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 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)

Science of Synthesis Reference Library

Catalytic Transformations via C—H Activation (2 Vols.)

Biocatalysis in Organic Synthesis (3 Vols.)

C-1 Building Blocks in Organic Synthesis (2 Vols.)

Multicomponent Reactions (2 Vols.)

Cross Coupling and Heck-Type Reactions (3 Vols.)

Water in Organic Synthesis

Asymmetric Organocatalysis (2 Vols.)

Stereoselective Synthesis (3 Vols.)

Abstracts

1.1.1 Arylation Using a Palladium(0) Catalyst

F. S. Melkonyan and V. Gevorgyan

The palladium(0)-catalyzed C—H arylation reaction is one of the pioneering transformations in C—H activation chemistry in general. In the past two decades, the method has been extensively developed and now represents a very powerful tool for the construction of C(sp²)—C(sp²) bonds. In this chapter, the palladium(0)-catalyzed C—H arylation of aromatic compounds is reviewed. The application of the method toward the synthesis of polycyclic aromatic hydrocarbons (PAHs), a variety of biaryl compounds, and natural products, with emphasis on the most practical and efficient protocols, are discussed.

Keywords: C—H activation • palladium catalysts • arylation • arenes • polycyclic compounds • biaryls • natural products

1.1.2 Arylation Using a Palladium(II)/Palladium(IV) Catalyst System

P. Gandeepan and C.-H. Cheng

Aryl—aryl bonds are important structural motifs that are found in many natural products, bioactive compounds, and functional materials. Due to their application in various fields of organic and materials chemistry, continuous efforts have been made to develop attractive methods for their synthesis. In particular, aryl—aryl bond formation involving a palladium(II)/palladium(IV) catalyst system has received much attention in recent years. Compared to the traditional cross-coupling reactions and C—H arylation involving palladium(II)/palladium(0), biaryl formation via a palladium(IV) intermediate has high potential for application due to its insensitivity toward air and moisture, tolerance of various functional groups, lack of ligand requirement, and the very mild reaction temperature. In this chapter, arylation reactions using a palladium(II)/palladium(IV) catalyst system are reviewed.

Keywords: palladium • arylation • C—H activation • biaryls • catalysis • chelation • palladium(IV) • oxidative coupling

1.1.3 Arylation Using a Palladium(II) Catalyst

M. Zhang and W. Su

This chapter focuses on the synthesis of biaryl C—C bonds via palladium(II)-catalyzed direct arylation of arenes with aryltin, arylboron, and arylsilicon reagents and aromatic carboxylic acids. Due to the ubiquity of C—H bonds in organic molecules, these methods represent an efficient and straightforward approach to biaryl C—C bonds. The chapter is organized based on the type of arylating reagent used.

Keywords: C—H activation • arenes • arylation • biaryls • cross-coupling reactions • carboxylic acids • organometallic reagents • palladium catalysis

1.1.4 Arylation Using a Ruthenium(II) Catalyst

M. Seki

The C—H arylation of α-functionalized benzenes proceeds smoothly in the presence of a ruthenium(II) catalyst. Key factors which control the reaction (catalyst, leaving group, additive, phosphine ligand, and base) are thoroughly discussed in terms of the efficiency and practicality of the process. Of particular interest is the synthesis of biaryls by means of C—H arylation, as these constitute a key feature of some important pharmaceutical compounds.

Keywords: arylation • biaryls • C—C bond formation • C—H activation • dihydroimidazoles • dihydrooxazoles • imidazoles • pyrazoles • pyridines • ruthenium(II) catalysis • tetrazoles • triazoles

1.1.5 Vinylation Using a Palladium Catalyst

P. K. Dornan and V. M. Dong

This chapter covers methods for the vinylation of non-heteroaromatic arene C—H bonds with palladium catalysts. Both oxidative methods (dehydrogenative coupling of an arene with an alkene) and direct arylation methods (coupling of an arene with a vinyl halide or equivalent) are discussed. In many cases, directing groups are used to enhance reactivity and ensure site-selective vinylation. Examples of non-directed cases are also discussed. These vinylation methods are advantageous over other cross-coupling methods since pre-activation of the arene component (via an aryl halide or arylmetal species) is not necessary.

