Science of Synthesis Knowledge Updates: 2016/3

 
Thieme (Verlag)
  • 1. Auflage
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  • erschienen am 26. Oktober 2016
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  • 560 Seiten
 
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978-3-13-220931-2 (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. Several annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.
  • Englisch
  • 5,98 MB
978-3-13-220931-2 (9783132209312)
3132209317 (3132209317)
weitere Ausgaben werden ermittelt
1 - Science of Synthesis Knowledge Updates 2016/3 [Seite 1]
2 - Title Page [Seite 6]
3 - Copyright [Seite 8]
4 - Preface [Seite 9]
5 - Abstract [Seite 11]
6 - Science of Synthesis Knowledge Updates 2016/3 [Seite 13]
7 - Table of Contents [Seite 15]
8 - 10.22 Product Class 22: Azaindoles and Their Derivatives [Seite 23]
9 - 10.22.1 Product Subclass 1: Azaindoles [Seite 23]
9.1 - 10.22.1.1 Synthesis by Ring-Closure Reactions [Seite 34]
9.1.1 - 10.22.1.1.1 By Annulation to a Pyridine [Seite 34]
9.1.1.1 - 10.22.1.1.1.1 By Formation of One N-C and One C-C Bond [Seite 34]
9.1.1.1.1 - 10.22.1.1.1.1.1 With Formation of 1-2 and 3-3a Bonds [Seite 34]
9.1.1.1.1.1 - 10.22.1.1.1.1.1.1 Method 1: From Pyridylhydrazones (Fischer Synthesis) [Seite 34]
9.1.1.1.1.1.1 - 10.22.1.1.1.1.1.1.1 Variation 1: Indolization with Pyridinium Hydrochloride [Seite 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 [Seite 40]
9.1.1.1.1.1.3 - 10.22.1.1.1.1.1.1.3 Variation 3: Using Microwave Activation [Seite 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 [Seite 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 [Seite 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) [Seite 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 [Seite 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 [Seite 49]
9.1.1.1.1.2 - 10.22.1.1.1.1.1.2 Method 2: From ortho-Substituted Nitropyridines (Bartoli Synthesis) [Seite 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) [Seite 57]
9.1.1.1.1.4 - 10.22.1.1.1.1.1.4 Method 4: From Pyridinamines and ?-Hydroxy Ketones (Bischler Synthesis) [Seite 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) [Seite 62]
9.1.1.1.1.6 - 10.22.1.1.1.1.1.6 Method 6: From Enamines of Pyridyl Ketones/Aldehydes [Seite 74]
9.1.1.1.1.7 - 10.22.1.1.1.1.1.7 Method 7: From Iodopyridinamines and Allyl Acetate [Seite 78]
9.1.1.1.1.8 - 10.22.1.1.1.1.1.8 Method 8: From Nitropyridines and Alkynes [Seite 80]
9.1.1.1.2 - 10.22.1.1.1.1.2 With Formation of 1-2 and 2-3 Bonds [Seite 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 [Seite 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 [Seite 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 [Seite 90]
9.1.1.1.2.3 - 10.22.1.1.1.1.2.3 Method 3: From a Methylpyridinamine and the Vilsmeier Reagent [Seite 91]
9.1.1.1.3 - 10.22.1.1.1.1.3 With Formation of 1-7a and 2-3 Bonds [Seite 92]
