Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles

By Kevin H. Shaughnessy, Engelbert Ciganek, Rebecca B. DeVasher and Scott E. Denmark

The metal-catalyzed amination of aryl and alkenyl electrophiles has developed into a widely used methodology for the synthesis of natural products, active pharmaceutical ingredients, agricultural chemicals, and materials for molecular electronics. Copper catalysts promote the coupling of a wide range of nitrogen nucleophiles, including amines, amides, and heteroaromatic nitrogen compounds with aryl and alkenyl halides. The reactivity profile of copper catalysts is complementary to that of palladium catalysts in many cases. Copper catalysts are highly effective with less nucleophilic nitrogen nucleophiles, such as amides and azoles, whereas palladium catalysts are more effective with more nucleophilic amine nucleophiles. Copper is an attractive alternative to palladium due to its significantly lower cost. In addition, high activity palladium catalysts require expensive and often air-sensitive ligands, whereas the modern copper systems use relatively stable and inexpensive diamine or amino acid ligands. Copper-catalyzed C–N coupling reactions are tolerant of a wide range of functional groups and have been applied to the synthesis of a variety of complex natural products. Significant work has also been done to understand the mechanism of these reactions. Current mechanistic understanding of these methodologies is covered in this monograph.

The contents of the book are taken from the comprehensive review of the topic in the Organic Reactions series. Optimal experimental conditions for the amination of aryl and alkenyl halides with all classes of nitrogen nucleophiles are presented. Specific experimental procedures from the literature are provided for the major classes of copper-catalyzed C–N coupling reactions. A tabular survey of all examples of Cu-catalyzed arylation and alkenylation of nitrogen nucleophiles is presented in 35 tables organized by nitrogen nucleophile and electrophilic coupling partner.

The literature is covered through December 2015 and provides 300 recent citations to supplement the 680 citations of the original hardbound chapter. These latest literature references have been collected in separate sections according to the sequence of the tables in the tabular survey section. In each of the sections, the individual citations have been arranged in alphabetic order of the author names.
Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles is intended to provide organic chemists with an accessible, but detailed, introduction to this important class of transformations.

• Language: English
• Publisher: Wiley
• Release date: Jan 3, 2017
• ISBN: 9781119347385

Book preview

Table of Contents

Cover

Title Page

Copyright

Foreword

Preface

Chapter 1: Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles

Acknowledgments

Introduction

Mechanism

Scope and Limitations

Applications to Synthesis

Side Reactions

Comparison with other Methods

Experimental Conditions

Experimental Procedures

Tabular Survey

References

Index

End User License Agreement

List of Illustrations

Chapter 1: Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles

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Figure 1 Common ligands for Cu-catalyzed C–N bond formation.

Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles

Kevin H. Shaughnessy, Engelbert Ciganek and Rebecca B. DeVasher

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Copyright © 2017 by Organic Reactions, Inc. All rights reserved.

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Library of Congress Catalog Card Number: 42-20265

ISBN: 978-1-119-34598-5

Foreword

Chemical synthesis is an intellectually and technically challenging enterprise. Over the many decades of progress in this discipline, spectacular advances in methods have made once intimidating transformations now routine. However, as the frontier advances and the demands for ready access to greater molecular complexity increases, so does the sophistication of the chemical reactions needed to achieve these goals. With this greater sophistication (and the attendant expectation of enhanced generality, efficiency, and selectivity) comes the challenge of adapting these technologies to the specific applications needed by the practitioner. In its 75-year history, Organic Reactions has endeavored to meet this challenge by providing focused, scholarly, and comprehensive overviews of a given transformation.

The impact of organometallic catalysis in organic synthesis can hardly be overstated. The advent of newer and more efficient methods for the construction of carbon-carbon and carbon-heteroatom bonds has truly transformed the practice of making new compounds in academic and industrial settings. The ability to introduce new carbon-nitrogen bonds onto aromatic and heteroaromatic rings through the agency of palladium-catalyzed amination with various nitrogen-based nucleophiles revolutionized the synthesis of aromatic amines. Although the impact of this method cannot be overstated, the cost of palladium precatalysts and highly engineered ligands provided incentives to revisit the use of earth-abundant copper catalysts and simpler ligand systems.

