Organic Reactions, Volume 92

Introduction to the Series Roger Adams, 1942

In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better-known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the authors have been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy, the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.

Introduction to the Series Scott E. Denmark, 2008

In the intervening years since The Chief wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.

From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on even greater significance for the practice of chemical experimentation in the 21st century.

Adams' description of the content of the intended chapters is still remarkably relevant today. The development of new chemical reactions over the past decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on the willingness of organic chemists to devote their time and efforts to the preparation of chapters. The fact that, at the dawn of the 21st century, the series continues to thrive is fitting testimony to those chemists whose contributions serve as the foundation of this edifice. Chemists who are considering the preparation of a manuscript for submission to Organic Reactions are urged to contact the Editor-in-Chief.

Preface to Volume 92

Something old,

something new,

something borrowed,

something blue,

Old English Rhyme, Lancaster Version

No, this volume is not a marriage in the traditional sense, but the union of old and new in the form of two chapters, one of which represents some of the most classical methods for the synthesis of indoles, pyrroles, and carbazoles together with a second chapter that describes some of the most modern methods for the construction of extraordinarily complex polycyclic compounds. To create this volume we have borrowed the expertise of one of our longest-serving editors (and a previous author at that), namely, Stuart W. McCombie. And of course, those familiar with the series will appreciate that since 1942, our bound volumes have maintained the same classic blue covers that at one time were proudly featured in libraries and researchers offices around the world.

The first chapter, authored by Antonio M. Echavarren, Michael E. Muratore, Verónica López-Carrillo, Ana Escribano-Cuesta, Núria Huguet, and Carla Obradors, represents a family of reactions that are truly the product of modern methods development, namely the remarkable ability of gold catalysts to effect a bewildering array of structural reorganizations in reactions between alkynes and alkenes or arenes. The ascendancy of gold catalysis over the past 15 years can be traced to an early report by Teles on the hydration of alkynes to ketones. The recognition that cationic gold complexes have a special ability to bind to alkynes and to catalyze addition reactions has led to a gold rush of developments that leverage this potential in a wide range of settings. Allied to the hydrofunctionalization of alkynes is the landmark report by Echavarren on the cycloisomerization reactions of enynes in 2004. When the field grew to the point where an authoritative overview of this remarkable family of transformations was warranted, naturally, we turned to Prof. Echavarren and were delighted that he agreed to invest the effort together with an impressive team of collaborators to accomplish this task. The result is the first comprehensive treatment of these reactions that introduces the reader to the broad scope of substrate patterns, their myriad mechanistic pathways, and the stunning diversity of product structures that can be generated under mild conditions. Because the structural reorganizations effected by gold catalysis in this family are so deep-seated and diverse, we have, for the first time in the history of the Organic Reactions series, incorporated color into a chapter to aid the readers in keeping track of the carbon atoms in these reactions. Creating a logical organization for the wide variety of structural settings and outcomes is extremely challenging, but the authors have done an outstanding job in guiding the reader through the complexities of these reactions and aiding the identification of conditions and catalysts that are recommended for the various permutations. The Tabular Survey comprises 23 tables organized by substrate structure with such a fine granularity as to facilitate with ease the identification of product types sought by those interested in using these methods. Even those not interested in executing this chemistry will find a gold mine of fascinating mechanistic puzzles for use in problem sessions.

The second chapter authored by William F. Berkowitz and Stuart W. McCombie details one of the most powerful methods for the construction of the privileged heterocycles, pyrroles, indoles, and carbazoles from vinyl and aryl azides. This classical transformation, sometimes known as the Hemestberger-Knittel reaction involves the controlled decomposition of azides into the corresponding nitrenoids by the agency of heat, light, and catalysis by metals as well as Brønsted and Lewis acids. Although a number of different mechanistic pathways are possible, the end result is the formation of a new carbon-nitrogen bond that forms a pyrrole ring either in isolation or fused to one or more aromatic nuclei. The scope of the reaction is remarkably broad and as nicely presented by the authors, the ease of introduction of the azide moiety using many different protocols greatly facilitates the implementation of this process. Given the possibility of effecting the azide decomposition by numerous methods, the authors have provided expert guidance for the preferred reaction conditions depending upon the structural setting and neighboring functionality. In view of the ubiquitous appearance of indoles and carbazoles in natural products and therapeutic agents, this process has found extensive application in synthesis which is thoroughly illustrated in the applications section. This chapter extends our indole synthesis franchise to three, including the most recent chapter in Volume 76 on palladium-catalyzed cyclizations to indoles and the chapter in Volume 20 on the classic Nenitzescu Reaction that forms 5-hydroxyindoles.