Keywords: C—H activation • C—H functionalization • styrenes • acrylates • palladium catalysts • vinylation • alkenylation • cross coupling • catalysis • oxidation • oxidative coupling • direct arylation

1.1.6 Vinylation Using a Rhodium(III) Catalyst

T. Satoh and M. Miura

Rhodium(III)-catalyzed oxidative and non-oxidative couplings of a wide range of arenes possessing a directing group with alkenes and alkynes are summarized in this chapter. The reaction takes place regioselectively at the ortho position to give rise to the corresponding ortho-vinylated arenes or benzannulated products.

Keywords: alkenylation • annulation • C—C coupling • C—H bond cleavage • dehydrogenation • fused heterocycles • oxidative coupling • rhodium catalysts • vinylarenes • vinylation

1.1.7 Metal-Catalyzed C—H Alkylation Using RX Compounds

C. S. Yi

This review covers transition-metal-catalyzed C(sp²)—H alkylation methods via carbon-heteroatom bond cleavage. The first part of the review delineates catalytic C(sp²)—H alkylation methods for arene and alkene substrates using various alkyl halides. Subsequently, alkylation by cleavage of C—B, C—Si, and C—Sn bonds is described. Finally, C(sp²)—H alkylation via C—O and C—S bond cleavage is reviewed.

Keywords: alkylation • C—H activation • arenes • alkenes • transition-metal catalysts

1.1.8 Metal-Catalyzed Alkylation Using Alkenes

T. Shibata and K. Tsuchikama

This review summarizes metal-catalyzed arene C—H bond activation using alkenes as alkylating reagents. Inter- and intramolecular reactions are covered, with examples leading selectively to either linear or branched products described.

Keywords: C—H activation • arenes • alkenes • alkylation • cobalt catalysts • iridium catalysts • rhenium catalysts • rhodium catalysts • ruthenium catalysts • scandium catalysts • styrenes • vinylsilanes • yttrium catalysts

1.2 C—C Bond Formation by Hetarene C—H Activation

Y. Nakao

Heteroaromatic compounds play key roles in pharmaceuticals, agrochemicals, and materials, and the development of efficient synthetic methods to access differently substituted hetarenes is therefore an important issue in organic synthesis. To circumvent the limitations associated with classical protocols to form hetaryl—carbon bonds, metal-catalyzed hetarene C—H activation followed by C—C bond-forming reactions has been developed extensively in recent decades. These transformations allow the construction of C—C bonds between hetaryl moieties and all the three differently hybridized carbons to result in alkylation, alkenylation, acylation, alkynylation, etc. of a diverse range of hetarenes irrespective of their electronic characters. This chapter deals with C—C bond formation by hetarene C—H activation achieved by transition-metal catalysis.

Keywords: hetarenes • alkylation • alkenylation • arylation • acylation • alkynylation • cyanation