9.1.1.1.3.1 - 10.22.1.1.1.1.3.1 Method 1: From an Alkylpyridine and a Nitrile [Seite 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 [Seite 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 [Seite 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 [Seite 96]
9.1.1.1.4 - 10.22.1.1.1.1.4 With Formation of 1-2 and 1-7a Bonds [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 103]
9.1.1.2 - 10.22.1.1.1.2 By Formation of One N-C Bond [Seite 103]
9.1.1.2.1 - 10.22.1.1.1.2.1 With Formation of the 1-2 Bond [Seite 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) [Seite 103]
9.1.1.2.1.2 - 10.22.1.1.1.2.1.2 Method 2: From a Halopyridinamine and an Enolate [Seite 111]
9.1.1.2.1.3 - 10.22.1.1.1.2.1.3 Method 3: From Alkynylpyridinamines [Seite 114]
9.1.1.2.1.3.1 - 10.22.1.1.1.2.1.3.1 Variation 1: Base-Mediated Cyclization [Seite 114]
9.1.1.2.1.3.2 - 10.22.1.1.1.2.1.3.2 Variation 2: Using Microwave Activation [Seite 125]
9.1.1.2.1.3.3 - 10.22.1.1.1.2.1.3.3 Variation 3: Copper(I) Iodide Mediated Cyclization [Seite 128]
9.1.1.2.1.3.4 - 10.22.1.1.1.2.1.3.4 Variation 4: Copper(II) Acetate Mediated Cyclization [Seite 133]
9.1.1.2.1.3.5 - 10.22.1.1.1.2.1.3.5 Variation 5: Indium(III) Bromide Mediated Cyclization [Seite 133]
9.1.1.2.1.3.6 - 10.22.1.1.1.2.1.3.6 Variation 6: Gold(III) Chloride Mediated Cyclization [Seite 134]
9.1.1.2.1.3.7 - 10.22.1.1.1.2.1.3.7 Variation 7: Acid-Mediated Cyclization [Seite 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 [Seite 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 [Seite 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 [Seite 137]
9.1.1.2.1.4 - 10.22.1.1.1.2.1.4 Method 4: From Allenylpyridinamines [Seite 139]
9.1.1.2.1.5 - 10.22.1.1.1.2.1.5 Method 5: From Nitropyridyl Enamines (Leimgruber-Batcho Synthesis) [Seite 140]
9.1.1.2.1.6 - 10.22.1.1.1.2.1.6 Method 6: From 2-(2-Nitropyridyl)enol Ethers [Seite 147]
9.1.1.2.1.7 - 10.22.1.1.1.2.1.7 Method 7: From Nitro(vinyl)pyridines [Seite 150]
9.1.1.2.1.8 - 10.22.1.1.1.2.1.8 Method 8: From Nitro(2-nitrovinyl)pyridines [Seite 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 [Seite 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 [Seite 157]
9.1.1.2.1.11 - 10.22.1.1.1.2.1.11 Method 11: From (2,2-Dihalovinyl)pyridinamines [Seite 158]
9.1.1.2.1.12 - 10.22.1.1.1.2.1.12 Method 12: From N-(Styrylpyridyl)hydroxylamines [Seite 162]
9.1.1.2.1.13 - 10.22.1.1.1.2.1.13 Method 13: From a 2-(Nitropyridyl)acetonitrile [Seite 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 [Seite 168]
9.1.1.2.2 - 10.22.1.1.1.2.2 With Formation of the 1-7a Bond [Seite 170]
9.1.1.2.2.1 - 10.22.1.1.1.2.2.1 Method 1: From a (2-Aminoethyl)halopyridine [Seite 170]
9.1.1.2.2.2 - 10.22.1.1.1.2.2.2 Method 2: From a Pyridylacetic Acid Hydrazide [Seite 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) [Seite 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 [Seite 177]
9.1.1.3 - 10.22.1.1.1.3 By Formation of One C-C Bond [Seite 177]