It is appropriate here to acknowledge the expert assistance of the entire editorial board, in particular Steven Weinreb who oversaw the early development of Chapter 1 as well as Dale Boger and Marisa Kozlowski who teamed up to shepherd Chapter 2 to completion. The contributions of the authors, editors, and the publisher were expertly coordinated by the board secretary, Robert M. Coates. In addition, the Organic Reactions enterprise could not maintain the quality of production without the dedicated efforts of its editorial staff, Dr. Danielle Soenen, Dr. Linda S. Press, Ms. Dena Lindsey, and Dr. Landy Blasdel. Insofar as the essence of Organic Reactions chapters resides in the massive tables of examples, the author's and editorial coordinators' painstaking efforts are highly prized.

Scott E. Denmark

Urbana, Illinois

Chapter 1

Gold-Catalyzed Cyclizations of Alkynes with Alkenes and Arenes

Antonio M. Echavarren, Michael E. Muratore, Verónica López-Carrillo, Ana Escribano-Cuesta, Núria Huguet, and Carla Obradors

Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007, Tarragona, Spain

Acknowledgments

Introduction

Mechanism and Stereochemistry

Structural Considerations of Gold Complexes

General Mechanisms and Stereochemical Aspects

Propargyl Migrations

Scope and Limitations

Intermolecular Reactions between Alkynes and Alkenes

Cycloisomerization Reactions

Cycloisomerizations and Skeletal Rearrangements of 1,5-Enynes

Cycloisomerizations and Skeletal Rearrangements of 1,6-Enynes

Cycloisomerizations and Skeletal Rearrangements of 1,7- and Higher Enynes

Cycloisomerizations toward the Formation of Cyclobutenes

Cycloisomerizations of Enamine and Enol-Constituted Enynes

Cycloisomerizations of Enamines

Cycloisomerizations of Enols Formed in Situ by Conia-Ene Reactions

Cycloisomerizations of Enol Ethers

Oxidative Cycloisomerizations of Enynes

Cyclopropanations by the Gold Carbene Intermediates

Cycloisomerizations of Enynes Bearing Propargylic Carboxylates

Cycloisomerizations of Enynes via Propargylic Acyloxy Migration

Migrations on 1,3-Enynes

Migrations on 1,4-Enynes

Migrations on 1,5-Enynes

Migrations on 1,6-Enynes

Migrations on 1,7- and Higher Enynes

Other Isomerizations of Propargylic Derivatives

Cycloisomerizations of Hydroxy- and Alkoxy-Substituted Enynes

Cycloisomerizations of 1,5-Enynes

Cycloisomerizations of 1,6-Enynes

Nucleophilic Additions to 1,n-Enynes

Hydroxy-, Alkoxy-, and Aminocyclizations of Enynes

Additions to 1,5-Enynes

Additions to 1,6-Enynes

Additions to 1,7-Enynes

Additions of Carbon Nucleophiles to Enynes

Additions of Aryl Nucleophiles

Additions of Dicarbonyl Nucleophiles

Additions of Alkenyl Nucleophiles

Cyclizations of Aryl- and Heteroarylalkynes

Cyclizations of Arylalkynes by Friedel–Crafts-Type Processes

Reactions of Indoles with Alkynes

Reactions of Furans with Alkynes

Applications to Synthesis

Comparison With Other Methods

Experimental Conditions

Experimental Procedures

Preparation of Gold Complexes

Gold(I) Chloro(tris(2,4-di-tert-butylphenyl)phosphite) [Synthesis of a Phosphite Gold(I) Chloride Complex from NaAuCl4]¹⁶²

