Science of Synthesis Knowledge Updates: 2016/3 E-Book

• Herausgeber: Thieme
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1153

Veröffentlichungsjahr: 2016

Beschreibung

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.

 

Leseprobe

Science of Synthesis

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Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

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Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the most impactful investigations are becoming more and more molecular. As an enabling science, synthetic organic chemistry is uniquely poised to provide access to compounds with exciting and valuable new properties. Organic molecules of extreme complexity can, given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that reveal the intimate workings of chemical, biological, or physical processes with stunning detail.

The sheer variety of chemical structural space required for these investigations and the design elements necessary to assemble molecular targets of increasing intricacy place extraordinary demands on the individual synthetic methods used. They must be robust and provide reliably high yields on both small and large scales, have broad applicability, and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.

The need to provide a dependable source of information on evaluated synthetic methods in organic chemistry embracing these characteristics was first acknowledged over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden der Organischen Chemie was first introduced. Recognizing the necessity to provide a modernized, comprehensive, and critical assessment of synthetic organic chemistry, in 2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature from the early 1800s until the year of publication. The accompanying online version of Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.

From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most up-to-date electronic database available for the documentation of validated synthetic methods.

Also from 2010, Science of Synthesis includes the Science of Synthesis Reference Library, comprising volumes covering special topics of organic chemistry in a modular fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis, Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expertevaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates, to make Science of Synthesis the complete information source for the modern synthetic chemist.

The overarching goal of the Science of Synthesis Editorial Board is to make the suite of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design and construction of organic molecules.

Throughout the years, the chemical community has benefited tremendously from the outstanding contribution of hundreds of highly dedicated expert authors who have devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process to make Science of Synthesis a reference work of the highest integrity and quality.

July 2010

The Editorial Board

E. M. Carreira (Zurich, Switzerland)C. P. Decicco (Princeton, USA)A. Fuerstner (Muelheim, Germany)G. Koch (Basel, Switzerland)G. A. Molander (Philadelphia, USA)E. Schaumann (Clausthal-Zellerfeld, Germany)M. Shibasaki (Tokyo, Japan)E. J. Thomas (Manchester, UK)B. M. Trost (Stanford, USA)

Abstract

10.22.1 Azaindoles

J.-Y. Mérour and B. Joseph

This chapter covers the synthesis and reactions of 4-azaindoles, 5-azaindoles, 6-azaindoles, and 7-azaindoles. It focuses on the literature published until mid-2014. Both classical methods and recent advances in synthetic preparations are reviewed for each isomer. Substituent modifications on the pyridine or pyrrole ring are also described.

Keywords: azaindoles • azaindole N-oxides • Fischer indole synthesis • Larock heteroannulation • cyclization • halogenation • lithiation • Vilsmeier formylation • Mannich reaction • cross-coupling reactions

Science of Synthesis Knowledge Updates 2016/3

Preface

Abstract

Table of Contents

10.22 Product Class 22: Azaindoles and Their Derivatives

10.22.1 Product Subclass 1: Azaindoles

J.-Y. Mérour and B. Joseph

Author Index

Abbreviations

Table of Contents

Volume 10: Fused Five-Membered Hetarenes with One Heteroatom

10.22 Product Class 22: Azaindoles and Their Derivatives

10.22.1 Product Subclass 1: Azaindoles

J.-Y. Mérour and B. Joseph

10.22.1 Product Subclass 1: Azaindoles

10.22.1.1 Synthesis by Ring-Closure Reactions

10.22.1.1.1 By Annulation to a Pyridine

10.22.1.1.1.1 By Formation of One N-C and One C-C Bond

10.22.1.1.1.1.1 With Formation of 1-2 and 3-3a Bonds

10.22.1.1.1.1.1.1 Method 1: From Pyridylhydrazones (Fischer Synthesis)

10.22.1.1.1.1.1.1.1 Variation 1: Indolization with Pyridinium Hydrochloride

10.22.1.1.1.1.1.1.2 Variation 2: From (6-Methoxypyridin-3-yl) hydrazine or (2-Methoxypyridin-3-yl) hydrazine

10.22.1.1.1.1.1.1.3 Variation 3: Using Microwave Activation

10.22.1.1.1.1.1.1.4 Variation 4: From a Pyridin-4-yldiazonium N-Oxide and a β-Oxo Acid

10.22.1.1.1.1.1.1.5 Variation 5: From a Pyridylhydrazine and an Enamine

10.22.1.1.1.1.1.1.6 Variation 6: From a Pyridylhydrazine and a γ-Halo Ketone (Grandberg Synthesis)

10.22.1.1.1.1.1.1.7 Variation 7: From 4-Hydrazino-6-methylpyridin-2(1H)-one

10.22.1.1.1.1.1.1.8 Variation 8: From a Pyridylboronic Acid and Di-tert-butyl Azodicarboxylate

10.22.1.1.1.1.1.2 Method 2: From ortho-Substituted Nitropyridines (Bartoli Synthesis)

10.22.1.1.1.1.1.3 Method 3: From N-Chloropyridin-2-amines and α-Alkylsulfanyl Ketones (Gassman Synthesis)

10.22.1.1.1.1.1.4 Method 4: From Pyridinamines and α-Hydroxy Ketones (Bischler Synthesis)

10.22.1.1.1.1.1.5 Method 5: From Halopyridin-2-amines and Alkynes (Larock Synthesis)

10.22.1.1.1.1.1.6 Method 6: From Enamines of Pyridyl Ketones/Aldehydes

10.22.1.1.1.1.1.7 Method 7: From Iodopyridinamines and Allyl Acetate

10.22.1.1.1.1.1.8 Method 8: From Nitropyridines and Alkynes

10.22.1.1.1.1.2 With Formation of 1-2 and 2-3 Bonds

10.22.1.1.1.1.2.1 Method 1: From an Alkyl-N-(tert-Butoxycarbonyl) pyridinamine and an Amide

10.22.1.1.1.1.2.1.1 Variation 1: From an Unprotected Alkylpyridinamine and an Ester

10.22.1.1.1.1.2.2 Method 2: From a 2-Aminopyridine-3-carbaldehyde and a Diazo Ester

10.22.1.1.1.1.2.3 Method 3: From a Methylpyridinamine and the Vilsmeier Reagent

10.22.1.1.1.1.3 With Formation of 1-7a and 2-3 Bonds

10.22.1.1.1.1.3.1 Method 1: From an Alkylpyridine and a Nitrile

10.22.1.1.1.1.3.1.1 Variation 1: From a 2-Fluoro (alkyl) pyridine and a Nitrile

10.22.1.1.1.1.3.2 Method 2: From a 2-(2-Chloropyridin-3-yl) oxirane and an Amine

10.22.1.1.1.1.3.3 Method 3: From a 2-Halopyridyl Aldehyde and Ethyl Isocyanoacetate

10.22.1.1.1.1.4 With Formation of 1-2 and 1-7a Bonds

10.22.1.1.1.1.4.1 Method 1: From a 2-Chloro-3-(2-chloroethyl) pyridine and an Amine

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

10.22.1.1.1.1.4.2 Method 2: From a 2-Bromo-3-(2-bromoalkenyl) pyridine and an Amine

10.22.1.1.1.1.4.3 Method 3: From a 2-Alkynyl-3-bromopyridine and a Carbamate

10.22.1.1.1.2 By Formation of One N-C Bond

10.22.1.1.1.2.1 With Formation of the 1-2 Bond

10.22.1.1.1.2.1.1 Method 1: From (3-Nitropyridin-2-yl) pyruvates (Reissert Synthesis)

10.22.1.1.1.2.1.2 Method 2: From a Halopyridinamine and an Enolate

10.22.1.1.1.2.1.3 Method 3: From Alkynylpyridinamines

10.22.1.1.1.2.1.3.1 Variation 1: Base-Mediated Cyclization

10.22.1.1.1.2.1.3.2 Variation 2: Using Microwave Activation

10.22.1.1.1.2.1.3.3 Variation 3: Copper(I) Iodide Mediated Cyclization

10.22.1.1.1.2.1.3.4 Variation 4: Copper(II) Acetate Mediated Cyclization

10.22.1.1.1.2.1.3.5 Variation 5: Indium(III) Bromide Mediated Cyclization

10.22.1.1.1.2.1.3.6 Variation 6: Gold(III) Chloride Mediated Cyclization

10.22.1.1.1.2.1.3.7 Variation 7: Acid-Mediated Cyclization

10.22.1.1.1.2.1.3.8 Variation 8: Palladium (0)-Mediated Cyclization with Concomitant Introduction of a 3-Aryl Substituent

10.22.1.1.1.2.1.3.9 Variation 9: Iodine-Mediated Cyclization with Concomitant Introduction of a 3-Iodo Substituent

10.22.1.1.1.2.1.3.10 Variation 10: Copper(I)-Mediated Cyclization with Concomitant Introduction of a 2-Dialkylamino Substituent

