Organic Reactions

ADVISORY BOARD

John E. Baldwin Michael J. MartinelliPeter Beak Stuart W. McCombieDale L. Boger Jerrold MeinwaldAndré B. Charette Scott J. MillerEngelbert Ciganek Larry E. OvermanDennis Curran Leo A. PaquetteSamuel Danishefsky Gary H. PosnerHuw M. L. Davies T. V. RajanBabuJohn Fried Hans J. ReichJacquelyn Gervay-Hague James H. RigbyHeinz W. Gschwend William R. RoushStephen Hanessian Scott D. RychnovskyLouis Hegedus Martin SemmelhackPaul J. Hergenrother Charles SihRobert C. Kelly Amos B. Smith, IIIAndrew S. Kende Barry M. TrostLaura Kiessling James D. WhiteSteven V. Ley Peter WipfJames A. Marshall

FORMER MEMBERS OF THE BOARDNOW DECEASED

Roger Adams Louis F. FieserHomer Adkins Ralph F. HirshmannWerner E. Bachmann Herbert O. HouseA. H. Blatt John R. JohnsonRobert Bittman Robert M. JoyceVirgil Boekelheide Willy LeimgruberGeorge A. Boswell, Jr. Frank C. McGrewTheodore L. Cairns Blaine C. McKusickArthur C. Cope Carl NiemannDonald J. Cram Harold R. SnyderDavid Y. Curtin Milán UskokovicWilliam G. Dauben Boris WeinsteinRichard F. Heck

Organic ReactionsV O L U M E 93

EDITORIAL BOARDScott E. Denmark, Editor-in-Chief

Jeffrey Aubé Donna M. HurynDavid B. Berkowitz Marisa C. KozlowskiCarl Busacca Gary A. MolanderJin K. Cha John MontgomeryP. Andrew Evans Albert PadwaPaul L. Feldman Tomislav RovisDennis G. Hall Steven M. Weinreb

Robert M. Coates, SecretaryUniversity of Illinois at Urbana-Champaign, Urbana, Illinois

Jeffery B. Press, SecretaryPress Consulting Partners, Brewster, New York

Danielle Soenen, Editorial Coordinator

Landy K. Blasdel, Editorial Assistant

Dena Lindsay, Editorial Assistant

Linda S. Press, Editorial Consultant

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

ALAN R. BURNSHON WAI LAM

IAIN D. ROY

Acknowledgments: The authors thank Daniel Best, David J. Burns, and Benjamin M. Partridge forassistance in the preparation of the Tables.

Copyright © 2017 by Organic Reactions, Inc. All rights reserved.

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10 9 8 7 6 5 4 3 2 1

INTRODUCTION TO THE SERIESROGER ADAMS, 1942

In the course of nearly every program of research in organic chemistry, the inves-tigator finds it necessary to use several of the better-known synthetic reactions. Todiscover the optimum conditions for the application of even the most familiar one to acompound not previously subjected to the reaction often requires an extensive searchof the literature; even then a series of experiments may be necessary. When the resultsof the investigation are published, the synthesis, which may have required months ofwork, is usually described without comment. The background of knowledge andexperience gained in the literature search and experimentation is thus lost to thosewho subsequently have occasion to apply the general method. The student of prepar-ative organic chemistry faces similar difficulties. The textbooks and laboratory manu-als furnish numerous examples of the application of various syntheses, but only rarelydo they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. Theplan of compiling critical discussions of the more important reactions thus wasevolved. The volumes of Organic Reactions are collections of chapters each devotedto a single reaction, or a definite phase of a reaction, of wide applicability. Theauthors have had experience with the processes surveyed. The subjects are presentedfrom the preparative viewpoint, and particular attention is given to limitations,interfering influences, effects of structure, and the selection of experimental tech-niques. Each chapter includes several detailed procedures illustrating the significantmodifications of the method. Most of these procedures have been found satisfactoryby the author or one of the editors, but unlike those in Organic Syntheses, theyhave not been subjected to careful testing in two or more laboratories. Each chaptercontains tables that include all the examples of the reaction under consideration thatthe author has been able to find. It is inevitable, however, that in the search of theliterature some examples will be missed, especially when the reaction is used as onestep in an extended synthesis. Nevertheless, the investigator will be able to use thetables and their accompanying bibliographies in place of most or all of the literaturesearch so often required. Because of the systematic arrangement of the material inthe chapters and the entries in the tables, users of the books will be able to findinformation 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 thecooperation of organic chemists and their willingness to devote time and effort tothe preparation of the chapters. They have manifested their interest already by thealmost unanimous acceptance of invitations to contribute to the work. The editors willwelcome their continued interest and their suggestions for improvements in OrganicReactions.

v

INTRODUCTION TO THE SERIESSCOTT E. DENMARK, 2008

In the intervening years since “The Chief” wrote this introduction to the second ofhis publishing creations, much in the world of chemistry has changed. In particular,the last decade has witnessed a revolution in the generation, dissemination, andavailability of the chemical literature with the advent of electronic publication andabstracting services. Although the exponential growth in the chemical literaturewas one of the motivations for the creation of Organic Reactions, Adams couldnever have anticipated the impact of electronic access to the literature. Yet, as oftenhappens with visionary advances, the value of this critical resource is now evengreater than at its inception.

From 1942 to the 1980’s the challenge that Organic Reactions successfullyaddressed was the difficulty in compiling an authoritative summary of a prepara-tively useful organic reaction from the primary literature. Practitioners interestedin executing such a reaction (or simply learning about the features, advantages,and limitations of this process) would have a valuable resource to guide theirexperimentation. As abstracting services, in particular Chemical Abstracts andlater Beilstein, entered the electronic age, the challenge for the practitioner was nolonger to locate all of the literature on the subject. However, Organic Reactionschapters are much more than a surfeit of primary references; they constitute adistillation of this avalanche of information into the knowledge needed to correctlyimplement a reaction. It is in this capacity, namely to provide focused, scholarly, andcomprehensive overviews of a given transformation, that Organic Reactions takeson 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 decadeshas greatly accelerated and has embraced more sophisticated reagents derived fromelements representing all reaches of the Periodic Table. Accordingly, the successfulimplementation of these transformations requires more stringent adherence to impor-tant experimental details and conditions. The suitability of a given reaction for anunknown application is best judged from the informed vantage point provided byprecedent and guidelines offered by a knowledgeable author.

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

vi

PREFACE TO VOLUME 93

Boron has all the best tunes

A. J. Downs in

“Chemistry of Aluminum, Gallium, Indium and Thallium”

It is ironic that a book dedicated to the chemistry of the heavier elements in Group13 would bemoan the dominance of the lightest, boron. The reality is, however, thatfor applications in synthetic chemistry, boron is unparalleled in its versatility to facil-itate the formation of new carbon-carbon and carbon-heteroatom bonds in myriadstructural settings with extraordinary generality and selectivity.

