Science of Synthesis: Knowledge Updates 2018 Vol. 2 E-Book

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

Seitenzahl: 946

Veröffentlichungsjahr: 2018

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. Several annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.

Leseprobe

Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

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

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Impressum

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Library of Congress Cataloging in Publication DataScience of synthesis : Houben–Weyl methods of molecular transformations.    p. cm.   Includes bibliographical references.   Contents: Science of Synthesis Knowledge Updates 2018/2/volume editors, J. A. Joule, T. Murai   ISBN 978-3-13-242317-6   1. Organic compounds–Synthesis. I. Title: Houben–Weyl methods of molecular transformations.   QD262.S35 2000   547'.2–dc21         00-061560

(Houben–Weyl methods of organic chemistry)

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISSN (print) 2510-5469ISSN (online) 2566-7297

ISBN (print) 978-3-13-242317-6ISBN (PDF) 978-3-13-242318-3ISBN (EPUB) 978-3-13-242319-0DOI 10.1055/b-006-160285

Structure searchable version available at: sos.thieme.com

Date of publication: June 13, 2018

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Warning! Read carefully the following: Although this reference work has been written by experts, the user must be advised that the handling of chemicals, microorganisms, and chemical apparatus carries potentially life-threatening risks. For example, serious dangers could occur through quantities being incorrectly given. The authors took the utmost care that the quantities and experimental details described herein reflected the current state of the art of science when the work was published. However, the authors, editors, and publishers take no responsibility as to the correctness of the content. Further, scientific knowledge is constantly changing. As new information becomes available, the user must consult it. Although the authors, publishers, and editors took great care in publishing this work, it is possible that typographical errors exist, including errors in the formulas given herein. Therefore, it is imperative that and the responsibility of every user to carefully check whether quantities, experimental details, or other information given herein are correct based on the user’s own understanding as a scientist. Scaleup of experimental procedures published in Science of Synthesis

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 highquality 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.

The Editorial Board

July 2010

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)

Abstracts

10.23 Product Class 23: Pyrido[X,Y-b]indoles (Carbolines)

J. A. Joule

Methods for the synthesis of the four isomeric carboline (pyrido[X,Y-b]indole) ring systems are discussed. Reports from 1919, when the word “carboline” was first coined, up to 2015 are covered, with some references from early 2016 also included.

30.3 Product Class 3: S, S-Acetals

T.-Y. Luh and M.-k. Leung

This section introduces acyclic and cyclic dithioacetals (S,S-acetals) and describes their use as protective groups or alternative functional groups for further transformations.

Keywords: dithioacetals • S,S-acetals • thiols • carbonyl compounds • sulfides • protecting groups

30.3.2.2 1,3-Dithietanes

T.-Y. Luh, M.-k. Leung, and C.-M. Chou

This section is an update to the earlier Science of Synthesiscontribution (30.3.2) describing the synthesis of 1,3-dithietanes. The preparation of symmetrical dithietanes by dimerization of various thiocarbonyl compounds and of unsymmetrical dithietanes from thioketones and imines, or from aldehydes and carbon disulfide is discussed.

Keywords: 1,3-dithietanes • Bunte salts • thioketones • thiophosgene • thiocarbonates • thioacetamides • carbon disulfide

30.3.3.2 1,3-Dithiolanes

M.-k. Leung, C.-M. Chou, and T.-Y. Luh

This section is an update to the earlier Science of Synthesiscontribution (30.3.3) describing the synthesis of 1,3-dithiolanes. As 1,3-dithiolanes are stable under various conditions and are easily converted back into carbonyl groups under mild conditions, they have been widely explored as protecting groups. This section explores newer catalysts as well as solid-supported catalysts for the conversion of carbonyl groups into 1,3-dithiolanes.

Keywords: 1,3-dithiolanes • aldehydes • ketones • carbonyl compounds • ethane-1,2-dithiol • protic acid catalysis • Lewis acid catalysis • heterogeneous catalysis • solid supports • ionic liquids • acetals

Science of Synthesis Knowledge Updates 2018/2

Preface

Abstracts

Table of Contents

10.23 Product Class 23: Pyrido[X,Y-b]indoles (Carbolines)

J. A. Joule

30.3 Product Class 3: S, S-Acetals

T.-Y. Luh and M.-k. Leung

30.3.2.2 1,3-Dithietanes (Update 2018)

T.-Y. Luh, M.-k. Leung, and C.-M. Chou

30.3.3.2 1,3-Dithiolanes (Update 2018)

M.-k. Leung, C.-M. Chou, and T.-Y. Luh

Author Index

Abbreviations

Table of Contents

Volume 10: Fused Five-Membered Hetarenes with One Heteroatom

10.23 Product Class 23: Pyrido[X,Y-b]indoles (Carbolines)

J. A. Joule

10.23 Product Class 23: Pyrido[X,Y-b]indoles (Carbolines)

10.23.1 Product Subclass 1: 9H-Pyrido[2,3-b]indoles (α-Carbolines)

10.23.1.1 Synthesis by Ring-Closure Reactions

10.23.1.1.1 By Annulation to an Arene

10.23.1.1.1.1 By Formation of Four N—C and Two C—C Bonds

10.23.1.1.1.1.1 With Formation of 1—2, 2—3, 4—4a, 1—9a, 8a—9, and 9—9a Bonds

10.23.1.1.1.1.1.1 Method 1: From 1-Bromo-2-(2,2-dibromovinyl)benzenes, Ammonia, and Alkyl Aldehydes

10.23.1.1.1.2 By Formation of Two N—C and One C—C Bonds

10.23.1.1.1.2.1 With Formation of 1—9a, 4—4a, and 9—9a Bonds

10.23.1.1.1.2.1.1 Method 1: From (2-Nitroaryl)acetonitriles and 3-Acetoxy-3-aryl-2-methylene Ketones

10.23.1.1.1.2.1.2 Method 2: From (2-Nitrophenyl)acetonitrile and 3-Arylenones

10.23.1.1.1.2.1.2.1 Variation 1: From (2-Nitrophenyl)acetonitrile and 4H-1-Benzopyran-4-ones

10.23.1.1.1.3 By Formation of Two N—C Bonds

10.23.1.1.1.3.1 With Formation of 8a—9 and 9—9a Bonds

10.23.1.1.1.3.1.1 Method 1: From Primary Amines and 3-(2-Bromophenyl)-2-chloropyridine

10.23.1.1.1.4 By Formation of One N—C Bond and One C—C Bond

10.23.1.1.1.4.1 With Formation of 4a—4b and 9—9a Bonds

10.23.1.1.1.4.1.1 Method 1: From 2,3-Dihalopyridines and Anilines

10.23.1.1.1.4.1.2 Method 2: From 2-Iodopyridine and a 2-Bromoaniline

10.23.1.1.1.5 By Formation of Two C—C Bonds

10.23.1.1.1.5.1 With Formation of 3—4 and 4a—9a Bonds

10.23.1.1.1.5.1.1 Method 1: From (2-Alkenylaryl)carbodiimides

10.23.1.1.1.5.1.2 Method 2: From N-Acyl-N-(2-alkynylaryl)pyrimidin-2-amines or 3-[(2-Alkynylphenyl)amino]pyrazin-2-ones

10.23.1.1.1.6 By Formation of One N—C Bond

10.23.1.1.1.6.1 With Formation of the 9—9a Bond

10.23.1.1.1.6.1.1 Method 1: From 3-(2-Azidoaryl)pyridines

10.23.1.1.1.6.1.1.1 Variation 1: From 3-(2-Azidoaryl)pyridinium Trifluoromethanesulfonates and a Rhodium Catalyst

10.23.1.1.1.6.1.2 Method 2: From 3-(2-Nitroaryl)pyridines

10.23.1.1.1.6.1.2.1 Variation 1: From 3-(2-Nitrosoaryl)pyridines

10.23.1.1.1.6.1.3 Method 3: From 2-(3-Pyridyl)-N-tosylanilines or N-Acetyl-2-(3-pyridyl)-anilines

10.23.1.1.1.6.1.4 Method 4: From N-[2-(2-Fluoropyridin-3-yl)phenyl]pivalamide

10.23.1.1.1.7 By Formation of One C—C Bond

10.23.1.1.1.7.1 With Formation of the 4a—4b Bond

10.23.1.1.1.7.1.1 Method 1: From N-Arylpyridin-2-amines

10.23.1.1.1.7.1.1.1 Variation 1: From N,N-Diphenylpyridin-2-amine or N-Methyl-N-phenylpyridin-2-amine

10.23.1.1.1.7.1.2 Method 2: From N2-Phenylpyridine-2,3-diamines

10.23.1.1.1.7.1.3 Method 3: From an N-Arylpyridin-2-amine with at Least One Halogen on at Least One Ring

10.23.1.1.1.7.1.3.1 Variation 1: From N-Aryl-3-chloropyridin-2-amines by Palladium Catalysis

10.23.1.1.1.7.1.3.2 Variation 2: From N-Aryl-3-bromopyridin-2-amines with Palladium Catalysis

10.23.1.1.1.7.1.3.3 Variation 3: From N-[3-Chloro-1-methylpyridin-2(1H)-ylidene]anilines

10.23.1.1.1.7.1.3.4 Variation 4: From N-(Chloroaryl)-3-chloro-1-methylpyridin-2(1H)-imines and Secondary Amines

10.23.1.1.1.7.1.3.5 Variation 5: From N-Aryl-3-halopyridin-2-amines by Photostimulated SRN1 Reactions

10.23.1.1.1.7.1.3.6 Variation 6: From 3-Bromo-N-(2-bromophenyl)pyridin-2-amines by Palladium(0)-Catalyzed Bond Formation via Tributylstannyl Intermediates

