Copper-Mediated Cross-Coupling Reactions E-Book

Gwilherm Evano

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 989

Veröffentlichungsjahr: 2013

Beschreibung

Providing comprehensive insight into the use of copper in cross-coupling reactions, Copper-Mediated Cross-Coupling Reactions provides a complete up-to-date collection of the available reactions and catalytic systems for the formation of carbon-heteroatom and carbon-carbon bonds. This essential reference covers a broad scope of copper-mediated reactions, their variations, key advances, improvements, and an array of academic and industrial applications that have revolutionized the field of organic synthesis. The text also discusses the mechanism of these transformations, the use of copper as cost-efficient alternative to palladium, as well as recently developed methods for conducting copper-mediated reactions with supported catalysts.

Leseprobe

Table of Contents

Title page

Copyright page

Foreword

Preface: Copper Catalysis from a Historical Perspective: A Legacy from the Past

The Historical and Remarkable First Discoveries by Fritz Ullmann and Irma Goldberg

Further Historical Developments: The Cyanation of Aryl Halides by Rosenmund and von Braun and the Arylation of Diketones and Malonates by Hurtley

From the Historical Discoveries to the Development of Modern Copper-Mediated Cross-Coupling Reactions

Modern Copper-Mediated Cross-Coupling Reactions and Their Impact in Organic Chemistry

Contributors

Part I: Formation of C–Heteroatom Bonds

1: Modern Ullmann–Goldberg Chemistry: Arylation of N-Nucleophiles with Aryl Halides

1.1 Introduction

1.2 Arylation of Amines

1.3 Arylation of Amides, Imides, and Carbamates

1.4 Arylation of Conjugated N-Heterocycles

1.5 Synthesis of Anilines by Coupling with Ammonia or Synthetic Equivalents

1.6 Conclusion and Future Prospects

2: Ullmann Condensation Today: Arylation of Alcohols and Thiols with Aryl Halides

2.1 Introduction

2.2 Formation of C–O Bonds via Copper-Catalyzed Cross-Coupling Reactions with Aryl Halides

2.3 Formation of C–S Bonds via Copper-Catalyzed Cross-Coupling Reactions with Aryl Halides

2.4 Conclusion

3: Copper-Catalyzed Formation of C–P Bonds with Aryl Halides

3.1 Introduction

3.2 Arylation of Phosphines

3.3 Arylation of Phosphine Oxides and Phosphites

3.4 Conclusion

4: Alternative and Emerging Reagents for the Arylation of Heteronucleophiles

4.1 Introduction

4.2 Chan–Lam–Evans Coupling: Copper(II)-Promoted Oxidative Aryl Transfer from Arylboron Derivatives

4.3 Copper-Promoted Aryl Transfer from Metallated Aryl Derivatives (Nonboron)

4.4 Copper-Catalyzed Arylation Reactions Involving Masked S- and N-Nucleophiles

4.5 Copper-Catalyzed Direct Heterofunctionalization of Aromatic C–H Bonds

4.6 Conclusion and Future Prospects

5: Beyond Ullmann–Goldberg Chemistry: Vinylation, Alkynylation, and Allenylation of Heteronucleophiles

5.1 Introduction

5.2 Copper-Mediated Alkenylation of Heteronucleophiles: Among the Best Routes to Heteroatom-Substituted Alkenes

5.3 Alkynylation of Heteronucleophiles: The Emergence of General Methods for the Synthesis of Heteroatom-Substituted Alkynes

5.4 Allenylation of Heteronucleophiles: New Tools for the Synthesis of Allenamides

5.5 Conclusion and Future Prospects

6: Aromatic/Vinylic Finkelstein Reaction

6.1 Introduction

6.2 Copper-Mediated Halogen Exchange Reactions in Aryl Halides

6.3 Most Recent Developments and Overview

7: Insights into the Mechanism of Modern Ullmann–Goldberg Coupling Reactions

7.1 General View and Key Mechanistic Aspects

7.2 Oxidation State of Copper Catalysts

7.3 Identity of the Active Copper(I) Complex

7.4 Activation Mode of Aryl Halides by Copper Complexes

7.5 Overview, Conclusions, and Future Prospects

Part II: Formation of C–C Bonds

8: Modern Copper-Catalyzed Hurtley Reaction: Efficient C-Arylation of CH-Acid Derivatives

8.1 Introduction

8.2 Classical Hurtley Reaction

8.3 Ligation Effect in Copper-Catalyzed Reactions of Aryl Halides with Carbanions

8.4 Cascade Reactions Proceeding via a Hurtley Arylation Reaction

8.5 Mechanism of the Copper-Catalyzed C-Arylation Reactions

8.6 Concluding Remarks

9: Copper-Catalyzed Cyanations of Aryl Halides and Related Compounds

9.1 Introduction

9.2 Modifications and Updates of Classical Cyanation Reactions (Rosenmund–von Braun, Sandmeyer)

9.3 Copper-Catalyzed Cyanations of Aryl Halides

9.4 Copper-Mediated Oxidative Cyanations

9.5 Conclusion

10: Copper-Mediated Aryl–Aryl Bond Formation Leading to Biaryls: A Century after the Ullmann Breakthrough

