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

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 expert-evaluated 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. A. Molander (Philadelphia, USA)

P. J. Reider (Princeton, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Volume Editor’s Preface

The use of transition-metal catalysts to effect the formation of carbon—carbon and carbon—heteroatom bonds is a field that has grown exponentially over the past two decades. In particular, metal-catalyzed N-arylation reactions between amines and aryl halides have largely supplanted traditional approaches to the formation of sp²-C—N bonds, and are broadly employed in both industry and academia on both small and large scales. Carbon—carbon bond-forming cross-coupling reactions have also had a large impact on a variety of fields, and play an important role in many chemical industries. The development of new catalyst systems has led to a rapid expansion in the scope of metal-catalyzed cross-coupling reactions, and research in this area has also led to fundamentally important discoveries in organometallic chemistry and catalysis that continue to drive many fields forward.

Given the importance of metal-catalyzed cross-coupling reactions for the generation of both carbon—heteroatom and carbon—carbon bonds, this topic was selected by the Editorial Board of Science of Synthesis for coverage in a three-volume set of the Science of Synthesis Reference Library. This volume is focused on the formation of carbon—heteroatom bonds and carbon—carbon bonds of acidic C—H nucleophiles, whereas the other two volumes cover other C—C bond-forming cross-coupling reactions (Suzuki, Stille, etc.) and Heck reactions. The chapters contained in this volume are intended to provide the reader with a practical guide to the most efficient, reliable, and useful metal-catalyzed cross-coupling reactions that generate C—N, C—P, C—O, C—S, C—B, C—Si, C—CN, and C—F bonds, and C—C bonds adjacent to carbonyl functional groups. The most up-to-date and modern methods are included, including those that facilitate replacement of typically unreactive C—H bonds with carbon—heteroatom bonds.

It has truly been a pleasure to be involved in this project, and I am enormously grateful to all of the people involved with the writing, editing, and production of this volume. In particular, I thank the extremely talented group of authors who were willing to contribute their time and knowledge in writing the chapters contained in this work. I am also privileged to have been supported by the dedicated and hardworking staff at Thieme, and I would especially like to acknowledge Dr. Toby Reeve, Dr. Alex Russell, Dr. Fiona Shortt de Hernandez, and Michaela Frey for all the effort they put into this volume.

October, 2012

John P. Wolfe (Ann Arbor, Michigan, USA)

Cross Coupling and Heck-Type Reactions Volumes

Cross Coupling and Heck-Type Reactions 1

C—C Cross Coupling Using Organometallic Partners

Volume Editor: G. A. Molander

Cross Coupling and Heck-Type Reactions 2

Carbon—Heteroatom Cross Coupling and C—C Cross Coupling of Acidic C—H Nucleophiles

Volume Editor: J. P. Wolfe

Cross Coupling and Heck-Type Reactions 3

Metal-Catalyzed Heck-Type Reactions and C—C Cross Coupling via C—H Activation

Volume Editor: M. Larhed

Abstracts

2.1.1.1 Alkylamines with Aryl and Alkenyl Electrophiles

M. Tomás-Camasa

This review covers selected efficient synthetic methods for metal-catalyzed cross-coupling reactions that can directly convert simple substrates, such aryl halides or arylboronic reagents and alkylamines or ammonia, into a range of N-alkylaniline derivatives under mild conditions. Emphasis is placed on copper- and palladium-catalyzed amination reactions, which are described in the first and second parts of the chapter, respectively.

Keywords: amination • C—N bond formation • copper catalysis • palladium catalysis • Ullmann reaction • Chan–Lam–Evans reaction • N-arylation • alkylamines • aryl halides • ammonia • boronic acid derivatives

2.1.1.2 Alkylamines with Hetaryl Electrophiles

U. Scholz, W. Dong, J. Feng, and W. Shi

Methods for cross-coupling reactions to form C—N bonds between hetaryl electrophiles and alkylamines are reviewed. The methods described focus mainly on reactions using palladium or copper catalysts. However, methods employing other metal catalysts are also summarized.