Benzonitrile(tris(2,4-di-tert-butylphenyl)phosphite)gold(I) Hexafluoroantimonate [Synthesis of a Cationic Phosphite Gold(I) Complex]¹³¹

Chloro[(2′,4′,6′-triisopropyl-1,1′-biphenyl-2-yl)di-tert-butylphosphine]gold(I), (t-BuXPhos)AuCl [Synthesis of a Phosphine Gold(I) Chloride Complex from (Me2S)AuCl]⁸⁹⁵

Gold(I) Chloro(1,3-di(2,6-diisopropylphenyl)-2-imidazolidinylidene), (sIPr)AuCl [Synthesis of an NHC Gold(I) Chloride Complex from (Me2S)AuCl]¹³²

Dichloro(2-pyridinecarboxylato)gold(III), PicAuCl2 [Synthesis of a Gold(III) Chloride Complex from NaAuCl4]⁸⁹⁶, ⁸⁹⁷

Gold-Catalyzed Alkyne Cyclizations

Dimethyl 3-((Z)-2,6-Dimethylhepta-1,5-dien-1-yl)cyclopent-3-ene-1,1-dicarboxylate [Cycloisomerization of a 1,6-Enyne]²²⁵

(3aR*,8aR*)-4-Phenyl-5,6,7,8-tetrahydro-1H-benzo[1,4]cyclobuta[1,2-c]furan-3(3aH)-one [Formation of a Cyclobutene from 1,6- and 1,7-Enynes]⁴²⁵

Triisopropyl((3-methyl-2,5-dihydro-[1,1′-biphenyl]-4-yl)oxy)silane [Cycloisomerization of a 1,5-Enyne]²⁹⁰, ²⁹¹

(3aR*,5R*,5aS*,5bS*)-2-Tosyloctahydro-3a,5-methanocyclopropa[4′,5′]cyclopenta[1′,2′:1,3]cyclopropa[1,2-c]pyrrole [Intramolecular Cyclopropanation by an Intermediate Enyne-Derived Gold Carbene]⁵⁰⁶

(5R*,6S*)-1-((1S*,8R*,9S*)-Bicyclo[6.1.0]non-4-en-9-yl)-6-phenyl-3-tosyl-3-azabicyclo[3.1.0]hexane [Intermolecular Cyclopropanation by an Intermediate Enyne-Derived Gold Carbene]⁵¹⁰

Dimethyl 3-(1-Ethoxy-1-methylethyl)-4-methylenecyclopentane-1,1-dicarboxylate [Alkoxycyclization of an Enyne]²²⁵

Dimethyl (R*)-3-Methylene-4- ((S*)-2-methyltetrahydrofuran-2-yl)cyclopentane-1,1-dicarboxylate [Cycloisomerization of a Hydroxy-Substituted 1,n-Enyne]²²⁵

3-(2-Phenylvinylidene)heptan-1-ol [Intramolecular Addition of an Enol Ether to an Alkyne]⁶¹⁵

1-Benzoyl-2-methylenecyclopentanecarboxylic Acid, Ethyl Ester [Intramolecular Addition of a β-Keto Ester to an Alkyne]⁴³⁹

(R*)-Dimethyl 3-((R*)-2-Benzoyl-3-oxo-1,3-diphenylpropyl)-4-methylenecyclopentane-1,1- Dicarboxylate [Intermolecular Addition of a β-Keto Ester to an Alkyne]¹³¹

(1R*5S*)-1,3,5-Trimethoxy-2-(2-((1R,5S)-2-methyl-5-(phenylsulfonyl)cyclopent-2-en-1-yl)propan-2-yl)benzene [Intermolecular Addition of an Aryl Nucleophile to a 1,5-Enyne]¹³¹