10.1 Introduction

10.2 Biaryl Synthesis by Coupling of Aryl Halides and Diazonium Salts

10.3 Biaryl Synthesis by Coupling of Aryltin, Boron, and Silanes

10.4 Biaryl Synthesis by Arylation Involving Arene C–H or C–C Bond Fission

10.5 Biaryl Synthesis by Oxidative Coupling of 2-Naphthols

10.6 Conclusions and Outlook

11: Copper-Catalyzed Alkynylation, Alkenylation, and Allylation Reactions of Aryl Derivatives

11.1 Introduction

11.2 Copper-Catalyzed Alkynylation of Aryl Derivatives

11.3 Copper-Catalyzed Alkenylation of Aryl Derivatives

11.4 Copper-Catalyzed Strategies for the Formation of Allyl–Aryl Bonds

11.5 Conclusion and Outlook

12: Copper-Catalyzed Alkynylation and Alkenylation Reactions of Alkynyl Derivatives: New Access to Diynes and Enynes

12.1 Introduction

12.2 Copper-Catalyzed Synthesis of Symmetrical and Unsymmetrical 1,3-Diynes

12.3 Copper-Catalyzed Synthesis of 1,4-Diynes

12.4 Synthesis of 1,3-Enynes by Direct Reaction of Vinyl Halides with Alkynes

12.5 Synthesis of 1,3-Enynes by Stille-Type Cross-Coupling Reaction

12.6 Synthesis of 1,3-Enynes by the Suzuki–Miyaura-Type Cross-Coupling Reaction

12.7 Synthesis of 1,4-Enynes by Allylation Reaction of Terminal Alkynes

12.8 Conclusion

13: Copper-Mediated Alkenylation Reaction of Alkenyl Derivatives: A Straightforward Elaboration of 1,3-Dienes

13.1 Introduction

13.2 Symmetrical 1,3-Dienes by Homocoupling Reaction of Vinyl Derivatives

13.3 Unsymmetrical 1,3-Dienes by Cross-Coupling Reactions

13.4 Conclusions

14: Emerging Areas in Copper-Mediated Trifluoromethylations of Aryl Derivatives: Catalytic and Oxidative Cross-Coupling Processes

14.1 Introduction

14.2 Copper-Catalyzed Trifluoromethylation of Aryl Halides: A Long-Lasting Quest Finally Reached

14.3 Copper-Mediated Oxidative Trifluoromethylation Reactions

14.4 Conclusion and Future Prospects

Part III: Applications of Copper-Catalyzed Cross-Coupling Reactions: Heterocycles, Natural Products, Process, and Sustainable Chemistry

15: Copper-Mediated Cyclization Reactions: New Entries to Heterocycles

15.1 Introduction

15.2 Cyclization by C–N Bond Formation

15.3 Cyclization by C–O Bond Formation

15.4 Cyclization by C–C Bond Formation

15.5 Copper-Catalyzed Double Cross-Coupling Reactions for the Assembly of Heterocycles

15.6 Conclusion and Future Prospects

16: Application of Copper-Mediated C–N Bond Formation in Complex Molecules Synthesis

16.1 Introduction

16.2 Aryl Amination in Complex Molecule Synthesis

16.3 Aryl Amidation in Complex Molecule Synthesis

16.4 Arylation of N-Heterocycles in Complex Molecule Synthesis

16.5 Vinyl Amidation in Complex Molecule Synthesis

16.6 Alkyne Amidation in Complex Molecule Synthesis

16.7 Intramolecular C–N Bond Formation in Natural Product Synthesis

16.8 Summary and Outlook

17: Natural Products and C–O/C–S Bond-Forming Reactions: Copper Showed the Way

17.1 Introduction

17.2 Total Synthesis of Naturally Occurring Diaryl Ethers by Arylation of Phenols

17.3 Intramolecular Diaryl Ether Bond-Forming Reactions

17.4 Arylation of Alcohols

17.5 Vinylation of Alcohols

17.6 Copper-Mediated C–S Bond Formation in Natural Product Synthesis

17.7 Conclusion and Future Prospects

18: Copper-Catalyzed C–C Bond Formation in Natural Product Synthesis: Elegant and Efficient Solutions to a Key Bond Disconnection

18.1 Introduction

18.2 Natural Biaryls by Copper-Catalyzed Cross Coupling

18.3 Copper-Catalyzed 1,3-Enyne Formation

18.4 Copper-Mediated Synthesis of Dienes, Trienes, and Extended Polyenes

18.5 Copper-Catalyzed Synthesis of 1,n-Polyynes Natural Products

18.6 Conclusions and Future Prospects

19: Process Chemistry and Copper Catalysis

19.1 Introduction and Scope

19.2 Copper versus Palladium

19.3 Applications

19.4 Conclusion

20: Reusable Catalysts for Copper-Mediated Cross-Coupling Reactions under Heterogeneous Conditions