Keywords: cross coupling • amination • hetaryl electrophiles • alkylamines • palladium catalysts • copper catalysts • nickel catalysts • cobalt catalysts • phosphorus ligands

2.1.2.1 Aryl- and Hetarylamines with Aryl and Alkenyl Electrophiles

M. B. Hay and J. D. Hicks

Palladium and copper complexes catalyze the formation of C—N bonds between aryl- or hetarylamines and aryl and alkenyl halides/pseudohalides. Recent work in this area has resulted in the development of highly active catalysts, which have improved substrate scope and allow reactions to be carried out under milder conditions.

Keywords: C—N bonds • palladium catalysis • copper catalysis • anilines • arylation

2.1.2.2 Aryl- and Hetarylamines with Hetaryl Electrophiles

Q. Shen, F. Guo, and J. F. Hartwig

The recent progress in palladium- and copper-catalyzed cross coupling of hetaryl electrophiles with aryl and hetarylamines is reviewed. Significant advances in this area have been achieved, and many of these advances have been driven by the development of new ligands and by careful evaluation of reactions conditions. Some of the challenges confronted by coupling reactions that form C—N bonds with different classes of heterocyclic electrophiles and nucleophiles are described.

Keywords: hetarenes • hetarylamines • palladium • copper • cross coupling

2.1.3 C—N Bond-Forming Reactions of Hetarenes

O. K. Ahmad and M. Movassaghi

Azaheterocycles are important substructures in a large number of natural products, pharmaceuticals, and fine chemicals. The synthesis of highly substituted hetarenes remains an important synthetic challenge in synthetic organic chemistry. Recent advances in transition-metal-catalyzed coupling reactions have led to the development of a wide range of methods for C—N bond-forming reactions of azaheterocyclic compounds. This account reviews the N-arylation and N-vinylation of hetarenes and is organized according to the metal used to catalyze the C—N bond formation.

Keywords: amination • amines • aza compounds • carbon—heteroatom bonds • C—N bonds • copper catalysts • imidazoles • indoles • nitrogen heterocycles • nitrogen ligands • palladium catalysts • pyrroles

2.1.4 C—N Bond-Forming Reactions of Amides and Carbamates

A. Klapars

Arylation and alkenylation reactions of amides and carbamates using copper and palladium catalysts are reviewed. The complementarity of the palladium- and copper-catalyzed amidation methods is emphasized and the substrate scope is outlined.

Keywords: C—N bond formation • arylation • aryl amidation • alkenyl amidation • alkynyl amidation • intramolecular amidation • arylboronic acids • amides • carbamates • oxazolidinones • palladium catalysts • copper catalysts

2.1.5 C—N Bond-Forming Reactions of Sulfonamides, Sulfoximides, and Other Nitrogen Nucleophiles

J. Duan, H. Chen, X. Hong, and M. Harmata

Sulfonamides, sulfoximides, guanidines, and ureas are highly important classes of compounds for the pharmaceutical industry and have been of enormous interest to synthetic chemists. This review presents the state of the art of C—N bond-forming reactions of sulfonamides, sulfoximides, and other nitrogen nucleophiles.

Keywords: sulfonamides • sulfoximides • sulfamides • sulfonimidamides • guanidines • ureas • C—N bond formation

2.1.6 C—N Bond-Forming Reactions of C—H Electrophiles

T. G. Driver

Recent transition-metal-mediated methods to construct C(sp²)—N and C(sp³)—N bonds from C—H bonds are examined within this chapter. These C—H bond aminations can be categorized into two different strategies: metal activation of the nitrogen atom or metal activation of the C—H bond. This chapter presents both the scope and challenges of the currently available methods and is organized according to the source of the nitrogen atom.

Keywords: metals • catalysis • amination • C—H activation • nitrenes • heterocycles • amines

2.2 C—P Bond-Forming Reactions

C. Petit and J.-L. Montchamp

This section covers the formation of C—P bonds via metal-catalyzed cross coupling, with particular focus placed upon the reactivity of aromatic sp²-carbon-containing electrophiles. The literature is reviewed up to the summer of 2011, and a discussion of all major phosphorus functional groups is included.