Catalytic Transformations via C—H Activation 1

Preface

Abstracts

Table of Contents

Introduction

J.-Q. Yu

1.1 C—C Bond Formation by Arene C—H Activation

1.1.1 Arylation Using a Palladium(0) Catalyst

F. S. Melkonyan and V. Gevorgyan

1.1.2 Arylation Using a Palladium(II)/Palladium(IV) Catalyst System

Gandeepan and C.-H. Cheng

1.1.3 Arylation Using a Palladium(II) Catalyst

M. Zhang and W. Su

1.1.4 Arylation Using a Ruthenium(II) Catalyst

M. Seki

1.1.5 Vinylation Using a Palladium Catalyst

P. K. Dornan and V. M. Dong

1.1.6 Vinylation Using a Rhodium(III) Catalyst

T. Satoh and M. Miura

1.1.7 Metal-Catalyzed C—H Alkylation Using RX Compounds

C. S. Yi

1.1.8 Metal-Catalyzed Alkylation Using Alkenes

T. Shibata and K. Tsuchikama

1.2 C—C Bond Formation by Hetarene C—H Activation

Y. Nakao

Keyword Index

Author Index

Abbreviations

Table of Contents

Introduction

J.-Q. Yu

Introduction

1.1 C—C Bond Formation by Arene C—H Activation

1.1.1 Arylation Using a Palladium(0) Catalyst

F. S. Melkonyan and V. Gevorgyan

1.1.1 Arylation Using a Palladium(0) Catalyst

1.1.1.1 Intramolecular C—H Arylation

1.1.1.1.1 Synthesis of Polycyclic Arenes

1.1.1.1.1.1 Coupling of Arenes with Haloarenes

1.1.1.1.1.2 Coupling of Arenes with Aryl Sulfonates

1.1.1.1.1.3 Coupling Involving Palladium Migration

1.1.1.1.2 Synthesis of Biaryls

1.1.1.1.2.1 Coupling of Arenes with Haloarenes

1.1.1.1.3 Synthesis of Hetarenes

1.1.1.1.3.1 Synthesis of Five-Membered Hetarenes

1.1.1.1.3.1.1 Coupling of Arenes with Haloarenes

1.1.1.1.3.1.2 Coupling of Arenes with Aryl Sulfonates

1.1.1.1.3.1.3 Coupling Involving Palladium Migration

1.1.1.1.3.2 Synthesis of Six- and Seven-Membered Hetarenes

1.1.1.1.3.2.1 Coupling of Arenes with Haloarenes

1.1.1.2 Intermolecular C—H Arylation

1.1.1.2.1 Non-Directed C—H Activation

1.1.1.2.1.1 Coupling of Arenes with Haloarenes

1.1.1.2.1.2 Coupling of Arenes with Aryl Sulfonates

1.1.1.2.2 Directing-Group-Assisted C—H Activation

1.1.1.2.2.1 Coupling of Arenes with Haloarenes

1.1.1.2.2.2 Coupling of Arenes with Aryl Sulfonates

1.1.2 Arylation Using a Palladium(II)/Palladium(IV) Catalyst System

P. Gandeepan and C.-H. Cheng

1.1.2 Arylation Using a Palladium(II)/Palladium(IV) Catalyst System

1.1.2.1 Chelation-Assisted C(sp²)—H Arylation

1.1.2.1.1 Reaction Using Diaryliodonium Salts

1.1.2.1.2 Reaction Using Aryl Halides

1.1.2.1.3 Reaction Using Arenes

1.1.2.2 Non-Chelation-Assisted C(sp²)—H Arylation

1.1.2.2.1 Reaction Using Organometallic Reagents

1.1.2.2.2 Reaction Using Aryl Halides

1.1.2.2.3 Reaction Using Arenes

1.1.2.3 Conclusions

1.1.3 Arylation Using a Palladium(II) Catalyst

M. Zhang and W. Su

1.1.3 Arylation Using a Palladium(II) Catalyst

1.1.3.1 Reaction with Organometallic Reagents

1.1.3.1.1 Reaction with Organotin Reagents

1.1.3.1.2 Reaction with Organoboron Reagents

1.1.3.1.3 Reaction with Organosilicon Reagents

1.1.3.2 Reaction with Carboxylic Acids by Decarboxylation

1.1.4 Arylation Using a Ruthenium(II) Catalyst

M. Seki

1.1.4 Arylation Using a Ruthenium(II) Catalyst

1.1.4.1 Factors Affecting Arylation

1.1.4.1.1 Catalyst Effects

