E-Book, Englisch, 560 Seiten, PDF
Reihe: Science of Synthesis
Fürstner / Schaumann / Shibasaki Science of Synthesis Knowledge Updates: 2016/3
1. Auflage 2016
ISBN: 978-3-13-220931-2
Verlag: Thieme
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
E-Book, Englisch, 560 Seiten, PDF
Reihe: Science of Synthesis
ISBN: 978-3-13-220931-2
Verlag: Thieme
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
Autoren/Hrsg.
Weitere Infos & Material
1;Science of Synthesis Knowledge Updates 2016/3;1
2;Title Page;6
3;Copyright;8
4;Preface;9
5;Abstract;11
6;Science of Synthesis Knowledge Updates 2016/3;13
7;Table of Contents;15
8;10.22 Product Class 22: Azaindoles and Their Derivatives;23
9;10.22.1 Product Subclass 1: Azaindoles;23
9.1;10.22.1.1 Synthesis by Ring-Closure Reactions;34
9.1.1;10.22.1.1.1 By Annulation to a Pyridine;34
9.1.1.1;10.22.1.1.1.1 By Formation of One N—C and One C—C Bond;34
9.1.1.1.1;10.22.1.1.1.1.1 With Formation of 1—2 and 3—3a Bonds;34
9.1.1.1.1.1;10.22.1.1.1.1.1.1 Method 1: From Pyridylhydrazones (Fischer Synthesis);34
9.1.1.1.1.1.1;10.22.1.1.1.1.1.1.1 Variation 1: Indolization with Pyridinium Hydrochloride;39
9.1.1.1.1.1.2;10.22.1.1.1.1.1.1.2 Variation 2: From (6-Methoxypyridin-3-yl)hydrazine or (2-Methoxypyridin- 3-yl)hydrazine;40
9.1.1.1.1.1.3;10.22.1.1.1.1.1.1.3 Variation 3: Using Microwave Activation;44
9.1.1.1.1.1.4;10.22.1.1.1.1.1.1.4 Variation 4: From a Pyridin-4-yldiazonium N-Oxide and a ?-Oxo Acid;45
9.1.1.1.1.1.5;10.22.1.1.1.1.1.1.5 Variation 5: From a Pyridylhydrazine and an Enamine;46
9.1.1.1.1.1.6;10.22.1.1.1.1.1.1.6 Variation 6: From a Pyridylhydrazine and a ?-Halo Ketone (Grandberg Synthesis);47
9.1.1.1.1.1.7;10.22.1.1.1.1.1.1.7 Variation 7: From 4-Hydrazino-6-methylpyridin-2(1H)-one;48
9.1.1.1.1.1.8;10.22.1.1.1.1.1.1.8 Variation 8: From a Pyridylboronic Acid and Di-tert-butyl Azodicarboxylate;49
9.1.1.1.1.2;10.22.1.1.1.1.1.2 Method 2: From ortho-Substituted Nitropyridines (Bartoli Synthesis);53
9.1.1.1.1.3;10.22.1.1.1.1.1.3 Method 3: From N-Chloropyridin-2-amines and ?-Alkylsulfanyl Ketones (Gassman Synthesis);57
9.1.1.1.1.4;10.22.1.1.1.1.1.4 Method 4: From Pyridinamines and ?-Hydroxy Ketones (Bischler Synthesis);58
9.1.1.1.1.5;10.22.1.1.1.1.1.5 Method 5: From Halopyridin-2-amines and Alkynes (Larock Synthesis);62
9.1.1.1.1.6;10.22.1.1.1.1.1.6 Method 6: From Enamines of Pyridyl Ketones/Aldehydes;74
9.1.1.1.1.7;10.22.1.1.1.1.1.7 Method 7: From Iodopyridinamines and Allyl Acetate;78
9.1.1.1.1.8;10.22.1.1.1.1.1.8 Method 8: From Nitropyridines and Alkynes;80
9.1.1.1.2;10.22.1.1.1.1.2 With Formation of 1—2 and 2—3 Bonds;81
9.1.1.1.2.1;10.22.1.1.1.1.2.1 Method 1: From an Alkyl-N-(tert-Butoxycarbonyl)pyridinamine and an Amide;81
9.1.1.1.2.1.1;10.22.1.1.1.1.2.1.1 Variation 1: From an Unprotected Alkylpyridinamine and an Ester;89