Keywords: copper catalysis • C—P bond formation • cross coupling • homogeneous catalysis • nickel catalysis • palladium catalysis • H-phosphinates • phosphine oxides • phosphines • phosphinic acids • phosphites • phosphonates • phosphonium salts • phosphorus compounds • silylphosphines

2.3.1 C—O and C—S Bond-Forming Reactions of C—X Electrophiles

C. C. Eichman and J. P. Stambuli

Various late transition metals catalyze the formation of C—O or C—S bonds in a general manner. These metal-catalyzed cross-coupling reactions proceed in high yields with proper ligand choice, and this section details the most efficient methods available for such bond formation.

Keywords: C—O bond formation • copper catalysis • cross-coupling reactions • C—S bond formation • etherification • ethers • palladium catalysis • sulfides • thioetherification • thioethers

2.3.2 C—O and C—S Bond-Forming Reactions of C—H Electrophiles

K. Inamoto

The formation of C—O and C—S bonds through transition-metal-catalyzed (or -mediated) C—H bond functionalization is described. Most examples employ a palladium catalyst, and both intermolecular and intramolecular processes are possible.

Keywords: C—H activation • carbon—heteroatom bonds • C—H bonds • C—N bonds • C—S bonds • copper catalysts • heterocycles • oxidative coupling • oxygen heterocycles • palladium catalysts • sulfur heterocycles

2.4.1 C—B and C—Si Bond-Forming Reactions of C—X Electrophiles

M. Murata

Metal-catalyzed cross-coupling reactions of M—M or M—H compounds (M = B, Si) provide a direct method for conversion of C—X bonds into C—M bonds. Tetraalkoxydiboron and dialkoxyboron species are excellent boron nucleophiles in the borylation of aryl, alk-1-enyl, allyl, and benzyl halides or pseudohalides. Catalytic silylation of aryl halides with disilanes has been significantly improved and, furthermore, hydrosilanes such as trialkoxysilanes and trialkylsilanes can be used as silicon nucleophiles. These reactions tolerate a wide variety of functional groups and proceed with excellent yields, thereby allowing the simple, convenient, and elegant preparation of functionalized C—M compounds.

Keywords: coupling reactions • borylation • silylation • chemoselectivity • C—B bonds • C—Si bonds • palladium catalysts • nickel catalysts • rhodium catalysts • arylboranes • vinylboranes • arylsilanes • vinylsilanes

2.4.2 C—B and C—Si Bond-Forming Reactions by C—H Functionalization

K.J.Szabó

Catalytic borylation and silylation based on C—H functionalization are very important tools for the synthesis of new organic reagents. This review covers the recent developments in this field, including the C—H borylation and silylation of aromatics and vinylic and allylic alkenes, and some examples of alkane functionalization. The performance and catalytic activity of iridium, rhodium, ruthenium, palladium, and other metal catalysts are reviewed, and particular attention is directed to the selectivity issues of C—H bond functionalization and to the mechanistic aspects of the reactions.

Keywords: C—B bond formation • C—H bond functionalization • C—Si bond formation • homogeneous catalysis • iridium catalysis • organoboronates • organosilanes • rhodium catalysis • ruthenium catalysis • palladium catalysis

2.5 C—CN Bond-Forming Reactions

G. Yan, Y. Zhang, and Jianbo Wang

The development of methodology for the preparation of nitriles is of significant interest to organic chemists. In the past few decades, numerous methods for the synthesis of nitriles have been developed. Among them, the transition-metal-catalyzed cyanation reaction has been a powerful tool for the straightforward construction of C—CN bonds in modern organic synthesis. In this chapter, some efficient transition-metal-catalyzed cyanation reactions are summarized.

Keywords: nitriles • transition-metal catalysis • cyanation • green chemistry • halides • boronic acids • alkenes • alkynes • alcohols • thiols • C—H activation

2.6 C—F Bond-Forming Reactions

K. B. McMurtrey and M. S. Sanford

This chapter describes both metal-mediated and metal-catalyzed procedures for converting aryl—X reagents (X = boronic acid, silyl, stannyl, hydrogen, or trifluoromethylsulfonyl) into aryl fluorides. Fluorination is accomplished using electrophilic or nucleophilic fluorinating reagents, and the metal catalysts are typically palladium or silver complexes.