Undoubtedly, the ease with which boron engages in so many diverse chemicaltransformations can be ascribed to its unique ability to exist in both tricoordinate andtetracoordinate constitutions and to interconvert between them with relative ease. Asa consequence, boron can function as a Lewis acidic species (6 electron, neutral)and a Lewis basic species (8 electron, anionic), which enables both electrophilic andnucleophilic character to be expressed. No other element has such chemical virtuosityand the manifestations of its unique behavior continue to be developed. As a testi-mony to the remarkable and enduring impact of organoboron chemistry, it is worthnoting that the 1979 Nobel Prize in Chemistry was shared by Herbert C. Brown andGeorg Wittig “for their development of the use of boron- and phosphorus-containingcompounds, respectively, into important reagents in organic synthesis.” Thirty-eightyears later, there has been no surcease in advances.

One of the most frequently employed classes of organoboron compounds areboronic acids and their esters. In the past 30 years, boronic acids have emerged as oneof the most capable placeholders for entry into dozens of catalytic cycles involvingtransition-metal catalysts. In this capacity, boron easily exchanges with varioustransition metals to deliver all manner of organic building blocks into constructive,bond forming cycles. Perhaps the most famous is the transmetalation to palladiumin the Suzuki-Miyaura cross-coupling reaction (also recognized with a shared NobelPrize in 2010).

In a landmark report in 1997, Tamio Hayashi and coworkers described anotherfacile transmetalation of boronic acids to rhodium complexes to enable the con-jugate addition of organic moieties to α,β-unsaturated carbonyl compounds. Fordecades, this powerful transformation, namely, 1,4-addition had been the purviewof organocopper chemistry, but the difficulty in developing enantioselective variantshindered widespread application. With the discovery that readily available and shelf-stable boronic acids could serve as precursors, the development of enantioselectiveadditions using chirally modified rhodium catalysts was very soon introduced.

vii

viii PREFACE TO VOLUME 93

Twenty years later, this reaction has achieved strategy level status, thanks to theefforts of many laboratories world-wide.

One of those laboratories is directed by Professor Hon Wai Lam (Nottingham, UK)who together with coworkers and coauthors Alan R. Burns and Iain D. Roy have takenon the enormous task of compiling the first, comprehensive disquisition on the entirescope and application of this tremendously powerful reaction. Professor Lam and hiscoauthors have constructed an outstanding chapter that encompasses the full range ofthe electron-deficient alkenes that successfully engage in the process, including thebreadth of substitution patterns most commonly employed in the additions. Moreoverthey have thoroughly evaluated the various families of chiral ligands that are effec-tive in promoting high enantioselectivities, including novel classes of phosphorus,sulfur, olefinic, and hybrid ligands. Not surprisingly, given the power of this trans-formation, applications in the synthesis of natural products abound, and the authorshave selected illustrative examples to highlight the utility of the reaction. In one ofthe most comprehensive treatments, the authors have detailed the use of other classesof organometallic reagents that are susceptible to catalysis by rhodium as well asother transition-metal catalyzed additions of organoboron reagents. Together withten detailed experimental procedures, this chapter constitutes a dream field guide forthe user to identify the best method applicable to solve their particular challenge.

The Tabular Survey comprises 25 tables organized by both substrate structure andorganoboron reagent with such a fine granularity as to facilitate with ease the identi-fication of product types sought by those interested in using these methods.

Volume 93 represents the fourteenth single chapter volume to be produced in our76-year history (seventh in the past fourteen volumes!). Such single-chapter volumesrepresent definitive treatises on extremely important chemical transformations. Theorganic chemistry community owes an enormous debt of gratitude to the authors ofsuch chapters for the generous contribution of their time, effort, and insights on reac-tions that we clearly value.

It is appropriate here to acknowledge the expert assistance of the entire edito-rial board, in particular Tomislav Rovis and Gary Molander who shepherded thischapter to completion. The contributions of the author, editors, and the publisherwere expertly coordinated by the board secretary, Robert M. Coates. In addition, theOrganic Reactions enterprise could not maintain the quality of production withoutthe dedicated efforts of its editorial staff, Dr. Danielle Soenen, Dr. Linda S. Press,Dr. Dena Lindsey, and Dr. Landy Blasdel. Insofar as the essence of Organic Reac-tions chapters resides in the massive tables of examples, the authors’ and editorialcoordinators’ painstaking efforts are highly prized.

Scott E. DenmarkUrbana, Illinois

CONTENTS

chapter page

1. Enantioselective, Rhodium-Catalyzed 1,4-Addition ofOrganoboron Reagents to Electron-Deficient Alkenes

Alan R. Burns, Hon Wai Lam, and Iain D. Roy . . . . . . . . . . . . . . . . . . 1

Cumulative Chapter Titles by Volume . . . . . . . . . . . . . . . . . . . . . . 687

Author Index, Volumes 1–93 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705

Chapter and Topic Index, Volumes 1–93 . . . . . . . . . . . . . . . . . . . . . . 711

ix

CHAPTER 1

ENANTIOSELECTIVE, RHODIUM-CATALYZED 1,4-ADDITIONOF ORGANOBORON REAGENTS TO ELECTRON-DEFICIENT

ALKENES

Alan R. Burns and Hon Wai Lam

School of Chemistry, University of Nottingham, University Park, Nottingham,NG7 2RD, UK

Iain D. Roy

School of Chemistry, University of Edinburgh, Joseph Black Building, The King’sBuildings, David Brewster Road, Edinburgh EH9 3FJ, UK

CONTENTS

Page

Acknowledgments . . . . . . . . . . . . . . . 4Introduction . . . . . . . . . . . . . . . . . 4Mechanism and Stereochemistry . . . . . . . . . . . . 6

General Catalytic Cycle . . . . . . . . . . . . . . 6Stereochemical Model . . . . . . . . . . . . . . . 9

Scope and Limitations . . . . . . . . . . . . . . . 12Organoboron Reagents Employed . . . . . . . . . . . . 12Rhodium Precatalysts Employed . . . . . . . . . . . . 14Overview of Common Classes of Chiral Ligands Employed . . . . . . 14

Chiral Bisphosphorus Ligands . . . . . . . . . . . . 15Chiral Monodentate Phosphorus Ligands . . . . . . . . . . 17Chiral Diene Ligands . . . . . . . . . . . . . . 19Chiral Bis-Sulfur Ligands . . . . . . . . . . . . . 21Mixed Donor Ligands . . . . . . . . . . . . . . 22

Chiral Phosphorus–Alkene Ligands . . . . . . . . . . 22Chiral Phosphorus–Sulfur Ligands . . . . . . . . . . 24Chiral Sulfur–Alkene Ligands . . . . . . . . . . . 24Chiral Nitrogen–Alkene Ligands . . . . . . . . . . . 26Chiral N-Heterocyclic Carbene Ligands . . . . . . . . . 27

Range of Electron-Deficient Alkenes Employed . . . . . . . . . 27

Hon.Lam@nottingham.ac.ukOrganic Reactions, Vol. 93, Edited by Scott E. Denmark et al.© 2017 Organic Reactions, Inc. Published in 2017 by John Wiley & Sons, Inc.