1.1.4.1.1.1 Use of Dimeric Ruthenium(II) Chloride–Benzene or Related Complexes as the Catalyst

1.1.4.1.1.2 Use of Dimeric Ruthenium(II) Chloride–p-Cymene as the Catalyst

1.1.4.1.1.3 Use of Ruthenium(III) Chloride Hydrate as the Catalyst

1.1.4.1.1.4 Use of Ruthenium(II) Carboxylate–p-Cymene Complexes as the Catalyst

1.1.4.1.1.5 Use of Ruthenium(II)–Alkylidene Complexes as the Catalyst

1.1.4.1.1.6 Use of Ruthenium(II)–Alkenylphosphine Complexes as the Catalyst

1.1.4.1.1.7 Use of Ruthenium/Cerium(IV) Oxide as the Catalyst

1.1.4.1.2 Ligand Effects

1.1.4.1.3 Additive Effects

1.1.4.1.3.1 Use of Phosphine Oxides as the Additive

1.1.4.1.3.2 Use of Potassium Acetate as the Additive

1.1.4.1.3.3 Use of Potassium Pivalate as the Additive

1.1.4.1.3.4 Use of Potassium Adamantane-1-carboxylate as the Additive

1.1.4.1.3.5 Use of Potassium Mesitylenecarboxylate as the Additive

1.1.4.1.4 Leaving Group Effects

1.1.4.1.4.1 Use of Iodide as the Leaving Group

1.1.4.1.4.2 Use of Bromide as the Leaving Group

1.1.4.1.4.3 Use of Chloride as the Leaving Group

1.1.4.1.4.4 Use of 4-Toluenesulfonate as the Leaving Group

1.1.4.1.5 Solvent Effects

1.1.4.1.5.1 Use of Arenes as the Solvent

1.1.4.1.5.2 Use of 1-Methylpyrrolidin-2-one as the Solvent

1.1.4.1.5.3 Use of Diethyl Carbonate as the Solvent

1.1.4.1.5.4 Use of Water as the Solvent

1.1.4.1.6 Directing Group Effects

1.1.4.1.6.1 ortho-Directed Reaction with Organometallic Compounds

1.1.4.2 Applications of Arylation in the Synthesis of Bioactive Compounds

1.1.4.2.1 Synthesis of Cholesteryl Ester Transfer Protein Inhibitors

1.1.4.2.2 Synthesis of Angiotensin II Receptor Blockers

1.1.4.3 Conclusions

1.1.5 Vinylation Using a Palladium Catalyst

P. K. Dornan and V. M. Dong

1.1.5 Vinylation Using a Palladium Catalyst

1.1.5.1 Vinylation by Oxidative Heck-Type Coupling

1.1.5.1.1 Vinylation with a Directing Group on the Arene Component

1.1.5.1.1.1 Use of Amide Directing Groups

1.1.5.1.1.2 Use of Trifluoromethanesulfonamide Directing Groups

1.1.5.1.1.3 Use of Urea and Guanidine Directing Groups

1.1.5.1.1.4 Use of Oxime Directing Groups

1.1.5.1.1.5 Use of Pyridine Directing Groups

1.1.5.1.1.6 Use of Amine Directing Groups

1.1.5.1.1.7 Use of Alcohol Directing Groups

1.1.5.1.1.8 Use of Carboxylic Acid Directing Groups

1.1.5.1.1.9 Use of Ether and Thioether Directing Groups

1.1.5.1.1.10 Use of Silanol Directing Groups

1.1.5.1.1.11 Use of Alkene Directing Groups

1.1.5.1.2 Vinylation with a Directing Group on the Alkene Component

1.1.5.1.3 Vinylation without a Directing Group

1.1.5.1.4 Enantioselective Oxidative Heck-Type Coupling

1.1.5.2 Vinylation by Direct Arylation of Vinyl Halides

1.1.5.2.1 Intramolecular Direct Arylation

1.1.5.2.2 Intermolecular Direct Arylation

1.1.5.2.3 Enantioselective Direct Arylation

1.1.6 Vinylation Using a Rhodium(III) Catalyst

T. Satoh and M. Miura

1.1.6 Vinylation Using a Rhodium(III) Catalyst

1.1.6.1 Oxidative Coupling of Arenes

1.1.6.1.1 Reaction with Alkenes

1.1.6.1.1.1 Vinylation/Esterification of Benzoic Acids

1.1.6.1.1.2 Vinylation/Decarboxylation of Benzoic Acids

1.1.6.1.1.3 Vinylation of Aryl Ketones