The Organic Reactions series is fortunate to have published a comprehensive chapter on this important process that constituted Volume 85. This timely chapter was authored by one of the internationally recognized leaders in this field, Prof. Kevin Shaughnessy together with his student and coauthor Rebecca DeVasher with expert assistance from Engelbert Ciganek, a longtime member of the Organic Reactions family. Although many reviews and book chapters have been written on transition-metal catalyzed aminations, this massive chapter constitutes the definitive work in the field. Thus, in keeping with our educational mission, the Board of Editors of Organic Reactions has decided to publish this chapter as a separate, soft cover book to make the work available to a wider audience of chemists. In addition, to keep pace with the rapid development of this field, Prof. Shaughnessy has provided updated references that bring the literature coverage up to December 2015. These references are appended at the end of the original reference section and organized by the Tabular presentation of the different aromatic electrophiles.

The publication of this book represents the fifth, soft cover reproduction of single-volume Organic Reactions chapters. The success of the first four, soft cover books has convinced us that the availability of low-cost, high-quality publications that cover broadly useful transformations is addressing an unmet need in the organic synthesis community. Thus, we will continue to identify candidates for the compilation of such individual volumes as opportunities present themselves.

Scott E. Denmark

Urbana, Illinois

Preface

The metal-catalyzed amination of aryl and alkenyl electrophiles has developed into a widely used methodology for the synthesis of natural products, active pharmaceutical ingredients, agricultural chemicals, and materials for molecular electronics. Copper-catalyzed C–N coupling was first reported over a century ago and remained the state-of-the art for 90 years. Over the past 20 years, palladium-catalyzed C–N couplings largely supplanted copper-catalyzed reactions due to their increased generality and reliability. The development of more active ligand-supported copper catalysts has resulted in a resurgence of interest in the use of copper, however. Copper catalysts promote the coupling of a wide range of nitrogen nucleophiles, including amines, amides, and heteroaromatic nitrogen compounds with aryl and alkenyl halides. The reactivity profile of copper catalysts is complementary to that of palladium catalysts in many cases. Copper catalysts are highly effective with less nucleophilic nitrogen nucleophiles, such as amides and azoles, whereas palladium catalysts are more effective with more nucleophilic amine nucleophiles. Copper is an attractive alternative to palladium due to its significantly lower cost. In addition, high activity palladium catalysts require expensive and often air-sensitive ligands, whereas the modern copper systems use relatively stable and inexpensive diamine or amino acid ligands. Copper-catalyzed C–N coupling reactions are tolerant of a wide range of functional groups and have been applied to the synthesis of a variety of complex natural products. Significant work has also been done to understand the mechanism of these reactions. Current mechanistic understanding of these methodologies is covered in this monograph.

Optimal experimental conditions for the amination of aryl and alkenyl halides with all classes of nitrogen nucleophiles are presented. Specific experimental procedures from the literature are provided for the major classes of copper-catalyzed C–N coupling reactions. A tabular survey of all examples of Cu-catalyzed arylation and alkenylation of nitrogen nucleophiles is presented in 34 tables organized by nitrogen nucleophile and electrophilic coupling partner. Tables are organized by increasing carbon count of the nitrogen nucleophile then by carbon count of the organic halide.

The literature is covered through December 2015 and provides over 300 recent citations to supplement the 680 citations of the original hardbound chapter. These latest literature references have been collected in separate sections according to the sequence of the tables in the tabular survey section. In each of the sections, the individual citations have been arranged in alphabetic order of the author names.

Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles is intended to provide organic chemists with an accessible, but detailed, introduction to this important class of transformations.