10.23.1.1.2 By Annulation to a Heterocycle

10.23.1.1.2.1 By Annulation to a Pyridine

10.23.1.1.2.1.1 By Formation of One N—C and One C—C Bond

10.23.1.1.2.1.1.1 With Formation of 4a—4b and 8a—9 Bonds

10.23.1.1.2.1.1.1.1 Method 1: From Pyridin-2,4,6-triamine

10.23.1.1.2.2 By Annulation to an Indole

10.23.1.1.2.2.1 By Formation of Two N—C and One C—C Bonds

10.23.1.1.2.2.1.1 With Formation of 1—2, 1—9a, and 4—4a Bonds

10.23.1.1.2.2.1.1.1 Method 1: From 2-Bromo-1H-indole

10.23.1.1.2.2.2 By Formation of One N—C and Two C—C Bonds

10.23.1.1.2.2.2.1 With Formation of 1—2, 2—3, and 4—4a Bonds

10.23.1.1.2.2.2.1.1 Method 1: From Ethyl 2-Amino-1H-indole-3-carboxylates, an Arylacetylene, and an Aryl Aldehyde

10.23.1.1.2.2.3 By Formation of Two N—C Bonds

10.23.1.1.2.2.3.1 With Formation of 1—2 and 1—9a Bonds

10.23.1.1.2.2.3.1.1 Method 1: From 1,5-Dicarbonyl Compounds or Equivalents

10.23.1.1.2.2.4 By Formation of One N—C and One C—C Bonds

10.23.1.1.2.2.4.1 With Formation of 1—2 and 4—4a Bonds

10.23.1.1.2.2.4.1.1 Method 1: From 1H-Indol-2-amines and Alkynones

10.23.1.1.2.2.4.1.1.1 Variation 1: From 1H-Indol-2-amines and 1,3-Diketones

10.23.1.1.2.2.4.1.1.2 Variation 2: From N-(Phosphoranylidene)indol-2-amines

10.23.1.1.2.2.4.1.2 Method 2: From N-(Arylsulfonyl)-3-diazo-1,3-dihydroindol-2-imines

10.23.1.1.2.2.4.2 With Formation of 1—2 and 2—3 Bonds

10.23.1.1.2.2.4.2.1 Method 1: From 3-Alkenyl-N-(triphenylphosphoranylidene)-1H-indol-2-amines

10.23.1.1.2.2.4.2.1.1 Variation 1: From 3-(2-Nitrovinyl)-N-(triphenylphosphoranylidene)-1H-indol-2-amines

10.23.1.1.2.2.4.3 With Formation of 1—2 and 3—4 Bonds

10.23.1.1.2.2.4.3.1 Method 1: From a 2-Amino-1H-indole-3-carbothioaldehyde

10.23.1.1.2.2.4.4 With Formation of 1—9a and 3—4 Bonds

10.23.1.1.2.2.4.4.1 Method 1: From 3-[Bis(methylsulfanyl)methylene]-1-methyl-1,3-dihydro-2H-indol-2-one

10.23.1.1.2.2.5 By Formation of Two C—C Bonds

10.23.1.1.2.2.5.1 With Formation of 3—4 and 4—4a Bonds

10.23.1.1.2.2.5.1.1 Method 1: From N-(1H-Indol-2-yl)acetamide

10.23.1.1.2.2.6 By Formation of One N—C Bond

10.23.1.1.2.2.6.1 With Formation of the 1—9b Bond

10.23.1.1.2.2.6.1.1 Method 1: From 3-(1H-Indol-3-yl)allyl Azides

10.23.1.1.2.2.6.1.2 Method 2: From 3-(1H-Indol-3-yl)propanone O-2,4-Dinitrophenyl Oximes

10.23.1.1.2.2.6.1.2.1 Variation 1: From 3-(1H-Indol-3-yl)propanone O-Pentafluorobenzoyl Oximes

10.23.1.1.2.2.6.1.2.2 Variation 2: From 3-(1H-Indol-3-yl)propanone O-Acetyl Oximes

10.23.1.1.2.2.6.1.2.3 Variation 3: From 3-(1H-Indol-3-yl)prop-2-enone O-Methyl Oximes

10.23.1.1.2.2.6.1.3 Method 3: From a 3-(2-Bromo-1H-indol-3-yl)allylamine

10.23.1.1.2.2.6.2 With Formation of the 1—2 Bond

10.23.1.1.2.2.6.2.1 Method 1: From a 3-Propargyl-1H-indol-2-amine

10.23.1.1.2.2.6.2.2 Method 2: From a 3-(2-Amino-1H-indol-3-yl)-2-cyanoacrylate

10.23.1.1.2.2.6.2.3 Method 3: From N′-[3-(2-Aroylvinyl)-1H-indol-2-yl]alkanimidamides

10.23.1.1.2.2.7 By Formation of One C—C Bond

10.23.1.1.2.2.7.1 With Formation of the 2—3 Bond

10.23.1.1.2.2.7.1.1 Method 1: From 3-Acetyl-2-(acylamino)-1H-indoles with Phosphoryl Chloride

10.23.1.1.2.2.7.1.1.1 Variation 1: From 3-Acetyl-2-(acylamino)-1H-indoles with Potassium tert-Butoxide

10.23.1.1.2.2.7.1.1.2 Variation 2: From N′-[3-(2-Aroylvinyl)-1H-indol-2-yl]alkanimidamides

10.23.1.1.2.2.7.2 With Formation of the 3—4 Bond

10.23.1.1.2.2.7.2.1 Method 1: From N′-(3-Cyano-1H-indol-2-yl)acetimidamides

10.23.1.1.2.2.7.2.2 Method 2: From N′-(3-Formyl-1H-indol-2-yl)alkanimidamides

10.23.1.1.2.2.7.2.3 Method 3: From a 2-Amino-1H-indole-3-carboxylate and a 1,3-Oxo Ester Equivalent

10.23.1.1.2.3 By Annulation to a 1H-Pyrrolo[2,3-b]pyridine (a 7-Azaindole)

10.23.1.1.2.3.1 By Formation of Three C—C Bonds

10.23.1.1.2.3.1.1 With Formation of 4b—5, 6—7, and 8—8a Bonds

10.23.1.1.2.3.1.1.1 Method 1: From a 1H-Pyrrolo[2,3-b]pyridine and Two Equivalents of Methyl Acrylate

10.23.1.1.2.3.2 By Formation of Two C—C Bonds

10.23.1.1.2.3.2.1 With Formation of 4b—5 and 8—8a Bonds

10.23.1.1.2.3.2.1.1 Method 1: From a 1H-Pyrrolo[2,3-b]pyridine-3-boronic Acid

10.23.1.1.2.3.2.2 With Formation of 4b—5 and 6—7 Bonds

10.23.1.1.2.3.2.2.1 Method 1: From a 2-Vinyl-1H-pyrrolo[2,3-b]pyridine

10.23.1.1.2.3.2.3 With Formation of 6—7 and 8—8b Bonds

10.23.1.1.2.3.2.3.1 Method 1: From a 3-Vinyl-1H-pyrrolo[2,3-b]pyridine

10.23.1.1.2.3.3 By Formation of One C—C Bond

10.23.1.1.2.3.3.1 With Formation of the 8—8a Bond

10.23.1.1.2.3.3.1.1 Method 1: Intramolecular Acylation

10.23.1.2 Synthesis by Ring Transformation

10.23.1.2.1 Method 1: From 1-(2-Pyridyl)-1H-benzotriazoles

10.23.1.2.2 Method 2: From 3-Aryl-3H-[1,2,3]-triazolo[4,5-b]pyridines

10.23.1.3 Aromatization

10.23.1.4 Synthesis by Substituent Modification

10.23.1.4.1 Substitution of Existing Substituents

10.23.1.4.1.1 Substitution of N-Hydrogen

10.23.1.4.1.1.1 Giving N-Sulfur 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.1.2 Giving N-Carbon 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.1.2.1 Method 1: Using an Alkyl or Aryl Halide

10.23.1.4.1.1.2.2 Method 2: Via 1-Alkyl-9H-pyrido[2,3-b]indol-1-ium Salts

10.23.1.4.1.1.2.3 Method 3: Using Acyl Halides or Anhydrides

10.23.1.4.1.2 Substitution of N-Carbon and N-Sulfur

10.23.1.4.1.2.1 Giving N-Hydrogen 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.2.1.1 Method 1: N-Deprotection

10.23.1.4.1.3 Substitution of C-Hydrogen

10.23.1.4.1.3.1 Direct Substitution by Electrophiles

10.23.1.4.1.3.1.1 Method 1: Giving C-Halogen 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.3.1.2 Method 2: Giving C-Sulfur 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.3.1.3 Method 3: Giving C-Nitrogen 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.3.1.4 Method 4: Giving C-Carbon 9H-Pyrido[2,3-b]indoles

