Palladium Reagents and Catalysts : New Perspectives for the 21st Century

Palladium Reagents and Catalysts New Perspectives for the 21st Century

Jiro Tsuji Emeritus Professor, Tokyo Institute of Technology, Japan

Palladium Reagents and Catalysts

Palladium Reagents and Catalysts New Perspectives for the 21st Century

Jiro Tsuji Emeritus Professor, Tokyo Institute of Technology, Japan

Copyright  2004

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777

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Library of Congress Cataloging-in-Publication Data Tsuji, Jiro, 1927– Palladium reagents and catalysts : new Perspectives for the 21st Century / Jiro Tsuji.—2nd ed. p. cm. Includes bibliographical references and index. ISBN 0-470-85032-9 (Cloth : alk. paper)—ISBN 0-470-85033-7 (Paper : alk. paper) 1. Organic compounds—Synthesis. 2. Palladium catalysts. I. Title. QD262.T785 2004 547
.2—dc22 2003026494 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0-470-85032-9 (HB) ISBN 0-470-85033-7 (PB) Typeset in 10.5/12.5pt Times by Laserwords Private Limited, Chennai, India Printed and bound in Great Britain by TJ International, Padstow, Cornwall This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

Contents

Preface Abbreviations 1

2

The Basic Chemistry of Organopalladium Compounds 1.1 Characteristic Features of Pd-Promoted or -Catalyzed Reactions 1.2 Palladium Compounds, Complexes, and Ligands Widely Used in Organic Synthesis 1.3 Fundamental Reactions of Pd Compounds 1.3.1 ‘Oxidative’ Addition 1.3.2 Insertion 1.3.3 Transmetallation 1.3.4 Reductive Elimination 1.3.5 β-H Elimination (β-Elimination, Dehydropalladation) 1.3.6 Elimination of β-Heteroatom Groups and β-Carbon 1.3.7 Electrophilic Attack by Organopalladium Species 1.3.8 Termination of Pd-Catalyzed or -Promoted Reactions and a Catalytic Cycle 1.3.9 Reactions Involving Pd(II) Compounds and Pd(0) Complexes References Oxidative Reactions with Pd(II) Compounds 2.1 Introduction 2.2 Reactions of Alkenes 2.2.1 Introduction 2.2.2 Reaction with Water 2.2.3 Reactions with Alcohols and Phenols 2.2.4 Reactions with Carboxylic Acids 2.2.5 Reactions with Amines 2.2.6 Reactions with Carbon Nucleophiles 2.2.7 Oxidative Carbonylation

xi xiii 1 1 1 6 6 11 13 14 15 17 19

21 23 24 27 27 29 29 32 35 39 41 44 45

vi

Contents 2.2.8 2.2.9

Reactions with Aromatic Compounds Coupling of Alkenes with Organometallic Compounds 2.3 Stoichiometric Reactions of π -Allyl Complexes 2.4 Reactions of Conjugated Dienes 2.5 Reactions of Allenes 2.6 Reaction of Alkynes 2.7 Homocoupling and Oxidative Substitution Reactions of Aromatic Compounds 2.8 Regioselective Reactions Based on Chelation and Participation of Heteroatoms 2.9 Oxidative Carbonylation of Alcohols and Amines 2.10 Oxidation of Alcohols 2.11 Enone Formation from Ketones and Cycloalkenylation References 3

Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.1 Introduction 3.2 Reactions with Alkenes (Mizoroki–Heck Reaction) 3.2.1 Introduction 3.2.2 Catalysts and Ligands 3.2.3 Reaction Conditions (Bases, Solvents, and Additives) 3.2.4 Halides and Pseudohalides 3.2.5 Alkenes 3.2.6 Formation of Neopentylpalladium and its Termination by Anion Capture 3.2.7 Intramolecular Reactions 3.2.8. Asymmetric Reactions 3.2.9 Reactions with 1,2-, 1,3-, and 1,4-Dienes 3.2.10 Amino Heck Reactions of Oximes References 3.3 Reactions of Aromatics and Heteroaromatics 3.3.1 Arylation of Heterocycles 3.3.2 Intermolecular Arylation of Phenols 3.3.3 Intermolecular Polyarylation of Ketones 3.3.4 Intramolecular Arylation of Aromatics References 3.4 Reactions with Alkynes 3.4.1 Introduction 3.4.2 Reactions of Terminal Alkynes to Form Aryl- and Alkenylalkynes (Sonogashira Coupling) References 3.4.3 Reactions of Internal and Terminal Alkynes with Aryl and Alkenyl Halides via Insertion References

