 5—6, 7—7a, and 1—7a Bonds 211
10.22.1.1.3.1.1.1 Method 1: From a Dialkynylsilane, an Isocyanide, and a Nitrile 211
10.22.1.1.3.2 By Formation of One N—C Bond and Two C—C Bonds 215
10.22.1.1.3.2.1 With Formation of the 3—3a, 4—5, and 7—7a Bonds 215
10.22.1.1.3.2.1.1 Method 1: From Ethyl Acrylate and a 3-[(Cyanomethyl)amino]acrylate 215
10.22.1.2 Synthesis by Ring Transformation 216
10.22.1.2.1 Ring Expansion 216
10.22.1.2.1.1 Method 1: From a 3-Azabicyclo[4.1.0]heptane and a Nitrile 216
10.22.1.2.2 Formal Exchange of Ring Members with Retention of the Ring Size 219
10.22.1.2.2.1 Method 1: From a 2,3-Dihydro-5-azabenzo[b]furan 219
10.22.1.2.2.2 Method 2: From 1,2,4-Triazines and an Alkyne 219
10.22.1.2.2.3 Method 3: From Pyrazolo[1,5-a]pyridines 221
10.22.1.2.3 Ring Contraction 223
10.22.1.2.3.1 Method 1: From a Naphthyridine Diazonium Salt 223
10.22.1.2.3.2 Method 2: From 3H-Azepines 224
10.22.1.3 Aromatization 225
10.22.1.3.1 Method 1: From 2,3-Dihydroazaindoles (Azaindolines) 225
10.22.1.3.2 Method 2: From Di- and Tetrahydropyridine Ring Azaindoles 227
10.22.1.4 Synthesis by Substituent Modification 228
10.22.1.4.1 Substitution of Existing Substituents 228
10.22.1.4.1.1 Pyridine Ring Substituents 228
10.22.1.4.1.1.1 Substitution of C-Hydrogen 228
10.22.1.4.1.1.1.1 Method 1: Introduction of C-Halogen to an Azaindole N-Oxide 228
10.22.1.4.1.1.1.2 Method 2: Introduction of C-Halogen via a C-Metalated Azaindole 235
10.22.1.4.1.1.1.3 Method 3: Introduction of C-Halogen to an Activated Azaindole 240
10.22.1.4.1.1.1.4 Method 4: Introduction of C-Sulfur 241
10.22.1.4.1.1.1.5 Method 5: Introduction of C-Oxygen to an Azaindole N-Oxide 242
10.22.1.4.1.1.1.6 Method 6: Introduction of C-Oxygen via a C-Metalated Azaindole 243
10.22.1.4.1.1.1.7 Method 7: Introduction of C-Nitrogen by Amination of an Azaindole N-Oxide 244
10.22.1.4.1.1.1.8 Method 8: Introduction of C-Nitrogen by Nitration of an Azaindole N-Oxide 249
10.22.1.4.1.1.1.9 Method 9: Introduction of C- Nitrogen via a C-Metalated Azaindole 251
10.22.1.4.1.1.1.10 Method 10: Introduction of C- Nitrogen to a 2,3-Dihydro-1H-pyrrolo[ 2,3-b]pyridine 252
10.22.1.4.1.1.1.11 Method 11: Introduction of C-Carbon to an Azaindole N-Oxide 253
10.22.1.4.1.1.1.12 Method 12: Introduction of C-Carbon via a C-Metalated Azaindole 255
10.22.1.4.1.1.1.13 Method 13: Introduction of C-Boron to a Metalated Azaindole 257
10.22.1.4.1.1.2 Substitution of C-Halogen 259
10.22.1.4.1.1.2.1 Method 1: Introduction of C-Hydrogen 259
10.22.1.4.1.1.2.2 Method 2: Introduction of C-Halogen 260
10.22.1.4.1.1.2.3 Method 3: Introduction of C-Sulfur by Nucleophilic Substitution 261
10.22.1.4.1.1.2.4 Method 4: Introduction of C-Sulfur by Lithium–Bromine Exchange 262
10.22.1.4.1.1.2.5 Method 5: Introduction of C-Oxygen 262
10.22.1.4.1.1.2.6 Method 6: Introduction of C-Nitrogen by Direct Reaction with Amines 265
10.22.1.4.1.1.2.7 Method 7: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amines 269
10.22.1.4.1.1.2.8 Method 8: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amides 281
10.22.1.4.1.1.2.9 Method 9: Introduction of a Cyano Group 283