(1R,3aS,4S,7S)-1,2,3,3a,4,5,6,7-Octahydro-1,4-dimethyl-7-(1-methylethyl)-1-(triethylsilyl)oxy-4,7-epoxyazulene [Intramolecular Addition of a Carbonyl Compound to an Alkyne]⁸⁴⁷

(E)-Dimethyl 3-(2,4,6-Trimethylstyryl)cyclopent-3-ene-1,1-dicarboxylate [Intermolecular Addition of a Carbonyl Compound to an Alkyne]⁶²⁸

6-Methyl-2H-chromene [Cyclization of an Arylalkyne by a Friedel–Crafts Process]⁶⁹⁶

(7-Hydroxy-6-methyl-2-((4-nitrophenyl)sulfonyl)isoindolin-5-yl)methyl Pivalate. [Intramolecular Reaction of a Furan with an Alkyne]⁷⁹¹

Tabular Survey

Chart 1 Phosphorus Ligands Used in Tables

Chart 2N-Heterocyclic Carbenes Used as Ligands in Tables

Chart 3 Other Ligands Used in Tables

Chart 4 Chiral Ligands Used in Tables

Chart 5 Gold(I) Complexes Used in Tables

Table 1 Cycloisomerizations of 1,5-Enynes

Table 2 Cycloisomerizations of 1,6-Enynes

Table 3 Cycloisomerizations of 1,7- and Higher Enynes

Table 4 Formation of Cyclobutenes and Related Compounds From 1,n-Enynes

Table 5 Intramolecular Additions of Enols and Enol Ethers to Alkynes

Table 6 Intermolecular Additions of Enols and Enol Ethers to Enynes

Table 7 Intramolecular Cyclopropanations of 1,6-Enynes

Table 8 Intermolecular Cyclopropanations of 1,6-Enynes

Table 9 Cycloisomerizations of 1,3-Enynes via Propargylic Acyloxy Migration

Table 10 Cycloisomerizations of 1,4-Enynes via Propargylic Acyloxy Migration

Table 11 Cycloisomerizations of 1,5-Enynes via Propargylic Acyloxy Migration

Table 12 Cycloisomerizations of 1,6-Enynes via Propargylic Acyloxy Migration

Table 13 Cycloisomerizations of 1,n-Enynes (n>6) via Propargylic Acyloxy Migration

Table 14 Cycloisomerizations of Hydroxy- and Alkoxy-Substituted 1,n-Enynes

Table 15 Hydroxy- and Alkoxycyclizations of 1,n-Enynes

Table 16 Aminocyclizations of 1,n-Enynes

Table 17 Intramolecular Additions of Aryl and Alkenyl Nucleophiles to Enynes

Table 18 Intermolecular Additions of Aryl Nucleophiles to Enynes

Table 19 Intramolecular Additions of Carbonyl Compounds to Enynes

Table 20 Intermolecular Additions of Carbonyl Compounds to Enynes

Table 21 Cyclizations of Arylalkynes by Friedel-Crafts Processes

Table 22 Intramolecular Reactions of Furans and Oxazoles with Alkynes

Table 23 Intermolecular Reactions of Furans with Alkynes

References

Acknowledgments

We thank our past and present coworkers who have contributed to the development of gold-catalyzed chemistry in our group at the Universidad Autónoma de Madrid and at the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona. We also thank the MINECO, the AGAUR, the European Research Council (Advanced Grant No. 321066), and the ICIQ Foundation for support.

Introduction

Gold salts and complexes are the most reactive catalysts for the electrophilic activation of alkynes under homogeneous conditions. This property was first demonstrated in the efficient additions of alcohols and water to alkynes, which occur under very mild conditions.¹, ²

Nucleophilic attack onto a [AuL]+-activated alkyne proceeds via π-complexes to form trans-alkenyl–gold complexes as intermediates in a regioselective Markovnikov-type addition (Scheme 1).³–²⁶ Reactions of allenes with nucleophiles proceed through a similar mechanism.²⁷, ²⁸ This type of activation also occurs in gold-catalyzed cycloisomerizations of 1,n-enynes in which the double bond acts as the nucleophile.