1

2 ORGANIC REACTIONS

α,β-Unsaturated Ketones . . . . . . . . . . . . . 28α,β-Unsaturated Aldehydes . . . . . . . . . . . . . 35α,β-Unsaturated Esters . . . . . . . . . . . . . . 37α,β-Unsaturated Amides . . . . . . . . . . . . . 44Alkenylphosphonyl Compounds . . . . . . . . . . . . 47Nitroalkenes . . . . . . . . . . . . . . . . 49Alkenylsulfonyl Compounds . . . . . . . . . . . . 51Alkenylazaarenes . . . . . . . . . . . . . . . 55Electron-Deficient Alkenylarenes . . . . . . . . . . . 58Borylalkenes . . . . . . . . . . . . . . . . 59Miscellaneous Acceptors . . . . . . . . . . . . . 59

Enantioselective, Domino Processes Involving a 1,4-Addition Step . . . . 60Applications to Synthesis . . . . . . . . . . . . . . 69

Baclofen and Rolipram . . . . . . . . . . . . . . 69Various Endothelin Receptor Antagonists . . . . . . . . . . 71Telcagepant (MK-0974) . . . . . . . . . . . . . . 72Isaindigotidione . . . . . . . . . . . . . . . . 73Hybridalactone and Ecklonialactones A, B, and C . . . . . . . . 73Pregabalin . . . . . . . . . . . . . . . . . 75Kainic Acid . . . . . . . . . . . . . . . . . 75Montanine-Type Amaryllidaceae Alkaloids . . . . . . . . . . 75

Comparison With Other Methods . . . . . . . . . . . . 76Enantioselective, Rhodium-Catalyzed 1,4-Additions of Organotitanium, Organozinc,

Organoaluminum, Organosilicon, Organotin, Organoindium, and OrganozirconiumReagents . . . . . . . . . . . . . . . . . 77Organotitanium Reagents . . . . . . . . . . . . . 77Organozinc Reagents . . . . . . . . . . . . . . 79Organoaluminum Reagents . . . . . . . . . . . . . 81Organosilicon Reagents . . . . . . . . . . . . . . 81Organotin Reagents . . . . . . . . . . . . . . . 82Organoindium Reagents . . . . . . . . . . . . . . 83Organozirconium Reagents . . . . . . . . . . . . . 84

Enantioselective Palladium-, Nickel-, or Copper-Catalyzed 1,4-Additions ofOrganoboron Reagents . . . . . . . . . . . . . 85Palladium Catalysis . . . . . . . . . . . . . . . 85Nickel Catalysis . . . . . . . . . . . . . . . 87Copper Catalysis . . . . . . . . . . . . . . . 88

Copper-Catalyzed, Enantioselective 1,4-Additions of Non-Boron-ContainingOrganometallic Reagents . . . . . . . . . . . . . 89

Experimental Conditions . . . . . . . . . . . . . . 90Experimental Procedures . . . . . . . . . . . . . . 90

(R)-3-Phenylcyclohexanone [1,4-Arylation of a Cyclic Enone with an ArylboronicAcid Using a Chiral Bisphosphine Ligand] . . . . . . . . 90

Benzyl (5S)-N,N-bis(tert-Butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-d-norleucinate [Large-Scale 1,4-Arylation of a Nitroalkene with anArylboronic Acid Using a Chiral Bisphosphine Ligand en route toTelcagepant] . . . . . . . . . . . . . . . 91

2,6-Dimethylphenyl (S)-3-Methyl-3,5-diphenylpentanoate [1,4-Arylation of aβ, β-Disubstituted α, β-Unsaturated Ester with a Sodium Tetraarylborate Using aChiral Diene Ligand] . . . . . . . . . . . . . 92

2-[(R)-4-(tert-Butyldimethylsilyloxy)-2-(4-fluorophenylbutyl]pyrimidine[1,4-Arylation of an Alkenylazaarene with an Arylboronic Acid Using a ChiralDiene Ligand] . . . . . . . . . . . . . . . 93

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 3

tert-Butyl (R)-4-(2-Methylprop-1-en-1-yl)-2-oxopyrrolidine-1-carboxylate[1,4-Alkenylation of a Cyclic α, β-Unsaturated Amide with a PotassiumAlkenyltrifluoroborate Using a Chiral Diene Ligand] . . . . . . 94

(1R,2S,3aR,7aR)-1-Acetyl-7a-hydroxy-3a-methyl-2-phenyloctahydro-4H-inden-4-one[Domino 1,4-Arylation of an Enone Followed by Aldol Cyclization onto a KetoneUsing a Chiral Bisphosphine Ligand] . . . . . . . . . 95

(R)-3-(Triethylsilyl)-3-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-inden-1-one[Synthesis of a 3,3-Disubstituted Indanone by a Domino Process Consisting ofAlkyne Arylation with an Arylboronic Ester, 1,4-Rhodium Shift, and Cyclizationonto an Enone Using a Chiral Bisphosphine Ligand] . . . . . . 95

(S)-tert-Butyl 3-(Benzo[d][1,3]dioxol-4-ylmethyl)-1-methyl-4-oxopyrrolidine-3-carboxylate [Domino 1,4-Arylation of an α, β-Unsaturated Ester Followed byDieckmann Cyclization onto an Ester Using a Chiral BisphosphineLigand] . . . . . . . . . . . . . . . . 96

Ethyl 2-Amino-5-(4-chlorophenyl)cyclopent-1-ene-1-carboxylate [Domino 1,4-Arylation of an α, β-Unsaturated Ester Followed by Cyclization onto a NitrileUsing a Chiral Bisphosphine Ligand] . . . . . . . . . 97

(R,E)-4′-Benzylidene-6′-methyl-3′,4′-dihydro-2′H-spiro[cyclopentane-1,1′-naphthalen]-3-one [Synthesis of a Spirocarbocycle by a Domino ProcessConsisting of Alkyne Arylation with a Sodium Tetraarylborate, 1,4-RhodiumShift, and Cyclization onto a Tethered Trisubstituted Enone Using a ChiralDiene Ligand] . . . . . . . . . . . . . . . 98