10.22.1.1.1.2.1.4 Method 4: From Allenylpyridinamines

10.22.1.1.1.2.1.5 Method 5: From Nitropyridyl Enamines (Leimgruber–Batcho Synthesis)

10.22.1.1.1.2.1.6 Method 6: From 2-(2-Nitropyridyl) enol Ethers

10.22.1.1.1.2.1.7 Method 7: From Nitro(vinyl)pyridines

10.22.1.1.1.2.1.8 Method 8: From Nitro(2-nitrovinyl)pyridines

10.22.1.1.1.2.1.9 Method 9: From Alkenylnitropyridines or Alkenylazidopyridine N-Oxides via Nitrenes

10.22.1.1.1.2.1.10 Method 10: From 2-(Arylamino)-3-(1-hydroxyalkyl) pyridines or 2-(Arylamino)-3-alkenylpyridines

10.22.1.1.1.2.1.11 Method 11: From (2,2-Dihalovinyl) pyridinamines

10.22.1.1.1.2.1.12 Method 12: From N-(Styrylpyridyl) hydroxylamines

10.22.1.1.1.2.1.13 Method 13: From a 2-(Nitropyridyl) acetonitrile

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

10.22.1.1.1.2.2 With Formation of the 1-7a Bond

10.22.1.1.1.2.2.1 Method 1: From a (2-Aminoethyl) halopyridine

10.22.1.1.1.2.2.2 Method 2: From a Pyridylacetic Acid Hydrazide

10.22.1.1.1.2.2.3 Method 3: From a 2-Azido-3-pyridylacrylate (Hemetsberger–Knittel Synthesis)

10.22.1.1.1.2.2.4 Method 4: From a 2-Amino-3-(3-bromopyridin-4-yl) acrylate

10.22.1.1.1.3 By Formation of One C-C Bond

10.22.1.1.1.3.1 With Formation of the 2-3 Bond

10.22.1.1.1.3.1.1 Method 1: From an Acylaminopyridyl Ketone (Fürstner Synthesis)

10.22.1.1.1.3.1.2 Method 2: From an Acylamino(methyl)pyridine (Madelung Synthesis)

10.22.1.1.1.3.1.2.1 Variation 1: From a 2-[3-(Acylamino) pyridin-2-yl]acetonitrile

10.22.1.1.1.3.2 With Formation of the 3-3a Bond

10.22.1.1.1.3.2.1 Method 1: From a 2-(Pyridin-2-ylamino) ethyl Ethylxanthate

10.22.1.1.1.3.2.2 Method 2: From an N-Allyl-3-halopyridin-2-amine

10.22.1.1.1.3.2.3 Method 3: From an N-(2-Halopyridin-3-yl) cycloalkanimine

10.22.1.1.1.3.2.4 Method 4: From an N-Alkynylhalopyridinamine

10.22.1.1.2 By Annulation to a Pyrrole

10.22.1.1.2.1 By Formation of One N-C Bond and Two C-C Bonds

10.22.1.1.2.1.1 With Formation of 3a-4, 5-6, and 6-7 Bonds

10.22.1.1.2.1.1.1 Method 1: From a Pyrrol-2-amine, a Ketone, and an Aldehyde

10.22.1.1.2.2 By Formation of One N-C Bond and One C-C Bond

10.22.1.1.2.2.1 With Formation of the 3a-4 and 4-5 Bonds

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

10.22.1.1.2.2.2 With Formation of 3a-4 and 6-7 Bonds

10.22.1.1.2.2.2.1 Method 1: From a Pyrrol-2-amine and a 1,3-Diketone

10.22.1.1.2.2.3 With Formation of 3a-4 and 7-7a Bonds

10.22.1.1.2.2.3.1 Method 1: From a 2,2-Dimethoxypyrrolidine and an Enaminone

10.22.1.1.2.3 By Formation of One N-C Bond

10.22.1.1.2.3.1 With Formation of the 1-7a Bond

10.22.1.1.2.3.1.1 Method 1: From Nicotine

10.22.1.1.2.3.2 With Formation of the 4-5 Bond

10.22.1.1.2.3.2.1 Method 1: From Ethyl 2-(2-Amino-1-hydroxyethyl)-1H-pyrrole-3-carboxylates

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

10.22.1.1.2.3.2.3 Method 3: From 3-(Ethoxycarbonyl) pyrrole-2-acetamide

10.22.1.1.2.3.3 With Formation of the 5-6 Bond

10.22.1.1.2.3.3.1 Method 1: From 3-Alkynyl-2-(azidomethyl) pyrroles

10.22.1.1.2.4 By Formation of One C-C Bond

10.22.1.1.2.4.1 With Formation of the 3a-4 Bond

10.22.1.1.2.4.1.1 Method 1: From a Pyrrole with a C2N-Chain at C2

10.22.1.1.2.4.1.2 Method 2: From a Pyrrole with a 2,2-Diethoxyethylimino Chain at C2

10.22.1.1.2.4.1.3 Method 3: From a Pyrrole with a 2-(Azidocarbonyl) vinyl Chain at C2

10.22.1.1.2.4.1.4 Method 4: From 2-Cyano-2-(pyrrolidin-2-ylidene) acetamide and Dimethylformamide Dimethyl Acetal

10.22.1.1.2.4.2 With Formation of the 4-5 Bond

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

10.22.1.1.2.4.2.2 Method 2: From a 2-Amino-1H-pyrrole-3-carbonitrile and a 3-Oxo Ester

10.22.1.1.2.4.3 With Formation of the 7-7a Bond

10.22.1.1.2.4.3.1 Method 1: From a 3-(1H-Pyrrol-3-yl) acryloyl Azide

10.22.1.1.2.4.3.2 Method 2: From N-Pyrrol-3-yl Enamines

10.22.1.1.2.4.3.3 Method 3: From 1-(Pyrrol-3-yl)-1-azaenynes

10.22.1.1.3 Without Annulation to an Existing Ring

10.22.1.1.3.1 By Formation of Two N-C and Three C-C Bonds

10.22.1.1.3.1.1 With Formation of the 2-3, 3a-4, 5-6, 7-7a, and 1-7a Bonds

10.22.1.1.3.1.1.1 Method 1: From a Dialkynylsilane, an Isocyanide, and a Nitrile

10.22.1.1.3.2 By Formation of One N-C Bond and Two C-C Bonds

10.22.1.1.3.2.1 With Formation of the 3-3a, 4-5, and 7-7a Bonds

10.22.1.1.3.2.1.1 Method 1: From Ethyl Acrylate and a 3-[(Cyanomethyl) amino]acrylate

10.22.1.2 Synthesis by Ring Transformation

10.22.1.2.1 Ring Expansion

10.22.1.2.1.1 Method 1: From a 3-Azabicyclo[4.1.0]heptane and a Nitrile

10.22.1.2.2 Formal Exchange of Ring Members with Retention of the Ring Size

10.22.1.2.2.1 Method 1: From a 2,3-Dihydro-5-azabenzo[b]furan

10.22.1.2.2.2 Method 2: From 1,2,4-Triazines and an Alkyne

10.22.1.2.2.3 Method 3: From Pyrazolo[1,5-a]pyridines

10.22.1.2.3 Ring Contraction

10.22.1.2.3.1 Method 1: From a Naphthyridine Diazonium Salt

10.22.1.2.3.2 Method 2: From 3H-Azepines

10.22.1.3 Aromatization

10.22.1.3.1 Method 1: From 2,3-Dihydroazaindoles (Azaindolines)

10.22.1.3.2 Method 2: From Di- and Tetrahydropyridine Ring Azaindoles

10.22.1.4 Synthesis by Substituent Modification

10.22.1.4.1 Substitution of Existing Substituents

10.22.1.4.1.1 Pyridine Ring Substituents

10.22.1.4.1.1.1 Substitution of C-Hydrogen

10.22.1.4.1.1.1.1 Method 1: Introduction of C-Halogen to an Azaindole N-Oxide

10.22.1.4.1.1.1.2 Method 2: Introduction of C-Halogen via a C-Metalated Azaindole

10.22.1.4.1.1.1.3 Method 3: Introduction of C-Halogen to an Activated Azaindole

10.22.1.4.1.1.1.4 Method 4: Introduction of C-Sulfur

10.22.1.4.1.1.1.5 Method 5: Introduction of C-Oxygen to an Azaindole N-Oxide

10.22.1.4.1.1.1.6 Method 6: Introduction of C-Oxygen via a C-Metalated Azaindole

10.22.1.4.1.1.1.7 Method 7: Introduction of C-Nitrogen by Amination of an Azaindole N-Oxide

10.22.1.4.1.1.1.8 Method 8: Introduction of C-Nitrogen by Nitration of an Azaindole N-Oxide

10.22.1.4.1.1.1.9 Method 9: Introduction of C-Nitrogen via a C-Metalated Azaindole

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

10.22.1.4.1.1.1.11 Method 11: Introduction of C-Carbon to an Azaindole N-Oxide

10.22.1.4.1.1.1.12 Method 12: Introduction of C-Carbon via a C-Metalated Azaindole