1.1.6.1.1.4 Vinylation of Benzoates and Benzaldehydes

1.1.6.1.1.5 Vinylation of Acetanilides and Benzanilides

1.1.6.1.1.6 Vinylation of Phenylazoles, Phenylpyridines, and (Phenylamino)pyridines

1.1.6.1.1.7 Vinylation of Phenylphosphine Oxides, Phenylphosphonates, and Phenylphosphonamides

1.1.6.1.2 Reaction with Alkynes

1.1.6.1.2.1 Annulation of Benzoic Acids

1.1.6.1.2.2 Annulation of Benzyl Alcohols and Phenols

1.1.6.1.2.3 Annulation of Aryl Ketones

1.1.6.1.2.4 Annulation of Acetanilides and Benzamides

1.1.6.1.2.5 Annulation of Aryl Imines

1.1.6.1.2.6 Annulation of Phenylazoles and Phenylindoles

1.1.6.1.2.7 Annulation of Arylphosphinic Acids and Arylphosphonamides

1.1.6.2 Non-Oxidative Coupling of Arenes

1.1.6.2.1 Reaction with Alkynes

1.1.7 Metal-Catalyzed C—H Alkylation Using RX Compounds

C. S. Yi

1.1.7 Metal-Catalyzed C—H Alkylation Using RX Compounds

1.1.7.1 Catalytic Arene C(sp²)—H Alkylation Reactions via C(sp³)—X Bond Cleavage (X = Cl, Br, I)

1.1.7.2 Catalytic Arene C(sp²)—H Alkylation Reactions via C—B, C—Si, and C—Sn Bond Cleavage

1.1.7.3 Catalytic Arene and Alkene C(sp²)—H Alkylation Reactions via C—O and C—S Bond Cleavage

1.1.7.4 Conclusions and Future Outlook

1.1.8 Metal-Catalyzed Alkylation Using Alkenes

T. Shibata and K. Tsuchikama

1.1.8 Metal-Catalyzed Alkylation Using Alkenes

1.1.8.1 Alkylation Using Ruthenium Catalysts

1.1.8.1.1 Carbonyl-Directed Reactions

1.1.8.1.2 Pyridine-Directed Reactions

1.1.8.1.3 Reactions Using a Bidentate Directing Group

1.1.8.2 Alkylation Using Rhodium Catalysts

1.1.8.2.1 Imine-Directed Reactions

1.1.8.2.2 Carbonyl-Directed Reactions

1.1.8.3 Alkylation Using Iridium Catalysts

1.1.8.3.1 Carbonyl-Directed Reactions

1.1.8.3.2 Pyridine-Directed Reactions

1.1.8.4 Alkylation Using Cobalt Catalysts

1.1.8.4.1 Pyridine-Directed Reactions

1.1.8.4.2 Imine-Directed Reactions

1.1.8.4.3 Amide-Directed Reactions

1.1.8.5 Alkylation Using Other Catalysts

1.1.8.5.1 Rhenium-Catalyzed Reactions

1.1.8.5.2 Yttrium- or Scandium-Catalyzed Reactions

1.1.8.6 Applications in Natural Product Synthesis

1.2 C—C Bond Formation by Hetarene C—H Activation

Y. Nakao

1.2 C—C Bond Formation by Hetarene C—H Activation

1.2.1 Hetarene C—C(sp³) Bond Formation

1.2.1.1 Hetarene C—H Activation/Alkylation Reactions

1.2.1.1.1 Alkylation with Alkyl Electrophiles

1.2.1.1.2 Alkylation with Alkenes

1.2.1.1.3 Reductive Alkylation with Alkynes

1.2.1.1.4 Alkylation with In Situ Generated Carbenes

1.2.1.2 Hetarene C—H Activation/Carbonyl Addition Reactions

1.2.2 Hetarene C—C(sp²) Bond Formation

1.2.2.1 Hetarene C—H Activation/Alkenylation Reactions

1.2.2.1.1 Alkenylation with Alkenyl Electrophiles

1.2.2.1.2 Alkenylation with Alkenes

1.2.2.1.3 Alkenylation with Alkynes

1.2.2.2 Hetarene C—H Activation/Cycloaddition Reactions

1.2.2.3 Hetarene C—H Activation/Arylation Reactions

1.2.2.3.1 Arylation with Aryl Electrophiles/Nucleophiles

1.2.2.3.2 Arylation with Arenes

1.2.2.3.3 Arylation with Hetarenes: Homocoupling of Hetarenes

1.2.2.3.4 Arylation with Hetarenes: Cross Coupling of Hetarenes

1.2.2.4 Hetarene C—H Activation/Acylation Reactions