9.1.1.3.1 - 10.22.1.1.1.3.1 With Formation of the 2-3 Bond [Seite 177]
9.1.1.3.1.1 - 10.22.1.1.1.3.1.1 Method 1: From an Acylaminopyridyl Ketone (Fürstner Synthesis) [Seite 177]
9.1.1.3.1.2 - 10.22.1.1.1.3.1.2 Method 2: From an Acylamino(methyl)pyridine (Madelung Synthesis) [Seite 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 [Seite 182]
9.1.1.3.2 - 10.22.1.1.1.3.2 With Formation of the 3-3a Bond [Seite 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 [Seite 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 [Seite 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 [Seite 185]
9.1.1.3.2.4 - 10.22.1.1.1.3.2.4 Method 4: From an N-Alkynylhalopyridinamine [Seite 186]
9.1.2 - 10.22.1.1.2 By Annulation to a Pyrrole [Seite 188]
9.1.2.1 - 10.22.1.1.2.1 By Formation of One N-C Bond and Two C-C Bonds [Seite 188]
9.1.2.1.1 - 10.22.1.1.2.1.1 With Formation of 3a-4, 5-6, and 6-7 Bonds [Seite 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 [Seite 188]
9.1.2.2 - 10.22.1.1.2.2 By Formation of One N-C Bond and One C-C Bond [Seite 189]
9.1.2.2.1 - 10.22.1.1.2.2.1 With Formation of the 3a-4 and 4-5 Bonds [Seite 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 [Seite 189]
9.1.2.2.2 - 10.22.1.1.2.2.2 With Formation of 3a-4 and 6-7 Bonds [Seite 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 [Seite 191]
9.1.2.2.3 - 10.22.1.1.2.2.3 With Formation of 3a-4 and 7-7a Bonds [Seite 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 [Seite 195]
9.1.2.3 - 10.22.1.1.2.3 By Formation of One N-C Bond [Seite 196]
9.1.2.3.1 - 10.22.1.1.2.3.1 With Formation of the 1-7a Bond [Seite 196]
9.1.2.3.1.1 - 10.22.1.1.2.3.1.1 Method 1: From Nicotine [Seite 196]
9.1.2.3.2 - 10.22.1.1.2.3.2 With Formation of the 4-5 Bond [Seite 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 [Seite 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 [Seite 198]
9.1.2.3.2.3 - 10.22.1.1.2.3.2.3 Method 3: From 3-(Ethoxycarbonyl)pyrrole-2-acetamide [Seite 198]
9.1.2.3.3 - 10.22.1.1.2.3.3 With Formation of the 5-6 Bond [Seite 199]
9.1.2.3.3.1 - 10.22.1.1.2.3.3.1 Method 1: From 3-Alkynyl-2-(azidomethyl)pyrroles [Seite 199]
9.1.2.4 - 10.22.1.1.2.4 By Formation of One C-C Bond [Seite 201]
9.1.2.4.1 - 10.22.1.1.2.4.1 With Formation of the 3a-4 Bond [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 205]
9.1.2.4.2 - 10.22.1.1.2.4.2 With Formation of the 4-5 Bond [Seite 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 [Seite 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 [Seite 207]
9.1.2.4.3 - 10.22.1.1.2.4.3 With Formation of the 7-7a Bond [Seite 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 [Seite 208]
9.1.2.4.3.2 - 10.22.1.1.2.4.3.2 Method 2: From N-Pyrrol-3-yl Enamines [Seite 209]
9.1.2.4.3.3 - 10.22.1.1.2.4.3.3 Method 3: From 1-(Pyrrol-3-yl)-1-azaenynes [Seite 210]
9.1.3 - 10.22.1.1.3 Without Annulation to an Existing Ring [Seite 211]