10.22.1.4.1.1.2.10 Method 10: Introduction of Aryl, Carboxy, Acyl, Alkynyl, Alkenyl, or Alkyl Groups 285
10.22.1.4.1.1.2.11 Method 11: Introduction of C-Boron to Metalated Azaindoles 304
10.22.1.4.1.1.2.12 Method 12: Introduction of C-Boron via Palladium(0) Catalysis 305
10.22.1.4.1.1.3 Substitution of C-Sulfur 307
10.22.1.4.1.1.3.1 Method 1: Introduction of C-Halogen 307
10.22.1.4.1.1.4 Substitution of C-Nitrogen 308
10.22.1.4.1.1.4.1 Method 1: Introduction of C-Oxygen 308
10.22.1.4.1.1.4.2 Method 2: Reduction of a Nitro Group 309
10.22.1.4.1.1.5 Substitution of C-Boron 310
10.22.1.4.1.1.5.1 Method 1: Introduction of C-Carbon 310
10.22.1.4.1.1.6 Modification of C-Carbon 311
10.22.1.4.1.1.6.1 Method 1: Giving C-Carbon 311
10.22.1.4.1.2 Pyrrole Ring Substituents 313
10.22.1.4.1.2.1 Substitution of C-Hydrogen at C3 313
10.22.1.4.1.2.1.1 Method 1: Introduction of Bromine 313
10.22.1.4.1.2.1.2 Method 2: Introduction of Chlorine 319
10.22.1.4.1.2.1.3 Method 3: Introduction of Iodine 320
10.22.1.4.1.2.1.4 Method 4: Giving C-Sulfur 324
10.22.1.4.1.2.1.5 Method 5: Giving C-Nitrogen 328
10.22.1.4.1.2.1.6 Method 6: Introduction of Ester or Amide Groups 330
10.22.1.4.1.2.1.7 Method 7: Introduction of a Formyl Group 332
10.22.1.4.1.2.1.8 Method 8: Introduction of Acyl Groups 338
10.22.1.4.1.2.1.9 Method 9: Introduction of an Oxyalkyl Group 348
10.22.1.4.1.2.1.10 Method 10: Introduction of an Aminoalkyl Group 355
10.22.1.4.1.2.1.11 Method 11: Introduction of a Sulfanylalkyl Group 361
10.22.1.4.1.2.1.12 Method 12: Introduction of Alkenyl Groups 361
10.22.1.4.1.2.1.13 Method 13: Introduction of Hetaryl Groups 364
10.22.1.4.1.2.1.14 Method 14: Introduction of Alkyl Groups 364
10.22.1.4.1.2.1.15 Method 15: Introduction of C-Boron 370
10.22.1.4.1.2.2 Substitution of C-Hydrogen at C2 372
10.22.1.4.1.2.2.1 Method 1: Introduction of C-Halogen 372
10.22.1.4.1.2.2.2 Method 2: Introduction of C-Carbon by Intermolecular Metal-Catalyzed Direct Substitution 374
10.22.1.4.1.2.2.3 Method 3: Introduction of C-Carbon by Palladium-Catalyzed Cyclization of 1-Substituted Azaindoles 378
10.22.1.4.1.2.2.4 Method 4: Introduction of C-Carbon by Radical Cyclization of 1-Substituted Azaindoles 382
10.22.1.4.1.2.2.5 Method 5: Introduction of C-Carbon by Acid-Mediated Cyclization of 1-Substituted Azaindoles 383
10.22.1.4.1.2.2.6 Method 6: Introduction of C-Carbon by Enzyme-Mediated Cyclization of 1-Substituted 1H-Pyrrolo[2,3-b]pyridines 384
10.22.1.4.1.2.2.7 Method 7: Introduction of C-Carbon Using 2-Metalated Azaindoles 384
10.22.1.4.1.2.2.8 Method 8: Introduction of C-Boron and C-Tin 400
10.22.1.4.1.2.3 Substitution of C-Halogen at C3 403
10.22.1.4.1.2.3.1 Method 1: Introduction of C-Sulfur 403
10.22.1.4.1.2.3.2 Method 2: Introduction of Acid, Ester, or Amide Groups 403
10.22.1.4.1.2.3.3 Method 3: Introduction of a Cyano Group 407
10.22.1.4.1.2.3.4 Method 4: Introduction of Formyl or Acyl Groups 407
10.22.1.4.1.2.3.5 Method 5: Introduction of Hydroxyalkyl, Aminoalkyl, or Alkyl Groups 409
10.22.1.4.1.2.3.6 Method 6: Introduction of Alkenyl or Alkynyl Groups 412
10.22.1.4.1.2.3.7 Method 7: Introduction of Aryl or Hetaryl Groups 413