TABULAR SURVEY . . . . . . . . . . . . . . . 99Chart 1. Chiral Bisphosphorus Ligands Used in Tables . . . . . . 102Chart 2. Chiral Monodentate Phosphorus Ligands Used in Tables . . . . 107Chart 3. Chiral Diene Ligands Used in Tables . . . . . . . . 110Chart 4. Chiral Phosphorus-Alkene Ligands Used in Tables . . . . . 115Chart 5. Chiral Bis-Sulfur Ligands Used in Tables . . . . . . . 117Chart 6. Chiral Phosphorus-Sulfur Ligands Used in Tables . . . . . 119Chart 7. Chiral Sulfur-Alkene Ligands Used in Tables . . . . . . . 120Chart 8. Chiral Nitrogen-Alkene Ligands Used in Tables . . . . . . 123Chart 9. Chiral N-Heterocyclic Carbene Ligands Used in Tables . . . . 124Chart 10. Miscellaneous Ligands Used in Tables . . . . . . . . 125Table 1A. Reactions of α, β-Unsaturated Ketones with Arylboron

Reagents . . . . . . . . . . . . . . . . 126Table 1B. Reactions of α, β-Unsaturated Ketones with Heteroarylboron

Reagents . . . . . . . . . . . . . . . . 426Table 1C. Reactions of α, β-Unsaturated Ketones with Alkenylboron

Reagents . . . . . . . . . . . . . . . . 432Table 2A. Reactions of α, β-Unsaturated Aldehydes with Arylboron

Reagents . . . . . . . . . . . . . . . . 448Table 2C. Reactions of α, β-Unsaturated Aldehydes with Alkenylboron

Reagents . . . . . . . . . . . . . . . . 451Table 3A. Reactions of α, β-Unsaturated Esters with Arylboron

Reagents . . . . . . . . . . . . . . . . 452Table 3B. Reactions of α, β-Unsaturated Esters with Heteroarylboron

Reagents . . . . . . . . . . . . . . . . 529Table 3C. Reactions of α, β-Unsaturated Esters with Alkenylboron

Reagents . . . . . . . . . . . . . . . . 530Table 4A. Reactions of α, β-Unsaturated Amides with Arylboron

Reagents . . . . . . . . . . . . . . . . 532Table 4B. Reactions of α, β-Unsaturated Amides with Heteroarylboron

Reagents . . . . . . . . . . . . . . . . 578

4 ORGANIC REACTIONS

Table 4C. Reactions of α, β-Unsaturated Amides with AlkenylboronReagents . . . . . . . . . . . . . . . . 579

Table 5A. Reactions of Alkenylphosphoryl Compounds with ArylboronReagents . . . . . . . . . . . . . . . . 583

Table 6A. Reactions of Nitroalkenes with Arylboron Reagents . . . . . 591Table 6C. Reactions of Nitroalkenes with Alkenylboron Reagents . . . . 625Table 7A. Reactions of Alkenylsulfonyl Compounds with Arylboron

Reagents . . . . . . . . . . . . . . . . 626Table 7C. Reactions of Alkenylsulfonyl Compounds with Alkenylboron

Reagents . . . . . . . . . . . . . . . . 635Table 8A. Reactions of Alkenylazaarenes with Arylboron Reagents . . . 636Table 8C. Reactions of Alkenylazaarenes with Alkenylboron Reagents . . . 639Table 9A. Reactions of Electron-Deficient Alkenylarenes with Arylboron

Reagents . . . . . . . . . . . . . . . . 640Table 10A. Reactions of Borylalkenes with Arylboron Reagents . . . . 643Table 11A. Reactions of Miscellaneous Acceptors with Arylboron

Reagents . . . . . . . . . . . . . . . . 645Table 12A. Domino Reactions with Arylboron Reagents . . . . . . 646Table 12B. Domino Reactions with Heteroarylboron Reagents . . . . . 677Table 12D. Domino Reactions with Alkylboron Reagents . . . . . . 678

References . . . . . . . . . . . . . . . . . 679

ACKNOWLEDGMENTS

Prof. Gary Molander and Prof. Tomislav Rovis are gratefully acknowledged fortheir guidance and assistance in the writing of this chapter. We are extremely gratefulto Dr. Linda S. Press for expert guidance in the preparation of the graphics and tables.

INTRODUCTION

The enantioselective 1,4-addition of organometallic reagents to electron-deficientalkenes is one of the most important methods for carbon–carbon bond formation.1–3

Within this field, the rhodium-catalyzed 1,4-addition of organoboron reagents toelectron-deficient alkenes (Scheme 1) occupies a prominent position owing to (1)the availability, stability, and functional group tolerance of organoboron reagents,(2) the wide range of acceptors that may be employed, (3) the ability of a broadrange of structurally distinct families of chiral ligands to induce high enantiose-lectivities in the reactions, and (4) the usually mild and experimentally convenientconditions, which generally do not require any special precautions to exclude air ormoisture.

EWGR1 R3 [B]

[Rh] (cat.)

chiral ligand (cat.)+ EWG

R1

R2R3 R2

*

R3 = aryl, heteroaryl, or alkenyl

[B] = boron-containing functional group

Scheme 1

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 5

The seminal report of the achiral/racemic version of this reaction appeared in1997, and this report described the 1,4-addition of arylboronic acids to enones andenals (Scheme 2).4 In the following year, the first enantioselective variant using(S)-BINAP (L1) [BINAP = (1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine)]as the chiral ligand was described (Scheme 3).5

O (HO)2B+

DMF/H2O (6:1),50°, 16 h

dppb (3.0 mol %),Rh(acac)(CO)2 (3.0 mol %)

(2.0 equiv)

O

(82%)

dppb = 1,4-bis(diphenylphosphino)butane

Scheme 2

(HO)2B+

dioxane/H2O (10:1),100°, 5 h

L1 (3.0 mol %),Rh(acac)(C2H4)2 (3.0 mol %)

(5.0 equiv)

(>99%)er 98.5:1.5

OO

PPh2

PPh2

Scheme 3

Since then, numerous variations of this process have been developed, allowingincreases in substrate scope and introducing new classes of chiral ligands thatexhibit improved activity, enantioselectivity, and/or ease of synthesis/variation.Alkenes activated by adjacent carbonyl groups, imines, nitriles, phosphonyl groups,nitro groups, sulfonyl groups, C=N-containing aromatic heterocycles, electron-deficient arenes, or boryl groups are effective acceptors in these reactions. Aryl-,heteroaryl-, and alkenylboron reagents have been successfully employed. However,alkylboron compounds are generally unsuitable, and the only known examplesinvolve methylboron6 (Table 12D) or cyclopropylboron7 reagents. In addition toboronic acids, other boron reagents that may be employed include boroxines, boronicesters, N-methyliminodiacetic acid (MIDA) boronates, potassium organotrifluo-roborates, trialkoxyborates, 9-BBN derivatives, and sodium tetraarylborates. Thechiral ligands most commonly employed are bidentate, containing combinations ofphosphorus, sulfur, nitrogen, or alkene donors, although monodentate ligands arealso successful. Furthermore, this reaction has found application in the synthesis ofvarious biologically active molecules.