10.22.1.4.1.1.1.13 Method 13: Introduction of C-Boron to a Metalated Azaindole

10.22.1.4.1.1.2 Substitution of C-Halogen

10.22.1.4.1.1.2.1 Method 1: Introduction of C-Hydrogen

10.22.1.4.1.1.2.2 Method 2: Introduction of C-Halogen

10.22.1.4.1.1.2.3 Method 3: Introduction of C-Sulfur by Nucleophilic Substitution

10.22.1.4.1.1.2.4 Method 4: Introduction of C-Sulfur by Lithium–Bromine Exchange

10.22.1.4.1.1.2.5 Method 5: Introduction of C-Oxygen

10.22.1.4.1.1.2.6 Method 6: Introduction of C-Nitrogen by Direct Reaction with Amines

10.22.1.4.1.1.2.7 Method 7: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amines

10.22.1.4.1.1.2.8 Method 8: Introduction of C-Nitrogen by Palladium-Catalyzed Cross Coupling with Amides

10.22.1.4.1.1.2.9 Method 9: Introduction of a Cyano Group

10.22.1.4.1.1.2.10 Method 10: Introduction of Aryl, Carboxy, Acyl, Alkynyl, Alkenyl, or Alkyl Groups

10.22.1.4.1.1.2.11 Method 11: Introduction of C-Boron to Metalated Azaindoles

10.22.1.4.1.1.2.12 Method 12: Introduction of C-Boron via Palladium (0) Catalysis

10.22.1.4.1.1.3 Substitution of C-Sulfur

10.22.1.4.1.1.3.1 Method 1: Introduction of C-Halogen

10.22.1.4.1.1.4 Substitution of C-Nitrogen

10.22.1.4.1.1.4.1 Method 1: Introduction of C-Oxygen

10.22.1.4.1.1.4.2 Method 2: Reduction of a Nitro Group

10.22.1.4.1.1.5 Substitution of C-Boron

10.22.1.4.1.1.5.1 Method 1: Introduction of C-Carbon

10.22.1.4.1.1.6 Modification of C-Carbon

10.22.1.4.1.1.6.1 Method 1: Giving C-Carbon

10.22.1.4.1.2 Pyrrole Ring Substituents

10.22.1.4.1.2.1 Substitution of C-Hydrogen at C3

10.22.1.4.1.2.1.1 Method 1: Introduction of Bromine

10.22.1.4.1.2.1.2 Method 2: Introduction of Chlorine

10.22.1.4.1.2.1.3 Method 3: Introduction of Iodine

10.22.1.4.1.2.1.4 Method 4: Giving C-Sulfur

10.22.1.4.1.2.1.5 Method 5: Giving C-Nitrogen

10.22.1.4.1.2.1.6 Method 6: Introduction of Ester or Amide Groups

10.22.1.4.1.2.1.7 Method 7: Introduction of a Formyl Group

10.22.1.4.1.2.1.8 Method 8: Introduction of Acyl Groups

10.22.1.4.1.2.1.9 Method 9: Introduction of an Oxyalkyl Group

10.22.1.4.1.2.1.10 Method 10: Introduction of an Aminoalkyl Group

10.22.1.4.1.2.1.11 Method 11: Introduction of a Sulfanylalkyl Group

10.22.1.4.1.2.1.12 Method 12: Introduction of Alkenyl Groups

10.22.1.4.1.2.1.13 Method 13: Introduction of Hetaryl Groups

10.22.1.4.1.2.1.14 Method 14: Introduction of Alkyl Groups

10.22.1.4.1.2.1.15 Method 15: Introduction of C-Boron

10.22.1.4.1.2.2 Substitution of C-Hydrogen at C2

10.22.1.4.1.2.2.1 Method 1: Introduction of C-Halogen

10.22.1.4.1.2.2.2 Method 2: Introduction of C-Carbon by Intermolecular Metal-Catalyzed Direct Substitution

10.22.1.4.1.2.2.3 Method 3: Introduction of C-Carbon by Palladium-Catalyzed Cyclization of 1-Substituted Azaindoles

10.22.1.4.1.2.2.4 Method 4: Introduction of C-Carbon by Radical Cyclization of 1-Substituted Azaindoles

10.22.1.4.1.2.2.5 Method 5: Introduction of C-Carbon by Acid-Mediated Cyclization of 1-Substituted Azaindoles

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

10.22.1.4.1.2.2.7 Method 7: Introduction of C-Carbon Using 2-Metalated Azaindoles

10.22.1.4.1.2.2.8 Method 8: Introduction of C-Boron and C-Tin

10.22.1.4.1.2.3 Substitution of C-Halogen at C3

10.22.1.4.1.2.3.1 Method 1: Introduction of C-Sulfur

10.22.1.4.1.2.3.2 Method 2: Introduction of Acid, Ester, or Amide Groups

10.22.1.4.1.2.3.3 Method 3: Introduction of a Cyano Group

10.22.1.4.1.2.3.4 Method 4: Introduction of Formyl or Acyl Groups

10.22.1.4.1.2.3.5 Method 5: Introduction of Hydroxyalkyl, Aminoalkyl, or Alkyl Groups

10.22.1.4.1.2.3.6 Method 6: Introduction of Alkenyl or Alkynyl Groups

10.22.1.4.1.2.3.7 Method 7: Introduction of Aryl or Hetaryl Groups

10.22.1.4.1.2.3.8 Method 8: Introduction of C-Boron

10.22.1.4.1.2.3.9 Method 9: Introduction of C-Tin

10.22.1.4.1.2.4 Substitution of C-Halogen at C2

10.22.1.4.1.2.4.1 Method 1: Introduction of C-Carbon

10.22.1.4.1.2.5 Substitution of C-Silicon at C2

10.22.1.4.1.2.5.1 Method 1: Introduction of C-Halogen

10.22.1.4.1.2.6 Substitution of C-Tin at C3

10.22.1.4.1.2.6.1 Method 1: Introduction of C-Carbon

10.22.1.4.1.2.7 Substitution of C-Tin at C2

10.22.1.4.1.2.7.1 Method 1: Introduction of C-Carbon

10.22.1.4.1.2.8 Substitution of C-Boron at C3

10.22.1.4.1.2.8.1 Method 1: Introduction of C-Carbon

10.22.1.4.1.2.9 Substitution/Modification of C-Carbon at C3

10.22.1.4.1.2.9.1 Method 1: Introduction of C-Carbonyl, C-Alkyl, and C-Vinyl Derivatives

10.22.1.4.1.2.10 Substitution/Modification of C-Carbon at C2

10.22.1.4.1.2.10.1 Method 1: Giving C-Halogen, C-Carbon, or C-Nitrogen

10.22.1.4.1.2.11 Substitution/Modification at N1

10.22.1.4.1.2.11.1 Method 1: Introduction of N-Nitrogen

10.22.1.4.1.2.11.2 Method 2: Introduction of N-Sulfur

10.22.1.4.1.2.11.3 Method 3: Introduction of Acid, Ester, or Amide Groups

10.22.1.4.1.2.11.4 Method 4: Introduction of Acyl Groups

10.22.1.4.1.2.11.5 Method 5: Introduction of Oxyalkyl or Aminoalkyl Groups

10.22.1.4.1.2.11.6 Method 6: Introduction of Alkenyl Groups

10.22.1.4.1.2.11.7 Method 7: Introduction of Alkyl Groups via Michael-Type Addition

10.22.1.4.1.2.11.8 Method 8: Introduction of Alkyl Groups by Reaction with Alkyl Halides, Alkyl Sulfonates, or Dimethyl Sulfate

10.22.1.4.1.2.11.9 Method 9: Introduction of Alkyl Groups by Reaction with Dimethylformamide Dimethyl Acetal

10.22.1.4.1.2.11.10 Method 10: Introduction of Alkyl Groups by Reaction with an Allylic Carbonate

10.22.1.4.1.2.11.11 Method 11: Introduction of Alkyl Groups by Reaction with an Oxirane, Aziridine, or Azirine

10.22.1.4.1.2.11.12 Method 12: Introduction of Aryl or Hetaryl Groups

10.22.1.4.1.2.11.13 Method 13: Introduction of N-Silicon

10.22.1.4.1.2.11.14 Method 14: N-Deprotection at N1

10.22.1.4.1.2.11.15 Method 15: Modification of N-Carbon at N1

10.22.1.4.2 Addition Reactions

10.22.1.4.2.1 Addition of Organic Groups

10.22.1.4.2.1.1 Method 1: Alkylation of the Pyridine Nitrogen Atom: Formation of Pyridinium Salt

10.22.1.4.2.1.2 Method 2: Bis-acylation of the Two Nitrogen Atoms of 1H-Pyrrolo[2,3-b]pyridine

Author Index

Abbreviations

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 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)