20.1 Introduction

20.2 Copper Nanoparticle-Catalyzed Cross-Coupling Reactions

20.3 Supported Copper-Catalyzed Cross-Coupling Reaction

20.4 Conclusion

Index

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Library of Congress Cataloging-in-Publication Data:

Copper-mediated cross-coupling reactions / edited by Gwilherm Evano, Laboratoire de chimie organique, Service de chimie et physicochimie organiques, Université libre de Bruxelles, Brussels, Belgium; Nicolas Blanchard, Université de Strasbourg, Ecole européenne de chimie, polymères et Matériaux, Laboratoire de chimie moléculaire associé au CNRS, Strasbourg, France.

pages cm

Includes bibliographical references and index.

ISBN 978-1-118-06045-2 (hardback)

1. Copper catalysts. 2. Copper—Reactivity. 3. Chemical bonds. 4. Organic compounds—Synthesis. I. Evano, Gwilherm, editor of compilation. II. Blanchard, Nicolas, editor of compilation.

QD505.C685 2013

546'.652595–dc23

Foreword

The development of efficient methods for use in organic synthesis, particularly applicable to polyfunctionalized molecules and heterocycles, remains one of the top challenges in organic chemistry. Oftentimes older reactions are rediscovered and improved, sometimes substantially, in order to solve modern problems. A prime example of this is copper-catalyzed methodology. This topic, studied at the beginning of the twentieth century by Ullmann, Goldberg, and others has experienced a renaissance in the past two decades. A significant reason for this is the development of new and improved ligands to facilitate the transformations of interest.

While the most obvious difference between catalysts based on palladium and copper is the lower cost of the latter, this is only a small part of what makes copper catalysts so attractive. For most chemists in academia or discovery chemistry, the cost is not a major issue. In addition, one must take in to account many factors, such as volumetric productivity (reactor time, labor cost), substrate cost, yield, and substrate scope, which affect the total cost when comparing any two processes. Among the major advantages of using copper catalysts (in addition to cost) are that they tend to show excellent functional group compatibility and, in fact, are often at their best in promoting reactions of substrates that contain coordinating functional groups. A prime example, as delineated in Evano and Blanchard's preface to this book, is seen in Ullmann's seminal work: he was able to accomplish the coupling of aniline with 2-chlorobenzoic acid well before the same transformation could be carried out with palladium catalysts. In fact, the chemistry based on these two metals is really quite complementary. In support of this notion, today these are used interchangeably for many synthetic operations depending on the nature of the substrate combination to be examined.

The chapters in the book cover a range of synthetically and mechanistically important topics. Many aspects of carbon-heteroatom and carbon–carbon, bond-forming reactions are described. These have become an everyday part of the practicing synthetic organic chemist's arsenal. In addition, topics such as the formation of trifluoromethylated organic molecules and the application of copper-catalyzed methods to the total synthesis of natural products and pharmaceuticals are also covered. Taken together, the chapters in this book provide an up-to-date overview of the state of the field, providing the reader with the knowledge of both what has been accomplished and what new areas remain for further investigation.

Stephen L. Buchwald

Massachusetts Institute of Technology

Preface

Copper Catalysis from a Historical Perspective: A Legacy from the Past

Gwilherm Evano and Nicolas Blanchard

The Historical and Remarkable First Discoveries by Fritz Ullmann and Irma Goldberg

It all started in 1901 in Geneva when Fritz Ullmann, born in 1875 in Fürth, where his father owned a fabric… of metallic powders,[1] reported, in a remarkable publication that we highly recommend, that “Erhitzt man o-Bromnitrobenzol mit fein vertheiltem Kupferpulver, so bemerkt man, dass letzteres seinen Glanz verliert und in eine matte graue Masse verwandelt wird. Bei Aufarbeitung des Reactionsproductes zeigte sich nun, dass das Kupfer zum grössten Theil in Cuprobromid und das Bromnitrobenzol in eine bromfreie Substanz verwandelt worden ist, welche sich bei näherer Untersuchung identisch, mit der von Tauber auf andere Weise dargestellten 2.2′-Dinitrobiphenyl, erwies.” (If one heats o-bromonitrobenzene with finely divided copper powder, so one recognizes that the last one is losing its shine and turns into a matt grey mass. After purification of the reaction products, it appears that copper has turned into copper bromide and that the bromonitrobenzene has turned into a bromine-free substance, which, on a closer look, turns out to be identical with the 2,2-dinitrobiphenyl synthesized in a different way by Tauber) (Fig. P.1).*,[2] The reaction can also be performed from aryl iodides and, which is just astonishing, even from aryl chlorides (Scheme P.1). Two molecules of aryl halides can be coupled together in the presence of stoichiometric amounts of metallic copper: The Ullmann reaction had just been discovered.