9.1.1.1.2.2;10.22.1.1.1.1.2.2 Method 2: From a 2-Aminopyridine-3-carbaldehyde and a Diazo Ester;90
9.1.1.1.2.3;10.22.1.1.1.1.2.3 Method 3: From a Methylpyridinamine and the Vilsmeier Reagent;91
9.1.1.1.3;10.22.1.1.1.1.3 With Formation of 1—7a and 2—3 Bonds;92
9.1.1.1.3.1;10.22.1.1.1.1.3.1 Method 1: From an Alkylpyridine and a Nitrile;92
9.1.1.1.3.1.1;10.22.1.1.1.1.3.1.1 Variation 1: From a 2-Fluoro(alkyl)pyridine and a Nitrile;93
9.1.1.1.3.2;10.22.1.1.1.1.3.2 Method 2: From a 2-(2-Chloropyridin-3-yl)oxirane and an Amine;94
9.1.1.1.3.3;10.22.1.1.1.1.3.3 Method 3: From a 2-Halopyridyl Aldehyde and Ethyl Isocyanoacetate;96
9.1.1.1.4;10.22.1.1.1.1.4 With Formation of 1—2 and 1—7a Bonds;97
9.1.1.1.4.1;10.22.1.1.1.1.4.1 Method 1: From a 2-Chloro-3-(2-chloroethyl)pyridine and an Amine;97
9.1.1.1.4.1.1;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
9.1.1.1.4.2;10.22.1.1.1.1.4.2 Method 2: From a 2-Bromo-3-(2-bromoalkenyl)pyridine and an Amine;101
9.1.1.1.4.3;10.22.1.1.1.1.4.3 Method 3: From a 2-Alkynyl-3-bromopyridine and a Carbamate;103
9.1.1.2;10.22.1.1.1.2 By Formation of One N—C Bond;103
9.1.1.2.1;10.22.1.1.1.2.1 With Formation of the 1—2 Bond;103
9.1.1.2.1.1;10.22.1.1.1.2.1.1 Method 1: From (3-Nitropyridin-2-yl)pyruvates (Reissert Synthesis);103
9.1.1.2.1.2;10.22.1.1.1.2.1.2 Method 2: From a Halopyridinamine and an Enolate;111
9.1.1.2.1.3;10.22.1.1.1.2.1.3 Method 3: From Alkynylpyridinamines;114
9.1.1.2.1.3.1;10.22.1.1.1.2.1.3.1 Variation 1: Base-Mediated Cyclization;114
9.1.1.2.1.3.2;10.22.1.1.1.2.1.3.2 Variation 2: Using Microwave Activation;125
9.1.1.2.1.3.3;10.22.1.1.1.2.1.3.3 Variation 3: Copper(I) Iodide Mediated Cyclization;128
9.1.1.2.1.3.4;10.22.1.1.1.2.1.3.4 Variation 4: Copper(II) Acetate Mediated Cyclization;133
9.1.1.2.1.3.5;10.22.1.1.1.2.1.3.5 Variation 5: Indium(III) Bromide Mediated Cyclization;133
9.1.1.2.1.3.6;10.22.1.1.1.2.1.3.6 Variation 6: Gold(III) Chloride Mediated Cyclization;134
9.1.1.2.1.3.7;10.22.1.1.1.2.1.3.7 Variation 7: Acid-Mediated Cyclization;135
9.1.1.2.1.3.8;10.22.1.1.1.2.1.3.8 Variation 8: Palladium(0)-Mediated Cyclization with Concomitant Introduction of a 3-Aryl Substituent;135
9.1.1.2.1.3.9;10.22.1.1.1.2.1.3.9 Variation 9: Iodine-Mediated Cyclization with Concomitant Introduction of a 3-Iodo Substituent;137
9.1.1.2.1.3.10;10.22.1.1.1.2.1.3.10 Variation 10: Copper(I)-Mediated Cyclization with Concomitant Introduction of a 2-Dialkylamino Substituent;137
9.1.1.2.1.4;10.22.1.1.1.2.1.4 Method 4: From Allenylpyridinamines;139
9.1.1.2.1.5;10.22.1.1.1.2.1.5 Method 5: From Nitropyridyl Enamines (Leimgruber–Batcho Synthesis);140
9.1.1.2.1.6;10.22.1.1.1.2.1.6 Method 6: From 2-(2-Nitropyridyl)enol Ethers;147
9.1.1.2.1.7;10.22.1.1.1.2.1.7 Method 7: From Nitro(vinyl)pyridines;150