9.1.3.1 - 10.22.1.1.3.1 By Formation of Two N-C and Three C-C Bonds [Seite 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 [Seite 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 [Seite 211]
9.1.3.2 - 10.22.1.1.3.2 By Formation of One N-C Bond and Two C-C Bonds [Seite 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 [Seite 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 [Seite 215]
9.2 - 10.22.1.2 Synthesis by Ring Transformation [Seite 216]
9.2.1 - 10.22.1.2.1 Ring Expansion [Seite 216]
9.2.1.1 - 10.22.1.2.1.1 Method 1: From a 3-Azabicyclo[4.1.0]heptane and a Nitrile [Seite 216]
9.2.2 - 10.22.1.2.2 Formal Exchange of Ring Members with Retention of the Ring Size [Seite 219]
9.2.2.1 - 10.22.1.2.2.1 Method 1: From a 2,3-Dihydro-5-azabenzo[b]furan [Seite 219]
9.2.2.2 - 10.22.1.2.2.2 Method 2: From 1,2,4-Triazines and an Alkyne [Seite 219]
9.2.2.3 - 10.22.1.2.2.3 Method 3: From Pyrazolo[1,5-a]pyridines [Seite 221]
9.2.3 - 10.22.1.2.3 Ring Contraction [Seite 223]
9.2.3.1 - 10.22.1.2.3.1 Method 1: From a Naphthyridine Diazonium Salt [Seite 223]
9.2.3.2 - 10.22.1.2.3.2 Method 2: From 3H-Azepines [Seite 224]
9.3 - 10.22.1.3 Aromatization [Seite 225]
9.3.1 - 10.22.1.3.1 Method 1: From 2,3-Dihydroazaindoles (Azaindolines) [Seite 225]
9.3.2 - 10.22.1.3.2 Method 2: From Di- and Tetrahydropyridine Ring Azaindoles [Seite 227]
9.4 - 10.22.1.4 Synthesis by Substituent Modification [Seite 228]
9.4.1 - 10.22.1.4.1 Substitution of Existing Substituents [Seite 228]
9.4.1.1 - 10.22.1.4.1.1 Pyridine Ring Substituents [Seite 228]
9.4.1.1.1 - 10.22.1.4.1.1.1 Substitution of C-Hydrogen [Seite 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 [Seite 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 [Seite 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 [Seite 240]
9.4.1.1.1.4 - 10.22.1.4.1.1.1.4 Method 4: Introduction of C-Sulfur [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 257]
9.4.1.1.2 - 10.22.1.4.1.1.2 Substitution of C-Halogen [Seite 259]
9.4.1.1.2.1 - 10.22.1.4.1.1.2.1 Method 1: Introduction of C-Hydrogen [Seite 259]
9.4.1.1.2.2 - 10.22.1.4.1.1.2.2 Method 2: Introduction of C-Halogen [Seite 260]
9.4.1.1.2.3 - 10.22.1.4.1.1.2.3 Method 3: Introduction of C-Sulfur by Nucleophilic Substitution [Seite 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 [Seite 262]
9.4.1.1.2.5 - 10.22.1.4.1.1.2.5 Method 5: Introduction of C-Oxygen [Seite 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 [Seite 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 [Seite 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 [Seite 281]
9.4.1.1.2.9 - 10.22.1.4.1.1.2.9 Method 9: Introduction of a Cyano Group [Seite 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 [Seite 285]
9.4.1.1.2.11 - 10.22.1.4.1.1.2.11 Method 11: Introduction of C-Boron to Metalated Azaindoles [Seite 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 [Seite 305]
9.4.1.1.3 - 10.22.1.4.1.1.3 Substitution of C-Sulfur [Seite 307]