10.23.1.4.1.3.2 Substitution via Metalation

10.23.1.4.1.3.3 Substitution via 1-Oxides

10.23.1.4.1.3.4 Substitution via Displacement of Halogen

10.23.1.4.1.3.4.1 Method 1: Direct Nucleophilic Displacement

10.23.1.4.1.3.4.2 Method 2: Substitution of Halogen via Cross-Coupling Processes

10.23.1.4.1.3.4.2.1 Variation 1: Forming Amines

10.23.1.4.1.3.4.2.2 Variation 2: Forming Phenolic Ethers

10.23.1.4.1.3.4.2.3 Variation 3: Adding Carbon Substituents

10.23.1.4.2 Modification of Substituents

10.23.1.4.2.1 Modification of C-Oxygen Functionalities

10.23.1.4.2.1.1 Method 1: Giving C-Halogen

10.23.1.4.2.1.2 Method 2: Giving Quinones

10.23.1.4.2.1.3 Method 3: Giving Phenolic Ethers

10.23.1.4.2.2 Modification of C-Nitrogen Functionalities

10.23.1.4.2.2.1 Method 1: Giving C-Nitrogen 9H-Pyrido[2,3-b]indoles

10.23.1.4.2.2.2 Method 2: Giving C-Halogen 9H-Pyrido[2,3-b]indoles

10.23.1.4.2.2.3 Method 3: Giving C-Carbon 9H-Pyrido[2,3-b]indoles

10.23.1.4.2.3 Modification of C-Carbon Functionalities

10.23.1.4.2.3.1 Method 1: Giving C-Carbon 5H-Pyrido[3,2-b]indoles

10.23.2 Product Subclass 2: 9H-Pyrido[3,4-b]indoles (β-Carbolines)

10.23.2.1 Synthesis by Ring-Closure Reactions

10.23.2.1.1 By Annulation to an Arene

10.23.2.1.1.1 By Formation of One N—C and Two C—C Bonds

10.23.2.1.1.1.1 With Formation of 1—2, 3—4, and 4a—9b Bonds

10.23.2.1.1.1.1.1 Method 1: From 2,N-Dialkynyl-N-tosylanilines and Methyl Cyanoformate

10.23.2.1.1.1.1.2 Method 2: By Intramolecular Reaction of a Cyano-Substituted 2,N-Dialkynyl-N-tosylaniline

10.23.2.1.1.2 By Formation of One N—C Bond and One C—C Bond

10.23.2.1.1.2.1 With Formation of 4a—4b and 9—9a Bonds

10.23.2.1.1.2.1.1 Method 1: From (2-Aminophenyl)boronic Acid

10.23.2.1.1.3 By Formation of Two C—C Bonds

10.23.2.1.1.3.1 With Formation of 3—4 and 4a—9a Bonds

10.23.2.1.1.3.1.1 Method 1: From 3-[(2-Alkynylphenyl)amino]pyrazin-2-ones

10.23.2.1.1.4 By Formation of One N—C Bond

10.23.2.1.1.4.1 With Formation of the 2—3 Bond

10.23.2.1.1.4.1.1 Method 1: From 3-Alkynyl-1H-indole-2-carbaldehyde Oximes

10.23.2.1.1.4.1.2 Method 2: From 3-Alkenyl-1H-indole-2-carbaldehyde Oximes

10.23.2.1.1.4.1.3 Method 3: From 3-Alkynyl-1H-indole-2-carboxamides

10.23.2.1.1.4.2 With Formation of the 8a—9 Bond

10.23.2.1.1.4.2.1 Method 1: From 4-Aryl-3-nitropyridines

10.23.2.1.1.4.2.2 Method 2: From 4-(2-Bromoaryl)pyridin-3-amines

10.23.2.1.1.4.2.3 Method 3: From 3-Acetamido-4-(2-bromoaryl)-3,4-dihydropyridin-2-ones

10.23.2.1.1.4.3 With Formation of the 9—9a Bond

10.23.2.1.1.4.3.1 Method 1: From a 4-(2-Azidophenyl)pyridine by Thermolysis

10.23.2.1.1.4.3.2 Method 2: From 4-(2-Azidoaryl)pyridinium Trifluoromethanesulfonates and a Rhodium Catalyst

10.23.2.1.1.4.3.3 Method 3: From 4-(2-Nitroaryl)pyridines

10.23.2.1.1.4.3.4 Method 4: From 2-(3-Halopyridin-4-yl)anilines

10.23.2.1.1.4.3.5 Method 5: From N-[2-(3-Fluoropyridin-4-yl)phenyl]pivalamides

10.23.2.1.1.4.3.6 Method 6: From 2-(2-Chloropyridin-4-yl)-N-tosylanilines

10.23.2.1.1.5 By Formation of One C—C Bond

10.23.2.1.1.5.1 With Formation of the 4a—4b Bond

10.23.2.1.1.5.1.1 Method 1: From an N-Arylpyridin-3-amine by Irradiation

10.23.2.1.1.5.1.2 Method 2: From N-(2-Haloaryl)pyridin-3-amines by Palladium(0)-Catalyzed Bond Formation

10.23.2.1.1.5.1.3 Method 3: From 4-Halo-N-phenylpyridin-3-amines by Intramolecular Palladium(0)-Catalyzed Bond Formation

10.23.2.1.1.5.1.4 Method 4: From 4-Bromo-N-phenylpyridin-3-amines by Intramolecular Photostimulated SRN1 Reaction

10.23.2.1.1.5.1.5 Method 5: From 4-Bromo-N-(2-bromophenyl)pyridin-3-amines by Palladium(0)-Catalyzed Bond Formation via Tributylstannyl Intermediates

10.23.2.1.1.5.1.6 Method 6: From an N-(2-Diazophenyl)-N-methylpyridin-3-amine

10.23.2.1.2 By Annulation to a Heterocycle

10.23.2.1.2.1 By Annulation to an Indole

10.23.2.1.2.1.1 By Formation of Two N—C Bonds

10.23.2.1.2.1.1.1 With Formation of 1—2 and 2—3 Bonds

10.23.2.1.2.1.1.1.1 Method 1: From 1H-Indolic 1,5-Dicarbonyls and Ammonia

10.23.2.1.2.1.1.1.1.1 Variation 1: From 2-Acyl-3-(2-ethoxyvinyl)-1H-indoles and Ammonia

10.23.2.1.2.1.1.1.1.2 Variation 2: From Ethyl 3-[1-(Dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-1-methyl-1H-indole-2-carboxylate

10.23.2.1.2.1.1.1.1.3 Variation 3: From 3-Alkynyl-1H-indole-2-carbaldehydes and Ammonia

10.23.2.1.2.1.1.1.1.4 Variation 4: From 2-Acyl-3-alkynyl-1H-indoles and Ammonia

10.23.2.1.2.1.2 By Formation of One N—C Bond and One C—C Bond

10.23.2.1.2.1.2.1 With Formation of 1—2 and 3—4 Bonds

10.23.2.1.2.1.2.1.1 Method 1: From Ethyl 3-(2-Ethoxy-2-oxoethyl)-1H-indole-2-carboxylate.

10.23.2.1.2.1.2.2 With Formation of 2—3 and 4—4a Bonds

10.23.2.1.2.1.2.2.1 Method 1: From tert-Butylimines of 1H-Indole-2-carbaldehydes

10.23.2.1.2.1.2.2.1.1 Variation 1: From tert-Butylimines of 3-Iodo-1H-indole-2-carbaldehydes

10.23.2.1.2.1.2.2.1.2 Variation 2: From tert-Butylimines of 3-Unsubstituted 1H-Indole-2-carbaldehydes

10.23.2.1.2.1.2.2.1.3 Variation 3: From O-Acetyloximes of 2-Acyl-1H-indoles and Internal Alkynes by a Copper/Rhodium Bimetallic Relay Catalyst

10.23.2.1.2.1.2.2.1.4 Variation 4: From a 2-(1-Azidovinyl)-1H-indole with an Internal Alkyne and Copper/Rhodium Bimetallic Catalysis

10.23.2.1.2.1.2.2.2 Method 2: From 1H-Indole-2-carboxamides

10.23.2.1.2.1.2.2.2.1 Variation 1: From 1-Alkyl-1H-indole-2-carboxamides with Internal Alkynes and Palladium(II) Acetate

10.23.2.1.2.1.2.2.2.2 Variation 2: From 1-Methyl-1H-indole-2-carboxamide with Diphenylacetylene and a Ruthenium Catalyst

10.23.2.1.2.1.2.2.2.3 Variation 3: From 1-Alkyl-1H-indole-2-carboxamides with Ethynyl N-Methyliminodiacetic Acid (MIDA) Boronate and a Rhodium Catalyst

10.23.2.1.2.1.2.2.2.4 Variation 4: From 1-Methyl-1H-indole-2-carboxamide with Vinyl Acetate

10.23.2.1.2.1.2.2.3 Method 3: From 2-(Azidomethyl)-1H-indoles and Ynamides

10.23.2.1.2.1.2.3 With Formation of 1—2 and 1—9a Bonds

10.23.2.1.2.1.2.3.1 Method 1: From 2-(1H-Indol-3-yl)ethan-1-amines (Tryptamines) and Aldehydes

10.23.2.1.2.1.2.3.1.1 Variation 1: With Hetaryl Aldehydes

10.23.2.1.2.1.2.3.1.2 Variation 2: With α-Oxoaldehydes

10.23.2.1.2.1.2.3.1.3 Variation 3: From Tryptamine with an Arylglyoxal and Palladium on Carbon

10.23.2.1.2.1.2.3.1.4 Variation 4: With Aryl Methyl Ketones or Styrenes

10.23.2.1.2.1.2.3.2 Method 2: From Tryptophan Esters or Amides and Trifluoroacetic Acid

10.23.2.1.2.1.2.3.3 Method 3: From Iminophosphoranes

10.23.2.1.2.1.2.4 With Formation of 2—3 and 1—9a Bonds

10.23.2.1.2.1.2.4.1 Method 1: From 3-Alkenyl-1H-indoles and an Oxime

10.23.2.1.2.1.3 By Formation of Two C—C Bonds

10.23.2.1.2.1.3.1 With Formation of 1—9a and 4—4a Bonds

10.23.2.1.2.1.3.1.1 Method 1: From a 1H-Indole and a 2-Aza-1,3-diene

10.23.2.1.2.1.3.1.2 Method 2: From 1H-Indoles and 1,2,4-Triazines via Cycloaddition then Elimination of Nitrogen

10.23.2.1.2.1.3.1.2.1 Variation 1: Intramolecularly from a 1-Acyl-1H-indole with a 1,2,4-Triazine Substituent

10.23.2.1.2.1.3.1.2.2 Variation 2: Intramolecularly from a 1-Alkyl-1H-indole with a 1,2,4-Triazine Substituent

10.23.2.1.2.1.3.1.2.3 Variation 3: Intermolecularly from 1H-Indoles and 1,2,4-Triazines

10.23.2.1.2.1.3.1.2.4 Variation 4: From 1H-Indoles and 1,2,4-Triazines Generated In Situ

10.23.2.1.2.1.4 By Formation of One N—C Bond

10.23.2.1.2.1.4.1 With Formation of the 1—2 Bond

10.23.2.1.2.1.4.1.1 Method 1: From a 2-[Bis(acetylsulfanyl)methyl]-1H-indole-3-pyruvate Oxime

10.23.2.1.2.1.4.1.2 Method 2: From a 2-{2-[Bis(methylsulfanyl)methylene]-2,3-dihydroindol-3-yl}acetonitrile

10.23.2.1.2.1.4.2 With Formation of the 2—3 Bond

10.23.2.1.2.1.4.2.1 Method 1: From 2-Acyl-3-alkenyl-1H-indole Oximes

10.23.2.1.2.1.4.2.2 Method 2: From 2-Acyl-3-alkynyl-1H-indole Imines or Oximes

10.23.2.1.2.1.4.2.3 Method 3: From tert-Butylimines of 3-Alkynyl-1H-indole-2-carbaldehydes

10.23.2.1.2.1.4.2.4 Method 4: From 3-Alkynyl-2-(azidomethyl)-1H-indoles

10.23.2.1.2.1.5 By Formation of One C—C Bond

10.23.2.1.2.1.5.1 With Formation of the 1—9a Bond

10.23.2.1.2.1.5.1.1 Method 1: From N-Acyltryptamines

10.23.2.1.2.1.5.2 With Formation of the 4—4a Bond

10.23.2.1.2.1.5.2.1 Method 1: From N-(2,2-Dialkoxyethyl)-1H-indole-2-carboxamides

10.23.2.1.2.1.5.2.2 Method 2: From an N-Allyl-3-iodo-1H-indole-2-carboxamide

10.23.2.1.2.1.5.2.3 Method 3: From an N-(2-Oxoalkyl)-1H-indole-2-carboxamide

10.23.2.1.2.1.5.2.4 Method 4: From an N-Propargyl-1H-indole-2-carboxamide

10.23.2.2 Synthesis by Ring Transformation

10.23.2.2.1 Method 1: From 1-(3-Pyridyl)-1H-benzotriazoles

10.23.2.2.2 Method 2: From 3-Aryl-3H-1,2,3-triazolo[4,5-c]pyridines

10.23.2.2.3 Method 3: From 4-[(1H-Indol-3-yl)methyl]oxazol-5(4H)-ones

10.23.2.2.4 Method 4: From Pyrano[3,4-b]indol-3(9H)-ones

10.23.2.3 Aromatization

10.23.2.3.1 Method 1: From 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indoles

10.23.2.3.2 Method 2: From 4,9-Dihydro-3H-pyrido[3,4-b]indoles

10.23.2.3.3 Method 3: From 2-Aryl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-iums

10.23.2.3.4 Method 4: From 2,9-Dihydro-1H-pyrido[3,4-b]indoles

10.23.2.3.5 Method 5: From 6,7,8,9-Tetrahydro-5H-pyrido[3,4-b]indoles

10.23.2.4 Synthesis by Substituent Modification

10.23.2.4.1 Substitution of Existing Substituents

10.23.2.4.1.1 Substitution of N-Hydrogen

10.23.2.4.1.1.1 Giving N-Carbon 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.1.1.1 Method 1: 9-Alkylation Using an Alkyl Halide