9.1.1.2.1.8;10.22.1.1.1.2.1.8 Method 8: From Nitro(2-nitrovinyl)pyridines;154
9.1.1.2.1.9;10.22.1.1.1.2.1.9 Method 9: From Alkenylnitropyridines or Alkenylazidopyridine N-Oxides via Nitrenes;156
9.1.1.2.1.10;10.22.1.1.1.2.1.10 Method 10: From 2-(Arylamino)-3-(1-hydroxyalkyl)pyridines or 2-(Arylamino)- 3-alkenylpyridines;157
9.1.1.2.1.11;10.22.1.1.1.2.1.11 Method 11: From (2,2-Dihalovinyl)pyridinamines;158
9.1.1.2.1.12;10.22.1.1.1.2.1.12 Method 12: From N-(Styrylpyridyl)hydroxylamines;162
9.1.1.2.1.13;10.22.1.1.1.2.1.13 Method 13: From a 2-(Nitropyridyl)acetonitrile;163
9.1.1.2.1.14;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
9.1.1.2.2;10.22.1.1.1.2.2 With Formation of the 1—7a Bond;170
9.1.1.2.2.1;10.22.1.1.1.2.2.1 Method 1: From a (2-Aminoethyl)halopyridine;170
9.1.1.2.2.2;10.22.1.1.1.2.2.2 Method 2: From a Pyridylacetic Acid Hydrazide;171
9.1.1.2.2.3;10.22.1.1.1.2.2.3 Method 3: From a 2-Azido-3-pyridylacrylate (Hemetsberger–Knittel Synthesis);171
9.1.1.2.2.4;10.22.1.1.1.2.2.4 Method 4: From a 2-Amino-3-(3-bromopyridin-4-yl)acrylate;177
9.1.1.3;10.22.1.1.1.3 By Formation of One C—C Bond;177
9.1.1.3.1;10.22.1.1.1.3.1 With Formation of the 2—3 Bond;177
9.1.1.3.1.1;10.22.1.1.1.3.1.1 Method 1: From an Acylaminopyridyl Ketone (Fürstner Synthesis);177
9.1.1.3.1.2;10.22.1.1.1.3.1.2 Method 2: From an Acylamino(methyl)pyridine (Madelung Synthesis);178
9.1.1.3.1.2.1;10.22.1.1.1.3.1.2.1 Variation 1: From a 2-[3-(Acylamino)pyridin-2-yl]acetonitrile;182
9.1.1.3.2;10.22.1.1.1.3.2 With Formation of the 3—3a Bond;183
9.1.1.3.2.1;10.22.1.1.1.3.2.1 Method 1: From a 2-(Pyridin-2-ylamino)ethyl Ethylxanthate;183
9.1.1.3.2.2;10.22.1.1.1.3.2.2 Method 2: From an N-Allyl-3-halopyridin-2-amine;184
9.1.1.3.2.3;10.22.1.1.1.3.2.3 Method 3: From an N-(2-Halopyridin-3-yl)cycloalkanimine;185
9.1.1.3.2.4;10.22.1.1.1.3.2.4 Method 4: From an N-Alkynylhalopyridinamine;186
9.1.2;10.22.1.1.2 By Annulation to a Pyrrole;188
9.1.2.1;10.22.1.1.2.1 By Formation of One N—C Bond and Two C—C Bonds;188
9.1.2.1.1;10.22.1.1.2.1.1 With Formation of 3a—4, 5—6, and 6—7 Bonds;188
9.1.2.1.1.1;10.22.1.1.2.1.1.1 Method 1: From a Pyrrol-2-amine, a Ketone, and an Aldehyde;188
9.1.2.2;10.22.1.1.2.2 By Formation of One N—C Bond and One C—C Bond;189
9.1.2.2.1;10.22.1.1.2.2.1 With Formation of the 3a—4 and 4—5 Bonds;189
9.1.2.2.1.1;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
9.1.2.2.2;10.22.1.1.2.2.2 With Formation of 3a—4 and 6—7 Bonds;191
9.1.2.2.2.1;10.22.1.1.2.2.2.1 Method 1: From a Pyrrol-2-amine and a 1,3-Diketone;191
9.1.2.2.3;10.22.1.1.2.2.3 With Formation of 3a—4 and 7—7a Bonds;195
9.1.2.2.3.1;10.22.1.1.2.2.3.1 Method 1: From a 2,2-Dimethoxypyrrolidine and an Enaminone;195
9.1.2.3;10.22.1.1.2.3 By Formation of One N—C Bond;196
9.1.2.3.1;10.22.1.1.2.3.1 With Formation of the 1—7a Bond;196