6 ORGANIC REACTIONS

This chapter presents a detailed overview of enantioselective, rhodium-catalyzed1,4-additions of organoboron reagents to electron-deficient alkenes. The scope ofthe discussion is limited to enantioselective and/or diastereoselective variants thatemploy chiral-ligand control. Racemic or purely substrate-controlled variants willnot be discussed. Enantioselective domino processes involving a 1,4-addition (whichmay not necessarily be the first step) will also be discussed, including those in whichthe 1,4-addition itself does not generate a new stereogenic center. The literature iscovered up to the end of 2013. Several reviews covering various aspects of this topichave already appeared.8–22

MECHANISM AND STEREOCHEMISTRY

General Catalytic Cycle

The generally accepted catalytic cycle for the rhodium-catalyzed 1,4-additionof organoboron reagents to electron-deficient alkenes under aqueous, basic con-ditions is depicted in Scheme 4, using 2-cyclohexenone and phenylboronic acidas representative reaction partners.23 First, the reaction usually involves the gen-eration of a chiral rhodium hydroxide complex, which is generally formed in situfrom the rhodium precatalyst, chiral ligand, and an aqueous base. Alternatively,the hydroxide ligand may come directly from a hydroxide-containing rhodiumprecatalyst. Other possibilities include the use of a pre-prepared rhodium chloridecomplex bound to the chiral ligand in conjunction with an aqueous base, or theuse of a pre-prepared rhodium hydroxide complex bound to the chiral ligand. Inwhat is the turnover-limiting step of the catalytic cycle, transmetalation of theorganoboron reagent with the rhodium hydroxide (presumably via intermediate 1)generates an organorhodium species, which then undergoes a migratory insertion ofthe electron-deficient alkene (this process can also be called carborhodation). Thismigratory insertion results in the formation of a new carbon–carbon bond alongwith generation of a stereogenic center, providing oxa-π-allylrhodium species 2.Because a protic co-solvent or additive (usually water) is normally employed inthese reactions, oxa-π-allylrhodium species 2 undergoes protonolysis to liberatethe product and regenerate the rhodium hydroxide species. Reactions conducted inalcohol solvents proceed in a similar manner through the intermediacy of a rhodiumalkoxide species. Acceptors other than α,β-unsaturated carbonyl compounds formintermediates that are slightly different than the oxa-π-allylrhodium species formedfrom carborhodation, but the general features of the catalytic cycle remain essentiallythe same.

Asymmetric reactions of α,α-disubstituted, β-unsubstituted, electron-deficientalkenes are also known.24–27 In these cases, a new stereogenic center is formed notduring the migratory insertion of the organorhodium species, but in a subsequentbond-forming event at the α-position.

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 7

RhLn OH

O

O RhLn

O

(HO)2B

RhLn

H2OB(OH)3

OB

Ph

OH

OH

H

RhLn

1

2

+

Scheme 4

Instead of undergoing 1,4-addition to the electron-deficient alkene, theorganorhodium species can also undergo protonolysis with water or anotherproton source, resulting in overall protodeboronation of the organoboron reagent.Because of this competing side reaction, an excess of the organoboron reagent isoften employed to ensure acceptable yields. However, the number of equivalentsof the organoboron reagent can be minimized by the use of more active catalystsystems that operate at lower temperatures, where the rate of protodeboronation isreduced.23

Evidence for the catalytic cycle has been obtained by a mechanistic study of thestoichiometric reactions of RhPh(PPh3)[(S)-BINAP] with tert-butyl vinyl ketone and2-cyclohexenone.23 Importantly, all of the key intermediates involved, namely theoxa-π-allylrhodium, rhodium hydroxide, and arylrhodium species, can be observedby 1H NMR spectroscopy, and the transformations between these intermediates arealso observed. Scheme 5 depicts this sequence for tert-butyl vinyl ketone. First,RhPh(PPh3)[(S)-BINAP] is prepared by the reaction of RhCl(PPh3)[(S)-BINAP]with phenyllithium. Upon addition of an excess (5.0 equivalents) of tert-butyl vinylketone, a diastereomeric mixture of oxa-π-allylrhodium species is formed, in whichPPh3 is no longer coordinated to rhodium. Addition of water (10.0 equivalents)to this mixture immediately generates [Rh{(S)-BINAP}OH]2. Finally, additionof an excess of phenylboronic acid to the solution results in the regeneration ofRhPh(PPh3)[(S)-BINAP] (PPh3 in the solution re-coordinates to rhodium). Notably,all of these transformations occur at room temperature, which is in contrast to thehigh temperatures required in the first, catalytic, enantioselective variant of this

8 ORGANIC REACTIONS

reaction (Scheme 3).5 The reason for this difference is that Rh(acac)[(S)-BINAP],which is the active catalytic species involved in Scheme 3, undergoes transmetalationwith phenylboronic acid at reasonable rates only at 80∘ or higher. On the basis ofthis information, [Rh{(S)-BINAP}OH]2 is identified as a much more active catalyst,and reactions using this complex occur at the much lower temperature of 35∘.Furthermore, the slower rate of protodeboronation at this lower temperature enablesthe use of reduced loadings of the arylboronic acid.

PRh

P

PPh3

*

O

t-BuO

t-Bu

PRh P

*

THF, rt

O

t-Bu

PRh P

*

+

H2O

(10.0 equiv)

+ PPh3

PRh

P

**

OH

HO

PRh

Pt-Bu+ + PPh3

PhB(OH)2P

RhP

PPh3

*

P P*

=

(S)-BINAP (L1)

PPh2

PPh2

O

(5.0 equiv)

Scheme 5

Further insight into the mechanism has been obtained through reaction calorime-try analysis of the addition of phenylboronic acid to methyl vinyl ketone in thepresence of boric acid (Scheme 6).28 This study reveals the reaction to be half-orderin rhodium concentration throughout, which is attributable to an equilibriumbetween the catalytically inactive dimeric complex [Rh{(R)-BINAP}OH]2 andthe active, weakly solvated rhodium hydroxide monomer. This equilibrium can becharacterized by the equilibrium constant Kdimer. The transmetalation of the rhodiumhydroxide monomer with phenylboronic acid to form the arylrhodium intermediateis characterized by the rate constant k1, whereas the migratory insertion of methylvinyl ketone into the arylrhodium species followed by protonolysis of the resultingoxa-π-allylrhodium intermediate are combined into the rate constant k2. Under theconditions employed, the dimerization equilibrium constant Kdimer is estimated to be8 × 102 M–1, thus demonstrating that the equilibrium favors the catalytically inactivedimeric rhodium species. Furthermore, k1 is determined to be 0.5 M–1s–1, whereasthe value of k2 is too large to be determined with a statistically meaningful value.Therefore, the transmetalation step from boron to rhodium is the turnover-limitingstep in the catalytic cycle.