Figure P.1 Fritz Ullmann (1875–1939) and an extract from his original publication.

Scheme P.1 1901: the discovery of the Ullmann reaction.

Obviously fascinated with the power of the metallic copper, Ullmann next reported in 1903 an equally fascinating reaction in a publication enti­­tled “Über eine neue Bildungsweise von Diphenylaminderivaten” (On a New Method for the Formation of Diphenylamine Derivatives). By mixing aniline (or other aniline derivatives) and ortho-chlorobenzoic acid in the presence of metallic copper at reflux, the aniline was smoothly arylated to the corresponding diarylamine with a remarkable efficiency (Scheme P.2).[3] Two years after his initial discovery of the biaryl synthesis, Ullmann continued to set the foundations of copper-mediated cross-coupling reactions and the arylation of amines that would later on be named after him was invented. Also remarkable is that the aryl halide substrate chosen for this study, ortho-chlorobenzoic acid, already possessed a non-innocent chelating group: the ortho-effect, which still has a deep impact in copper catalysis today and which was crucial to the success of many copper-mediated transformations including in Nicolaou's synthesis of vancomycin (see further), was already touched upon in 1903.

Scheme P.2 1903: the discovery of the Ullmann condensation reaction for the synthesis of diarylamines.

Following these two reports, Ullmann's assistant in Geneva, Irma Goldberg, reported 3 years later that a related reaction could be performed using only catalytic amounts of copper. By reacting anthranilic acid and bromobenzene in the presence of potassium carbonate and catalytic amounts of “Naturkupfer C” in refluxing nitrobenzene for 3 hours, the reaction proceeded with a remarkable efficiency, the corresponding condensation product being isolated in 99% yield (Scheme P.3).[4] The arylation could also be efficiently performed with para-nitro-bromobenzene and, even better, the arylation of amides (benzamide in this case), known nowadays as the Goldberg condensation reaction, could also be catalyzed by traces of metallic copper. These three remarkable reactions published between 1901 and 1906 mark the beginning of cross-coupling reactions and clearly paved the way for all recent developments.

Scheme P.3 1906: the discovery of the copper-catalyzed arylation of anilines and amides by Irma Goldberg.

Last but not least, Ullmann also studied the cross coupling involving phenols and reported in 1905 that “if you try to react potassium phenoxide with bromobenzene, the yield of the biphenyl ether is 0.9%. If you however add small quantities of copper to the reaction mixture, the yield goes to 90%” (Scheme P.4).[5] It is therefore possible to catalyze the cross coupling between phenols and aryl bromides with small amounts of copper, which obviously have a dramatic effect on the reaction rate and yields.

Scheme P.4 1905: the discovery of the copper-catalyzed arylation of phenols by Fritz Ullmann.

Further Historical Developments: The Cyanation of Aryl Halides by Rosenmund and von Braun and the Arylation of Diketones and Malonates by Hurtley

In a series of just four publications, Fritz Ullmann and Irma Goldberg, who eventually got married in 1910, clearly set the foundations of modern copper catalysis. This pioneering work was followed by other key reports in the next 30 years or so, which further demonstrated the potential of copper-mediated cross-coupling reactions.

The next major development in this field was stimulated by the interest in the copper-mediated cyanation of aryl halides, which appeared closely after the seminal publications of Ullmann and Goldberg. Although this transfor­mation is known as the “Rosenmund–von Braun” reaction, many academic and industrial research groups contributed to the development of this very useful reaction.[6–8] Indeed, the first report of such a reaction appeared in the patent literature in 1913 by the Meister, Lucius & Brüning Company who found that chloro- and bromoanthraquinones reacted with copper(I) cyanide in pyridine at 150°C to give the corresponding nitriles (Fig. P.2 and Scheme P.5).[8]

Figure P.2 The 1913 Meister, Lucius & Brüning Company patent.

Scheme P.5 1913: The first copper(I)-mediated cyanations of haloanthraquinones by the Meister, Lucius & Brüning Company.

Karl W. Rosenmund and his PhD student Erich Struck described next in 1919 that potassium cyanide in combination with copper(I) cyanide converted aryl halides to the corresponding benzoic acids in water at 200°C under pressure. The intermediate nitriles were not isolated, but the central role of the copper(I) species was put forward (Scheme P.6, Eq. 1).[9a] Rosenmund disclosed a year later[9b] that stoichiometric copper(I) thiocyanate in pyridine converted aryl bromides to intermediate aryl thiocyanates, which spontaneously gave the corresponding nitriles at 180°C in the presence of the copper species,[6] the nitriles being characterized as carboxylic acids after aqueous acidic treatment (Scheme P.6, Eq. 2). Shortly after, Henri de Diesbach reported in two back-to-back articles in 1923 that dibromoxylene derivatives could be converted to the corresponding dinitriles in excellent yield using an excess of copper(I) cyanide in pyridine at 200°C (Scheme P.6, Eq. 3),[10] and even aryl chlorides could be transformed to the corresponding nitriles, as seen in Scheme P.6, Eq. 4.[11]

Scheme P.6 1919–1923: Karl W. Rosenmund and Henri de Diesbach early reports on the cyanation of aryl halides.