9.4.1.1.3.1 - 10.22.1.4.1.1.3.1 Method 1: Introduction of C-Halogen [Seite 307]
9.4.1.1.4 - 10.22.1.4.1.1.4 Substitution of C-Nitrogen [Seite 308]
9.4.1.1.4.1 - 10.22.1.4.1.1.4.1 Method 1: Introduction of C-Oxygen [Seite 308]
9.4.1.1.4.2 - 10.22.1.4.1.1.4.2 Method 2: Reduction of a Nitro Group [Seite 309]
9.4.1.1.5 - 10.22.1.4.1.1.5 Substitution of C-Boron [Seite 310]
9.4.1.1.5.1 - 10.22.1.4.1.1.5.1 Method 1: Introduction of C-Carbon [Seite 310]
9.4.1.1.6 - 10.22.1.4.1.1.6 Modification of C-Carbon [Seite 311]
9.4.1.1.6.1 - 10.22.1.4.1.1.6.1 Method 1: Giving C-Carbon [Seite 311]
9.4.1.2 - 10.22.1.4.1.2 Pyrrole Ring Substituents [Seite 313]
9.4.1.2.1 - 10.22.1.4.1.2.1 Substitution of C-Hydrogen at C3 [Seite 313]
9.4.1.2.1.1 - 10.22.1.4.1.2.1.1 Method 1: Introduction of Bromine [Seite 313]
9.4.1.2.1.2 - 10.22.1.4.1.2.1.2 Method 2: Introduction of Chlorine [Seite 319]
9.4.1.2.1.3 - 10.22.1.4.1.2.1.3 Method 3: Introduction of Iodine [Seite 320]
9.4.1.2.1.4 - 10.22.1.4.1.2.1.4 Method 4: Giving C-Sulfur [Seite 324]
9.4.1.2.1.5 - 10.22.1.4.1.2.1.5 Method 5: Giving C-Nitrogen [Seite 328]
9.4.1.2.1.6 - 10.22.1.4.1.2.1.6 Method 6: Introduction of Ester or Amide Groups [Seite 330]
9.4.1.2.1.7 - 10.22.1.4.1.2.1.7 Method 7: Introduction of a Formyl Group [Seite 332]
9.4.1.2.1.8 - 10.22.1.4.1.2.1.8 Method 8: Introduction of Acyl Groups [Seite 338]
9.4.1.2.1.9 - 10.22.1.4.1.2.1.9 Method 9: Introduction of an Oxyalkyl Group [Seite 348]
9.4.1.2.1.10 - 10.22.1.4.1.2.1.10 Method 10: Introduction of an Aminoalkyl Group [Seite 355]
9.4.1.2.1.11 - 10.22.1.4.1.2.1.11 Method 11: Introduction of a Sulfanylalkyl Group [Seite 361]
9.4.1.2.1.12 - 10.22.1.4.1.2.1.12 Method 12: Introduction of Alkenyl Groups [Seite 361]
9.4.1.2.1.13 - 10.22.1.4.1.2.1.13 Method 13: Introduction of Hetaryl Groups [Seite 364]
9.4.1.2.1.14 - 10.22.1.4.1.2.1.14 Method 14: Introduction of Alkyl Groups [Seite 364]
9.4.1.2.1.15 - 10.22.1.4.1.2.1.15 Method 15: Introduction of C-Boron [Seite 370]
9.4.1.2.2 - 10.22.1.4.1.2.2 Substitution of C-Hydrogen at C2 [Seite 372]
9.4.1.2.2.1 - 10.22.1.4.1.2.2.1 Method 1: Introduction of C-Halogen [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 384]
9.4.1.2.2.8 - 10.22.1.4.1.2.2.8 Method 8: Introduction of C-Boron and C-Tin [Seite 400]
9.4.1.2.3 - 10.22.1.4.1.2.3 Substitution of C-Halogen at C3 [Seite 403]
9.4.1.2.3.1 - 10.22.1.4.1.2.3.1 Method 1: Introduction of C-Sulfur [Seite 403]
9.4.1.2.3.2 - 10.22.1.4.1.2.3.2 Method 2: Introduction of Acid, Ester, or Amide Groups [Seite 403]
9.4.1.2.3.3 - 10.22.1.4.1.2.3.3 Method 3: Introduction of a Cyano Group [Seite 407]
9.4.1.2.3.4 - 10.22.1.4.1.2.3.4 Method 4: Introduction of Formyl or Acyl Groups [Seite 407]
9.4.1.2.3.5 - 10.22.1.4.1.2.3.5 Method 5: Introduction of Hydroxyalkyl, Aminoalkyl, or Alkyl Groups [Seite 409]
9.4.1.2.3.6 - 10.22.1.4.1.2.3.6 Method 6: Introduction of Alkenyl or Alkynyl Groups [Seite 412]
9.4.1.2.3.7 - 10.22.1.4.1.2.3.7 Method 7: Introduction of Aryl or Hetaryl Groups [Seite 413]