Keywords: fluorination • palladium • silver • boronic acids • silanes • stannanes • C—H activation

2.7.1 C—C Cross-Coupling Reactions of Acidic C—H Nucleophiles with One Activating Group

S. P. Marsden

Nucleophiles generated by deprotonation of activated C—H positions undergo cross coupling with aryl halides and pseudohalides under palladium or nickel catalysis. The range of activating groups includes aldehydes, ketones, esters, amides, nitriles, sulfonyl, and nitro groups.

Keywords: arylation • aryl compounds • asymmetric catalysis • C—C bonds • C—C coupling • enolates • nickel catalysts • palladium catalysts

2.7.2 C—C Cross-Coupling Reactions of Acidic C—H Nucleophiles with Two Activating Groups

Y. Wu, Jun Wang, and F. Y. Kwong

This chapter describes the recent advances in C—C cross-coupling reactions of acidic C—H nucleophiles with two neighboring activating groups. Both copper- and palladium-catalyzed protocols are reviewed, focusing predominantly on the literature published in the period 1990–2011.

Keywords: arylation • carbonyl compounds • copper catalysis • cross-coupling reactions • malonates • C—H nucleophiles • palladium catalysis

Cross Coupling and Heck-Type Reactions 2

Carbon—Heteroatom Cross Coupling and C—C Cross Coupling of Acidic C—H Nucleophiles

Preface

Volume Editor’s Preface

Abstracts

Table of Contents

Introduction

J.P.Wolfe

2.1 C—N Bond-Forming Reactions

2.1.1 C—N Bond-Forming Reactions of Alkylamines

2.1.1.1 Alkylamines with Aryl and Alkenyl Electrophiles

M. Tomás-Gamasa

2.1.1.2 Alkylamines with Hetaryl Electrophiles

U.Scholz, W.Dong, J. Feng, and W.Shi

2.1.2 C—N Bond-Forming Reactions of Aryl- and Hetarylamines

2.1.2.1 Aryl- and Hetarylamines with Aryl and Alkenyl Electrophiles

M. B. Hay and J. D. Hicks

2.1.2.2 Aryl- and Hetarylamines with Hetaryl Electrophiles

Q. Shen, F. Guo, and J. F. Hartwig

2.1.3 C—N Bond-Forming Reactions of Hetarenes

O. K.Ahmad and M. Movassaghi

2.1.4 C—N Bond-Forming Reactions of Amides and Carbamates

A. Klapars

2.1.5 C—N Bond-Forming Reactions of Sulfonamides, Sulfoximides, and Other Nitrogen Nucleophiles

J. Duan, H. Chen, X. Hong, and M. Harmata

2.1.6 C—N Bond-Forming Reactions of C—H Electrophiles

T. G. Driver

2.2 C—P Bond-Forming Reactions

C. Petit and J.-L. Montchamp

2.3 C—O and C—S Bond-Forming Reactions

2.3.1 C—O and C—S Bond-Forming Reactions of C—X Electrophiles

C. C. Eichman and J. P. Stambuli

2.3.2 C—O and C—S Bond-Forming Reactions of C—H Electrophiles

K. Inamoto

2.4 C—B and C—Si Bond-Forming Reactions

2.4.1 C—B and C—Si Bond-Forming Reactions of C—X Electrophiles

M.Murata

2.4.2 C—B and C—Si Bond-Forming Reactions by C—H Functionalization

K.J.Szabó

2.5 C—CN Bond-Forming Reactions

G. Yan, Y. Zhang, and Jianbo Wang

2.6 C—F Bond-Forming Reactions

K. B. McMurtrey and M. S. Sanford

2.7 C—C Cross-Coupling Reactions of Acidic C—H Nucleophiles

2.7.1 C—C Cross-Coupling Reactions of Acidic C—H Nucleophiles with One Activating Group

S. P. Marsden

2.7.2 C—C Cross-Coupling Reactions of Acidic C—H Nucleophiles with Two Activating Groups

Y.Wu, Jun Wang, and F.Y.Kwong

Keyword Index

Author Index

Abbreviations

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