In 1927, Alfred Pongratz described that copper(I) cyanide in refluxing quinoline was efficient for the cyanation of perylene-3,9-dibromide (Scheme P.7, Eq. 1) and that the corresponding chloride could be converted in the absence of solvent at 300°C, although no yield was given in the latter case.[12] Finally, during investigation on the chemistry of fluoranthene derivatives, Julius von Braun, who gave his name to this cyanation reaction, demonstrated that 4-bromo-fluoranthene could be transformed to the corresponding nitrile in 80% yield when reacted with copper(I) cyanide at 260°C (Scheme P.7, Eq. 2).[13]

Scheme P.7 1927–1931: Alfred Pongratz and Julius von Braun cyanation of aryl halides.

The pioneering investigations of Ullmann, Goldberg and Rosenmund[8b] were a source of inspiration for William R. H. Hurtley, who recognized their contributions in his seminal 1929 report, stating that “under the catalytic influence of copper, the halogen in o-bromo-benzoic acid is much more reactive than is commonly realized.”[14] Hurtley showed that copper bronze or copper acetate can promote the C-arylation of some families of CH-acids in reaction with o-bromobenzoic acid in the presence of sodium ethoxide as a base (Scheme P.8). Since then, this transformation, commonly known as the “Hurtley reaction”, has triggered mechanistic investigations as well as very elegant applications in organic synthesis. Mild conditions are now available thanks to new classes of ligands that even allowed the development of an asymmetric version of the Hurtley reaction.

Scheme P.8 1929: the discovery of the copper-mediated arylation of CH-acid derivatives by William R. H. Hurtley.

From the Historical Discoveries to the Development of Modern Copper-Mediated Cross-Coupling Reactions

While remarkable, these reactions, however, have found only a limited number of applications, especially when compared to their impressive potential. Indeed, drawbacks associated with the use of harsh reaction conditions (strong bases, stoichiometric amounts of copper in some cases, and high reaction temperatures) have clearly hampered the development of these copper-mediated cross-coupling reactions. From the first discoveries in the early 1900s up to the beginning of the twenty-first century, no real breakthrough was made to significantly improve the original systems and the strategy was to tailor the substrate, not the catalyst, to obtain systems that would perform under milder conditions. Nicolaou's remarkable total synthesis of vancomycin is one of the most representative example of such a strategy. Capitalizing on the well-known ortho-effect in copper-mediated transformations, a mild copper-mediated arylation reaction was designed based on the ingenious incorporation of a triazene unit in the starting material strategically placed ortho to the bromine: this internal helper auxiliary served both as a potential “electron sink” and to coordinate the intermediate copper species. The triazene indeed considerably helped the reaction, which enabled the formation of the C–O–D and D–O–E ring systems under remarkably mild conditions since the reaction could be performed in refluxing acetonitrile (Scheme P.9).[15]

Scheme P.9 The Ullmann condensation reaction under milder conditions: redesigning the substrate to improve the efficiency (Nicolaou's total synthesis of vancomycin).

Besides these strategies based on substrate modifications, the inherent shortcomings of the original copper-mediated cross-coupling reactions were still not overcome at the end of the twentieth century and palladium was in most cases preferred to copper. Despite remarkable work done with palladium catalysis for the construction of an impressive and ever-increasing number of C–C and C–heteroatom bonds, limitations still exist and the high cost of palladium and ligands has forced chemists to consider alternative metals. This evolution eventually led to the renaissance of copper catalysis, which has been extremely revisited over the past decade. Following extensive and remarkable studies of the Ullmann condensation by Payne,[16] who showed that the active catalytic species are soluble cuprous ions and pioneering work by Bryant,[17] Capdevielle,[18] and Goodbrand,[19] who investigated the idea of a “ligated copper catalysis”, the key breakthrough was the introduction of chelating ligands for copper.

Remarkable and pioneering studies in this area from, among others, the Buchwald, Ma, and Taillefer groups had a strong impact in the renaissance of copper catalysis, and the Ullmann, Goldberg, Rosenmund–von Braun, Hurtley, and other related copper-mediated processes can now be conducted under much milder conditions together with dramatically enhanced yield. Recent advances in the arylation of N-, O-, and S- as well as P-nucleophiles with aryl halides will be described in Chapters 1, 2, and 3, respectively.

In addition to the development of improved protocols for the arylation of various heteronucleophiles, the introduction of chelating ligands also considerably expanded the scope of the original procedures and allowed for the use of new reaction partners for the introduction of vinyl, alkyne, and allene functional groups. These copper-mediated syntheses of heterosubstituted alkenes, alkynes, and allenes will be overviewed in Chapter 5. Copper-catalyzed aromatic versions of the Finkelstein reaction have also been recently reported: they proceed with remarkable efficiencies and will be covered in Chapter 6.