10.23.2.4.1.1.1.2 Method 2: 9-Arylation Using an Aryl Halide

10.23.2.4.1.1.1.3 Method 3: 9-Acylation

10.23.2.4.1.1.1.4 Method 4: 2-Alkylation Giving 2-Alkyl-9H-pyrido[3,4-b]indol-2-ium Salts and thence 2-Alkyl-2H-pyrido[3,4-b]indoles

10.23.2.4.1.2 Substitution of N-Carbon and N-Sulfur

10.23.2.4.1.2.1 Giving N-Hydrogen 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.2.1.1 Method 1: N-Deprotection

10.23.2.4.1.3 Substitution of C-Hydrogen

10.23.2.4.1.3.1 Direct Substitution by Electrophiles

10.23.2.4.1.3.1.1 Method 1: Giving C-Halogen 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.3.1.2 Method 2: Giving C-Sulfur 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.3.1.3 Method 3: Giving C-Nitrogen 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.3.1.4 Method 4: Giving C-Carbon 9H-Pyrido[3,4-b]indoles

10.23.2.4.1.3.2 Direct Substitution by Radicals

10.23.2.4.1.3.3 Substitution via Metalation

10.23.2.4.1.3.4 Substitution via 2-Oxides (N-Oxides)

10.23.2.4.1.3.4.1 Variation 1: With Formation of 9H-Pyrido[3,4-b]indole-1-carbonitriles

10.23.2.4.1.3.4.2 Variation 2: With Formation of 9H-Pyrido[3,4-b]indol-1-ols (2,9-Dihydro-1H-pyrido[3,4-b]indol-1-ones)

10.23.2.4.1.3.4.3 Variation 3: With Formation of 1-Halo-9H-pyrido[3,4-b]indoles

10.23.2.4.1.3.4.4 Variation 4: With Formation of 1-Carbon-9H-pyrido[3,4-b]indoles

10.23.2.4.1.3.5 Substitution via Displacement of Halogen

10.23.2.4.1.3.5.1 Method 1: Direct Nucleophilic Displacement

10.23.2.4.1.3.5.1.1 Variation 1: With Formation of Amines

10.23.2.4.1.3.5.1.2 Variation 2: With Formation of Ethers

10.23.2.4.1.3.5.1.3 Variation 3: With Formation of Halides

10.23.2.4.1.3.5.2 Method 2: Substitution of Halogen (or Trifluoromethanesulfonate) via Cross-Coupling Processes

10.23.2.4.1.3.5.2.1 Variation 1: Reaction at C1

10.23.2.4.1.3.5.2.2 Variation 2: Reaction at C4

10.23.2.4.1.3.5.2.3 Variation 3: Reaction at Benzene Ring Positions

10.23.2.4.1.3.6 Substitution via Displacement of Oxygen

10.23.2.4.2 Modification of Substituents

10.23.2.4.2.1 Modification of C-Oxygen Functionalities

10.23.2.4.2.1.1 Method 1: Giving C-Halogen

10.23.2.4.2.1.2 Method 2: Giving C-Oxygen

10.23.2.4.2.2 Modification of C-Nitrogen Functionalities

10.23.2.4.2.2.1 Method 1: Giving C-Nitrogen

10.23.2.4.2.2.2 Method 2: Giving C-Halogen

10.23.2.4.2.2.3 Method 3: Giving C-Oxygen

10.23.2.4.2.3 Modification of C-Carbon Functionalities

10.23.2.4.2.3.1 Method 1: Giving C-Carbon 9H-Pyrido[3,4-b]indoles

10.23.2.4.2.3.1.1 Variation 1: From Alkyl-Substituted 9H-Pyrido[3,4-b]indoles

10.23.2.4.2.3.1.2 Variation 2: From 9H-Pyrido[3,4-b]indolyl Alcohols

10.23.2.4.2.3.1.3 Variation 3: From 9H-Pyrido[3,4-b]indolyl Aldehydes and Ketones

10.23.2.4.2.3.1.4 Variation 4: From 9H-Pyrido[3,4-b]indole Acids, Esters, and Amides

10.23.2.4.2.3.2 Method 2: Giving C-Nitrogen 9H-Pyrido[3,4-b]indoles

10.23.2.4.2.3.3 Method 3: Giving C-Hydrogen 9H-Pyrido[3,4-b]indoles

10.23.3 Product Subclass 3: 5H-Pyrido[4,3-b]indoles (γ-Carbolines)

10.23.3.1 Synthesis by Ring-Closure Reactions

10.23.3.1.1 By Annulation to an Arene

10.23.3.1.1.1 By Formation of One N—C and Two C—C Bonds

10.23.3.1.1.1.1 With Formation of 1—2, 3—4, and 4a—9b Bonds

10.23.3.1.1.1.1.1 Method 1: From 2,N-Dialkynyl-N-tosylanilines and Methyl Cyanoformate

10.23.3.1.1.2 By Formation of One N—C Bond and One C—C Bond

10.23.3.1.1.2.1 With Formation of 4a—5 and 9a—9b Bonds

10.23.3.1.1.2.1.1 Method 1: From Arylhydrazines

10.23.3.1.1.2.1.1.1 Variation 1: Using a 4-Hydroxypyridin-2-one

10.23.3.1.1.2.1.1.2 Variation 2: Using 1-Acetyl-3-bromopiperidin-4-one

10.23.3.1.1.2.1.2 Method 2: From 4-Fluoro-3-iodopyridine

10.23.3.1.1.2.2 With Formation of 1—2 and 1—9b Bonds

10.23.3.1.1.2.2.1 Method 1: From Iminophosphoranes

10.23.3.1.1.3 By Formation of One N—C Bond

10.23.3.1.1.3.1 With Formation of the 4a—5 Bond

10.23.3.1.1.3.1.1 Method 1: From 3-(2-Azidoaryl)pyridines

10.23.3.1.1.3.1.1.1 Variation 1: From 3-(2-Azidoaryl)pyridinium Salts and a Ruthenium Catalyst

10.23.3.1.1.3.1.2 Method 2: From 3-(2-Nitrosoaryl)pyridines

10.23.3.1.1.3.1.3 Method 3: From 2-(3-Pyridyl)-N-tosylanilines or N-Acetyl-2-(3-pyridyl)-anilines

10.23.3.1.1.3.1.4 Method 4: From 4-Fluoro-3-(2-pivaloylaminophenyl)pyridine

10.23.3.1.1.4 By Formation of One C—C Bond

10.23.3.1.1.4.1 With Formation of the 9a—9b Bond

10.23.3.1.1.4.1.1 Method 1: From N-Arylpyridin-4-amines

10.23.3.1.1.4.1.2 Method 2: From an N-Arylpyridin-4-amine with at Least One Halogen on at Least One Ring

10.23.3.1.1.4.1.2.1 Variation 1: From an N-(2-Bromophenyl)pyridin-4-amine

10.23.3.1.1.4.1.2.2 Variation 2: From an N-Aryl-3-bromopyridin-4-amine

10.23.3.1.1.4.1.2.3 Variation 3: From an N-(2-Bromophenyl)-3-bromopyridin-4-amine by Palladium(0)-Catalyzed Bond Formation via Tributylstannyl Intermediates