Scheme 1

Gold(I) complexes are highly selective Lewis acids with a strong affinity for the π-bonds of alkynes, allenes, alkenes, and other unsaturated functional groups.¹⁵, ¹⁹, ²⁹–³² This high π Lewis acidity (alkynophilicity) has been correlated with relativistic effects, which reach a maximum with gold.¹⁷, ³³–³⁶ Although the vast majority of cyclizations of 1,n-enynes catalyzed by gold(I) can be explained by the selective activation of the alkyne by gold, these alkyne–gold complexes are in equilibrium with complexes formed between gold(I) and the alkene moiety of the enyne.³⁷ A number of alkyne–gold complexes have been characterized,³⁸–⁴⁶ studied in solution⁴³, ⁴⁷–⁵⁰ or studied theoretically or in the gas phase.⁵¹–⁵³ Well-characterized complexes of gold(I) with alkenes,⁵⁴–⁷⁶ allenes,⁷⁷ and 1,3-dienes⁷⁸–⁸⁰ are also known, and their structures have been studied in solution.⁶⁸, ⁶⁹, ⁷⁹, ⁸¹, ⁸² A few gold(III)–alkene complexes have also been reported.⁸³, ⁸⁴ In addition, the solid-state structure of a cationic allene–gold(I) complex has been determined.⁸⁵ Alkenyl–⁸⁶–⁸⁹ and aryl–⁹⁰–⁹² digold complexes with Au2C three-center two-electron bonds have also been observed.⁹³

Many gold(I)-catalyzed reactions of alkynes with alkenes and arenes show some similarity with carbocationic processes initiated by Brønsted or main-group Lewis acids. However, gold(I) stabilizes carbocationic intermediates to a significant extent, often controlling the regio- and stereoselectivities of catalytic transformations. Although in a few cases the reactions take place through open carbocations, most transformations catalyzed by gold(I) are stereospecific.

This chapter covers gold-catalyzed cyclization reactions of alkynes with alkenes, and mechanistically related reactions of arenes, heteroarenes, and analogous nucleophiles with alkynes. Cyclizations that proceed with concomitant addition of hetero and carbon nucleophiles onto 1,n-enynes are also reviewed. Reactions of dienes, allenenes, and allenynes are not covered. Several reviews have been published on gold(I)-catalyzed reactions of enynes and related substrates.³–¹⁸, ²⁰–²⁵, ³⁰–³² Moreover, specific reviews cover gold(I)-catalyzed reactions of allenes.²⁷, ²⁸, ⁹⁴, ⁹⁵ The reader will notice that many reaction times are not specified in the Schemes and Tables. The missing reaction times are not given in the references cited.