10.22.1.4.1.2.3.8 Method 8: Introduction of C-Boron 417
10.22.1.4.1.2.3.9 Method 9: Introduction of C-Tin 418
10.22.1.4.1.2.4 Substitution of C-Halogen at C2 421
10.22.1.4.1.2.4.1 Method 1: Introduction of C-Carbon 421
10.22.1.4.1.2.5 Substitution of C-Silicon at C2 429
10.22.1.4.1.2.5.1 Method 1: Introduction of C-Halogen 429
10.22.1.4.1.2.6 Substitution of C-Tin at C3 430
10.22.1.4.1.2.6.1 Method 1: Introduction of C-Carbon 430
10.22.1.4.1.2.7 Substitution of C-Tin at C2 432
10.22.1.4.1.2.7.1 Method 1: Introduction of C-Carbon 432
10.22.1.4.1.2.8 Substitution of C-Boron at C3 433
10.22.1.4.1.2.8.1 Method 1: Introduction of C-Carbon 433
10.22.1.4.1.2.9 Substitution/Modification of C-Carbon at C3 436
10.22.1.4.1.2.9.1 Method 1: Introduction of C-Carbonyl, C-Alkyl, and C-Vinyl Derivatives 436
10.22.1.4.1.2.10 Substitution/Modification of C-Carbon at C2 455
10.22.1.4.1.2.10.1 Method 1: Giving C-Halogen, C-Carbon, or C-Nitrogen 455
10.22.1.4.1.2.11 Substitution/Modification at N1 462
10.22.1.4.1.2.11.1 Method 1: Introduction of N-Nitrogen 462
10.22.1.4.1.2.11.2 Method 2: Introduction of N-Sulfur 463
10.22.1.4.1.2.11.3 Method 3: Introduction of Acid, Ester, or Amide Groups 467
10.22.1.4.1.2.11.4 Method 4: Introduction of Acyl Groups 473
10.22.1.4.1.2.11.5 Method 5: Introduction of Oxyalkyl or Aminoalkyl Groups 474
10.22.1.4.1.2.11.6 Method 6: Introduction of Alkenyl Groups 477
10.22.1.4.1.2.11.7 Method 7: Introduction of Alkyl Groups via Michael-Type Addition 479
10.22.1.4.1.2.11.8 Method 8: Introduction of Alkyl Groups by Reaction with Alkyl Halides, Alkyl Sulfonates, or Dimethyl Sulfate 481
10.22.1.4.1.2.11.9 Method 9: Introduction of Alkyl Groups by Reaction with Dimethylformamide Dimethyl Acetal 488
10.22.1.4.1.2.11.10 Method 10: Introduction of Alkyl Groups by Reaction with an Allylic Carbonate 489
10.22.1.4.1.2.11.11 Method 11: Introduction of Alkyl Groups by Reaction with an Oxirane, Aziridine, or Azirine 490
10.22.1.4.1.2.11.12 Method 12: Introduction of Aryl or Hetaryl Groups 492
10.22.1.4.1.2.11.13 Method 13: Introduction of N-Silicon 498
10.22.1.4.1.2.11.14 Method 14: N-Deprotection at N1 499
10.22.1.4.1.2.11.15 Method 15: Modification of N-Carbon at N1 502
10.22.1.4.2 Addition Reactions 503
10.22.1.4.2.1 Addition of Organic Groups 503
10.22.1.4.2.1.1 Method 1: Alkylation of the Pyridine Nitrogen Atom: Formation of Pyridinium Salt 503
10.22.1.4.2.1.2 Method 2: Bis-acylation of the Two Nitrogen Atoms of 1H-Pyrrolo[2,3-b]pyridine 505
Author Index 527
Abbreviations 559
10.22 Product Class 22: Azaindoles and Their Derivatives
10.22.1 Product Subclass 1: Azaindoles
J.-Y. Mérour and B. Joseph
General Introduction
Formally, azaindoles are the products of replacing the benzene ring of indole with a pyridine ring. This results in four isomeric azaindoles: 1H-pyrrolo[3,2-b]pyridine (1, 4-azaindole), 1H-pyrrolo[3,2-c]pyridine (2, 5-azaindole), 1H-pyrrolo[2,3-c]pyridine (3, 6-azaindole), and 1H-pyrrolo[2,3-b]pyridine (4, 7-azaindole; ▶ Scheme 1). These systems are occasionally called diazaindenes: 1,4-diazaindene (1), 1,5-diazaindene (2), 1,6-diazaindene (3), and 1,7-diazaindene (4).