10.23.3.1.1.4.1.3 Method 3: From N-Aryl-3-halopyridin-4-amines by Photostimulated SRN1 Reactions

10.23.3.1.2 By Annulation to a Heterocycle

10.23.3.1.2.1 By Annulation to a Pyridine

10.23.3.1.2.2 By Annulation to an Indole

10.23.3.1.2.2.1 By Formation of Two N—C and One C—C Bonds

10.23.3.1.2.2.1.1 With Formation of 1—2, 2—3, and 4—4a Bonds

10.23.3.1.2.2.1.1.1 Method 1: From 3-Acetyl-1H-indole, an Alkyne and a Primary Amine

10.23.3.1.2.2.1.2 With Formation of 1—2, 2—3, and 3—4 Bonds

10.23.3.1.2.2.1.2.1 Method 1: From 2-(2-Oxoalkyl)-1H-indole-3-carbaldehydes and Aryl Aldehydes

10.23.3.1.2.2.2 By Formation of Two N—C Bonds

10.23.3.1.2.2.2.1 With Formation of 1—2 and 2—3 Bonds

10.23.3.1.2.2.2.1.1 Method 1: From 2-(3-Acetyl-1H-indol-2-yl)acetonitrile

10.23.3.1.2.2.2.1.2 Method 2: From 2-(3-Formyl-1H-indol-2-yl)acrylates

10.23.3.1.2.2.2.1.2.1 Variation 1: From a 2-Alkynyl-1H-indole-3-carbaldehyde

10.23.3.1.2.2.2.1.2.2 Variation 2: From a 2-Alkenyl-1H-indole-3-carbaldehyde

10.23.3.1.2.2.2.1.3 Method 3: From (3-Acyl-1H-indol-2-yl)malonates

10.23.3.1.2.2.3 By Formation of One N—C Bond and One C—C Bond

10.23.3.1.2.2.3.1 With Formation of 2—3 and 3—4 Bonds

10.23.3.1.2.2.3.1.1 Method 1: From Secondary 2-Alkyl-1H-indole-3-carboxamides

10.23.3.1.2.2.3.2 With Formation of 2—3 and 4—4a Bonds

10.23.3.1.2.2.3.2.1 Method 1: From Oxime O-Methyl Ethers of 1H-Indol-3-yl Aldehydes or Ketones

10.23.3.1.2.2.3.2.1.1 Variation 1: Reaction with Alkynes and Alkenes

10.23.3.1.2.2.3.2.1.2 Variation 2: Reaction with Diphenylacetylene under Rhodium Catalysis

10.23.3.1.2.2.3.2.2 Method 2: From Tosylhydrazones of 1H-Indol-3-yl Aldehydes and Ketones

10.23.3.1.2.2.3.2.3 Method 3: From tert-Butylimines of 1H-Indole-3-carbaldehydes

10.23.3.1.2.2.3.2.3.1 Variation 1: From tert-Butylimines of 2-Halo-1H-indole-3-carbaldehydes

10.23.3.1.2.2.3.2.3.2 Variation 2: From tert-Butylimines of 2-Unsubstituted 1H-Indole-3-carbaldehydes

10.23.3.1.2.2.3.2.4 Method 4: From N-Methoxy or N-Alkyl/Aryl 1-Methyl-1H-indole-3-carboxamides

10.23.3.1.2.2.4 By Formation of Two C—C Bonds

10.23.3.1.2.2.4.1 With Formation of 1—9b and 4—4a Bonds

10.23.3.1.2.2.4.1.1 Method 1: From Triethyl 1,2,4-Triazine-3,5,6-tricarboxylate

10.23.3.1.2.2.5 By Formation of One N—C Bond

10.23.3.1.2.2.5.1 With Formation of the 1—2 Bond

10.23.3.1.2.2.5.1.1 Method 1: From a 3-Methyl-1H-indole-2-carbaldehyde

10.23.3.1.2.2.5.2 With Formation of the 2—3 Bond

10.23.3.1.2.2.5.2.1 Method 1: From a 3-Acyl-2-alkenyl-1H-indole Oxime

10.23.3.1.2.2.5.2.2 Method 2: From tert-Butylimines of 2-Alkynyl-1H-indole-3-carbaldehydes

10.23.3.1.2.2.6 By Formation of One C—C Bond

10.23.3.1.2.2.6.1 With Formation of the 4—4a Bond

10.23.3.1.2.2.6.1.1 Method 1: From 3-{[(2,2-Diethoxyethyl)imino]methyl}-1H-indoles

10.23.3.1.2.2.6.1.1.1 Variation 1: From 3-{[(2,2-Diethoxyethyl)amino]methyl}-1H-indoles

10.23.3.1.2.2.6.1.2 Method 2: From Ethyl [(1H-Indol-3-yl)methyl]glycinates

10.23.3.1.2.2.6.1.3 Method 3: From N-Allyl-2-iodo-1H-indole-3-carboxamides

10.23.3.2 Synthesis by Ring Transformation

10.23.3.2.1 Method 1: From 1-(4-Pyridyl)-1H-benzotriazoles

10.23.3.2.2 Method 2: From 1-Aryl-1H-1,2,3-triazolo[4,5-c]pyridines

10.23.3.2.3 Method 3: By Ring Expansion of 5-Azidocyclopent-2-en-1-ols To Form Pyridines

10.23.3.3 Aromatization

10.23.3.3.1 Method 1: From Tetrahydro-5H-pyrido[4,3-b]indoles and Octahydro-5H-pyrido[4,3-b]indoles

10.23.3.3.2 Method 2: From Dihydro-5H-pyrido[4,3-b]indoles

10.23.3.4 Synthesis by Substituent Modification

10.23.3.4.1 Substitution of Existing Substituents

10.23.3.4.1.1 Substitution of N-Hydrogen

10.23.3.4.1.1.1 Giving N-Sulfur 5H-Pyrido[4,3-b]indoles

10.23.3.4.1.1.2 Giving N-Carbon 5H-Pyrido[4,3-b]indoles

10.23.3.4.1.1.2.1 Method 1: 5-Alkylation Using an Alkyl Halide

10.23.3.4.1.1.2.2 Method 2: 5-Arylation Using an Aryl Halide

10.23.3.4.1.1.2.3 Method 3: 2-Alkylation Giving 2-Alkyl-5H-pyrido[4,3-b]indol-2-ium Salts and thence 5-Alkylation

10.23.3.4.1.2 Substitution of N-Carbon and N-Sulfur

10.23.3.4.1.2.1 Giving N-Hydrogen 5H-Pyrido[4,3-b]indoles

10.23.3.4.1.2.1.1 Method 1: N-Deprotection

10.23.3.4.1.3 Substitution of C-Hydrogen

10.23.3.4.1.3.1 Direct Substitution by Electrophiles

10.23.3.4.1.3.1.1 Method 1: Giving C-Halogen

10.23.3.4.1.3.1.2 Method 2: Giving C-Sulfur

10.23.3.4.1.3.1.3 Method 3: Giving C-Nitrogen

10.23.3.4.1.3.1.4 Method 4: Giving C-Carbon

10.23.3.4.1.3.2 Substitution via Metalation

10.23.3.4.1.3.3 Substitution via 2-Oxides

10.23.3.4.1.3.4 Substitution via Displacement of Halogen

10.23.3.4.1.3.4.1 Method 1: Direct Nucleophilic Displacement

10.23.3.4.1.3.4.2 Method 2: Substitution of Halogen via Cross-Coupling Processes

10.23.3.4.2 Modification of Substituents

10.23.3.4.2.1 Modification of C-Oxygen Functionalities

10.23.3.4.2.1.1 Method 1: Giving C-Halogen

10.23.3.4.2.2 Modification of C-Nitrogen Functionalities

10.23.3.4.2.2.1 Method 1: Giving C-Nitrogen

10.23.3.4.2.3 Modification of C-Carbon Functionalities

10.23.3.4.2.3.1 Method 1: Giving C-Carbon 5H-Pyrido[4,3-b]indoles

10.23.3.4.2.3.2 Method 2: Giving C-Nitrogen 5H-Pyrido[4,3-b]indoles

10.23.3.4.2.3.3 Method 3: Giving C-Hydrogen 5H-Pyrido[4,3-b]indoles

10.23.4 Product Subclass 4: 5H-Pyrido[3,2-b]indoles (δ-Carbolines)

10.23.4.1 Synthesis by Ring-Closure Reactions

10.23.4.1.1 By Annulation to an Arene

10.23.4.1.1.1 By Formation of One N—C and Two C—C Bonds

10.23.4.1.1.1.1 With Formation of 2—3, 4a—5, and 9a—9b Bonds

10.23.4.1.1.1.1.1 Method 1: From 2-Iodoanilines and N-Tosyl Enynamines

10.23.4.1.1.2 By Formation of Two N—C Bonds

10.23.4.1.1.2.1 With Formation of 4a—5 and 5—5a Bonds

10.23.4.1.1.2.1.1 Method 1: From Primary Amines and 3-Bromo-2-(2-bromophenyl)pyridine

10.23.4.1.1.3 By Formation of Two C—C Bonds

10.23.4.1.1.3.1 With Formation of 2—3 and 4a—9b Bonds

10.23.4.1.1.3.1.1 Method 1: From 2-(Aminomethyl)aniline Cinnamaldehyde Diimine

10.23.4.1.1.4 By Formation of One N—C Bond

10.23.4.1.1.4.1 With Formation of the 4a—5 Bond

10.23.4.1.1.4.1.1 Method 1: From 1-Methyl-2-(2-Azidoaryl)pyridinium Trifluoromethanesulfonates

10.23.4.1.1.4.1.2 Method 2: From 3-Fluoro-2-[2-(pivaloylamino)phenyl]pyridines

10.23.4.1.1.4.2 With Formation of the 5—5a Bond

10.23.4.1.1.4.2.1 Method 1: From 3-Azido-2-phenylpyridine

10.23.4.1.1.4.2.2 Method 2: From 2-Aryl-3-nitropyridines

10.23.4.1.1.4.2.3 Method 3: From 2-(2-Chlorophenyl)pyridin-3-amine by Intramolecular Photostimulated SRN1 Reaction

10.23.4.1.1.5 By Formation of One C—C Bond

10.23.4.1.1.5.1 With Formation of the 9a—9b Bond

10.23.4.1.1.5.1.1 Method 1: From N-Arylpyridin-3-amines by Irradiation

10.23.4.1.1.5.1.2 Method 2: From N-Arylpyridin-3-amines by Palladium(0)-Catalyzed Bond Formation

10.23.4.1.1.5.1.2.1 Variation 1: From Cyclohexanone and Pyridin-3-amine

10.23.4.1.1.5.1.3 Method 3: From N-(2-Halophenyl)pyridin-3-amines by Palladium(0)-Catalyzed Bond Formation

10.23.4.1.1.5.1.4 Method 4: From N-Aryl-2-halopyridin-3-amines by Intramolecular Palladium(0)-Catalyzed Bond Formation

10.23.4.1.1.5.1.5 Method 5: From N-Aryl-2-bromopyridin-3-amines by Intramolecular Photostimulated SRN1 Reaction

10.23.4.1.1.5.1.6 Method 6: From 2-Bromo-N-(2-bromophenyl)pyridin-3-amines by Palladium(0)-Catalyzed Bond Formation via Tributylstannyl Intermediates

10.23.4.1.1.5.1.7 Method 7: From an N-(2-Diazophenyl)-N-methylpyridin-3-amine

10.23.4.1.2 By Annulation to a Heterocycle

10.23.4.1.2.1 By Annulation to a Pyridine

10.23.4.1.2.1.1 By Formation of One N—C Bond and One C—C Bond

10.23.4.1.2.1.1.1 With Formation of 5—5a and 9a—9b Bonds

10.23.4.1.2.1.1.1.1 Method 1: From Benzyne and an N-Tosylpyridinium Imide

10.23.4.1.2.2 By Annulation to an Indole

10.23.4.1.2.2.1 By Formation of One N—C and Two C—C Bonds

10.23.4.1.2.2.1.1 With Formation of 1—9b, 2—3, and 4—4a Bonds

10.23.4.1.2.2.1.1.1 Method 1: From 3-Acetyl-1H-indole Oxime and Acetylene

10.23.4.1.2.2.1.2 With Formation of 1—2, 2—3, and 4—4a Bonds

10.23.4.1.2.2.1.2.1 Method 1: From N-(tert-Butoxycarbonyl)indol-3-amines, Aryl Aldehydes, and Terminal Arylalkynes

10.23.4.1.2.2.2 By Formation of One N—C Bond and One C—C Bond

10.23.4.1.2.2.2.1 With Formation of 1—9b and 3—4 Bonds

10.23.4.1.2.2.2.1.1 Method 1: From 2-[Bis(methylsulfanyl)methylene]-1-methyl-1,3-dihydro-2H-indol-3-one and a β-(Lithioamino)acrylonitrile