–

q

3

–

q

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

H

-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 protonation of the pyridine nitrogen were potentiometrically determined and indicate the push–pull interaction between the two rings (▶ Table 3).[31]

Table 3 pKa Values of Azaindoles[31]

Compound

p

K

a

(H

2

O)

Ref

1

6.94

[

31

]

2

8.26

[

31

]

3

7.95

[

31

]

4

4.59

[

31

]

pyridine

5.20

[

31

]

For instance, the pKa values of 1H-pyrrolo[3,2-c]pyridine (2) and 1H-pyrrolo[2,3-b]pyridine (4) mirror the relative pKa values of pyridin-4-amine and pyridin-2-amine, respectively, and are partly explained by the more favorable γ-interaction between the donating and accepting groups in 1H-pyrrolo[3,2-c]pyridine (2). This differential reactivity is enhanced for example in the mildly acidic solutions used in Mannich reactions, where 1H-pyrrolo[3,2-c]pyridine (2) is mainly present as a protonated species 11 whereas 1H-pyrrolo[2,3-b]pyridine (4) stays in its neutral form (▶ Scheme 4).[32]

Scheme 4 Trifluoroacetate Salt of 1H-Pyrrolo[3,2-c]pyridine[32]

Yakhontov and co-workers reported experimental pKa values for 1H-pyrrolo[3,2-b]pyridines 12 (▶ Table 4) and 1H-pyrrolo[3,2-c]pyridines 13 (▶ Table 5).[33,34] Gas-phase basicities of azaindoles have also been calculated.[21,35]

Table 4 pKa Values of 1H-Pyrrolo[3,2-b]pyridine Derivatives[33]

R

1

R

2

p

K

a

a

Ref

H

Br

3.44 ± 0.03

[

33

]

H

Cl

3.91 ± 0.04

[

33

]

H

NO

2

2.88 ± 0.07

[

33

]

H

CH

2

CO

2

Et

5.02 ± 0.02

[

33

]

H

CH

2

NMe

2

8.13 ± 0.04

[

33

]

Ac

H

2.68 ± 0.04

[

33

]

Ac

Br

2.05 ± 0.06

[

33

]

Ac

NHAc

2.05 ± 0.06

[

33

]

a

Experimental data.

Table 5 pKa Values of 1H-Pyrrolo[3,2-c]pyridine Derivatives[33]

R

1

R

2

p

K

a

a

Ref

Ph

H

5.68 ± 0.04

[

33

]

H

Br

5.35 ± 0.05

[

33

]

H

NO

2

3.58 ± 0.05

[

33

]

a

Experimental data.

The ground-state and singlet-excited-state prototropisms of 1H-pyrrolo[3,2-b]pyridine (1) in acid and basic aqueous solutions have been studied using absorption and fluorescence spectroscopic techniques (▶ Scheme 5).[36] The changes in the 1H-pyrrolo[3,2-b]pyridine (1) absorption spectra reveal four ground-state species: the pyridinic protonated cation 14 (pKa14 7.5 ± 0.1), the neutral molecule 1 (pKa1 15.5 ± 0.5), a dication 15 (pKa15 –4.6 ± 0.4), unknown before this study, and the pyrrolic deprotonated anion 16. Besides the emission of these species, a new fluorescent profile appears in alkaline solution at ca. 500 nm, which is ascribed to the neutral phototautomer 18. The formation of dication 15 supports the hypothetical presence of an additional cation 17 (emission band at 418 nm). The obtained pKa14→1 value (7.5) is somewhat higher than that (6.94) obtained from potentiometric measurements.[31]

Scheme 5 Sites of Protonation of 1H-Pyrrolo[3,2-b]pyridine[36]

The 1H NMR and 13C NMR spectroscopic data, recorded in deuterochloroform, for each azaindole are summarized in ▶ Scheme 6 and ▶ Scheme 7.[37–43] The coupling constant between H2 and H3 is around 3 Hz. The signal of H1 is always broad and is easily identified by an exchange with deuterium oxide. Upon heating in deuterated sulfuric acid, 1H-pyrrolo[3,2-b]pyridine (1) and 1H-pyrrolo[3,2-c]pyridine (2) also undergo a deuterium exchange at C3. Protonation of the pyridine ring of 1H-pyrrolo[3,2-c]pyridine (2) in trifluoroacetic acid leads to a deshielding effect on H2 (δ 7.80), H3 (δ 7.13), and H7 (δ 7.99) protons.[32] 1H-Pyrrolo[2,3-b]pyridine (4) is capable of self-association which has been studied by NMR techniques. In benzene-d6 solution, the chemical shift of H1 moves downfield as the concentration is increased, which is typical of the formation of a hydrogen bond.[41]

Scheme 61H NMR Spectroscopic Data of Azaindoles in Deuterochloroform (400 MHz)[37–42]

Scheme 713C NMR Spectroscopic Data of Azaindoles in Deuterochloroform (125 MHz)[39–43]

15N NMR measurements have rarely been reported for the azaindoles.[44,45] The 15NNMR chemical shifts of 1H-pyrrolo[2,3-b]pyridine (4) have been recorded in several solvents (▶ Table 6).[44,45]

Table 615N NMR Chemical Shifts of 1H-Pyrrolo[2,3-b]pyridine[44]

Solvent

δ (ppm)

Ref

N1

N7

CCl

4

–237.35

–117.36

[

44

]

EtOH

–239.93

–119.30

[

44

]

HCl (0.1 mol/L)

–239.93

–210.15

[

44

]

Infrared bands and assignments for the four azaindoles and numerous derivatives have been determined by Willette:[16]

1H-Pyrrolo[3,2-b]pyridine (1): (KBr): 3200 (NH), 3125, 3077, 3030, 2985 (CH), 1942, 1887, 1842, 1754, 1733 (ring overtone), 1572 m, 1506, 1458, 1410 vs, 1374, 1333 (ring), 1294 vs, 1263 m, 1133 m, 1068 (β-CH), 1115 (β-NH), 903 vs, 892 vs, 803, 796 vs, 780 vs, 763, and 725 cm–1 (γ-CH, β-ring, and γ-ring).

1H-Pyrrolo[3,2-c]pyridine (2): (KBr): 3200 (NH), 3106, 3077, 3040, 2967 (CH), 1887, 1859, 1754, 1739 (ring overtone weak), 1623 vs, 1587, 1477, 1453, 1418, 1364 vs (ring), 1311 vs, 1279, 1208, 1170, 1030 vs (β-CH), 1112 (β-NH), 917, 902 vs, 889, 803 vs, 738, 735 vs, and 730 cm–1 (γ-CH, β-ring, and γ-ring).

1H-Pyrrolo[2,3-c]pyridine (3): (KBr): 3200 (NH), 3125, 3067, 3030, 2959 (CH), 1916, 1786, 1761, 1742 (ring overtone weak), 1626, 1515, 1475 vs, 1435, 1372 vs (ring), 1314 vs, 1274, 1227, 1164 vs, 1072 (β-CH), 1131, 912, 900 vs, 885 m, 832 vs, 778, 770, and 740 vs cm–1 (γ-CH, β-ring, and γ-ring).

1H-Pyrrolo[2,3-b]pyridine (4): (KBr): 3200 (NH), 3125, 3077, 3021, 2985 (CH), 1923, 1887, 1848, 1736, 1704 (ring overtone weak), 1613, 1595 vs, 1511, 1433 vs, 1357 vs, 1346 vs (ring), 1289 vs, 1261 m, 1133 m, 1072 m (β-CH), 1114, 905 vs, 889, 799, 768 vs, 731, and 724 cm–1 (γ-CH, β-ring, and γ-ring).

The azaindole NH bond absorbs at ca. 3200 cm–1 for the four azaindoles; the ring overtone regions are quite similar; the ring stretching patterns are different with six strong bands.

The UV absorption spectra of azaindole derivatives, generally in hydroxylic solvents, have been fully investigated.[46–49] The absorption maxima are organized into bands which are all ascribable to π–π* transitions and correspond to the three principal bands of indole.

1H-Pyrrolo[3,2-b]pyridine (1): λmax (log ∊, H2O, pH 4.7): 284 nm (3.85), 327 nm (3.70); λmax (log ∊,H2O, pH 9.2): 292 nm (3.92).

1H-Pyrrolo[3,2-c]pyridine (2): λmax nm (log ∊,H2O, pH 6): 268 nm (3.46), 293 nm (3.29).

1H-Pyrrolo[2,3-c]pyridine (3): λmax nm (log ∊,H2O, pH 6): 261 nm (3.70), 319 nm (3.73).