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 9

O+

B(OH)3, [Rh(L)OH]2

dioxane/H2O (10:1)

O

[Rh]OH

[Rh]

HO

[Rh]OH

Sol[Rh]

Sol

PhB(OH)2 B(OH)3

OO+ H2O

Kdimer

k1

k2

[Rh] = Rh(R)-BINAP or Rh(cod)

(HO)2B

L(R)-BINAP (L2)cod

Temp (°)5030

Scheme 6

The kinetic analysis performed using [Rh(cod)OH]2 in place of [Rh{(R)-BINAP}OH]2 under identical conditions shows the reaction to be 20 times faster.29

Furthermore, the value of Kdimer for [Rh(cod)OH]2 is lower, whereas the valueof k1 is higher. The higher catalytic activity of [Rh(cod)OH]2 compared with[Rh{(R)-BINAP}OH]2 is therefore attributable to both a higher concentration of theactive monomeric rhodium hydroxide species and a faster rate of transmetalationwith phenylboronic acid.

Although the majority of rhodium-catalyzed 1,4-additions of organoboronreagents are conducted under protic conditions, reactions of 9-BBN reagents areconducted under aprotic conditions because of their sensitivity toward protonolysis.In these cases, the initially formed oxa-π-allylrhodium species undergoes trans-metalation with the organoboron reagent to regenerate the reactive organorhodiumspecies and release a 9-BBN enolate, which can be used in subsequent carbon–carbonbond-forming reactions.30

Stereochemical Model

A generalized model can be used to explain the stereochemical outcome ofenantioselective rhodium-catalyzed 1,4-addition reactions of β-substituted, electron-deficient alkenes. Scheme 7 depicts the addition of an arylrhodium species to2-cyclohexenone.17 The binding of chiral bidentate ligands to rhodium(I) oftenresults in complexes in which the chiral environment can be depicted by a simplifiedrepresentation of four quadrants of higher and lower steric hindrance.31 In thearylrhodium species containing the bound electron-deficient alkene, the aryl group

10 ORGANIC REACTIONS

occupies a quadrant of higher steric hindrance, whereas the substrate occupies aquadrant of lower steric hindrance. The substrate binds to rhodium in a mannersuch that the carbon–carbon double bond is parallel to the rhodium–aryl bond (tofacilitate subsequent migratory insertion), and to minimize unfavorable non-bondinginteractions. For α,β-unsaturated carbonyl compounds, this leads to conformationsin which the carbonyl group projects into a quadrant of lower steric hindrance.

lower steric hindrance

higher steric hindranceRh

L L

ArO

O

Ar

O

R

Ar

RhL L

ArOR

Scheme 7

The following examples illustrate the application of this stereochemical modelto two of the most common classes of chiral ligands employed in enantiose-lective rhodium-catalyzed 1,4-additions of organoboron reagents: biaryl-basedbisphosphines such as (R)-BINAP (L2), and dienes such as L3.

BINAP adopts a highly skewed structure when bound to rhodium(I), resulting fromthe axial chirality of this ligand.31 In the arylrhodium species bound to (R)-BINAP(L2), coordination of a (Z)-alkene such as 2-cyclohexenone from the α-Re face isfavored, as coordination from the α-Si face would place the carbonyl group into aquadrant of higher steric hindrance, leading to a repulsion with one of the phenylrings of (R)-BINAP (L2) (Scheme 8). As a result, arylation leads to preferential for-mation of the (R)-isomer of the product.5 A similar model can be used to explain thestereochemical outcome when chiral dienes such as L3 are employed.32,33 Applica-tion of the model to acyclic (E)-alkenes also successfully predicts the stereochemicaloutcome (Scheme 9).32,34

(HO)2B+

L2

OO

PPh2

PPh2

Rh(I)/ligand (cat.)

ligand = orPh

Ph

L3

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 11

disfavored favored

RhPh

P P

O

P P

PhRh

O steric repulsion

PhRh

Ph

Ph

OPh

Ph

RhPh

O

disfavored favored

steric repulsion

With L2:

With L3:

Scheme 8

(HO)2B+

O

RO

R

RhPh

P PP P

PhRh

ORR

O steric repulsion

disfavored favored

Rh(I)/ligand (cat.)

L2

PPh2

PPh2ligand = or

Ph

Ph

L3

PhRh

Ph

Ph

Ph

Ph

RhPh

ORR

O steric repulsion

disfavored favored

With L2:

With L3:

Scheme 9

12 ORGANIC REACTIONS

A number of computational studies involving DFT calculations to analyze variousaspects of the mechanism of enantioselective rhodium-catalyzed 1,4-additions ofarylboronic acids, using different chiral ligands, have been reported.25,35–46 Ingeneral, these studies show strong agreement with the generalized stereochemicalmodel discussed above in predicting the sense of enantioselection in thesereactions. However, the enantioselectivity-determining step is calculated to bemigratory insertion of the alkene into the rhodium–aryl bond, rather than initialbinding of the alkene to rhodium. Furthermore, computation suggests that, inaddition to steric effects, electronic factors have a significant influence on theenantioselectivity.37–39,41,42

SCOPE AND LIMITATIONS

Organoboron Reagents Employed

Since their use in the first report of enantioselective rhodium-catalyzed 1,4-additions,5 boronic acids (especially arylboronic acids) remain the most commonlyemployed class of organoboron reagents in these reactions for several reasons.First, many boronic acids are commercially available, owing to the utility andwidespread application of the palladium-catalyzed Suzuki–Miyaura cross-couplingreaction. Second, they exhibit high thermal stability and, in the absence of transitionmetals, are usually very stable toward moisture and oxygen. Furthermore, the rateof transmetalation from boronic acids to rhodium is usually high. However, severalother types of organoboron reagents can also be employed in rhodium-catalyzed1,4-additions, and these can offer advantages over the corresponding boronic acids(Figure 1).

RB(OH)2OB

OBO

BR

R R OB

OR

RBF3K

OO

MeN

OO

RB

Li[RB(OMe)3]O B–

O

OR

Li+ Ar4BNa

R = (hetero)aryl or alkenyl

OB

OR

RB

Figure 1. Organoboron reagents employed in enantioselective Rh-catalyzed 1,4-additions.

One disadvantage of boronic acids is that they exist in equilibrium with boroxinesand water (Scheme 10). This feature renders boronic acids less suitable for reactionswhere anhydrous conditions are required, or if a precise quantity of water is needed.In addition, the exact stoichiometry of the reaction with respect to the transferableorganic group can be difficult to control. However, these disadvantages can be avoided

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 13

by using the preformed boroxines.47 Furthermore, boroxines are usually more stabletoward protodeboronation than boronic acids. The boroxines can be prepared in highyield by dehydration of the corresponding boronic acids with concomitant removalof water (e.g., using a Dean–Stark apparatus).