9.1.2.3.1.1;10.22.1.1.2.3.1.1 Method 1: From Nicotine;196
9.1.2.3.2;10.22.1.1.2.3.2 With Formation of the 4—5 Bond;196
9.1.2.3.2.1;10.22.1.1.2.3.2.1 Method 1: From Ethyl 2-(2-Amino-1-hydroxyethyl)-1H-pyrrole-3-carboxylates;196
9.1.2.3.2.2;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
9.1.2.3.2.3;10.22.1.1.2.3.2.3 Method 3: From 3-(Ethoxycarbonyl)pyrrole-2-acetamide;198
9.1.2.3.3;10.22.1.1.2.3.3 With Formation of the 5—6 Bond;199
9.1.2.3.3.1;10.22.1.1.2.3.3.1 Method 1: From 3-Alkynyl-2-(azidomethyl)pyrroles;199
9.1.2.4;10.22.1.1.2.4 By Formation of One C—C Bond;201
9.1.2.4.1;10.22.1.1.2.4.1 With Formation of the 3a—4 Bond;201
9.1.2.4.1.1;10.22.1.1.2.4.1.1 Method 1: From a Pyrrole with a C2N-Chain at C2;201
9.1.2.4.1.2;10.22.1.1.2.4.1.2 Method 2: From a Pyrrole with a 2,2-Diethoxyethylimino Chain at C2;202
9.1.2.4.1.3;10.22.1.1.2.4.1.3 Method 3: From a Pyrrole with a 2-(Azidocarbonyl)vinyl Chain at C2;203
9.1.2.4.1.4;10.22.1.1.2.4.1.4 Method 4: From 2-Cyano-2-(pyrrolidin-2-ylidene)acetamide and Dimethylformamide Dimethyl Acetal;205
9.1.2.4.2;10.22.1.1.2.4.2 With Formation of the 4—5 Bond;206
9.1.2.4.2.1;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
9.1.2.4.2.2;10.22.1.1.2.4.2.2 Method 2: From a 2-Amino-1H-pyrrole-3-carbonitrile and a 3-Oxo Ester;207
9.1.2.4.3;10.22.1.1.2.4.3 With Formation of the 7—7a Bond;208
9.1.2.4.3.1;10.22.1.1.2.4.3.1 Method 1: From a 3-(1H-Pyrrol-3-yl)acryloyl Azide;208
9.1.2.4.3.2;10.22.1.1.2.4.3.2 Method 2: From N-Pyrrol-3-yl Enamines;209
9.1.2.4.3.3;10.22.1.1.2.4.3.3 Method 3: From 1-(Pyrrol-3-yl)-1-azaenynes;210
9.1.3;10.22.1.1.3 Without Annulation to an Existing Ring;211
9.1.3.1;10.22.1.1.3.1 By Formation of Two N—C and Three C—C Bonds;211
9.1.3.1.1;10.22.1.1.3.1.1 With Formation of the 2—3, 3a—4, 5—6, 7—7a, and 1—7a Bonds;211
9.1.3.1.1.1;10.22.1.1.3.1.1.1 Method 1: From a Dialkynylsilane, an Isocyanide, and a Nitrile;211
9.1.3.2;10.22.1.1.3.2 By Formation of One N—C Bond and Two C—C Bonds;215
9.1.3.2.1;10.22.1.1.3.2.1 With Formation of the 3—3a, 4—5, and 7—7a Bonds;215
9.1.3.2.1.1;10.22.1.1.3.2.1.1 Method 1: From Ethyl Acrylate and a 3-[(Cyanomethyl)amino]acrylate;215
9.2;10.22.1.2 Synthesis by Ring Transformation;216
9.2.1;10.22.1.2.1 Ring Expansion;216
9.2.1.1;10.22.1.2.1.1 Method 1: From a 3-Azabicyclo[4.1.0]heptane and a Nitrile;216
9.2.2;10.22.1.2.2 Formal Exchange of Ring Members with Retention of the Ring Size;219
9.2.2.1;10.22.1.2.2.1 Method 1: From a 2,3-Dihydro-5-azabenzo[b]furan;219
9.2.2.2;10.22.1.2.2.2 Method 2: From 1,2,4-Triazines and an Alkyne;219
9.2.2.3;10.22.1.2.2.3 Method 3: From Pyrazolo[1,5-a]pyridines;221
9.2.3;10.22.1.2.3 Ring Contraction;223
9.2.3.1;10.22.1.2.3.1 Method 1: From a Naphthyridine Diazonium Salt;223
9.2.3.2;10.22.1.2.3.2 Method 2: From 3H-Azepines;224
9.3;10.22.1.3 Aromatization;225