These recent developments also had a strong impact on the develop­­ment of new and improved protocols for the formation of C–C bonds, and a variety of robust, mild, and reliable procedures have been designed with the assistance of copper complexes.

The classical Hurtley-type transformation as well as the tremendous progresses that have been reported recently in this central C-arylation reaction of CH-acid derivatives will be presented in Chapter 8, with an emphasis on the importance of the different types of ligands, mechanisms, and synthetic applications. The copper-catalyzed synthesis of nitriles from aryl halides is then covered in Chapter 9, including discussions on the different catalytic systems and sources of cyanide that have been greatly improved in the past two decades.

A central reaction in the realm of copper-catalyzed and copper-mediated transformations is of course the aryl–aryl coupling that has continuously evolved into an efficient and practical tool with multiple applications. Chapter 10 is devoted to this vibrant field of research that has recently witnessed a shift of paradigm with even more direct reactions such as the copper-catalyzed direct C–H arylations. The next three chapters, Chapters 11, 12, and 13, have captured relevant advances in some of the most practical and efficient copper-catalyzed transformations that have clearly modified our conception of carbon–carbon bond disconnections: the alkenylation and alkynylation of aryl, alkynyl, and vinyl derivatives.

To close this section dedicated to the formation of carbon–carbon bonds, the central role of copper catalysts in methods aiming at the introduction of the trifluoromethyl moiety will be exposed. Indeed, the occurrence of the trifluoromethyl motif in pharmaceutical and agrochemical active ingredients is well recognized and has triggered the development of new methodologies for its selective introduction. The copper-catalyzed trifluoromethylation reaction and copper-mediated oxidative processes are efficient strategies in this context and are developed in detail in Chapter 14.

Besides substrate modifications and the design of more efficient catalytic systems, the drawbacks associated with the harsh conditions of the classical Ullmann–Goldberg and related transformations also motivated the search for alternative reagents to aryl halides that would enable the arylation of heteronucleophiles under milder reaction conditions. In 1998, independent back-to-back publications by Chan,[20] Evans,[21] and Lam[22] revolutionized the arylation of heteronucleophiles as they reported generally applicable protocols for the copper-mediated oxidative cross coupling with arylboronic acids at room temperature. This reaction is now widely applied and other reagents such as organobismuth, -lead, -stannanes, -siloxanes, or hypervalent iodonium salts have also been used. They are sometimes more reactive than aryl halides, allow overcoming some limitations met with these reagents, or are just more readily available in some cases. Advances in copper-mediated cross coupling using these reagents are covered in Chapter 4 as well as the heteroarylation involving masked nucleophiles and the direct introduction of a heteronucleophile from a C–H bond. The use of these alternative reagents for the alkenylation/alkynylation of heteronucleophiles will be overviewed in Chapter 5.

If the modern copper-catalyzed Ullmann and Goldberg cross-coupling reactions have recently evolved as reliable and efficient methods for the construction of products relevant to both industry and academic settings, their mechanisms have been studied only recently. Mechanistic insights into these reactions, which will be crucial for the development of even more efficient catalytic systems, will be described in Chapter 7.

Modern Copper-Mediated Cross-Coupling Reactions and Their Impact in Organic Chemistry

We have all heard that we have arrived at a point where it is possible to make almost any conceivable chemical structure by a rational approach, using the large toolbox of synthetic methods available today and that there was basically nothing left to do in organic synthesis. The impact that had the renaissance of copper catalysis over the past 10 years is one of the most striking examples that this is just as stupid as it seems. Many long-standing synthetic problems have been solved using copper-mediated cross-coupling technologies, which had an important impact on the way chemists design their synthetic routes. These transformations have found remarkable applications in heterocyclic synthesis, which are detailed in Chapter 15, or in natural product synthesis, as shown in Chapters 16–18, an area where chemical transformations are clearly challenged and pushed way beyond their limits. Copper-mediated cross-coupling reactions have also been readily integrated in process chemistry where remarkably efficient procedures have been developed on the basis of copper catalysis as shown by examples collected in Chapter 19.

Copper is cheap, at least for the moment, but high catalyst loading is still required in most cases and catalyst recovery is therefore a quite important issue. Reusable catalysts for copper-mediated cross-coupling reactions under heterogeneous conditions have also been developed recently and will be overviewed in Chapter 20.

As a concluding remark, all advances reported in the last decade in copper-mediated cross-coupling reactions are truly remarkable and had strong impact, in a relatively short period of time, in organic synthesis. Many of the transformations presented in this book are already classics in organic synthesis and, in many areas, copper really showed the way.

Note

* The editors are truly indebted to Dr. Théophile Tschamber from the University of Mulhouse (France) for his expertise in translating the numerous original German research papers and patents that are cited in the Preface.