Chapter 1

Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles

Kevin H. Shaughnessy

Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, Alabama 35487-0336, USA

Engelbert Ciganek

121 Spring House Way, Kennett Square, Pennsylvania 19348, USA

Rebecca B. DeVasher

Department of Chemistry, Rose-Hulman Institute of Technology, Terre Haute, Indiana 47803, USA

Acknowledgments

Introduction

Mechanism

Oxidation State of Catalytically Active Copper Species

Nucleophile Coordination

Organic Halide Activation Step

Mechanistic Studies of Aryl Halide Activation by Ligand-Supported Copper Species

Computational Studies of Copper-Catalyzed Amination Mechanisms

Mechanistic Studies of Ligand Effects on Copper-Catalyzed Amination

Scope and Limitations

The Carbon Electrophile

Aromatic Halides and Sulfonates

Heteroaryl Halides

Alkenyl Halides

The Nitrogen Nucleophile

Aromatic Amines

Ammonia, Hydrazine, and Hydroxylamine

Alkyl Amines

Azole Nucleophiles

Amides, Sulfonamides, and Related Compounds

Other Nitrogen Nucleophiles

Applications to Synthesis

Synthesis of Natural Products and Biologically Active Compounds

Electronic Materials

Tandem Reactions for the Synthesis of Heterocyclic Compounds

Side Reactions

Comparison with other Methods

Experimental Conditions

Copper Precursors

Ligands

Bases

Solvents

Other Reaction Conditions

Experimental Procedures

N-(1-Naphthyl)anthranilic Acid (Ligand-Free Ullmann Arylation of an Aryl Amine).

N-Phenylbenzamide (Ligand-Free Goldberg Arylation of an Amide).

N-Phenyl-p-anisidine (CuI/l-Proline-Catalyzed Arylation of an Aniline Derivative).

N-(3-Aminophenyl)-5-amino-1-pentanol (CuI/Diketonate-Catalyzed Arylation of an Alkyl Amine).

1-(3,5-Dichlorophenyl)-2-methyl-1H-imidazole (Cu/Phenanthroline-Catalyzed Arylation of an Azole).

N-(3-Hydroxymethylphenyl)-2-pyrrolidinone (Cu/DMEDA-Catalyzed Arylation of an Amide).

(2S)-2-(N-((1E)-6-(2-Furyl)hex-1-enyl)amino)-4-methylpentanamide (Cu/DMEDA-Catalyzed Vinylation of an Amide).

Tabular Survey

Chart 1. Catalysts Used in Tables

Chart 2. Ligands Used in Tables

Table 1A. Preparation of Primary Aryl Amines

Table 1B. Preparation of Primary Heteroaryl Amines

Table 2A. N-Arylation of Primary Alkyl Amines

Table 2B. N-Heteroarylation of Primary Alkyl Amines

Table 3A. N-Arylation of Acyclic Secondary Alkyl Amines

Table 3B. N-Heteroarylation of Acyclic Secondary Alkyl Amines

Table 4A. N-Arylation of Cyclic Secondary Alkyl Amines

Table 4B. N-Heteroarylation of Cyclic Secondary Alkyl Amines

Table 5A. N-Arylation of Primary Aryl Amines

Table 5B. N-Arylation of Primary Heteroaryl Amines

Table 5C. N-Heteroarylation of Primary Aryl and Heteroaryl Amines

Table 6A. N-Arylation of Secondary Aryl, Alkyl, and Diaryl Amines

Table 6B. N-Arylation of Secondary Heteroaryl Amines

Table 6C. N-Heteroarylation of Secondary Aryl and Heteroaryl Amines

Table 7A. N-Arylation of Pyrroles

Table 7B. N-Heteroarylation of Pyrroles

Table 8A. N-Arylation of Pyrazoles

Table 8B. N-Heteroarylation of Pyrazoles

Table 9A. N-Arylation of Imidazoles

Table 9B. N-Heteroarylation of Imidazoles

Table 10A. N-Arylation of Triazoles

Table 10B. N-Heteroarylation of Triazoles

Table 11A. N-Arylation of Indoles

Table 11B. N-Heteroarylation of Indoles

Table 12A. N-Arylation of Indazoles

Table 12B. N-Heteroarylation of Indazoles

Table 13A. N-Arylation of Benzimidazoles

Table 13B. N-Heteroarylation of Benzimidazoles

Table 14A. N-Arylation of Carbazoles

Table 14B. N-Heteroarylation of Carbazoles

Table 15A. N-Arylation of Miscellaneous Heteroaromatic Nitrogen Nucleophiles

Table 15B. N-Heteroarylation of Miscellaneous Heteroaromatic Nitrogen Nucleophiles