9.3.1;10.22.1.3.1 Method 1: From 2,3-Dihydroazaindoles (Azaindolines);225
9.3.2;10.22.1.3.2 Method 2: From Di- and Tetrahydropyridine Ring Azaindoles;227
9.4;10.22.1.4 Synthesis by Substituent Modification;228
9.4.1;10.22.1.4.1 Substitution of Existing Substituents;228
9.4.1.1;10.22.1.4.1.1 Pyridine Ring Substituents;228
9.4.1.1.1;10.22.1.4.1.1.1 Substitution of C-Hydrogen;228
9.4.1.1.1.1;10.22.1.4.1.1.1.1 Method 1: Introduction of C-Halogen to an Azaindole N-Oxide;228
9.4.1.1.1.2;10.22.1.4.1.1.1.2 Method 2: Introduction of C-Halogen via a C-Metalated Azaindole;235
9.4.1.1.1.3;10.22.1.4.1.1.1.3 Method 3: Introduction of C-Halogen to an Activated Azaindole;240
9.4.1.1.1.4;10.22.1.4.1.1.1.4 Method 4: Introduction of C-Sulfur;241
9.4.1.1.1.5;10.22.1.4.1.1.1.5 Method 5: Introduction of C-Oxygen to an Azaindole N-Oxide;242
9.4.1.1.1.6;10.22.1.4.1.1.1.6 Method 6: Introduction of C-Oxygen via a C-Metalated Azaindole;243
9.4.1.1.1.7;10.22.1.4.1.1.1.7 Method 7: Introduction of C-Nitrogen by Amination of an Azaindole N-Oxide;244
9.4.1.1.1.8;10.22.1.4.1.1.1.8 Method 8: Introduction of C-Nitrogen by Nitration of an Azaindole N-Oxide;249
9.4.1.1.1.9;10.22.1.4.1.1.1.9 Method 9: Introduction of C- Nitrogen via a C-Metalated Azaindole;251
9.4.1.1.1.10;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
9.4.1.1.1.11;10.22.1.4.1.1.1.11 Method 11: Introduction of C-Carbon to an Azaindole N-Oxide;253
9.4.1.1.1.12;10.22.1.4.1.1.1.12 Method 12: Introduction of C-Carbon via a C-Metalated Azaindole;255
9.4.1.1.1.13;10.22.1.4.1.1.1.13 Method 13: Introduction of C-Boron to a Metalated Azaindole;257
9.4.1.1.2;10.22.1.4.1.1.2 Substitution of C-Halogen;259
9.4.1.1.2.1;10.22.1.4.1.1.2.1 Method 1: Introduction of C-Hydrogen;259
9.4.1.1.2.2;10.22.1.4.1.1.2.2 Method 2: Introduction of C-Halogen;260
9.4.1.1.2.3;10.22.1.4.1.1.2.3 Method 3: Introduction of C-Sulfur by Nucleophilic Substitution;261
9.4.1.1.2.4;10.22.1.4.1.1.2.4 Method 4: Introduction of C-Sulfur by Lithium–Bromine Exchange;262
9.4.1.1.2.5;10.22.1.4.1.1.2.5 Method 5: Introduction of C-Oxygen;262
9.4.1.1.2.6;10.22.1.4.1.1.2.6 Method 6: Introduction of C-Nitrogen by Direct Reaction with Amines;265
9.4.1.1.2.7;10.22.1.4.1.1.2.7 Method 7: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amines;269
9.4.1.1.2.8;10.22.1.4.1.1.2.8 Method 8: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amides;281
9.4.1.1.2.9;10.22.1.4.1.1.2.9 Method 9: Introduction of a Cyano Group;283
9.4.1.1.2.10;10.22.1.4.1.1.2.10 Method 10: Introduction of Aryl, Carboxy, Acyl, Alkynyl, Alkenyl, or Alkyl Groups;285
9.4.1.1.2.11;10.22.1.4.1.1.2.11 Method 11: Introduction of C-Boron to Metalated Azaindoles;304
9.4.1.1.2.12;10.22.1.4.1.1.2.12 Method 12: Introduction of C-Boron via Palladium(0) Catalysis;305
9.4.1.1.3;10.22.1.4.1.1.3 Substitution of C-Sulfur;307