10.23.4.1.2.2.2.1.1.1 Variation 1: From 2-[Bis(methylsulfanyl)methylene]-1-methyl-1,3-dihydro-2H-indol-3-one and Malononitrile

10.23.4.1.2.2.2.2 With Formation of 1—2 and 4—4a Bonds

10.23.4.1.2.2.2.2.1 Method 1: From an N-Acetyl-1H-indol-3-amine and a 1,3-Dialdehyde Equivalent

10.23.4.1.2.3 By Annulation to a 1H-Pyrrolo[3,2-b]pyridine (a 4-Azaindole)

10.23.4.1.2.3.1 By Formation of Two C—C Bonds

10.23.4.1.2.3.1.1 With Formation of 7—8 and 9—9a Bonds

10.23.4.1.2.3.1.1.1 Method 1: From a 2-Vinyl-1H-Pyrrolo[3,2-b]pyridine and Dimethyl Acetylenedicarboxylate

10.23.4.2 Synthesis by Ring Transformation

10.23.4.2.1 Method 1: From 1-(3-Pyridyl)-1H-benzotriazoles

10.23.4.2.2 Method 2: From 2-Alkoxypyrano[3,2-b]indoles and Hydroxylamine

10.23.4.3 Aromatization

10.23.4.4 Synthesis by Substituent Modification

10.23.4.4.1 Substitution of Existing Substituents

10.23.4.4.1.1 Substitution of N-Hydrogen

10.23.4.4.1.1.1 Giving N-Carbon 5H-Pyrido[3,2-b]indoles

10.23.4.4.1.1.1.1 Method 1: Using an Alkyl Halide and Sodium Hydride

10.23.4.4.1.1.1.2 Method 2: Demethylation of a 1-Methyl-5H-pyrido[3,2-b]indol-1-ium Iodide

10.23.4.4.1.1.1.3 Method 3: 5-Arylation Using an Aryl Halide

10.23.4.4.1.2 Substitution of C-Hydrogen

10.23.4.4.1.2.1 Substitution by Electrophiles

10.23.4.4.1.2.1.1 Method 1: Giving C-Nitrogen 5H-Pyrido[3,2-b]indoles

10.23.4.4.1.2.2 Substitution via Metalation

10.23.4.4.2 Modification of Substituents

10.23.4.4.2.1 Modification of C-Carbon Functionalities

10.23.4.4.2.1.1 Method 1: Giving C-Nitrogen 5H-Pyrido[3,2-b]indoles

10.23.4.4.2.1.2 Method 2: Giving C-Carbon 5H-Pyrido[3,2-b]indoles

Volume 30: Acetals: O/N, S/S, S/N, and N/N and Higher Heteroatom Analogues

30.3 Product Class 3: S, S-Acetals

T.-Y. Luh and M.-k. Leung

30.3 Product Class 3: S, S-Acetals

30.3.2.2 1,3-Dithietanes

T.-Y. Luh, M.-k. Leung, and C.-M. Chou

30.3.2.2 1,3-Dithietanes

30.3.2.2.1 Symmetrical Dithietanes

30.3.2.2.1.1 Method 1: Dimerization of Thioketones Formed In Situ from Bunte Salts

30.3.2.2.1.2 Method 2: Synthesis from Thiophosgene: Dimerization of Thiocarbonates

30.3.2.2.1.3 Method 3: Dimerization of Thioacetamides

30.3.2.2.2 Unsymmetrical Dithietanes

30.3.2.2.2.1 Method 1: Synthesis from Thioketones and Imines

30.3.2.2.2.2 Method 2: Synthesis from Aromatic Aldehydes and Carbon Disulfide

30.3.2.2.2.3 Method 3: Synthesis of Dithietane Cations

30.3.3.2 1,3-Dithiolanes

M.-k. Leung, C.-M. Chou, and T.-Y. Luh

30.3.3.2 1,3-Dithiolanes

30.3.3.2.1 Method 1: Reaction of Ethane-1,2-dithiol with Aldehydes or Ketones Catalyzed by Protic Acids

30.3.3.2.1.1 Variation 1: Catalyzed by Hydrogen Chloride

30.3.3.2.1.2 Variation 2: Catalyzed by 4-Toluenesulfonic Acid

30.3.3.2.1.3 Variation 3: Catalyzed by Sulfuric Acid on Silica Gel

30.3.3.2.1.4 Variation 4: Catalyzed by Alumina Sulfuric Acid, Silica Sulfuric Acid, and Tungstate Sulfuric Acid

30.3.3.2.1.5 Variation 5: Catalyzed by Sulfamic Acid on Silica Gel

30.3.3.2.1.6 Variation 6: Catalyzed by Sulfonic Acids on Solid Supports and Ionic Liquids

30.3.3.2.1.7 Variation 7: Catalyzed by Sodium Hydrogen Sulfate on Silica Gel

30.3.3.2.1.8 Variation 8: Catalyzed by Solid-Supported Perchloric Acid

30.3.3.2.1.9 Variation 9: Catalyzed by Trichloroacetic Acid in Sodium Dodecyl Sulfate Micelles

30.3.3.2.2 Method 2: Reactions of Ethane-1,2-dithiol with Aldehydes or Ketones Catalyzed by Lewis Acids

30.3.3.2.2.1 Variation 1: Catalyzed by Boron-Based Reagents

30.3.3.2.2.2 Variation 2: Catalyzed by Aluminum Chloride and Related Reagents

30.3.3.2.2.3 Variation 3: Catalyzed by Indium(III) Reagents

30.3.3.2.2.4 Variation 4: Catalyzed by Silicon-Based Reagents

30.3.3.2.2.5 Variation 5: Catalyzed by Tin-Based Reagents

30.3.3.2.2.6 Variation 6: Catalyzed by Titanium-Based Reagents

30.3.3.2.2.7 Variation 7: Catalyzed by Vanadium-Based Reagents

30.3.3.2.2.8 Variation 8: Catalyzed by Iron-Based Reagents

30.3.3.2.2.9 Variation 9: Catalyzed by Ruthenium-Based Reagents

30.3.3.2.2.10 Variation 10: Catalyzed by Nickel-Based Reagents

30.3.3.2.2.11 Variation 11: Promoted by Copper-Based Reagents

30.3.3.2.2.12 Variation 12: Catalyzed by Zinc-Based Reagents

30.3.3.2.2.13 Variation 13: Catalyzed by Hafnium-Based Reagents

30.3.3.2.3 Method 3: Reaction of Ethane-1,2-dithiol with Aldehydes or Ketones Catalyzed by Heterogeneous Catalysts

30.3.3.2.3.1 Variation 1: Catalyzed by Phosphorus Pentoxide on Alumina and Silica Gel Reagents

30.3.3.2.3.2 Variation 2: Using Dithiolanylium Tetrafluoroborate Salts on Solid Support

30.3.3.2.3.3 Variation 3: Catalyzed by Graphene Oxide

30.3.3.2.4 Method 4: Reaction of Ethane-1,2-dithiol with Aldehydes or Ketones Catalyzed by Halogens and Derivatives

30.3.3.2.4.1 Variation 1: Catalyzed by Iodine

30.3.3.2.4.2 Variation 2: Catalyzed by Tribromide Salts

30.3.3.2.4.3 Variation 3: Catalyzed by N-Bromosuccinimide

30.3.3.2.4.4 Variation 4: Catalyzed by Poly(N-bromoacrylamide)

30.3.3.2.4.5 Variation 5: Catalyzed by N,N,N′,N′-Tetrabromobenzene-1,3-disulfonamide and Poly(ethylene-N,N′-dibromobenzene-1,3-disulfonamide)

30.3.3.2.4.6 Variation 6: Catalyzed by Trichloromelamine

30.3.3.2.5 Method 5: Reaction of Ethane-1,2-dithiol with Aldehydes or Ketones Catalyzed by Ionic Liquids

30.3.3.2.5.1 Variation 1: Catalyzed by Iminium Salts Structurally Similar to Ionic Liquids

30.3.3.2.6 Method 6: Reaction of Ethane-1,2-dithiol with Masked Carbonyl Groups

30.3.3.2.6.1 Variation 1: Conversion of (E)-2-Chlorovinyl Sulfones into 1,3-Dithiolane Derivatives

30.3.3.2.6.2 Variation 2: One-Pot Conversion of Ethoxyacetylene, an α,β-Unsaturated Aldehyde, and Ethane-1,2-dithiol into a 2-(Buta-1,3-dienyl)-1,3-dithiolane