1.2.2.4.1 Acylation with Acyl Electrophiles

1.2.2.4.2 Acylation through Carbonylation

1.2.2.5 Hetarene C—H Activation/Carboxylation Reactions

1.2.3 Hetarene C—C(sp) Bond Formation

1.2.3.1 Hetarene C—H Activation/Alkynylation Reactions

1.2.3.2 Hetarene C—H Activation/Cyanation Reactions

Keyword Index

Author Index

Abbreviations

Introduction

J.-Q. Yu

The inertness of C—H bonds (excluding acidic C—H bonds) has, since the 1960s, fueled curiosity-driven chemical research. The potential to replace C—H bonds with C—C and C—heteroatom bonds has fascinated chemists in the field of catalysis and synthesis as this offers an untapped avenue for developing new reactions that can be used as new disconnections for making molecules. As a consequence, a number of approaches have been developed to cleave and functionalize C—H bonds: Biomimetic oxidation based on iron, manganese, copper, or cobalt catalysts has led to the accumulation of a vast amount of fundamental knowledge of oxidation chemistry; carbene and nitrene insertion are among the earliest C—H activation reactions that have found their way into synthetic applications; and radical C—H abstraction has also been explored in the past and has recently attracted new interest. That said, based on the sheer number of publications, it is probably fair to say that metal insertions into C—H bonds to form well-defined carbon–metal species and subsequent functionalization of these intermediates is the most extensively investigated of the C—H functionalization techniques. Despite the rich history of C—H activation chemistry, the pace of growth of the field in the past decade is unprecedented. Major advances in two directions are mainly responsible for these new developments: First, many new redox catalytic cycles have been invented or improved to accommodate C—H activation reactions. Second, new reactivity has been obtained through weak coordination of a broad range of substrates with metal catalysts.

Given the advances made in the field of C—H activation, and the breadth of applicability of this technique in modern organic synthesis, the editors of Science of Synthesis consider that the time is ripe for an up to date and focused new addition to the Reference Library on this high-impact topic that is sure to help shape the future direction of chemical science. The organization of this two-volume series is based on the nature of the bond formed to carbon in place of the C—H bond. Each chapter covers a specific methodology so that the hierarchy of the work is kept as flat as possible. As such, experts in the field critically review the state of the art in areas of C—H activation chemistry, and a wide variety of methods by which various bonds to carbon (i.e., C—C, C—Hal, C—N, C—O, and C—B bonds) may be formed are examined. Specific focus is applied to the nature of the substrate, the transition-metal catalyst used, and any specific reagents or techniques that may be applied. To aid practical application of the information contained herein, both for teaching and research, the authors have been encouraged to include typical or general experimental procedures for the best methods.