9.4.1.2.3.8 - 10.22.1.4.1.2.3.8 Method 8: Introduction of C-Boron [Seite 417]
9.4.1.2.3.9 - 10.22.1.4.1.2.3.9 Method 9: Introduction of C-Tin [Seite 418]
9.4.1.2.4 - 10.22.1.4.1.2.4 Substitution of C-Halogen at C2 [Seite 421]
9.4.1.2.4.1 - 10.22.1.4.1.2.4.1 Method 1: Introduction of C-Carbon [Seite 421]
9.4.1.2.5 - 10.22.1.4.1.2.5 Substitution of C-Silicon at C2 [Seite 429]
9.4.1.2.5.1 - 10.22.1.4.1.2.5.1 Method 1: Introduction of C-Halogen [Seite 429]
9.4.1.2.6 - 10.22.1.4.1.2.6 Substitution of C-Tin at C3 [Seite 430]
9.4.1.2.6.1 - 10.22.1.4.1.2.6.1 Method 1: Introduction of C-Carbon [Seite 430]
9.4.1.2.7 - 10.22.1.4.1.2.7 Substitution of C-Tin at C2 [Seite 432]
9.4.1.2.7.1 - 10.22.1.4.1.2.7.1 Method 1: Introduction of C-Carbon [Seite 432]
9.4.1.2.8 - 10.22.1.4.1.2.8 Substitution of C-Boron at C3 [Seite 433]
9.4.1.2.8.1 - 10.22.1.4.1.2.8.1 Method 1: Introduction of C-Carbon [Seite 433]
9.4.1.2.9 - 10.22.1.4.1.2.9 Substitution/Modification of C-Carbon at C3 [Seite 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 [Seite 436]
9.4.1.2.10 - 10.22.1.4.1.2.10 Substitution/Modification of C-Carbon at C2 [Seite 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 [Seite 455]
9.4.1.2.11 - 10.22.1.4.1.2.11 Substitution/Modification at N1 [Seite 462]
9.4.1.2.11.1 - 10.22.1.4.1.2.11.1 Method 1: Introduction of N-Nitrogen [Seite 462]
9.4.1.2.11.2 - 10.22.1.4.1.2.11.2 Method 2: Introduction of N-Sulfur [Seite 463]
9.4.1.2.11.3 - 10.22.1.4.1.2.11.3 Method 3: Introduction of Acid, Ester, or Amide Groups [Seite 467]
9.4.1.2.11.4 - 10.22.1.4.1.2.11.4 Method 4: Introduction of Acyl Groups [Seite 473]
9.4.1.2.11.5 - 10.22.1.4.1.2.11.5 Method 5: Introduction of Oxyalkyl or Aminoalkyl Groups [Seite 474]
9.4.1.2.11.6 - 10.22.1.4.1.2.11.6 Method 6: Introduction of Alkenyl Groups [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 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 [Seite 490]
9.4.1.2.11.12 - 10.22.1.4.1.2.11.12 Method 12: Introduction of Aryl or Hetaryl Groups [Seite 492]
9.4.1.2.11.13 - 10.22.1.4.1.2.11.13 Method 13: Introduction of N-Silicon [Seite 498]
9.4.1.2.11.14 - 10.22.1.4.1.2.11.14 Method 14: N-Deprotection at N1 [Seite 499]
9.4.1.2.11.15 - 10.22.1.4.1.2.11.15 Method 15: Modification of N-Carbon at N1 [Seite 502]
9.4.2 - 10.22.1.4.2 Addition Reactions [Seite 503]
9.4.2.1 - 10.22.1.4.2.1 Addition of Organic Groups [Seite 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 [Seite 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 [Seite 505]
10 - Author Index [Seite 527]
11 - Abbreviations [Seite 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]

Scheme 2 Structures of 7-Methyl-1H-pyrrolo[2,3-c]pyridine and Variolins[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 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 kJmol-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...

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