Scheme 1 Structures of Azaindoles
Historically, the first azaindole derivative was synthesized by Fischer in 1885 by decomposition of harmonic acid[1] and it was later identified as 7-methyl-1H-pyrrolo[2,3-c]pyridine (5) by Perkin and Robinson.[2,3] In 1943, 1H-pyrrolo[2,3-b]pyridine (4) was isolated from coal tar by Kruber.[4] Simple azaindole structures do not occur in nature but polycyclic 1H-pyrrolo[2,3-b]pyridine derivatives 6–9 named variolins were isolated in 1994 from the Antarctic sponge Kirkpatrickia variolosa (▶ Scheme 2). Variolins are the first examples of either terrestrial or marine natural products with an azaindole framework.[5,6]
A very important feature of azaindole derivatives, compared to those of indole, is the association of an electron-rich pyrrole ring fused to an electron-poor pyridine ring. Azaindoles show the typical reactivity of both component systems with a reduced and varying degree that decreases electron density in the five-membered pyrrole ring and increases electron density in the six-membered pyridine ring. Functional-group transformations of both rings and side-chain substituents generally proceed normally. Perhaps most significant to azaindole transformations are: (1) the use of organometallic, particularly organolithium, derivatives as nucleophiles, and (2) cross-coupling processes, most often using palladium as catalyst, with halogen, tin, zinc, boron, and trifluoromethanesulfonate derivatives of azaindoles. Several excellent general reviews of azaindole chemistry are available.[7–19]
The electronic structures have been the subject of numerous theoretical studies. In 1976, a SCF-CI π-electron semiempirical method showed that the nitrogen of the pyrrole ring is a π-donor and a σ-acceptor whereas the nitrogen of the pyridine ring is a σ- and π-acceptor.[20] In 1983, Catalán and co-workers carried out ab initio calculations using a STO-3G minimal basis set for the four azaindoles and their tautomeric forms (▶ Table 1).[21,22] The most interesting features are the minimal dependence of the charge distribution of the five-membered ring depending on the position of the pyridine nitrogen atom. The geometry of the pyrrole ring is also little affected in the four isomeric azaindoles. As for indoles, the C3 of azaindoles possesses the highest electronic density, which correlates with experimental behavior, but Catalán found that azaindoles are less reactive than indole toward electrophilic reagents. Comparison of the fused pyridine ring to pyridine itself shows C4 and C6 of 1H-pyrrolo[2,3-b]pyridine to be the likely sites of nucleophilic attack, but they show less electron depletion than the C2 and C4 of pyridine itself. In prototropic tautomerism, the accumulation of charge is found at C3 and N1 as indicated by ab initio calculations and in the drawings of resonance contributors. Other ab initio studies have been performed on substituted azaindoles.[22,23]
Table 1 Charge Densities for Azaindoles[21]
| Atom Position | Charge Density (10–3 e) | Ref |
| 1 | 2 | 3 | 4 |
| 1 | –562 | –567 | –559 | –560 | [21] |
| 2 | +239 | +234 | +242 | +231 | [21] |
| 3 | 0 | +21.5 | +16 | +24 | [21] |
| 3a | +216 | +29 | +78 | +29 | [21] |
| 4 | –555 | +259 | +53 | +108 | [21] |
| 5 | +231 | –583 | +224 | +24 | [21] |
| 6 | +50 | +247 | –561 | +250 | [21] |
| 7 | +70 | +16 | +221 | –594 | [21] |
| 7a | +204 | +249 | +200 | +378 | [21] |
A semiempirical AM1 study was carried out to calculate the enthalpies of formation, ionization energies, electron affinities, energy differences between HOMO and LUMO, atom charges, bond orders, and dipole moments (▶ Table 2).[24,25] The stability of the four azaindoles decreases in the order: 1H-pyrrolo[3,2-c]pyridine (2)>1H-pyrrolo[2,3-c]pyridine (3)>1H-pyrrolo[3,2-b]pyridine (1)>1H-pyrrolo[2,3-b]pyridine (4).