9.4.1.1.3.1;10.22.1.4.1.1.3.1 Method 1: Introduction of C-Halogen;307
9.4.1.1.4;10.22.1.4.1.1.4 Substitution of C-Nitrogen;308
9.4.1.1.4.1;10.22.1.4.1.1.4.1 Method 1: Introduction of C-Oxygen;308
9.4.1.1.4.2;10.22.1.4.1.1.4.2 Method 2: Reduction of a Nitro Group;309
9.4.1.1.5;10.22.1.4.1.1.5 Substitution of C-Boron;310
9.4.1.1.5.1;10.22.1.4.1.1.5.1 Method 1: Introduction of C-Carbon;310
9.4.1.1.6;10.22.1.4.1.1.6 Modification of C-Carbon;311
9.4.1.1.6.1;10.22.1.4.1.1.6.1 Method 1: Giving C-Carbon;311
9.4.1.2;10.22.1.4.1.2 Pyrrole Ring Substituents;313
9.4.1.2.1;10.22.1.4.1.2.1 Substitution of C-Hydrogen at C3;313
9.4.1.2.1.1;10.22.1.4.1.2.1.1 Method 1: Introduction of Bromine;313
9.4.1.2.1.2;10.22.1.4.1.2.1.2 Method 2: Introduction of Chlorine;319
9.4.1.2.1.3;10.22.1.4.1.2.1.3 Method 3: Introduction of Iodine;320
9.4.1.2.1.4;10.22.1.4.1.2.1.4 Method 4: Giving C-Sulfur;324
9.4.1.2.1.5;10.22.1.4.1.2.1.5 Method 5: Giving C-Nitrogen;328
9.4.1.2.1.6;10.22.1.4.1.2.1.6 Method 6: Introduction of Ester or Amide Groups;330
9.4.1.2.1.7;10.22.1.4.1.2.1.7 Method 7: Introduction of a Formyl Group;332
9.4.1.2.1.8;10.22.1.4.1.2.1.8 Method 8: Introduction of Acyl Groups;338
9.4.1.2.1.9;10.22.1.4.1.2.1.9 Method 9: Introduction of an Oxyalkyl Group;348
9.4.1.2.1.10;10.22.1.4.1.2.1.10 Method 10: Introduction of an Aminoalkyl Group;355
9.4.1.2.1.11;10.22.1.4.1.2.1.11 Method 11: Introduction of a Sulfanylalkyl Group;361
9.4.1.2.1.12;10.22.1.4.1.2.1.12 Method 12: Introduction of Alkenyl Groups;361
9.4.1.2.1.13;10.22.1.4.1.2.1.13 Method 13: Introduction of Hetaryl Groups;364
9.4.1.2.1.14;10.22.1.4.1.2.1.14 Method 14: Introduction of Alkyl Groups;364
9.4.1.2.1.15;10.22.1.4.1.2.1.15 Method 15: Introduction of C-Boron;370
9.4.1.2.2;10.22.1.4.1.2.2 Substitution of C-Hydrogen at C2;372
9.4.1.2.2.1;10.22.1.4.1.2.2.1 Method 1: Introduction of C-Halogen;372
9.4.1.2.2.2;10.22.1.4.1.2.2.2 Method 2: Introduction of C-Carbon by Intermolecular Metal-Catalyzed Direct Substitution;374
9.4.1.2.2.3;10.22.1.4.1.2.2.3 Method 3: Introduction of C-Carbon by Palladium-Catalyzed Cyclization of 1-Substituted Azaindoles;378
9.4.1.2.2.4;10.22.1.4.1.2.2.4 Method 4: Introduction of C-Carbon by Radical Cyclization of 1-Substituted Azaindoles;382
9.4.1.2.2.5;10.22.1.4.1.2.2.5 Method 5: Introduction of C-Carbon by Acid-Mediated Cyclization of 1-Substituted Azaindoles;383
9.4.1.2.2.6;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
9.4.1.2.2.7;10.22.1.4.1.2.2.7 Method 7: Introduction of C-Carbon Using 2-Metalated Azaindoles;384
9.4.1.2.2.8;10.22.1.4.1.2.2.8 Method 8: Introduction of C-Boron and C-Tin;400
9.4.1.2.3;10.22.1.4.1.2.3 Substitution of C-Halogen at C3;403
9.4.1.2.3.1;10.22.1.4.1.2.3.1 Method 1: Introduction of C-Sulfur;403
9.4.1.2.3.2;10.22.1.4.1.2.3.2 Method 2: Introduction of Acid, Ester, or Amide Groups;403