References

[1] Meyer, K. H. Helv. Chim. Acta 1940, 23, 93–100.

[2] Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174–2185.

[3] Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384.

[4] Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691–1692.

[5] Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211–2212.

[6] Mowry, D. T. Chem. Rev. 1948, 42, 189–283.

[7] Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779–794.

[8] Farbwerke vormals Meister, Lucius & Brüning, assignee. Verfahren zur Darstellung von Anthrachinon-α-nitrilen. German patent 271,790. 1913 February 18.

[9] (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 52, 1749–1746. (b) Rosenmund, K. W.; Harms, H. Ber. Dtsch. Chem. Ges. 1920, 53, 2226–2240.

[10] (a) de Diesbach, H. Helv. Chim. Acta 1923, 6, 539–548. (b) de Diesbach, H.; Schmidt, V.; Decker, E. Helv. Chim. Acta 1923, 6, 548–549.

[11] Newman, M. S. J. Am. Chem. Soc. 1937, 59, 2472.

[12] Pongratz, A. Monatsh. Chem. 1927, 48, 585–591.

[13] von Braun, J.; Manz, G. Liebigs Ann. Chem. 1931, 488, 111–126.

[14] Hurtley, W. R. H. J. Chem. Soc. 1929, 1870–1873.

[15] (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Bräse, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421–3422. (b) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584–2601. (c) Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughues, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602–2621. (d) Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughues, R. Chem. Eur. J. 1999, 5, 2622–2647. (e) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes, R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem. Eur. J. 1999, 5, 2648–2667. (f) Nicolaou, K. C.; Boddy, C. N. C. J. Am. Chem. Soc. 2002, 124, 10451–10455.

[16] Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496–1502.

[17] Bryant, R. J., inventor; Sterwin A.-G., assignee. Substitution of aromatic organic compounds. G. B. patent 2,089,672. 1982 June 30.

[18] Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007–1010.

[19] Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670–674.

[20] Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winter, M. P. Tetrahedron Lett. 1998, 39, 2933–2936.

[21] Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940.

[22] Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944.

Contributors

Carole Alayrac, Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, INC3M, FR3038, ENSICAEN & Université de Caen Basse-Normandie, 6 boulevard du Maréchal Juin, 14050 Caen, France

Irina P. Beletskaya, Moscow M.V. Lomonosov State University, Chemical Faculty, Department of Organic Chemistry, Leninskie gory 1, Moscow 119991, Russian Federation

Matthias Beller, Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany

Nicolas Blanchard, Université de Strasbourg, Ecole Européenne de Chimie, Polymères et Matériaux, Laboratoire de Chimie Moléculaire Associé au CNRS, 25 rue Becquerel 67087 Strasbourg, France

Alicia Casitas, QBIS Group, Departament de Química, Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain

Morgan Donnard, Université de Strasbourg, Faculté de Pharmacie, Laboratoire d'Innovation Thérapeutique Associé au CNRS, 74 route du Rhin—CS60024, 67401 Illkirch Cedex, France

Gwilherm Evano, Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université Libre de Bruxelles, Avenue F. D. Roosevelt 50, CP160/06, B-1050 Brussels, Belgium

Alexey Yu. Fedorov, N.I. Lobachevky Nizhny Novgorod State University, Chemical Faculty, Department of Organic Chemistry, Gagarin avenue 23, 603950 Nizhny Novgorod, Russian Federation

Hua Fu, Key Laboratory of Bio-organic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China

Annie-Claude Gaumont, Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, INC3M, FR3038, ENSICAEN & Université de Caen Basse-Normandie, 6 boulevard du Maréchal Juin, 14050 Caen, France

Céline Guissart, Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université Libre de Bruxelles, Avenue F. D. Roosevelt 50, CP160/06, B-1050 Brussels, Belgium

Ruimao Hua, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China

Yongwen Jiang, State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China

Kévin Jouvin, Institut Lavoisier de Versailles, Université de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats Unis, 78035 Versailles Cedex, France

Klaus Kunz, Bayer Crop Science AG, Alfred-Nobel-Strasse 50, 40789 Monheim, Germany

Jihoon Lee, Department of Chemistry and Center for Chemical, Methodology and Library Development, Metcalf Center for Science and Engineering, 590 Commonwealth Avenue, Boston University, Boston, MA 02215, USA

Hao Li, Department of Chemistry, Atwood Hall, 1515 Dickey Drive, Emory University, Atlanta, GA, 30322-2210, USA

Jin-Heng Li, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China

Lanny S. Liebeskind, Department of Chemistry, Atwood Hall, 1515 Dickey Drive, Emory University, Atlanta, GA, 30322-2210, USA

Songbai Liu, Department of Food Science and Nutrition, Zhejiang University, 388 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China

Norbert Lui, Bayer Crop Science AG, Alfred-Nobel-Strasse 50, 40789 Monheim, Germany

