No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and authors have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

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.