Mechanism and Stereochemistry

Structural Considerations of Gold Complexes

Ligands play a fundamental role in modulating the reactivity of gold(I) catalysts in the activation of alkynes, allenes, and alkenes.¹³, ⁹⁶ In general, complexes with donating ligands that are sterically hindered are the most useful catalysts. Gold(I) complexes 1–4 with bulky biarylphosphines (Fig. 1), which are excellent ligands for palladium-catalyzed reactions, form catalytically active species upon activation with silver(I) salts.⁹⁷, ⁹⁸ Copper(II) salts can also be used to generate active catalysts.⁹⁹ Cationic complexes 5–7 are more convenient catalysts¹⁰⁰–¹⁰² since reactions of enynes and related compounds can be carried out in the absence of Ag(I) salts.¹⁰³, ¹⁰⁴ Complexes 8–10 have similar properties, but with the weakly coordinating bis(trifluoromethanesulfonyl)amide group (NTf2, Tf = CF3SO2).¹⁰⁵ Other complexes with bulky phosphines have also been used as catalysts in gold(I)-catalyzed cyclizations.¹⁰⁶–¹⁰⁸ Although nitriles are often used as neutral, relatively weakly coordinating ligands, 1,2,3-triazoles¹⁰⁹–¹¹² and other related ligands¹¹³ have also been employed. Complexes with N-heterocyclic carbene (NHC) ligands¹¹⁴–¹³⁰ such as 11–14,¹⁰³, ¹³¹–¹³⁷ cationic 15 and 16,¹³¹, ¹³⁸–¹⁴⁰ as well as neutral 17 and 18¹⁴¹, ¹⁴² and related carbenes,¹⁴³ are less electrophilic than those with phosphine ligands, and are usually selective catalysts in many transformations. Gold hydroxo complex IPrAuOH (IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene) can also be used as a precatalyst that is activated in the presence of Brønsted acids.¹⁴⁴, ¹⁴⁵ Open carbenes¹⁴⁶–¹⁵² and related complexes³⁹, ¹¹⁹, ¹⁵³–¹⁶⁰ give rise to selective catalysts of moderate electrophilicity. Cyclopropenylylidene-stabilized phosphenium cations, which behave in a manner similar to classical triaryl- and trialkylphosphines, have also been used as ligands in gold-catalyzed reactions.¹⁶¹ The most electrophilic catalysts for the activation of alkynes are gold(I) complexes with less-donating phosphites such as 19/AgSbF6 or 20,¹³¹ or other complexes with related ligands.¹⁶³–¹⁶⁷

The complex [Au(tmbn)2]SbF6 (tmbn = 2,4,6-trimethoxybenzonitrile), in which gold(I) is coordinated to two nitrile ligands, is indefinitely stable at room temperature and can be used for the in situ preparation of a variety of chiral and achiral cationic [L(tmbn)Au]SbF6 complexes, including ones immobilized on a polymeric support.¹⁶⁸ Other immobilized gold(I) catalysts have also been prepared.¹⁶⁹–¹⁷² Chiral gold complexes have been examined in a variety of enantioselective transformations.¹⁶³, ¹⁶⁴, ¹⁷³–¹⁸⁴ In addition, gold(III) chloride and other gold(III) salts and complexes have been used as catalysts.¹¹, ¹⁶, ¹⁷ However, it is important to note that gold(III) may be reduced to gold(I) by oxidizable substrates.¹⁸⁵ Platinum(II) salts and complexes are less reactive than gold complexes, although cationic platinacycles¹⁸⁶ and PtCl2 (in the presence of 1 atmosphere of carbon monoxide) are also effective catalysts for the activation of alkynes.¹⁸⁷, ¹⁸⁸

Figure 1 Representative gold(I) complexes used as catalysts or precatalysts.

The effect of counterions has been studied in detail for a series of [t-BuXPhos(MeCN)Au]Y (t-BuXPhos = 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl) complexes in several gold(I)-catalyzed reactions.¹⁸⁹ Yields for the intermolecular reaction of phenyl acetylene with α-methylstyrene increases in the order Y = OTf– < NTf2– < BF4– < SbF6– < BARF (BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate). In general, the best results are obtained with complex 7b, which possesses the bulky and soft anion BARF. Using catalyst 7b, yields are often increased by 10–30% compared with those obtained with 7a (Y = SbF6), probably due to a decrease in the formation of unproductive σ,π-(alkyne)–digold(I) complexes from the initial alkynes.

Complexes [LAuY] only exist as neutral species when Y– is a coordinating anion (halide, carboxylate, sulfonate, or triflimide). The corresponding complexes with less coordinating anions (such as SbF6–, PF6–, or BF4–) are not stable. When the catalytically active species are generated in situ by mixing [LAuCl] with AgY, chloride-bridged dinuclear species [LAuClAuL]Y and complexes [L(S)Au]Y (S = substrate or solvent molecule), which are substantially less reactive as catalysts, are readily formed.¹⁹⁰, ¹⁹¹ This could explain, at least partially, the somewhat erratic results that have been ascribed to silver effects.¹⁹²