Regarding the values of dipole moments, 1H-pyrrolo[3,2-b]pyridine (2) is the most polar and 1H-pyrrolo[2,3-b]pyridine (4) is the least polar compound, which reflects to some extent the value of the charge on the N1 atom.[24]
The values of the charges on carbons C2 and C3 (q2 and q3) indicate that C3 is a nucleophilic center (as in indole, ▶ Table 2). In addition it seems that 1H-pyrrolo[3,2-c]pyridine (2) is the most reactive and 1H-pyrrolo[3,2-b]pyridine (1) is the least reactive. The authors established a correlation between the calculated physicochemical parameters and the Hammett para substituent and inductive constants.
Table 2 Ionization Energies, Dipole Moments, and Atom Charges of Azaindoles[25]
| Compound | I (eV) | μ (D) | –q3 | –q2 | Ref |
| 1 | 8.9 | 3.68 | 0.182 | 0.075 | [25] |
| 2 | 8.7 | 3.87 | 0.180 | 0.085 | [25] |
| 3 | 8.8 | 3.28 | 0.204 | 0.070 | [25] |
| 4 | 8.8 | 1.44 | 0.192 | 0.076 | [25] |
| 1H-indole | 8.4 | 1.89 | 0.200 | 0.081 | [25] |
1H-Pyrrolo[2,3-b]pyridine (4) can exist in a second tautomeric form, 7H-pyrrolo[2,3-b]pyridine (10), as shown by spectroscopic methods. The difference in enthalpy between the two forms is 66.9 kJ•mol–1, which indicates an endothermic process for the N1 to N7 proton transfer (▶ Scheme 3). It is assumed that this process occurs via dimer formation.[25,26] For the three other isomers, the enthalpy of activation for such a process is high, precluding the existence of comparable tautomeric forms. Other AM1 studies have been performed on substituted azaindoles.[27–29]
Scheme 3 Tautomeric Equilibrium of 1H-Pyrrolo[2,3-b]pyridine and 7H-Pyrrolo[2,3-b]pyridine[25]
In 10% deuterated sulfuric acid (D2SO4), a slow hydrogen exchange occurs only at C3 for 1H-pyrrolo[3,2-b]pyridine (1) and 1H-pyrrolo[3,2-c]pyridine (2). At 150 °C in 27.5% deuterated sulfuric acid, the same C3 exchange is observed with 4-methyl-1H-pyrrolo[2,3-b]pyridine with additional exchanges at C2 and C5.[30]
Indole derivatives do not show appreciable basic properties but this is not the case for azaindoles. Of the two nitrogen atoms present in an azaindole, only the pyridine nitrogen shows appreciable basicity because the lone pair is not involved in the aromaticity. The various pKa values for...
| Erscheint lt. Verlag | 26.10.2016 |
|---|---|
| Verlagsort | Stuttgart |
| Sprache | englisch |
| Themenwelt | Naturwissenschaften ► Chemie ► Organische Chemie |
| Technik | |
| Schlagworte | Organic Chemistry • organic reactions • organic synthesis • Organische Chemie • Referenzwerk • Review • Synthese |
| ISBN-10 | 3-13-220941-4 / 3132209414 |
| ISBN-13 | 978-3-13-220941-1 / 9783132209411 |
| Haben Sie eine Frage zum Produkt? |
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