1H-Pyrrolo[2,3-b]pyridine (4): λmax (log ∊, H2O, pH 2.1): 293 nm (3.94): λmax (log ∊, H2O, pH 7.0): 290 nm (3.91).[31]

Examination of the absorption and luminescence spectra of 1H-pyrrolo[2,3-b]pyridine (4) in ethanol revealed a two-proton phototautomerism between species 19 and 20 (▶ Scheme 8).[50] The spectrum of 1H-pyrrolo[2,3-b]pyridine (4) in an aprotic solvent has two fluorescent maxima, the relative intensity of which depend on the concentration, pH, and temperature. The second maximum is apparently caused by the tautomeric form produced as a result of the rapid intramolecular migration of the proton doublet in the excited state and constitutes a doubly hydrogen-bonded dimer.[51–55] Some authors[55] concluded that only a small fraction (<20%) of 1H-pyrrolo[2,3-b]pyridine (4) molecules in pure water are capable of excited-state tautomerism on a 1-nanosecond time scale; the majority of solvated 1H-pyrrolo[2,3-b]pyridine (4) molecules are not able to tautomerize. The 70-picosecond time constant observed in fluorescence and absorption measurements reflects a subsequent reorientation of the solvent that establishes a cyclic complex between solvent and solute; formation of this complex permits a 1-picosecond tautomerization step as has been discussed for 1H-pyrrolo[2,3-b]pyridine (4) in alcohols and 1H-pyrrolo[2,3-b]pyridine dimers in nonpolar solvents.

Scheme 8 Phototautomerism of 1H-Pyrrolo[2,3-b]pyridine[50]

The molecular symmetry and electronic spectroscopy of 1H-pyrrolo[2,3-b]pyridine dimer have been studied.[56] Excited-state proton-transfer (ESPT) in which hydrogen bonding plays an important role has received much attention.[57] Among various ESPT reactions, excited-state double-proton-transfer (ESDPT) has been investigated; 1H-pyrrolo[2,3-b]pyridine (4) has been thoroughly studied as a prototype of molecules showing the ESDPT phenomenon.[58,59] A series of 1H-pyrrolo[2,3-b]pyridine derivatives {1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (21), 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (22), and 1H-pyrrolo[2,3-b]pyridine-3,5-dicarbonitrile (23)} have been investigated (▶ Scheme 9).[60,61]

Scheme 9 Structures of 1H-Pyrrolo[2,3-b]pyridinecarbonitriles

The excited-state double-proton-transfer of 1H-pyrrolo[2,3-b]pyridine dimer has been investigated with picosecond time-resolved resonance-enhanced multiphoton ionization spectroscopy.[62] The molecular structure and properties of 1H-pyrrolo[2,3-b]pyridine (4) in its first four singlet states were studied with a view to improving current understanding of the photophysical behavior of its dimer.[63] This dimer, which exhibits a double proton-transfer via its two hydrogen bonds upon electronic excitation, has been used as a model for the photophysical behavior of DNA base pairs. Electronic excitation of 1H-pyrrolo[2,3-b]pyridine (4) simultaneously increases its acidity and basicity. These changes facilitate a concerted mechanism for the double proton-transfer in the dimer. A cleavage of 1H-pyrrolo[2,3-b]pyridine dimer in 3-ethylpentane has been investigated by fluorescence studies at 77 K and 4.2 K and led to the determination of the potential energy barrier to the double prototropic intermolecular reaction.

The hydrogen bond as one of the important types of solute–solvent interaction has been used to investigate the properties of electronic states. Many early reports showed that the HOMO and LUMO orbitals in 1H-pyrrolo[2,3-b]pyridine (4) are largely localized on pyrrole and pyridine moieties,[64,65] which was recently confirmed by a theoretical study[57] using time-dependent density functional theory (TDDFT). The intermolecular hydrogen bonds of 1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (21)/methanol, 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (22)/methanol, and 1H-pyrrolo[2,3-b]pyridine-3,5-dicarbonitrile (23)/methanol complexes are strengthened in the excited state and weakened in the tautomer excited state, which indicates that the reverse proton-transfer reaction does not take place easily.

Despite their low propensity to tautomerize in the ground state, the azaindoles easily tautomerize upon photoexcitation. The fluorescence spectra show extended emission bands attributed to the phototautomers.

The excited states of 7-azatryptophan [24, 2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl) propanoic acid] have attracted much attention to better understand the photophysical behavior of the tryptophanyl residue of protein side chains (▶ Scheme 10). Investigations of excited-state proton-transfer in the azaindole dimer may provide information about mutations of DNA induced by UV irradiation. Catalán and Kasha first studied the 1H-pyrrolo[2,3-b]pyridine dimer and provided a model for hydrogen bonding in DNA base pairs.[66]

1H-Pyrrolo[2,3-b]pyridine (4) is isoelectronic with purine and exhibits a close relationship with the bases adenine and guanine; thus, the 1H-pyrrolo[2,3-b]pyridine dimer shows structural similarities to the adenine–thymine and guanine–cytosine interactions in DNA. Several studies have been performed relating to the involvement of 1H-pyrrolo[2,3-b]pyridine derivatives such as 7-azatryptophan (24) as biological tools to probe protein structure and dynamics optically. 7-Azatryptophan (24) mimics tryptophan with a red-shifted fluorescence in cellular proteins. 7-Azamelatonin {25, N-[2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl) ethyl]acetamide} in aqueous solution exhibits a unique excited-state double proton-transfer property resulting in dual emission bands (405 and 560 nm), which makes 7-azamelatonin (25) a potential molecular probe (▶ Scheme 10).[67]

Scheme 10 Structures of 7-Azatryptophan and 7-Azamelatonin

In vivo expression of colored protein is highly desirable for biological studies. However, the phototautomer 1H-pyrrolo[2,3-c]pyridine (3) has only recently been used as a fluorescent model of tryptophan.[68] Until the Balón paper,[36] phototautomerisms of 1H-pyrrolo[3,2-b]pyridine (1) and 1H-pyrrolo[3,2-c]pyridine (2) had not been studied.

Azaindoles are considered bioisosteres of indole or purine in diverse therapeutic areas, which explains the very numerous patents.[7,8,10,69–71]

Another facet of azaindole chemistry is the aptitude of 1H-pyrrolo[2,3-b]pyridine (4) to form complexes. 1H-Pyrrolo[2,3-b]pyridine (4) and its derivatives display unusual bonding with metal ions leading to mononuclear or polynuclear metal complexes. The coordination sites of the binding types η1-N7, η1-N1, and μ-N,N are illustrated in structures 26–28, respectively (▶ Scheme 11).[12,72]

Scheme 11 Sites of Coordination of 1H-Pyrrolo[2,3-b]pyridine[12,72]

Ligands based on 1H-pyrrolo[2,3-b]pyridine (4) also promote magnetic exchange between paramagnetic centers. 1H-Pyrrolo[2,3-b]pyridine (4) emits a weak π*–π transition-based fluorescence with the maximum wave number (λmax) in the range of 350 to 360 nm in solution and the solid state, whereas its anion is a blue luminophore. By using functionalized 1H-pyrrolo[2,3-b]pyridines or by complexing metal ions, various luminescent derivatives have been obtained. 1H-Pyrrolo[2,3-b]pyridine (4) and its anion exhibit various coordination types in complexes. The neutral ligand and 1-aryl-1H-pyrrolo[2,3-b]pyridines are typically coordinated to a metal ion or main-group element through the pyridine nitrogen binding type η1-N7.[73] The 1H-pyrrolo[2,3-b]pyridine anion displays either η1-N1[74] or μ-N,N[75] binding types, the latter being the most reported. The red-colored diamagnetic nickel(II) complex obtained by Martin and co-workers in 1974 by reacting 1H-pyrrolo[2,3-b]pyridine (4) with nickel(II) acetate was one of the first examples.[75] Other copper and cobalt complexes were also reported by the same group. A drawback of 1H-pyrrolo[2,3-b]pyridine complexes is their tendency to form non-regular complexes due to the similarity in size of the five- and six-membered rings.

A wide range of 1H-pyrrolo[2,3-b]pyridine complexes have been prepared to evaluate their luminescence properties. The Wang group have developed this area considerably.[72,74,76,77] Thus, the reaction of potassium borohydride at 180 °C in the presence of an excess of 1H-pyrrolo[2,3-b]pyridine (4) provides the potassium borohydride complex 29 in 87% yield after 1 hour (▶ Scheme 12).[78] Formation of a B-N bond results in the generation of a stable, blue luminescent scorpionate ligand.[79]

Scheme 12 Synthesis of a 1H-Pyrrolo[2,3-b]pyridine Borohydride Complex[78]

Wang and co-workers have also carried out extensive studies on three-coordinate boron compounds that have emerged as promising materials for electroluminescent devices. These new organoboranes 30 and 31 can be synthesized in two steps from 1H-pyrrolo[2,3-b]pyridine (4; ▶ Scheme 13).[80,81]

Cyclometalated rhenium complexes (e.g., 32), synthesized for photochemistry studies, exhibit green luminescence (▶ Scheme 13).[82]

Scheme 13 Structures of Organoboron and Rhenium Complexes of 1H-Pyrrolo[2,3-b]pyridine[80–82]

The blue luminescent and electroluminescent properties of promising zinc(II) complexes of 1-(2-pyridyl)-1H-pyrrolo[2,3-b]pyridine have been examined, in particular, the brightblue luminescent complex 33 (▶ Scheme 14).[83] The use of the 1-(2-pyridyl) substituent improves the stability of the complex by chelating the metal center.