30.3.3.2.7 Method 7: Reaction of O,O-Acetals or Hemiacetals with Ethane-1,2-dithiol

30.3.3.2.7.1 Variation 1: Catalyzed by Protic Acids

30.3.3.2.7.2 Variation 2: Catalyzed by Lewis Acids

30.3.3.2.7.3 Variation 3: Catalyzed by Heterogeneous Catalysts

30.3.3.2.7.4 Variation 4: Catalyzed by Halogens and Derivatives

30.3.3.2.8 Method 8: Dithioacetalization from a 1,3-Dithiolane to Another Carbonyl Group

30.3.3.2.9 Method 9: Addition of Ethane-1,2-dithiol to Alkynes

30.3.3.2.9.1 Variation 1: Gold(I)/Silver(I) Tetrafluoroborate Catalyzed Bishydrothiolation of Alkynes

30.3.3.2.9.2 Variation 2: Calcium Nonafluorobutane-1-sulfonate Catalyzed anti-Markovnikov Bishydrothiolation of Alkynes

30.3.3.2.9.3 Variation 3: Double Michael Addition of Ethane-1,2-dithiol to Propargylic Carbonyl Systems

30.3.3.2.10 Method 10: Metalation

30.3.3.2.10.1 Variation 1: 2-(Trimethylsilyl)-1,3-dithiolanes as Masked 1,3-Dithiolane Anions

30.3.3.2.11 Method 11: Annulation

30.3.3.2.11.1 Variation 1: Tandem Hydride Shift/Cyclization

30.3.3.2.11.2 Variation 2: [6 + 3] Cycloaddition

30.3.3.2.11.3 Variation 3: [4 + 2] Cycloaddition

30.3.3.2.12 Method 12: Metal-Free Cross-Dehydrogenative Coupling of 1H-Benzimidazoles with 1,3-Dithiolane

30.3.3.2.13 Method 13: Reduction of Ketene S,S-Acetals

30.3.3.2.14 Method 14: [3 + 2] Cycloaddition of Ketene S,S-Acetals

30.3.3.2.15 Method 15: Intramolecular Cyclization of Ketene S,S-Acetals

30.3.3.2.15.1 Variation 1: Nazarov Cyclization–Halovinylation of α-Alkenoyl Ketene S,S-Acetals

30.3.3.2.15.2 Variation 2: Intramolecular Michael Reaction

30.3.3.2.16 Method 16: Double-Bond Migration in Ketene S,S-Acetals

Author Index

Abbreviations

10.23 Product Class 23: Pyrido[X,Y-b]indoles (Carbolines)

J. A. Joule

General Introduction

The four isomeric pyrido[X,Y-b]indoles are most frequently referred to as “carbolines”, thus 9H-pyrido[2,3-b]indole (1) is α-carboline, 9H-pyrido[3,4-b]indole (2) is β-carboline, 5H-pyrido[4,3-b]indole (3) is γ-carboline, and 5H-pyrido[3,2-b]indole (4) is δ-carboline (▶ Scheme 1).

Scheme 1 Structures, Names, and Numbering of the Pyrido[X,Y-b]indoles (Carbolines)

The name “carboline” was coined by W. H. Perkin Jr. and Robert Robinson[1] during their work on the structural elucidation of the harmala alkaloids, e.g. harmine (12; see below), and was chosen to indicate the structural similarity between the tricyclic nucleus of the alkaloid and carbazole on one hand and isoquinoline on the other; it was then extrapolated for other isomers with designations to indicate the location of the pyridine ring nitrogen. All the carbolines are stable, colorless, almost odorless solids with melting points in the range of 200–220°C.

There are only a few reviews of carboline synthesis and chemistry: α-carboline synthesis,[2] α-, γ-, and δ-carboline properties,[3] α-, γ-, and δ-carboline synthesis,[4] β-carbolines as synthetic intermediates,[5] γ-carbolines,[6] β-carboline synthesis,[7] carbolines (mainly β-carbolines and mainly reduced derivatives),[8] and carbolines.[9]

In each of the carbolines, the typical characters of a pyridine ring nitrogen and an indole/pyrrole ring N-hydrogen can be discerned and are illustrated in ▶ Scheme 2 using the β-isomer. Thus, reaction with an alkyl halide leads easily to a quaternary (carbolinium) salt (e.g., 5),[10,11] whereas by using a strong base to deprotonate the N-hydrogen, and then reaction with an alkyl halide, indole nitrogen alkylation is achieved, giving for example 6.[12,13]

Scheme 2 Alkylation of the Pyridine and Indole Nitrogens of β-Carboline[10–13]

The basicities of the pyridine ring nitrogens measured by the pKa values of their conjugate acids in water are shown in ▶ Table 1.[14,15] The acidities of the N-hydrogens, measured by their pKa values, are shown in ▶ Table 2.[6,14] One may compare these values with the pKa for the pyridine-type nitrogen in isoquinoline (5.4) and the pKa for the indole N-hydrogen (16.2).

Table 1 pKa Values of Pyridine Ring Nitrogens in Carbolines[14–16]

Compound

p

K

a

(H

2

O)

Ref

1

4.2

[

14

]

2

6.9 (7.2)

a

[

14

,

15

]

3

7.5

[

14

]

4

5.3

[

14

]

isoquinoline

5.4

[

16

]

a

The two references cited give slightly different values for the p

K

a

.

Table 2 pKa Values of N-Hydrogens in Carbolines[14,17]

Compound

p

K

a

(H

2

O)

Ref

1

14.7

[

14

]

2

14.5

[

14

,

17

]

3

14.0

[

14

]

4

15.1

[

14

]

indole

16.2

[

16

]

The N-hydrogens of carbolinium salts are more acidic (▶ Table 3).[18,19] These figures measure the formation of “anhydronium bases”, e.g. in the γ-series 2-methyl-2H-pyrido[4,3-b]indole 8 from 2-methyl-5H-pyrido[4,3-b]indol-2-ium salt 7 (▶ Scheme 3). The yellow-orange anhydronium bases can be isolated;[19–22] neutral and dipolar resonance forms contribute to their structures, thus 8A and 8B for 8.

Table 3 pKa Values of the N-Hydrogens of Pyridine-N-methyl Carbolinium Salts[18,19]

Compound

p

K

a

(H

2

O)

Ref

7.75 (7.6)

a

[

18

,

19

]

11.1 (10.9)

a

[

18

,

19

]

10.5

[

18

]

10.8

[

18

]

a

The two references cited give slightly different values for the p

K

a

.

Scheme 3 Formation of an Anhydronium Base from γ-Carbolinium Iodide[19–22]

Anhydronium bases such as 9 react with alkyl halides at the five-membered ring nitrogen to give carbolinium salts (e.g., 10) from which the N-alkylated carboline (e.g., 6) can be obtained by demethylation on strong heating (▶ Scheme 4).[22–24]

Scheme 4 Formation of an Anhydronium Base from a β-Carbolinium Iodide, Its Reaction with Iodomethane, and Demethylation of a β-Carbolinium Methiodide[22–24]

All carbolinium salts can be easily selectively reduced in the pyridinium ring to give tetrahydro derivatives using sodium borohydride. For example, 2-methyl-9H-pyrido[3,4-b]indol-2-ium iodide (5) is reduced to 2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (11) in 99% yield (▶ Scheme 5).[25]

▶ Scheme 5 Conversion of 2-Methyl-9H-pyrido[3,4-b]indol-2-ium Iodide into 2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole[25]

The role of electrophilic substitution in the chemistry of carbolines is relatively minor. All of them are attacked only in the benzene ring mainly para to the pyrrolic nitrogen but occasionally ortho to it.

The 13C and 1H NMR spectra of the four carboline isomers are summarized in ▶ Scheme 6.[26,27]

Scheme 613C (90.6 MHz) and 1H (360.1 MHz) NMR Shifts and Coupling Constants for the Four Carbolines in DMSO-d6[26,27]

β-Carboline units occur naturally in various indole alkaloids ranging in complexity from harmine (12) from Peganum harmala and congeners[28,29] and canthinone (13) from Pentaceras australis[30] through the β-carbolinium-containing flavopereirine (14) from Geissospermum vellosii[31] to the very large number of alkaloids that contain a 1,2,3,4-tetrahydro-β-carboline unit,[32–39] yohimbine (15)[34–37] from Pausinystalia johimbe may be considered typical (▶ Scheme 7). The synthesis of carbolines with a further fused aromatic ring such as 14 and the synthesis of 1,2,3,4-tetrahydrocarbolines are not covered in this chapter (except in so far as reduced carbolines can lead to fully aromatic systems by dehydrogenation). Lavendamycin (16) from Streptomyces lavendulae has significant activity against topoisomerase I, but has high toxicity.[40] Manzamine C (17) is the simplest of a family of oncolytic marine alkaloids isolated from Okinawan marine sponges;[41] the others also all have a β-carboline unit but with a more complex C1 substituent.

Scheme 7 Carboline Units in Natural Products[28–47]

By comparison, there are only a few natural substances containing any of the other carboline isomers. α-Carboline-containing grossularine-2 (18) was isolated from Dendrodoa grossularia and is cytotoxic.[42]Streptomyces griseoflavus produces mescengricin (19), another α-carboline, which prevents L-glutamate toxicity.[43]

Isocanthinone (20)[44] and isoperlolyrine (21; from Gloriosa superba)[45] were named by analogy with β-carboline analogues canthinone (13) and perlolyrine (22; from perenial rye grass Lolium perenne).[46] δ-Carboline-containing cryptolepine (23) and its γ-isomer isocryptolepine (24) are two of several alkaloids from Cryptolepis sanguinolenta. Cryptolepine and isocryptolepine have antimalarial properties.[47] The synthesis of systems with a further fused aromatic ring, such as 23 and 24, is not covered in this chapter.

10.23.1 Product Subclass 1: 9 H-Pyrido[2,3-b]indoles (α-Carbolines)

10.23.1.1 Synthesis by Ring-Closure Reactions

10.23.1.1.1 By Annulation to an Arene

10.23.1.1.1.1 By Formation of Four N—C and Two C—C Bonds

10.23.1.1.1.1.1 With Formation of 1—2, 2—3, 4—4a, 1—9a, 8a—9, and 9—9a Bonds

10.23.1.1.1.1.1.1 Method 1: From 1-Bromo-2-(2,2-dibromovinyl)benzenes, Ammonia, and Alkyl Aldehydes

Scheme 8 Reaction of 1-Bromo-2-(2,2-dibromovinyl)benzenes with Ammonia and Aldehydes[48]

R

1

R

2

R

3

Yield (%)

Ref

H

H

H

38

[

48

]

H

H

Me

43

[

48

]

H

H

Et

46

[

48

]

H

H

iPr

42

[

48

]

H

H

Bn

52

[

48

]

F

H

Et

46

[

48

]

H

Cl

Et

47

[

48

]

H

CF

3

Et

49

[

48

]

H

OMe

Et

41

[

48

]

OCH

2

O

Et

44

[

48

]

Scheme 9 Suggested Sequence for Formation of 9H-Pyrido[2,3-b]indoles from 1-Bromo-2-(2,2-dibromovinyl)benzenes[48]

10.23.1.1.1.2 By Formation of Two N—C and One C—C Bonds

10.23.1.1.1.2.1 With Formation of 1—9a, 4—4a, and 9—9a Bonds

10.23.1.1.1.2.1.1 Method 1: From (2-Nitroaryl)acetonitriles and 3-Acetoxy-3-aryl-2-methylene Ketones

The key steps in the ring synthesis are summarized in ▶ Scheme 11: thus, following reduction of the nitro group, the aromatic amino group of 37 adds to the cyano group generating a presumed imine 38 for the second ring closure. Intermediate 39 then loses water and the exocyclic double bond moves into conjugation.