9.4.1.2.3.3;10.22.1.4.1.2.3.3 Method 3: Introduction of a Cyano Group;407
9.4.1.2.3.4;10.22.1.4.1.2.3.4 Method 4: Introduction of Formyl or Acyl Groups;407
9.4.1.2.3.5;10.22.1.4.1.2.3.5 Method 5: Introduction of Hydroxyalkyl, Aminoalkyl, or Alkyl Groups;409
9.4.1.2.3.6;10.22.1.4.1.2.3.6 Method 6: Introduction of Alkenyl or Alkynyl Groups;412
9.4.1.2.3.7;10.22.1.4.1.2.3.7 Method 7: Introduction of Aryl or Hetaryl Groups;413
9.4.1.2.3.8;10.22.1.4.1.2.3.8 Method 8: Introduction of C-Boron;417
9.4.1.2.3.9;10.22.1.4.1.2.3.9 Method 9: Introduction of C-Tin;418
9.4.1.2.4;10.22.1.4.1.2.4 Substitution of C-Halogen at C2;421
9.4.1.2.4.1;10.22.1.4.1.2.4.1 Method 1: Introduction of C-Carbon;421
9.4.1.2.5;10.22.1.4.1.2.5 Substitution of C-Silicon at C2;429
9.4.1.2.5.1;10.22.1.4.1.2.5.1 Method 1: Introduction of C-Halogen;429
9.4.1.2.6;10.22.1.4.1.2.6 Substitution of C-Tin at C3;430
9.4.1.2.6.1;10.22.1.4.1.2.6.1 Method 1: Introduction of C-Carbon;430
9.4.1.2.7;10.22.1.4.1.2.7 Substitution of C-Tin at C2;432
9.4.1.2.7.1;10.22.1.4.1.2.7.1 Method 1: Introduction of C-Carbon;432
9.4.1.2.8;10.22.1.4.1.2.8 Substitution of C-Boron at C3;433
9.4.1.2.8.1;10.22.1.4.1.2.8.1 Method 1: Introduction of C-Carbon;433
9.4.1.2.9;10.22.1.4.1.2.9 Substitution/Modification of C-Carbon at C3;436
9.4.1.2.9.1;10.22.1.4.1.2.9.1 Method 1: Introduction of C-Carbonyl, C-Alkyl, and C-Vinyl Derivatives;436
9.4.1.2.10;10.22.1.4.1.2.10 Substitution/Modification of C-Carbon at C2;455
9.4.1.2.10.1;10.22.1.4.1.2.10.1 Method 1: Giving C-Halogen, C-Carbon, or C-Nitrogen;455
9.4.1.2.11;10.22.1.4.1.2.11 Substitution/Modification at N1;462
9.4.1.2.11.1;10.22.1.4.1.2.11.1 Method 1: Introduction of N-Nitrogen;462
9.4.1.2.11.2;10.22.1.4.1.2.11.2 Method 2: Introduction of N-Sulfur;463
9.4.1.2.11.3;10.22.1.4.1.2.11.3 Method 3: Introduction of Acid, Ester, or Amide Groups;467
9.4.1.2.11.4;10.22.1.4.1.2.11.4 Method 4: Introduction of Acyl Groups;473
9.4.1.2.11.5;10.22.1.4.1.2.11.5 Method 5: Introduction of Oxyalkyl or Aminoalkyl Groups;474
9.4.1.2.11.6;10.22.1.4.1.2.11.6 Method 6: Introduction of Alkenyl Groups;477
9.4.1.2.11.7;10.22.1.4.1.2.11.7 Method 7: Introduction of Alkyl Groups via Michael-Type Addition;479
9.4.1.2.11.8;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
9.4.1.2.11.9;10.22.1.4.1.2.11.9 Method 9: Introduction of Alkyl Groups by Reaction with Dimethylformamide Dimethyl Acetal;488
9.4.1.2.11.10;10.22.1.4.1.2.11.10 Method 10: Introduction of Alkyl Groups by Reaction with an Allylic Carbonate;489
9.4.1.2.11.11;10.22.1.4.1.2.11.11 Method 11: Introduction of Alkyl Groups by Reaction with an Oxirane, Aziridine, or Azirine;490
9.4.1.2.11.12;10.22.1.4.1.2.11.12 Method 12: Introduction of Aryl or Hetaryl Groups;492