3 RB(OH)2

–3 H2O

+3 H2O

OB

OBO

BR

RR

Scheme 10

Boronic esters, such as pinacol or catechol boronates, can also be used in rhodium-catalyzed 1,4-additions.48–51 The rate of 1,4-addition using boronic esters is relatedto the rate of their hydrolysis back to the corresponding boronic acids. Sterically hin-dered pinacol boronates react relatively slowly in rhodium-catalyzed 1,4-additions,whereas catechol boronates are more reactive. MIDA boronates exhibit high bench-top stability and are very resistant toward protodeboronation.52 Under mildly basicconditions, hydrolysis occurs and they slowly release boronic acids.52 This featurerenders MIDA boronates advantageous in situations where the corresponding boronicacid is susceptible to decomposition.53–55

Potassium organotrifluoroborates are commonly utilized in rhodium-catalyzed1,4-additions due to their high stability toward protodeboronation and ease ofhandling.56–58 These compounds do not transmetalate directly with rhodium; rather,hydroxyborates formed in the presence of aqueous base59 are the likely reactiveintermediates (Scheme 11).60,61

ArBF3K + H2O + base ArBF2(OH)K

+ base•HF

[Rh] OH KBF2(OH)2

[Rh] Ar

Scheme 11

Lithium trimethoxy(hetero)arylborates can be prepared by treatment of a(hetero)aryllithium with trimethoxyborane. These reagents are highly reactive inrhodium-catalyzed 1,4-additions, but are not stable toward air or moisture.62–64

Cyclic triolborates derived from 1,1,1-tris(hydroxymethyl)ethane, however, exhibithigher stability.65,66 Boranes containing the 9-BBN group are not air- or moisture-stable, and are generally prepared shortly prior to their use in rhodium-catalyzed1,4-additions.30 Reactions using these reagents are conducted under anhydrousconditions, which leads to the formation of boron enolates that can be employed infurther carbon–carbon bond-forming reactions.30 Finally, sodium tetraarylborates

14 ORGANIC REACTIONS

are highly reactive in rhodium-catalyzed 1,4-additions and can undergo trans-metalation to rhodium under neutral conditions.67–70 However, one disadvantage ofthese reagents is their poor atom-economy, as only one of the four aryl groups istransferred in the reaction.

Rhodium Precatalysts Employed

The chiral rhodium complexes employed in enantioselective rhodium-catalyzed1,4-additions of organoboron reagents may be formed in situ by mixing arhodium precatalyst with the chiral ligand. The most commonly used precatalystis [Rh(C2H4)2Cl]2. The highly labile ethylene ligands in this salt are readilydisplaced by the chiral ligand, ensuring complete formation of the chiral rhodiumcomplex. Other rhodium salts that contain labile alkene ligands have been employed,including Rh(C2H4)2(acac) and [Rh(coe)2Cl]2 (coe = cyclooctene). However,Rh(C2H4)2(acac) exhibits relatively poor activity because rhodium acetylacetonatecomplexes undergo slow transmetalation with organoboron reagents,23 and further-more, its use generates pentane-2,4-dione (acac–H), which readily protonates themore reactive rhodium hydroxide species.23 Although 1,5-cyclooctadiene (cod),being a bidentate ligand, is not as easily displaced from rhodium by a chiral ligand,rhodium complexes containing cod ligands have also been successfully employed.These include neutral complexes such as [Rh(cod)Cl]2, [Rh(cod)OH]2, and[Rh(cod)OMe]2, and cationic complexes such as [Rh(cod)2]PF6 and [Rh(cod)2]BF4.However, it should be noted that 1,5-cyclooctadienyl–rhodium complexes arethemselves very active in catalyzing 1,4-additions,28 and therefore trace quantitiesof these complexes (remaining from incomplete chiral ligand complexation) canresult in reduced enantioselectivities. Therefore, the use of norbornadiene (nbd) as aligand in the precatalyst [Rh(nbd)2]BF4 can be advantageous because [Rh(nbd)OH]2exhibits poor catalytic activity. In addition, the cationic nature of this complexleads to faster complexation of the chiral ligand relative to when a neutral rhodiumcomplex is employed. A further benefit of cationic rhodium precatalysts is thattriethylamine can be used in place of hydroxide bases, leading to greater compat-ibility with base-sensitive functional groups. Instead of forming the chiral rhodiumcomplex in situ, another approach is to introduce the pre-prepared, purified chiralrhodium complex that is formed by allowing a rhodium precatalyst to react with thechiral ligand.

Overview of Common Classes of Chiral Ligands Employed

A huge number of diverse, chiral ligands provide excellent results in enantio-selective rhodium-catalyzed 1,4-additions of organoboron reagents. Indeed, thesereactions (especially the addition of phenylboronic acid to 2-cyclohexenone) areoften used as a benchmark to evaluate newly developed chiral ligands. A compre-hensive list of these chiral ligands, arranged according to the nature of the donoratoms/groups of those ligands, is provided in Charts 1–9, and the reader is urgedto examine these charts to gain a full appreciation of the breadth and diversity of

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 15

ligands that have been employed. Given the large number of ligands that have beendescribed, the following section provides only a brief overview of the differentclasses of ligands available, using selected examples of their application to providehistorical context or to illustrate points of particular interest.

Chiral Bisphosphorus Ligands. (S)-BINAP (L1) is the first chiral ligandreported in enantioselective, rhodium-catalyzed 1,4-additions of organoboronreagents (Scheme 3),5 and since then, chiral bisphosphines have remained broadlyapplicable ligands for these reactions. Given the initial success of BINAP, it isunsurprising that other bisphosphines containing an axially chiral biaryl backboneare generally effective ligands. Functionalization of the parent ligand on either thebackbone or on the substituents attached to the phosphorus atoms can result inbeneficial properties. For example, because of the presence of two guanidiniumgroups, ligand L4 (see Scheme 12) exhibits high solubility in water and other proticsolvents.71 The 1,4-addition of phenylboronic acid to 2-cyclohexenone conductedwith L4 in ethylene glycol occurs at a catalyst loading of 0.005 mol % and providesthe product in 66% yield (TON = 13,200) and er 94.0:6.0 (Scheme 12). Furthermore,the cationic nature of the ligand allows easy separation of the product from thecatalyst using a simple workup procedure.

(5.0 equiv)

L4 (0.01 mol %),Rh(acac)(C2H4)2 (0.005 mol %)(HO)2B

OO

PPh2PPh2

NH

HN

H2N

NH•HCl

H2N

NH•HCl

Na2CO3 (2.0 equiv),ethylene glycol, 100°, 48 h

(66%) er 94.0:6.0

+

Scheme 12

The immobilized ligand L5, formed by linking BINAP onto a polystyrene–polyethylene glycol copolymer (PS–PEG) resin, is effective for the rhodium-catalyzed 1,4-addition of arylboronic acids to α,β-unsaturated ketones in water,and provides good yields and enantioselectivities (Scheme 13).72 Furthermore,the catalyst can be readily recycled after 1,4-addition is complete: extracting the1,4-addition product into Et2O leaves a solution of the active catalyst in water, towhich further α,β-unsaturated ketone and arylboronic acid can be added. Heatingthe mixture to 100∘ for three hours then promotes further 1,4-addition. The catalystmaintains high activity and enantioselectivity after four recycles.