▶ Scheme 10 Reaction between (2-Nitroaryl)acetonitriles and 3-Acetoxy-3-aryl-2-methylene Ketones, Followed by Reduction[49]

R

1

R

2

R

3

R

4

R

5

Yield (%)

Ref

H

Me

H

H

H

52

[

49

]

H

Et

H

H

H

67

[

49

]

H

Me

H

H

Me

53

[

49

]

H

Me

H

H

Cl

55

[

49

]

H

Me

H

H

Br

59

[

49

]

H

Me

H

Br

H

57

[

49

]

H

Me

H

OMe

H

50

[

49

]

Me

Me

H

H

H

56

[

49

]

Me

Et

H

H

H

62

[

49

]

Me

Me

H

H

Me

50

[

49

]

Me

Me

H

H

Cl

53

[

49

]

Me

Me

H

H

Br

58

[

49

]

Me

Me

H

Br

H

55

[

49

]

OMe

Et

H

H

H

60

[

49

]

H

Me

Cl

H

H

51

[

49

]

H

Me

Br

H

H

48

[

49

]

H

Me

Me

H

H

52

[

49

]

▶ Scheme 11 Key Steps in the Conversion of 2-Benzylidene-4-cyano-4-(2-nitroaryl) Ketones into 9H-Pyrido[2,3-b]indoles[49]

10.23.1.1.1.2.1.2 Method 2: From (2-Nitrophenyl)acetonitrile and 3-Arylenones

In a second exploitation of (2-nitrophenyl)acetonitrile (40), it can be reacted with conjugated enones 41 carrying a 3-aryl substituent. The Michael-type addition of the anion from the benzylic nitrile to the enone and subsequent reduction of the nitro group, leading to ring closure to 2-alkyl-4-aryl-9H-pyrido[2,3-b]indoles 42, are carried out in one pot (▶ Scheme 12).[50]

Scheme 12 Reaction between (2-Nitrophenyl)acetonitrile and 3-Arylenones, Followed by Reduction[50]

R

1

R

2

R

3

R

4

Yield (%)

Ref

Me

H

H

H

58

[

50

]

Me

H

H

Me

52

[

50

]

Me

H

H

OMe

56

[

50

]

Me

H

H

NMe

2

52

[

50

]

Me

H

H

OH

73

[

50

]

Me

H

H

F

58

[

50

]

Me

H

H

Cl

52

[

50

]

Me

H

H

Br

56

[

50

]

Me

H

H

CF

3

52

[

50

]

Me

Me

H

H

55

[

50

]

Me

OH

H

H

62

[

50

]

Me

H

Me

H

61

[

50

]

Me

H

OH

OMe

60

[

50

]

CF

3

H

H

H

57

[

50

]

In mechanistic terms, it is believed that Michael-type addition to the enone occurs first. Then, reduction of the nitro to the amino group leads to amine 43 and the two ring closures, first to imine 44 and then to imino alcohol 45. Loss of water leads to an intermediate 46 that must be oxidized, perhaps by air, to arrive at the fully aromatic products 42 (▶ Scheme 13).[50]

▶ Scheme 13 Key Steps in the Conversion of 3-Aryl-4-cyano-4-(2-nitrophenyl) Ketones into 4-Aryl-9H-pyrido[2,3-b]indoles[50]

10.23.1.1.1.2.1.2.1 Variation 1: From (2-Nitrophenyl)acetonitrile and 4 H-1-Benzopyran-4-ones

A comparable sequence can be employed using 4H-1-benzopyran-4-ones (chromones, e.g. 47) as the acceptor of the nucleophile, (2-nitrophenyl)acetonitrile (40), to furnish 2-(2-hydroxyaryl)-9H-pyrido[2,3-b]indoles 48 (▶ Scheme 14).[50] It is significant that it is not necessary to postulate an oxidation step in this variant to rationalize the formation of products 48 and, doubtless as a consequence of this, the yields are much higher.

▶ Scheme 14 Reaction between (2-Nitrophenyl)acetonitrile and 4H-1-Benzopyran-4-ones, Followed by Reduction[50]

R

1

R

2

R

3

R

4

Yield (%)

Ref

H

H

H

H

82

[

50

]

H

H

Me

H

86

[

50

]

H

H

OMe

H

90

[

50

]

H

H

F

H

76

[

50

]

H

H

Cl

H

85

[

50

]

H

H

Br

H

88

[

50

]

H

OMe

H

H

84

[

50

]

H

F

H

H

92

[

50

]

H

H

H

OMe

80

[

50

]

H

H

(CH=CH)

2

76

[

50

]

(CH=CH)

2

H

H

92

[

50

]

10.23.1.1.1.3 By Formation of Two N—C Bonds

10.23.1.1.1.3.1 With Formation of 8a—9 and 9—9a Bonds

10.23.1.1.1.3.1.1 Method 1: From Primary Amines and 3-(2-Bromophenyl)-2-chloropyridine

3-(2-Bromophenyl)-2-chloropyridine (49) can be formed in very high yield by the palladium-catalyzed reaction between 3-bromo-2-chloropyridine and (2-bromophenyl)boronic acid. The dihalide 49 condenses with primary aromatic amines, primary benzylic amines, and propylamine, again with palladium catalysis using either 1,1′-bis(diphenylphosphino)ferrocene (dppf) or bis[2-(diphenylphosphino)phenyl] ether (DPEPhos) as ligand, to produce 9-substituted 9H-pyrido[2,3-b]indoles 50 (▶ Scheme 15).[51] An analogous approach can be used to make 5H-pyrido[3,2-b]indoles (see ▶ Section 10.23.4.1.1.2.1.1).

▶ Scheme 15 Condensation of Primary Amines with 3-(2-Bromophenyl)-2-chloropyridine[51]

R

1

Ligand

Yield (%)

Ref

Ph

dppf

92

[

41

]

4-Tol

dppf

95

[

51

]

4-

t

-BuC

6

H

4

dppf

94

[

51

]

4-FC

6

H

4

dppf

89

[

51

]

3-F

3

CC

6

H

4

dppf

88

[

51

]

4-MeOCC

6

H

4

dppf

98

[

51

]

4-MeSC

6

H

4

dppf

92

[

51

]

4-NCC

6

H

4

dppf

83

[

51

]

Bn

DPEPhos

88

[

51

]

4-FC

6

H

4

CH

2

DPEPhos

87

[

51

]

3-F

3

CC

6

H

4

CH

2

DPEPhos

90

[

51

]

Pr

DPEPhos

91

[

51

]

This approach lends itself to the construction of molecules with two 9H-pyrido[2,3-b]indole units (▶ Scheme 15), for example 51 (46% from benzene-1,4-diamine) and the potential ligand 52 (50% from 2,6-diaminopyridine).[51]

Aniline (52 μL, 0.56 mmol) was added to a pressure tube charged with 3-(2-bromophenyl)-2-chloropyridine (49; 100 mg, 0.37 mmol), Pd2(dba)3 (17 mg, 19 μmol), the ligand dppf (21 mg, 37 μmol), and t-BuONa (107 mg, 1.12 mmol) under argon. The flask was back-filled with argon several times. The mixture was dissolved in anhyd toluene (10 mL), heated at 110°C for 7 h, cooled, diluted with CH2Cl2 (20 mL), and filtered through a Celite pad, washing with CH2Cl2 (40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, heptanes/EtOAc 3:1) to give the product as a white solid; yield: 84 mg (92%); mp 110–111°C.

10.23.1.1.1.4 By Formation of One N—C Bond and One C—C Bond

10.23.1.1.1.4.1 With Formation of 4a—4b and 9—9a Bonds

10.23.1.1.1.4.1.1 Method 1: From 2,3-Dihalopyridines and Anilines

Under appropriate conditions, both the 4a—4b and 9—9a bonds of a 9H-pyrido[2,3-b]indole can be made in one practical step using an aniline derivative and a pyridine with appropriate halides at positions C2 and C3. Thus, 2,3-dichloro-5-(trifluoromethyl)pyridine (54) reacts with diphenylamine (53) under palladium catalysis to give 9-phenyl-3-(trifluoromethyl)-9H-pyrido[2,3-b]indole (55; ▶ Scheme 16).[52]

Scheme 16 Reaction of 2,3-Dichloro-5-(trifluoromethyl)pyridine with Diphenylamine[52]

Rather different is the use of [2-(mesylamino)phenyl]boronic acid ester 56; regioselective cross coupling with 3-bromo-2-fluoropyridine (57) and then displacement of fluoride in an SNAr second intramolecular step in the sequence involving presumed intermediate 58 produces 9-mesyl-9H-pyrido[2,3-b]indole (59; ▶ Scheme 17).[53] There are many more examples in which 9H-pyrido[2,3-b]indoles are made by forming these two bonds in succession rather than in a single reaction step (see ▶ Sections 10.23.1.1.1.6.1 and ▶ 10.23.1.1.1.7.1) and this does seem to be a better strategy.

▶ Scheme 17 Reaction of 3-Bromo-2-fluoropyridine with a [2-(Mesylamino)phenyl]boronic Acid Ester[53]

9-Phenyl-3-(trifluoromethyl)-9 H-pyrido[2,3-b]indole (55); Typical Procedure:[52]

A soln of Pd(OAc)2 (11 mg, 0.05 mmol, 5 mol%), Cy3P (29 mg, 0.10 mmol, 10 mol%), t-BuONa (288 mg, 3.00 mmol), Ph2NH (53; 203 mg, 1.20 mmol), and 2,3-dichloro-5-(trifluoromethyl)pyridine (54; 220 mg, 1.00 mmol) in anhyd toluene (10.0 mL) was stirred at 105°C for 18 h under N2. Et2O (25 mL) and H2O (25 mL) were added at rt, and the separated aqueous phase was extracted with Et2O (2 × 75 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pentane) to give the product as a light-yellow solid; yield: 289 mg (93%); mp 108.3–109.6°C.

9-Mesyl-9 H-pyrido[2,3-b]indole (59); Typical Procedure:[53]

A 10-mL microwave-compatible vial was charged with 3-bromo-2-fluoropyridine (57; 176 mg, 1.00 mmol), boronate ester 56 (327 mg, 1.10 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol, 2 mol%), K2CO3 (414 mg, 3.00 mmol), and DME/H2O (4:1; 2 mL). The tube was sealed and heated in a Biotage Personal Chemistry Emrys Optimizer (automated microwave synthesizer) at 140°C for 15 min, and then cooled to rt. The mixture was diluted with CH2Cl2