Volume 1 concerns the formation of C—C bonds by both arene and hetarene C—H activation. For arene C—H activation the material is subdivided by coupling partner (arylation, vinylation, and alkylation) and also by the catalyst system used. The first four sections cover arylation. A chapter by V. Gevorgyan and F. S. Melkonyan (▶ Section 1.1.1) discusses reaction using a palladium(0) catalyst. Both intra- and intermolecular coupling to give various polycyclic and biaryl products, and the effects on reaction of directing groups are described. The second chapter, by C.-H. Cheng and P. Gandeepan (▶ Section 1.1.2), covers arylation using a palladium(II)/palladium(IV) catalyst system, and the role of chelation assistance in reaction is again emphasized. The third contribution, written by W. Su and M. Zhang (▶ Section 1.1.3), discusses arylation using palladium(II) catalysts in the presence of organometallic reagents. The role of palladium in decarboxylative coupling of carboxylic acids is also described. The fourth chapter, by M. Seki (▶ Section 1.1.4), features arylation using ruthenium(II) catalysts; the factors affecting the reaction (including catalyst, ligand, additive, leaving group, and solvent effects) are described in a logical, systematic manner. The next two contributions cover vinylation of arenes. The first of these, by V. M. Dong and P. K. Dornan (▶ Section 1.1.5), discusses vinylation using palladium catalysts, including oxidative Heck-type coupling of arenes (and the effect thereupon of directing groups) and direct arylation of vinyl halides. The second vinylation section, by M. Miura and T. Satoh (▶ Section 1.1.6), covers vinylation using rhodium(III) catalysts and focuses upon both oxidative and non-oxidative coupling of arenes with alkenes and alkynes. This is followed by two chapters on the alkylation of arenes. The first of these, written by C. S. Yi (▶ Section 1.1.7), covers metal-catalyzed alkylation using various electrophiles [RX compounds, where X is a halogen (Cl, Br, I), metalloid (B, Si, Sn), or chalcogen (O, S)]. The second alkylation section, by T. Shibata and K. Tsuchikama (▶ Section 1.1.8), discusses metal-catalyzed alkylation using alkenes; the role of various catalysts (Ru, Rh, Ir, Co, etc.) and substrate-bound directing groups is described. The formation of C—C bonds by hetarene C—H activation is, in contrast, covered by Y. Nakao as a single topic in ▶ Section 1.2. The coupling of hetarenes with a variety of C(sp³) centers (alkylation), C(sp²) centers (arylation, vinylation), and C(sp) centers (alkynylation, cyanation) is described systematically in this sizable contribution in a logical, easily digested fashion.

Volume 2 concerns the formation of C—C bonds by C—H activation of non-(het)arene substrates as well as by C—H activation using special reagents or techniques. The formation of C—heteroatom bonds by (predominantly arene) C—H activation is also included here. For C—C bond formation, the material is initially subdivided by substrate. The first contribution, by G. Liu and P. Chen (Section 2.1), covers allylic C—H activation and the material is categorized systematically depending on the catalyst used. The second chapter, by O. Baudoin (Section 2.2), covers alkyl C—H activation. Various directing effects, including heteroatom direction, and oxidative addition processes are described therein. A number of “special topics” for C—C bond formation are then discussed independently of the substrate used. The first of these techniques, the use of carbenes for C—H activation, is presented by X. P. Zhang and X. Cui (Section 2.3) with both intra- and intermolecular carbene insertion discussed. This is followed by coverage of C—H activation using radicals, as presented by W.-Y. Yu and W.-W. Chan (Section 2.4), which includes discussion of transition-metal-catalyzed acylation, metal-free arylation, and Minisci-type hetarene functionalization. Subsequently, double C—H activation is described by S.-L. You and J.-B. Xia (Section 2.5), who discuss oxidative homocoupling and cross-coupling methods as well less common intramolecular double C—H activation processes. The next contribution, by C. Liu, H. Zhang, and A. Lei (Section 2.6), covers C—C bond formation by carboxylation or carbonylation and, as in several other areas, the effect of directing groups is highlighted.