16 ORGANIC REACTIONS

(HO)2BL5 (3.5 mol %),

Rh(acac)(C2H4)2 (3.0 mol %)

(5.0 equiv)

PS Ligand Recycle—FirstSecondThirdFourth

Yield (%)9585949499

er97.0:3.097.0:3.096.5:3.597.0:3.097.0:3.0

O

O

PPh2

PPh2

NH

OO

OPS

n

H2O, 100°, 3 h+

PS = polystyrene support

Scheme 13

The catalytic activity of axially chiral, biaryl-based bisphosphines is increasedby the presence of highly electron-deficient aryl groups attached to the phospho-rus atoms.73–79 These modifications increase the π-accepting ability of the ligands,which accelerate the turnover-limiting transmetalation of the organoboron reagent torhodium. For example, the 1,4-addition of phenylboronic acid to maleimide occurs ata reasonable rate even at –80∘ using the biphenylphosphine ligand L6, which contains3,4,5-trifluorophenyl substituents (Scheme 14).79

(HO)2BL6 (3.0 mol %),

[Rh(cod)OH]2 (1.5 mol %)

(5.0 equiv)

HN

O

O

HN

O

O

MeOMeO

PAr2

PAr2

Ar = 3,4,5-F3C6H2

Et2O/H2O (20:3), –80°, 24 h+ (70%)

er 93.5:6.5

Scheme 14

The high catalytic activity of L6 is further demonstrated by its performance in the1,4-addition of phenylboronic acid to 2-cyclohexenone, which proceeds well at lowcatalyst loadings. For example, the reaction of 19.2 g (0.20 mol) of 2-cyclohexenonewith 36.6 g (0.30 mol) of phenylboronic acid at a catalyst loading of 0.00025 mol %rhodium(I) affords 27.9 g of the product in 80% yield and er 99.0:1.0 (TON =320,000) (Scheme 15).75

ASYMMETRIC Rh-CATALYZED 1,4-ADDITION OF ORGANOBORON REAGENTS 17

L6 (0.00025 mol %), [Rh(C2H4)2Cl]2 (0.000125 mol %)

NaHCO3 (0.4 equiv),toluene/H2O (3:2), 100°, 24 h

MeOMeO

PAr2

PAr2

Ar = 3,4,5-F3C6H2

(HO)2B+

27.9 g(80%) er 99.0:1.0

OO

19.2 g (0.20 mol) 36.6 g (0.30 mol)

Scheme 15

In addition to those ligands containing an axially chiral, biaryl backbone, numer-ous other types of chiral bisphosphines provide good results in rhodium-catalyzed1,4-additions of organoboron reagents. These include bisphosphines containingaliphatic or ferrocenyl backbones and those containing P-stereogenic phosphines(see Chart 1 for a full list of examples).

Chiral Monodentate Phosphorus Ligands. Even though the first examplesof enantioselective, homogeneous, transition-metal catalysis employ chiral mono-dentate phosphines,80,81 chiral bisphosphines have long been dominant in this field.However, in recent times, chiral monodentate phosphorus ligands have also provento be highly effective in diverse transformations.82 The most commonly employedclass of chiral monodentate phosphorus ligands in rhodium-catalyzed 1,4-additionsof organoboron reagents are phosphites and phosphoramidites containing a biarylbackbone (see Chart 2). Compared with chiral bisphosphines, these ligands are oftensimpler in structure, more readily prepared, and hence more easily tuned. In addition,they often exhibit high reactivity because of their strong π-accepting properties.Particularly effective ligands in this class are H8-BINOL-derived phosphoramiditeL7 (BINOL = 1,1′-bi-2-naphthol) and its enantiomer L8, which have been usedin the 1,4-arylation of simple cyclic α,β-unsaturated ketones (Scheme 16)83 and2,3-dihydro-4-pyridones (Scheme 17).84

L7 (7.5 mol %),Rh(C2H4)2(acac) (3.0 mol %)

OP

ONEt2

dioxane/H2O (10:1), 100°, 5 h

95% conv by 1H NMRer 98.0:2.0

(HO)2B

(3.0 equiv)

OO

+

Scheme 16

18 ORGANIC REACTIONS

L8 (7.5 mol %),Rh(C2H4)2(acac) (3.0 mol %)

(86%) er 99.5:0.5

N

O

N

O

OP

ONEt2

Ar = 3-MeC6H4

(3.0 equiv)

(ArBO)3+ dioxane, H2O (3.0 equiv),

100°, 2 h

(H2O added by syringe pump)

Cbz Cbz

Scheme 17

Because the active catalytic species formed from monodentate phosphorus ligandsusually contains two such ligands bound to rhodium, libraries of chiral rhodium com-plexes can be prepared by mixing together various different monodentate phosphorusligands. In this combinatorial approach, large numbers of chiral rhodium complexescan be screened without having to prepare new types of ligands, which can expe-dite the identification of effective catalysts. However, a complicating feature is thatmixtures of two different monodentate ligands La and Lb can form up to three dif-ferent complexes when bound to rhodium (other counterions not shown): [Rh(La)2],[Rh(Lb)2], and [Rh(La)(Lb)], all of which may contribute to the overall yield andenantiopurity of the product. For this combinatorial approach to be effective, the com-plex [Rh(La)(Lb)] formed from two different ligands must exhibit higher reactivityand enantioselectivity than the complexes [Rh(La)2] and [Rh(Lb)2] formed from twoequivalents of the same ligand.85

An early example of this method is shown in Scheme 18. Although the rhodiumcomplex formed from two equivalents of the achiral phosphoramidite L9 exhibitshigh catalytic activity in the 1,4-addition of phenylboroxine to 2-cyclohexenone,the corresponding complex formed from the chiral ligand L10 results in zeroconversion.86 However, the rhodium complex formed from one equivalent each ofL9 and L10 results in high conversion and a low enantioselectivity. A further study ofthis approach using larger libraries of chiral tropos phosphites and phosphoramiditeshas been performed with excellent results.87

Ligand A (2.5 mol %),Ligand B (2.5 mol %)

Ligand AL9L10L9

Ligand BL9L10L10

% Conva

100098

er50.0:50.0

—61.0:39.0

OO

OP

ON

Ph

PhOP

ON

(PhBO)3

(1.3 equiv) Rh(acac)(C2H4)2 (2.0 mol %),dioxane/H2O (10:1), 60°, 3 h

+

L9

L10a The percent conversion was determined by GC analysis.

Scheme 18