Organoplatinum complexes are also an important class of molecules because of their well-established roles in catalysis and photochemistry. The binuclear platinum complex 34 is obtained by reaction of 1,2,4,5-tetrakis (1H-pyrrolo[2,3-b]pyridin-1-yl) benzene with bis (dimethyl sulfide) tetramethyldiplatinum [Pt2Me4(SMe2)2].[84] Numerous other platinum complexes (e.g., 35) have also been prepared (▶ Scheme 14).[85] Cytotoxic platinum(II) complexes of 1H-pyrrolo[2,3-b]pyridine (4) bind to DNA in a manner similar to cisplatin.[86]

The novel blue luminescent boron complex 36 is obtained in 83% yield by heating a solution of 1H-pyrrolo[2,3-b]pyridine (4) and 4-methyleneoxetan-2-one (diketene) in toluene at 90 °C, followed by the addition of triphenylborane.[87]

Scheme 14 Examples of Zinc, Platinum, and Boron Complexes of 1H-Pyrrolo[2,3-b]pyridine[83–85,87]

Rigid-rod complexes 37 and 38 are utilized in the field of molecular electronics (▶ Scheme 15).[88–90]

Scheme 15 Structures of Rigid-Rod Complexes[88–90]

The luminescent properties of 1H-pyrrolo[2,3-b]pyridine complexes with miscellaneous metals have been reviewed.[72,75,76,91] The highly reactive acetone imine, obtained from acetone and ammonia, can be stabilized by coordination to a silver atom itself bound to the N1 nitrogen atom of a 1H-pyrrolo[2,3-b]pyridine moiety stabilized by tris (pentafluorophenyl) platinum(II).[92] 1H-Pyrrolo[2,3-b]pyridine derivatives are also involved in a different field of investigation, suggesting potential ferromagnetic interactions of some new complexes such as heterobridged μ-alkoxo-μ-1H-pyrrolo[2,3-b]pyridine dicopper(II) complexes.[92]

10.22.1.1 Synthesis by Ring-Closure Reactions

10.22.1.1.1 By Annulation to a Pyridine

10.22.1.1.1.1 By Formation of One N-C and One C-C Bond

10.22.1.1.1.1.1 With Formation of 1-2 and 3-3a Bonds

10.22.1.1.1.1.1.1 Method 1: From Pyridylhydrazones (Fischer Synthesis)

The Fischer synthesis, first discovered in 1883,[93] is one of the historical and most used methods for the synthesis of indoles from phenylhydrazones, but, generally, the analogous reactions of pyridylhydrazones 39 either fail or give the desired azaindoles 40 in low yields. Deactivation of the pyridine ring and protonation of the nitrogen atom in the acidic medium may explain the low reactivity. The Fischer reaction involves the functionalization of an unactivated aromatic CH position by way of a [3,3]-sigmatropic rearrangement (▶ Scheme 16) and has been used to form all four azaindole structures.

Scheme 16 The Fischer Azaindole Synthesis

Azaindolization is effective under thermaland/oracidicconditions. The first step is atautomerization of a pyridylhydrazone (e.g., 41) to give ene-hydrazine 42 (probably in some degree of protonation, as suggested). The rate-determining step may well vary according to experimental conditions. The key step is the formation of the C3-C3a bond through a [3,3]-sigmatropic rearrangement. The intermediate 43 rapidly aromatizes to afford 44. Ring closure by amine-to-iminium intramolecular nucleophilic addition gives intermediate 45. Final loss of ammonia generates the desired azaindole, e.g. 46 (▶ Scheme 17).

Scheme 17 Adapted Mechanism of Fischer Azaindole Synthesis[93]

Among the first failed attempts of azaindolization, those of Perkin[94] and Fargher[95] can be mentioned. Fargher and co-workers failed to obtain 1H-pyrrolo[2,3-b]pyridine derivatives from (2-pyridyl) hydrazones. The first positive result was published in the 1940s with the synthesis of 5-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine (48) in 12% yield from acetone and (6-chloropyridin-3-yl) hydrazine (47) by heating at 200 °C with zinc(II) chloride (▶ Scheme 18).[96] In 1953, cyclohexanone (2-methylpyridin-3-yl) hydrazone (49) was converted into 1-methyl-5,6,7,8-tetrahydro-9H-pyrido[3,4-b]indole (50) in low yield (▶ Scheme 18).[97] Cyclohexanone (2-pyridyl) hydrazone (41) can be cyclized in concentrated hydrochloric acid over alumina[98] or better still in polyphosphoric acid to produce the 5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indole (46) in 53% yield (▶ Scheme 18).[99] In the case of (2-pyridyl) hydrazones of acetaldehyde, acetone, or pyruvic acid, the attempted cyclizations failed.[99] By heating (240 °C) in the presence of zinc(II) chloride, cyclohexanone (4-pyridyl) hydrazone (51) gives 6,7,8,9-tetrahydro-5H-pyrido[4,3-b]indole (52) in 48% yield.[100] In the same manner, the (2-pyridyl) hydrazone of isopropyl methyl ketone and the corresponding (3-pyridyl) hydrazone give 2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine (53, 2,3,3-trimethyl-7-azaindolenine) and 2,3,3-trimethyl-3H-pyrrolo[3,2-b]pyridine (54, 2,3,3-trimethyl-4-azaindolenine) in 29 and 23% yields, respectively (▶ Scheme 18).[101] Thermal azaindolization in boiling diethylene glycol was also achieved by Crooks and Robinson.[102,103] In this way, 2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (55) was prepared from 2-methylpropanal and 4-pyridylhydrazine in 14.5% yield. From butan-2-one, the same compound was obtained in 51.5% yield (▶ Scheme 18). The authors[102,103] suggest that the 3,3-dimethyl-3H-pyrrolo[2,3-b]pyridine structure reported by Kelly and Parrick[104] is in fact the rearranged product, i.e. 2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine.

Scheme 18 Examples of Fischer Azaindole Syntheses[96–103,105]

The cyclization of the (3-pyridyl) hydrazone of cyclohexanone under thermal conditions with zinc(II) chloride leads to a mixture of isomeric azaindole derivatives 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole 56 and the 5,6,7,8-tetrahydro-9H-pyrido[3,4-b]indole 57 (▶ Scheme 18).[105]

Abramovitch discussed some of these reactions, pointing out the necessity for more vigorous conditions than are required for indole synthesis.[106] Until the beginning of the 1960s, the synthesis of substituted azaindoles (e.g., 58) via Fischer-type reactions was scarcely reported (▶ Scheme 19).[96,102,104,107]

Scheme 19 Substituted Azaindoles from Fischer Synthesis[99,100,104,107]

R

1

R

2

Conditions

Yield (%)

Ref

Me

H

diethylene glycol, reflux, 14 h

25

[

104

]

Et

H

diethylene glycol, reflux, 22 h

37

[

104

]

Ph

H

diethylene glycol, reflux, 9 h

88

[

104

]

H

Ph

triethylene glycol, reflux, 4 h

63

[

104

]

(CH

2

)

3

diethylene glycol, reflux, 9 h

67

[

104

]

(CH

2

)

3

diethylene glycol, reflux, 1 h

78

[

107

]

Ph

Ph

diethylene glycol, reflux, 7 h

56

[

107

]

Ph

Ph

PPA,110 °C, 1 h

12

[

99

]

(CH

2

)

4

diethylene glycol, reflux, 7 h

70

[

107

]

(CH

2

)

4

PPA, 160–220 °C

53

[

99

]

Me

Me

diethylene glycol, reflux, 7 h

43

[

104

]

Me

Me

diethylene glycol, reflux, 3 h

65

[

107

]

Heterogeneous catalyzed aza-Fischer reactions of acetaldehyde or acetone with 2-pyridylhydrazine in the presence of alumina and fluorinated alumina give, respectively, 1H-pyrrolo[2,3-b]pyridine (4) at 450 °C or 2-methyl-1H-pyrrolo[2,3-b]pyridine (59) at 315 °C in 15 and 50% yields (▶ Scheme 20).[108] In the search for new water-soluble benzodiazepine receptor ligands the synthesis of compound 61 was carried out via a Fischer reaction of 2-pyridylhydrazine with ketone 60; the sigmatropic rearrangement is effected under thermal conditions (160 °C; ▶ Scheme 20).[109,110] (4-Pyridyl) hydrazine did not react and (3-pyridyl) hydrazine provided a mixture of isomers (no yields reported).[110]

Scheme 20 Further Examples of Aza-Fischer Reactions[108–111]

2-Methyl-3-(phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (62) is prepared in 20% yield via a Fischer indole approach starting with 2-pyridylhydrazine and 1-(phenylsulfanyl) propan-2-one (▶ Scheme 20).[111]

5,6,7,8-Tetrahydro-9H-pyrido[2,3-b]indole (46); Typical Procedure:[99]

Addition of cyclohexanone (4.90 g, 0.05 mol) to 2-pyridylhydrazine (5.45 g, 0.05 mmol) initiated an exothermic reaction. After about 10 min, the product crystallized on scratching from the turbid liquid, and the resulting white powder of cyclohexanone (2-pyridyl) hydrazone (41) was collected by filtration after trituration with H2O; yield: 9.12 g (96%); mp 90.5–92.5 °C. An analytical sample (white plates; mp 92–92.5 °C) was prepared by recrystallization (cyclohexane and EtOH/H2O). In both cases some darkening of the solns, indicating decomposition, was noted.