It is important to stress that in gold(I) chemistry, ligand substitutions usually occur by associative mechanisms.²³, ¹⁹³, ¹⁹⁴ Therefore, in most processes, the active species re-enters the catalytic cycle by a ligand substitution between [L(product)Au]+ and [L(substrate)Au]+, which can be rate-determining. Although species [LAu]+ (naked gold complexes) are often proposed in catalytic transformations, structural evidence for their existence as stable, isolable species is still lacking. However, for the sake of simplicity in mechanistic schemes throughout this chapter, L¹Au+ is used as a surrogate of [L¹L²Au]+ complexes, where L² is a relatively weakly bound substrate (alkyne or alkene), product, or donor solvent molecule.

General Mechanisms and Stereochemical Aspects

Reactions catalyzed by gold(I) are mechanistically related to those catalyzed by other electrophilic metal complexes or by Brønsted acids, and they proceed through carbocationic intermediates. However, in contrast to proton-catalyzed processes, gold(I) significantly stabilizes the cationic intermediates, thus exerting control over possible competitive reaction pathways. In gold(I)-catalyzed reactions of polyunsaturated substrates containing alkynes, the first step is the activation of the alkyne functionality by formation of an η²-alkyne–gold(I) complex, which could have a rather skewed η¹-alkyne-gold(I) structure in the case of terminal alkynes or alkynes substituted with strongly electron-donating (alkynyl ethers and ynamides) or electron-withdrawing substituents (propiolates and related substrates). Importantly, in contrast to palladium(II),¹⁹⁵–¹⁹⁷ platinum(II),¹⁹⁸–²⁰¹ and ruthenium(II),¹⁹⁸, ²⁰² gold(I) does not undergo oxidative cyclometalations with 1,n-enynes to form gold(III) intermediates.¹⁸, ²³

From a mechanistic perspective, the best-studied reactions are cycloisomerizations of 1,n-enynes; reactions of 1,6-enynes are particularly well explored because these substrates have often been used as models for the discovery of new reactions in the presence of electrophilic metal complexes. In general, 1,6-enynes react with electrophilic metal catalysts to provide products of three types of skeletal rearrangement (Scheme 2).¹¹, ¹⁴, ²⁰³ The major pathways from 1,6-enyne 21 lead to 1,3-dienes 22 and/or 23 by reactions known as single-cleavage (type I) and double-cleavage (type II) rearrangements, respectively.²⁰⁴–²²³ In a single-cleavage rearrangement, the initial alkene C–C bond is cleaved and these two carbons are not connected to one another in the final product. A double-cleavage rearrangement is analogous except that, in this case, both the alkene and the alkyne C–C bonds are cleaved, and the two carbons comprising each unsaturated bond are not connected to one another in the final product. Although other electrophilic metal catalysts can also be used, these transformations proceed under milder conditions using gold(I) catalysts.¹⁸⁶, ²²⁴–²²⁶ Product 24 results from a third type of rearrangement (endo-type single-cleavage, type III) that was first observed with gold(I) catalysts,²²⁴, ²²⁵, ²²⁷ and later with InCl3,²¹⁰, ²¹¹ iron(III),²²⁵ or ruthenium(II) catalysts.²²⁸ In these rearrangements, the exo/endo terminology refers to the attack of the alkene at C(2) or C(1) of the alkyne; in the context of 1,6-enynes, these rearrangements lead to the formation of 5- or 6-membered rings, respectively. Type III skeletal rearrangements proceed by attack of the internal carbon of the alkene at the C(2) carbon of the alkyne. The term "endo-type" is used to indicate that the product is similar to that of an endo reaction, even though this reaction occurs via an exo process. For example, when a 1,6-enyne undergoes an endo-type rearrangement, it cyclizes in a 5-exo-dig fashion but, ultimately, forms a 6-membered ring after rearrangement.

Scheme 2

1,6-Enynes can react via an endo pathway to provide 6-membered rings 25 with no cleavage of either the alkyne or the alkene (Scheme 2). If the alkene is unsubstituted (R² =