For C—heteroatom bond formation, the material discussed concerns predominantly arene substrates, and is thus subdivided by the nature of the bond formed. The first chapter on this topic, by M. S. Sanford and A. Cook (Section 2.7), concerns C—halogen bond formation; various ligand effects, as well as reaction in the absence of directing groups, are described. The discussion of the formation of C—N bonds is divided into two parts: The first contribution, by P. Dauban and B. Darses (Section 2.8), concerns C—N bond formation using palladium catalysis. Intramolecular reaction to form five- and six-membered rings is described, as is ortho-amidation in intermolecular processes. The second contribution, by S. B. Blakey and N. Mace Weldy (Section 2.9), covers nitrene insertion; both inter- and intramolecular amination are discussed. Coverage of the formation of C—O bonds is likewise split into two chapters. The first of these, by Y. Hitomi and K. Arakawa (Section 2.10), covers biomimetic and organocatalytic methods for arene C—H oxidation and comments upon the use of various metal complexes (porphyrin, non-heme iron, etc.) and reagents (e.g., phthaloyl peroxide). The second oxidation chapter, by G.-W. Wang and D.-D. Li (Section 2.11), describes arene C—H activation via metal-catalyzed oxidation, and the use of various metal catalysts in inter- and intramolecular processes is discussed systematically. The second volume concludes with discussion of the formation of C—B bonds via arene C—H activation in a chapter by J. M. Lassaletta, A. Ros, and R. Fernández (Section 2.12). Non-directed borylation is covered, as are various directed methods including site-selective, relay-directed, and outer-sphere ortho-C—H borylation. The formation of C—B bonds is of special interest because of the potential applications of aromatic organoboranes in synthesis, not only in cross-coupling (Suzuki–Miyaura) chemistry, but also in many other transformations.

Looking to the future, numerous challenges are ahead for practitioners in the C—H activation field. For example, how do we achieve catalyst-controlled regioselectivity and stereoselectivity of C—H activation through ligand design? Improving the practicality of catalytic systems, especially reducing catalyst loading, will be another exciting direction that will lead to the development of new tools and consequently new chemistry. At the same time, the application of C—H activation technologies to more complex systems, such as the synthesis of complex molecules and the manipulation of biologic molecules and polymers, remains a significant challenge. Nevertheless, the practitioners of C—H activation chemistry have thus far collectively moved the field forward to a point where it is certain that C—H activation technology is destined to have a significant impact on how we make and manipulate organic molecules.

1.1 C—C Bond Formation by Arene C—H Activation

1.1.1 Arylation Using a Palladium(0) Catalyst

F. S. Melkonyan and V. Gevorgyan

General Introduction

Discovered in the early 1960s,[1] the transition-metal-catalyzed/transition-metal-mediated C—H bond activation methodology has developed greatly over the last two decades.[2–6] Nowadays, C—H activation[7] represents a very powerful tool for the formation of a variety of C—C[8–11] and C—heteroatom[12–15] bonds, and the ubiquitous nature of the C—H bond in organic molecules truly breaks the limit on the number of potential substrates available for functionalization.[16] Thus, C—H bonds of unsaturated and aliphatic[17–20] carbon atoms can now be employed successfully in many transition-metal-catalyzed C—H functionalization processes. Another important advantage of this approach is the ability to perform late-stage modifications of complex organic molecules including natural products and drugs.[21,22] Finally, of special note is the great potential that transition-metal-catalyzed activation exhibits with traditionally inert C—H bonds, which has been illustrated using a number of methods operating under very mild conditions.[23]

Although the capable catalysts for C—H activation span the width of the periodic table, palladium-based catalysts are, arguably, the most popular.[24–28] It seems that the abundance of palladium-based catalysts available for cross coupling[29] has ultimately translated into catalysts for C—H activation.[30,31] Among the different transition-metal-catalyzed C—H transformations, arylation (by all means) represents the most important and highly developed methodology.[32–38] In this chapter, the arylation of unactivated arene C—H bonds via palladium(0) catalysis is discussed, with an emphasis placed on the most practical methods. This approach finds broad application in the synthesis of heterocycles, natural products, and important building blocks for material chemistry. However, the palladium(0)-catalyzed C—H arylation of hetarenes is beyond the scope of this chapter (see  ).

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