A mixture of cyclohexanone (2-pyridyl) hydrazone (41; 5.68 g, 0.03 mmol) and PPA (18 g) was heated gradually to about 160 °C with a thermometer in the liquid. Usually, a slight exothermic reaction was observed at about 110 °C as the hydrazone melted. At 160 °C, a vigorous exothermic reaction took place and the temperature rose to 220 °C, in spite of external cooling. When the reaction subsided, the mixture was cooled and dissolved in H2O (100 mL), and the turbid soln was extracted with Et2O, to remove nonbasic materials, and then neutralized with aq NH4OH. The resulting tan solid was sublimed at 110 °C (0.2 Torr) and recrystallized (EtOH/H2O); yield: 2.75 g (53%); mp 155–156 °C.

6,7,8,9-Tetrahydro-5H-pyrido[4,3-b]indole (52); Typical Procedure:[107]

A soln of cyclohexanone (4-pyridyl) hydrazone (51; 3 g, 16 mmol) in diethylene glycol (20 mL) was heated at reflux for 11 h, cooled, and poured into H2O. The solid was collected by filtration; yield: 2.6 g (95%). The crude product was recrystallized (EtOH, charcoal); yield: 2.6 g (95%); mp 268.5–270 °C.

A mixture of benzyl phenyl ketone (2-pyridyl) hydrazone (6.5 g, 22.6 mmol) in diethylene glycol (20 mL) was heated at reflux for 7 h. The mixture was cooled and the solid was collected by filtration and washed with H2O. The dry solid was sublimed at 230 °C (1.5 Torr); yield: 3.42 g (56%); mp 153.5–154.5 °C.

2-Methyl-3-(phenylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (62); Typical Procedure:[111]

1-(Phenylsulfanyl) propan-2-one and 2-pyridylhydrazine were heated in EtOH at reflux for 24 h. The soln was concentrated under reduced pressure. The residue was treated with propane-1,3-diol and the mixture was heated at reflux for 3 h; yield: 20%; mp 180–181 °C.

10.22.1.1.1.1.1.1.1 Variation 1: Indolization with Pyridinium Hydrochloride

So far, only pyrrolo[2,3-c]pyridines have been prepared by this variation of the Fischer synthesis.

Lachance and co-workers[112] performed the Fischer reaction of (2,6-dichloropyridin-3-yl) hydrazine (63) with cyclohexanone in the presence of pyridinium hydrochloride in N-methylpyrrolidin-2-one at high temperature to provide the 1,3-dichloro-5,6,7,8-tetrahydro-9H-pyrido[3,4-b]indole [64, R1,R2 =(CH2)4] in 63% yield, if pyridine liberated from the pyridinium hydrochloride is allowed to escape from the reaction vessel (the presence of pyridine completely inhibits the reaction). Several other compounds 64 are similarly obtained from (2,6-dichloropyridin-3-yl) hydrazine (63) and the appropriate ketones (▶ Scheme 21).

Scheme 21 Fischer Reactions of (2,6-Dichloropyridin-3-yl) hydrazine[112]

R

1

R

2

Yield (%)

Ref

(CH

2

)

4

63

[

112

]

Me

Me

39

[

112

]

Ph

Me

29

[

112

]

(CH

2

)

3

37

[

112

]

(CH

2

)

5

55

[

112

]

5,7-Dichloro-1H-pyrrolo[2,3-c]pyridines 64; General Procedure:[112]

All reactions were performed under ambient atmosphere (i.e., no septum, no cap, no reflux condenser) on an 8.43-mmol scale. The ketone (1.1 equiv) was added to a soln of (2,6-dichloropyridin-3-yl) hydrazine (63; 1.50 g, 8.43 mmol) in NMP (7.50 mL) in a 25-mL round-bottomed flask, and the mixture was stirred at rt for 30–60 min (for ethyl phenyl ketone, the mixture was stirred an additional 15 min at 160 °C). Anhyd py•HCl (2.92 g, 25.3 mmol) was added at 20 °C and the flask was immersed in a preheated oil bath at 160 °C. The mixture was heated for 1–6 h (the reaction progress was monitored by removal of free pyridine), cooled, neutralized with aq NaHCO3, and extracted with EtOAc (when necessary, the phases were filtered through a pad of Celite before their separation). The aqueous layer was further extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane to EtOAc/hexane 1:1).

10.22.1.1.1.1.1.1.2 Variation 2: From (6-Methoxypyridin-3-yl) hydrazine or (2-Methoxypyridin-3-yl) hydrazine

This variation has been applied to the synthesis of pyrrolo[3,2-b]- and pyrrolo[2,3-c]pyridines.

The introduction of electron-donating substituents into the pyridylhydrazine facilitates the normal Fischer reaction but electron-accepting groups hinder the indolization and can promote an anomalous course of the reaction with formation of pyridinamine products of cyclization.[113–117]

An improvement reported by Suzenet and co-workers involves a clean and easy Fischer pathway to achieve the synthesis of 1H-pyrrolo[3,2-b]pyridines and 1H-pyrrolo[2,3-c]pyridines in an acidic medium.[118] All previous attempts with polyphosphoric acid or zinc(II) chloride needed drastic conditions under which labile substituents are affected. With (6-methoxypyridin-3-yl) hydrazine (65), aza-Fischer indolization could in principle lead to both 1H-pyrrolo[3,2-b]pyridine and 1H-pyrrolo[2,3-c]pyridine isomers. In the experimental conditions used, only the 1H-pyrrolo[3,2-b]pyridine framework is obtained whatever carbonyl compound is used.

Scheme 22 Aza-Fischer Indolization Using (6-Methoxypyridin-3-yl) hydrazine[118]

R

1

R

2

Yield (%)

Ref

H

Pr

80

[

118

]

Et

Me

45

[

118

]

Me

Et

45

[

118

]

(CH

2

)

4

80

[

118

]

R

1

R

2

Yield (%)

Ref

(CH

2

)

2

NHAc

Et

69

[

118

]

Ph

Me

70

[

118

]

SMe

Me

48

[

118

]

In the absence of a methoxy group or if this substituent is located at the 6-position [e.g., (6-methoxypyridin-2-yl) hydrazine], no reaction occurs and 1H-pyrrolo[2,3-b]pyridine derivatives are not produced.

To explain the crucial role played by the electron-donating methoxy group on the considerably increased reactivity and high regioselectivity of this cyclization, a push–pull effect on the N-N bond cleavage of intermediate 72, derived from cyclohexanone (2-methoxypyridin-5-yl) hydrazone (71), is postulated and attributed to the mesomeric effect of the methoxy group (▶ Scheme 23).[103,118,120] Concomitantly, the pyridinium nitrogen may help in the formation of the new C-C bond by a second push–pull effect. Therefore, a tandem push–pull effect can explain the unusual reactivity, and the cyclization at the α-position of the pyridine ring is in accord with literature results.[96,105] Classical intermediates 73–75 are also postulated to give the final compound 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole (76).

Scheme 23 Postulated Mechanism for Fischer Cyclization of (2-Methoxypyridin-5-yl) hydrazones[118]

On the basis of these considerations, the reaction of (2-methoxypyridin-3-yl) hydrazine (77) with cyclohexanone gives the 1H-pyrrolo[2,3-c]pyridine 78 cleanly in 55% yield but no reaction is observed with (6-methoxypyridin-2-yl) hydrazine (79; ▶ Scheme 24). A methylsulfanyl substituent at the 6-position of [6-(methylsulfanyl) pyridin-3-yl]hydrazine (80) allows the formation of the 5-(methylsulfanyl)-3-propyl-1H-pyrrolo[3,2-b]pyridine (81) in 57% yield from 2-(methylsulfanyl) pyridin-5-amine (▶ Scheme 24). This approach allows the preparation of 1H-pyrrolo[3,2-b]pyridine or 1H-pyrrolo[2,3-c]pyridine but not 1H-pyrrolo[2,3-b]pyridine derivatives. It should be noted that a 5-methoxy substituent can be easily transformed into a trifluoromethanesulfonate substituent, for example derivative 82 (▶ Scheme 24), suitable for elaboration via palladium-catalyzed cross-coupling reactions.