Table 16A. N-Arylation of Primary Amides

Table 16B. N-Heteroarylation of Primary Amides

Table 17A. N-Arylation of Acyclic Secondary Amides

Table 17B. N-Heteroarylation of Acyclic Secondary Amides

Table 18A. N-Arylation of Lactams, Oxazolidinones, and Cyclic Imides

Table 18B. N-Heteroarylation of Lactams, Oxazolidinones, and Cyclic Imides

Table 19A. N-Arylation of Heteroaromatic Lactams

Table 19B. N-Heteroarylation of Heteroaromatic Lactams

Table 20. N-Arylation and N-Heteroarylation of Hydrazine Derivatives

Table 21. N-Arylation of Hydroxylamine Derivatives

Table 22A. N-Arylation of Ureas and Guanidines

Table 22B. N-Heteroarylation of Ureas and Guanidines

Table 23A. N-Arylation of Sulfonamides and Sulfonimidamides

Table 23B. N-Heteroarylation of Sulfonamides

Table 24A. N-Arylation of Sulfoximines

Table 24B. N-Heteroarylation of Sulfoximines

Table 25. Preparation of Aryl and Heteroaryl Azides

Table 26. Intramolecular Arylations

A. Synthesis of Five-Membered Nitrogen Heterocycles

B. Synthesis of Six-Membered Nitrogen Heterocycles

C. Synthesis of Seven-Membered Nitrogen Heterocycles

D. Synthesis of Eight- and Higher-Membered Nitrogen Heterocycles

Table 27. N-Arylations in Multi-Step Reactions

A. Synthesis of Five-Membered Rings

B. Synthesis of Six-Membered Rings

C. Synthesis of Seven- and Higher-Membered Rings

Table 28. N-Vinylation of Amines

Table 29A. N-Vinylation of Pyrroles, Pyrazoles, Triazoles, and Tetrazoles

Table 29B. N-Vinylation of Imidazoles

Table 29C. N-Vinylation of Indoles

Table 29D. N-Vinylation of Indazoles, Benzimidazoles, Benzotriazoles, and Carbazoles

Table 30A. N-Vinylation of Primary Acyclic Amides

Table 30B. N-Vinylation of Secondary Acyclic Amides

Table 30C. N-Vinylation of Lactams, Oxazolidinones, and Cyclic Imides

Table 31. N-Vinylation of Hydrazine Derivatives

Table 32. N-Vinylation of Sulfoximines

Table 33. Preparation of Vinyl Azides

Table 34. Intramolecular Vinylations

A. Synthesis of Four-Membered Nitrogen Heterocycles

B. Synthesis of Five-Membered Nitrogen Heterocycles

C. Synthesis of Six-Membered Nitrogen Heterocycles

D. Synthesis of Seven-Membered Nitrogen Heterocycles

E. Synthesis of Eight- and Higher-Membered Nitrogen Heterocycles

Table 35. N-Vinylations in Multi-Step Reactions

References

Acknowledgments

We thank Ms. Hannah Box for assistance in collecting references for this manuscript.

Introduction

Metal-catalyzed amination of aryl and alkenyl electrophiles has developed into a highly useful synthetic strategy for preparing N-aryl- and N-alkenyl- containing structures. Ullmann¹ first reported Cu-mediated N-arylation reactions of amines in 1903 (Scheme 1) followed closely by Goldberg's² report of amide N-arylations (Scheme 2). In these reactions, an aryl halide is condensed with an amine or amide in the presence of base and copper powder or a copper salt at high temperature. The need for stoichiometric amounts of copper and high reaction temperatures combined with the modest yields of product in most cases limits the application of these methods. Despite these limitations, Ullmann and Goldberg condensation reactions represented the state-of-the-art in metal-mediated C–N bond formation for nearly a century.³ The development of efficient Pd-catalyzed C–N bond-forming reactions that could be carried out under mild conditions with less reactive substrates, such as aryl chlorides, resulted in palladium displacing copper as the preferred metal for aryl amination reactions in the late 1990s.⁴–⁷

c01f001

Scheme 1

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Scheme 2

Interest in Cu-mediated reactions