Dawei Ma, State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China

Luc Neuville, Centre de Recherche de Gif, Laboratoire International Associé, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France

James S. Panek, Department of Chemistry and Center for Chemical, Methodology and Library Development, Metcalf Center for Science and Engineering, 590 Commonwealth Avenue, Boston University, Boston, MA, 02215, USA

Doron Pappo, Department of Chemistry, Ben-Gurion University, P.O. Box 653, Be'er-Sheva 84105, Israel

Xavi Ribas, QBIS Group, Departament de Química, Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain

Thomas Schareina, Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany

Ren-Jie Song, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China

Marc Taillefer, Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex 5, France

Cédric Theunissen, Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université Libre de Bruxelles, Avenue F. D. Roosevelt 50, CP160/06, B-1050 Brussels, Belgium

Anis Tlili, Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex 5, France

Changfeng Wan, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China

Ye Wang, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China

Zhiyong Wang, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China

Yoshihiko Yamamoto, Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan

Daoshan Yang, Key Laboratory of Bio-organic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China

Part I

Formation of C–Heteroatom Bonds

1

Modern Ullmann–Goldberg Chemistry: Arylation of N-Nucleophiles with Aryl Halides

Yongwen Jiang and Dawei Ma

1.1 Introduction

The copper-catalyzed arylation of N-nucleophiles with aryl halides, named after their inventors (the “Ullmann reaction”[1]for the cross coupling with amines or the “Goldberg reaction”[2]for the cross coupling with amides), is a valuable transformation that has been widely applied in the preparation of an ever-growing number of pharmaceutically important compounds and in materials sciences as well. For quite a long time, however, these two reactions suffered from the requirement of high reaction temperatures, strong bases, and, in most cases, stoichiometric amounts of copper. Since the late 1990s, a great number of ligands, especially N,N-, N,O-, and O,O-bidentate ligands, have been demonstrated to have the ability to efficiently promote these copper-catalyzed arylation reactions.[3] With the assistance of these ligands, the copper-catalyzed arylation of most N-nucleophiles now proceeds smoothly and under relatively mild conditions, and the amounts of copper salt can be greatly reduced. These advantages not only make these two old reactions become real catalytic ones but also broaden their scope because more substrates—especially those that are sensitive to high reaction temperatures or basic conditions—can now be used in these arylation reactions.

In this chapter, we will present the developments in this field with emphasis on the most general procedures. This chapter has been divided into four sections, according to the nature of the N-nucleophile: amines, amides/imides/carbamates and related nucleophiles, conjugated N-heterocycles, and ammonia or synthetic equivalents. The arylation of these nucleophiles will be overviewed starting with the arylation of amines, a reaction that yields highly valuable, polysubstituted anilines from readily available starting materials. An impressive number of systems have been reported for each type of nucleophile. Instead of a fully exhaustive list of catalytic systems, this chapter will focus on the most versatile ones and on the ones that rely on the use of mild conditions. For example, systems that require the use of a strong base when others allow performing the same reaction in the presence of a milder one have been omitted for clarity.

1.2 Arylation of Amines

A major step forward toward the design of efficient catalytic systems that would allow performing the arylation of amines under mild/milder conditions was reported in the late 1990s based on the use of amino acids as ligands for copper. Indeed, amino acids have been demonstrated to have strong accelerating effects on the Ullmann arylation of amines. They could serve as both promoters and coupling partners, affording the corresponding -aryl amino acids at 90°C, a temperature that is remarkably low for such a cross-coupling reaction (, Eq. 1). Besides being arylated under mild conditions, amino acids can also serve efficiently as accelerating ligands to promote the arylation of various amines, provided they possess either a secondary (such as proline) or a tertiary (such as ,-dimethylglycine) amine that will prohibit their competitive arylation. For the arylation of simple amines, -proline was identified as the best ligand, although -methylglycine and ,-dimethylglycine gave similar results in some cases (, Eq. 2). Under the assistance of -proline, the reaction of cyclic secondary amines with aryl (or heteroaryl) halides proceeded well, while the use of more bulky acyclic secondary amines as coupling partners resulted in low yields of the corresponding coupling products (, Eq. 3).When switching to less-reactive anilines as nucleophiles, -proline promoted the copper(I) iodide-catalyzed arylation at 90°C; but only electron-rich anilines gave complete conversion, while electron-deficient anilines were more sluggish reaction partners and resulted in low yields of the arylated products (, Eq. 4). Considering the aryl halide coupling partner, the cross coupling of aryl iodides and amines typically proceeds at a lower temperature than that of aryl bromides. The use of aryl chlorides, which are generally poor coupling partners in the Ullmann-type amination reaction, was found to be more sluggish and resulted in very low yields of the cross-coupling products, even with aryl chlorides bearing strongly electron-withdrawing groups. The general trend for reactivity, which is typical for most Ullmann-type cross-coupling reactions, is the following: I > Br >> Cl.