Scheme 24 Fischer Reaction with (Pyridin-3-yl) hydrazine Derivatives[118]

Scheme 25 Fischer Synthesis of 2-Aryl-3-pyridyl-1H-pyrrolo[3,2-b]pyridines[121]

Ar

1

Ar

2

Yield (%)

Ref

4-pyridyl

Ph

52

[

121

]

4-pyridyl

4-HOC

6

H

4

30

[

121

]

4-pyridyl

3-HOC

6

H

4

34

[

121

]

4-pyridyl

2-HOC

6

H

4

9

[

121

]

4-pyridyl

3-FC

6

H

4

30

[

121

]

3-pyridyl

3-HOC

6

H

4

19

[

121

]

2-pyridyl

3-HOC

6

H

4

34

[

121

]

To a soln of (6-methoxypyridin-3-yl) hydrazine (65; 300 mg, 2.16 mmol) in 4% aq H2SO4 (15 mL) was added pentanal (240 μL, 2.26 mmol). This mixture was stirred at 100 °C for 2 h and then quenched with sat. aq Na2CO3 (15 mL). The crude material was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with H2O (10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 9:1); yield: 328 mg (80%); mp 55 °C.

2-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl) ethan-1-ol (68); Typical Procedure:[118]

To a soln of (6-methoxypyridin-3-yl) hydrazine (65; 200 mg, 1.44 mmol) in 4% aq H2SO4 (10 mL) was added 2-(3-chloropropyl)-1,3-dioxolane (67; 190 μL, 1.44 mmol). This mixture was stirred at 100 °C for 24 h and then quenched with sat. aq Na2CO3 (15 mL). The crude material was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with H2O (10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:1); yield: 110 mg (40%); mp 111 °C.

N-[2-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl) ethyl]acetamide [70,R1 =(CH2)2NHAc; 4-Azamelatonin]; Typical Procedure:[118]

10.22.1.1.1.1.1.1.3 Variation 3: Using Microwave Activation

This variation of the Fischer reaction has been applied to the synthesis of pyrrolo[3,2-b]-, pyrrolo[2,3-c]-, and pyrrolo[2,3-b]pyridines but not to pyrrolo[3,2-c]pyridines.

Scheme 26 Fischer Synthesis under Microwave Irradiation[122]

R

1

R

2

R

3

Yield (%)

Ref

F

(CH

2

)

4

72

[

122

]

Cl

(CH

2

)

4

60

[

122

]

Br

(CH

2

)

4

70

[

122

]

Me

(CH

2

)

4

98

[

122

]

Me

H

Pr

25

[

122

]

2-Fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole [86,R1 =F; R2,R3 =(CH2)4]; Typical Procedure:[122]

Microwave irradiation was carried out in sealed 2–5 mL vessels in a Biotage Initiator system using a standard absorbance level (300-W maximum power). The temperatures were measured externally by an IR probe that determined the temperature on the surface of the vial and could be read directly from the instrument screen. The reaction time was measured from when the mixture had reached the stated temperature for temperaturecontrolled experiments.

10.22.1.1.1.1.1.1.4 Variation 4: From a Pyridin-4-yldiazonium N-Oxide and a β-Oxo Acid

This variation has only been applied to the synthesis of pyrrolo[3,2-c]pyridines.

5-Azatryptamine [92, 2-(1H-pyrrolo[3,2-c]pyridin-3-yl) ethan-1-amine] was synthesized by Pietra and co-workers (▶ Scheme 27). Treatment of diazotized 4-aminopyridine 1-oxide with 2-oxopiperidine-3-carboxylic acid at –10 °C gives the pyridylhydrazone 88 in 72% yield. The cyclization is realized at 200 °C in a mixture of zinc(II) chloride and sodium chloride to give the 2,6-diazacarbazole 6-oxide 89 in 32% yield. Hydrolysis of the amide bond is carried out (acidic or basic medium) to give N-oxide 90 in 87% yield. Reduction of the N-oxide with hydrogen gas over palladium produces the acid 91 (82% yield), which is smoothly decarboxylated in a boiling copper/quinoline system to provide 92 in 71% yield.[124]

Scheme 27 Synthesis of 2-(1H-Pyrrolo[3,2-c]pyridin-3-yl) ethan-1-amine[124]

10.22.1.1.1.1.1.1.5 Variation 5: From a Pyridylhydrazine and an Enamine

This variation has so far only been applied to the synthesis of pyrrolo[3,2-c]- and pyrrolo[2,3-b]pyridines.

Scheme 28 Synthesis of 2-(1H-Pyrrolo[2,3-b]pyridin-3-yl) ethan-1-amine and 2-(1H- Pyrrolo[2,3-b]pyridin-3-yl) propan-1-amine[125]

10.22.1.1.1.1.1.1.6 Variation 6: From a Pyridylhydrazine and a γ-Halo Ketone (Grandberg Synthesis)

This variation has only been applied to the synthesis of pyrrolo[2,3-b]pyridines.

The synthesis of 2-methyl-7-azatryptamine [102, 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) ethan-1-amine] was achieved by Grandberg and co-workers by reaction of 2-pyridylhydrazine with 5-chloropentan-2-one (96) in aqueous ethanol at 160 °C.[126,127] The reaction also works with 1-methyl-1-(2-pyridyl) hydrazine to produce 2-(1,2-dimethyl-1H- pyrrolo[2,3-b]pyridin-3-yl) ethan-1-amine in 65% yield. The nitrogen usually lost during the Fischer process is incorporated as the nitrogen of the aminoethyl side chain via intermediates 97–101 (▶ Scheme 29).

Scheme 29 Synthesis of 2-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) ethan-1-amine[126,127]

The replacement of 5-chloropentan-2-one (96) with 5-chloro-3-methylpentan-2-one (103) affords the tricyclic compound 3a,8a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[3′,2′:4,5]pyrrolo[2,3-b]pyridine (104), which cannot aromatize, in 70% yield (▶ Scheme 30).[127]

Scheme 30 Synthesis of 3a,8a-Dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[3′,2′:4,5]pyrrolo[2,3-b]pyridine[127]

2-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) ethan-1-amine (102); Typical Procedure:[126]

To a soln of 2-pyridylhydrazine (10.8 g, 0.1 mol) in 80% aq EtOH (200 mL) was added 5-chloropentan-2-one (96; 12.3 g, 0.1 mol). The mixture was heated at 160 °C for 6 h in an autoclave, cooled, and concentrated under reduced pressure. The residue was dissolved in 0.1 M aq HCl (200 mL) and the soln was washed with benzene (50 mL) (CAUTION:carcinogen). The aqueous layer was basified with solid KOH with cooling and then extracted with Et2O (50 mL). The organic phase was dried and concentrated, and the residue was dried under reduced pressure; yield: 13.2 g (75%); bp 180–183 °C (1 Torr).

10.22.1.1.1.1.1.1.7 Variation 7: From 4-Hydrazino-6-methylpyridin-2(1H)-one

This variation has only been applied to the synthesis of pyrrolo[3,2-c]pyridines.

Bisagni and co-workers[128] obtained 1H-pyrrolo[3,2-c]pyridine derivatives with substituents on the pyridine ring starting from 4-hydrazino-6-methylpyridin-2(1H)-one (105) and ketones. The hydrazones 106 are obtained in refluxing ethanol and the cyclization is achieved in boiling diphenyl ether to give 1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-ones 107 which are aromatized with phosphoryl chloride at 100 °C to give the corresponding 4-chloro-6-methyl-1H-pyrrolo[3,2-c]pyridines 108 (▶ Scheme 31).

Scheme 31 Fischer Reaction of 6-Methyl-4-[2-(alkan-2-ylidene) hydrazino]pyridin-2(1H)-ones[128]

R

1

R

2

Yield (%)

Ref

106

107

108

Me

H

73

47

20

[

128

]

Me

Me

70

70

31

[

128

]

Ph

Me

40

30

30

[

128

]

Me

Ph

41

24

31

[

128

]

Ph

Et

40

30

60

[

128

]

4-Chloro-6-methyl-1H-pyrrolo[3,2-c]pyridines 108; General Procedure:[128]

A stirred mixture of a hydrazone 106 (0.02 mol) in Ph2O (50 mL) was heated at reflux for 15 h and then cooled. The crystals were collected by filtration, washed with benzene (CAUTION:carcinogen), and recrystallized (H2O or EtOH) to give a 1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one 107. A mixture of this compound (0.03 mol) in POCl3 (200 mL) was heated at ca. 95 °C for 2 h. Excess POCl3