9.4.1.2.11.13;10.22.1.4.1.2.11.13 Method 13: Introduction of N-Silicon;498
9.4.1.2.11.14;10.22.1.4.1.2.11.14 Method 14: N-Deprotection at N1;499
9.4.1.2.11.15;10.22.1.4.1.2.11.15 Method 15: Modification of N-Carbon at N1;502
9.4.2;10.22.1.4.2 Addition Reactions;503
9.4.2.1;10.22.1.4.2.1 Addition of Organic Groups;503
9.4.2.1.1;10.22.1.4.2.1.1 Method 1: Alkylation of the Pyridine Nitrogen Atom: Formation of Pyridinium Salt;503
9.4.2.1.2;10.22.1.4.2.1.2 Method 2: Bis-acylation of the Two Nitrogen Atoms of 1H-Pyrrolo[2,3-b]pyridine;505
10;Author Index;527
11;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: 1-pyrrolo[3,2-]pyridine (1, 4-azaindole), 1-pyrrolo[3,2-]pyridine (2, 5-azaindole), 1-pyrrolo[2,3-]pyridine (3, 6-azaindole), and 1-pyrrolo[2,3-]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-1-pyrrolo[2,3-]pyridine (5) by Perkin and Robinson.[2,3] In 1943, 1-pyrrolo[2,3-]pyridine (4) was isolated from coal tar by Kruber.[4] Simple azaindole structures do not occur in nature but polycyclic 1-pyrrolo[2,3-]pyridine derivatives 6–9 named variolins were isolated in 1994 from the Antarctic sponge (? 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 p-electron semiempirical method showed that the nitrogen of the pyrrole ring is a p-donor and a s-acceptor whereas the nitrogen of the pyridine ring is a s- and p-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 1-pyrrolo[2,3-]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: 1-pyrrolo[3,2-]pyridine (2)>1-pyrrolo[2,3-]pyridine (3)>1-pyrrolo[3,2-]pyridine (1)>1-pyrrolo[2,3-]pyridine (4).
Regarding the values of dipole moments, 1-pyrrolo[3,2-]pyridine (2) is the most polar and 1-pyrrolo[2,3-]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 (2 and 3) indicate that C3 is a nucleophilic center (as in indole, ? Table 2). In addition it seems that 1-pyrrolo[3,2-]pyridine (2) is the most reactive and 1-pyrrolo[3,2-]pyridine (1) is the least reactive. The authors established a correlation between the calculated physicochemical parameters and the Hammett substituent and inductive constants.
Table 2 Ionization Energies, Dipole Moments, and Atom Charges of Azaindoles[25]
| Compound | (eV) | µ (D) | –3 | –2 | 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] |
| 1-indole | 8.4 | 1.89 | 0.200 | 0.081 | [25] |
1-Pyrrolo[2,3-]pyridine (4) can exist in a second tautomeric form, 7-pyrrolo[2,3-]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 1-Pyrrolo[2,3-]pyridine and 7-Pyrrolo[2,3-]pyridine[25]
In 10% deuterated sulfuric acid (D2SO4), a slow hydrogen exchange occurs only at C3 for 1-pyrrolo[3,2-]pyridine (1) and 1-pyrrolo[3,2-]pyridine (2). At 150 °C in 27.5% deuterated sulfuric acid, the same C3 exchange is observed with 4-methyl-1-pyrrolo[2,3-]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 pa values for...