50 52 54 56 58 61 77 79 86 90 95 97 105 105 109 109 113 114 119 125

133 135 148 155 169 171 176 177 184 189 190 200 201 201 201 229 231 264

Contents 3.5

Carbonylation and Reactions of Acyl Chlorides 3.5.1 Introduction 3.5.2 Formation of Carboxylic Acids, Esters, and Amides 3.5.3 Formation of Aldehydes and Ketones 3.5.4 Reactions of Acyl Halides and Related Compounds 3.5.5 Miscellaneous Reactions References 3.6 Cross-Coupling Reactions with Organometallic Compounds of the Main Group Metals via Transmetallation 3.6.1 Introduction 3.6.2 Organoboron Compounds (Suzuki–Miyaura Coupling) References 3.6.3 Organostannanes (Kosugi–Migita–Stille Coupling) 3.6.4 Organozinc Compounds (Negishi Coupling) 3.6.5 Organomagnesium Compounds 3.6.6 Organosilicon Compounds (Hiyama Coupling) References 3.7 Arylation and Alkenylation of C, N, O, S, and P Nucleophiles 3.7.1 α-Arylation and α-Alkenylation of Carbon Nucleophiles 3.7.2 Intramolecular Attack of Aryl Halides on Carbonyl Groups References 3.7.3 Arylation of Nitrogen Nucleophiles References 3.7.4 Arylation of Phenols, Alcohols, and Thiols References 3.7.5 Arylation of Phosphines, Phosphonates, and Phosphinates References 3.8 Miscellaneous Reactions of Aryl Halides 3.8.1 The Catellani Reactions using Norbornene as a Template for ortho-Substitution References 3.8.2 Reactions of Alcohols with Aryl Halides Involving β-Carbon Elimination References 3.8.3 Hydrogenolysis with Various Hydrides 3.8.4 Homocoupling of Organic Halides (Reductive Coupling) References

vii 265 265 266 275 282 286 286

288 288 289 310 313 327 335 338 348 351 351 369 371 373 390 392 398 398 408 409 409 415 416 426 427 428 430

viii 4

5

Contents Pd(0)-Catalyzed Reactions of Allylic Compounds via π-Allylpalladium Complexes 4.1 Introduction and Range of Leaving Groups 4.2 Allylation 4.2.1 Stereo- and Regiochemistry of Allylation 4.2.2 Asymmetric Allylation 4.2.3 Allylation of Stabilized Carbon Nucleophiles 4.2.4 Allylation of Oxygen and Nitrogen Nucleophiles 4.2.5 Allylation with Bis-Allylic Compounds and Cycloadditions 4.3 Reactions with Main Group Organometallic Compounds via Transmetallation 4.3.1 Cross-Coupling with Main Group Organometallic Compounds 4.3.2 Formation of Allylic Metal Compounds 4.3.3 Allylation Involving Umpolung 4.3.4 Reactions of Amphiphilic Bis-π -Allylpalladium Compounds 4.4 Carbonylation Reactions 4.5 Intramolecular Reactions with Alkenes and Alkynes 4.6 Hydrogenolysis of Allylic Compounds 4.6.1 Preparation of 1-Alkenes by Hydrogenolysis with Formates 4.6.2 Hydrogenolysis of Internal and Cyclic Allylic Compounds 4.7 Allyl Group as a Protecting Group 4.8 1,4-Elimination 4.9 Reactions via π -Allylpalladium Enolates 4.9.1 Generation of π -Allylpalladium Enolates from Silyl and Tin Enolates 4.9.2 Reactions of Allyl β-Keto Carboxylates and Related Compounds 4.10 Pd(0) and Pd(II)-Catalyzed Allylic Rearrangement 4.11 Reactions of 2,3-Alkadienyl Derivatives via Methylene-π -allylpalladiums References Pd(0)-Catalyzed Reactions of 1,3-Dienes, 1,2-Dienes (Allenes), and Methylenecyclopropanes 5.1 Reactions of Conjugated Dienes 5.2 Reactions of Allenes 5.2.1 Introduction 5.2.2 Reactions with Pronucleophiles 5.2.3 Carbonylation 5.2.4 Hydrometallation and Dimetallation 5.2.5 Miscellaneous Reactions

431 431 438 438 443 451 456 466 469 469 471 473 476 479 483 485 485 487 490 494 500 500 503 508 509 511

519 519 525 525 527 531 532 536

Contents

6

7

ix

5.3

Reactions of Methylenecyclopropanes 5.3.1 Introduction 5.3.2 Hydrostannation and Dimetallation 5.3.3 Hydrocarbonation and Hydroamination References

537 537 537 538 541

Pd(0)-Catalyzed Reactions of Propargyl Compounds 6.1 Introduction and Classification of Reactions 6.2 Reactions via Insertion of Alkenes and Alkynes 6.3 Carbonylations 6.4 Reactions of Main Group Metal Compounds 6.5 Reactions of Terminal Alkynes; Formation of 1,2-Alkadien-4-ynes 6.6 Reactions of Nucleophiles on Central sp Carbon of Allenylpalladium Intermediates 6.7 Hydrogenolysis and Elimination of Propargyl Compounds References

543 543 545 548 552 554 555 560 562

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes 7.1 Reactions of Alkynes 7.1.1 Carbonylation 7.1.2 Hydroarylation 7.1.3 Hydroamination, Hydrocarbonation, and Related Reactions 7.1.4 Hydrometallation and Hydro-Heteroatom Addition 7.1.5 Dimetallation and Related Reactions 7.1.6 Cyclization of 1,6-Enynes and 1,7-Diynes 7.1.7 Benzannulation 7.1.8 Homo- and Cross-Coupling of Alkynes 7.1.9 Miscellaneous Reactions 7.2 Reactions of Benzynes 7.2.1 Cyclotrimerization and Cocyclization 7.2.2 Addition Reactions of Arynes References

569 572 576 578 583 589 591 592 592 595 597

8

Pd(0)-Catalyzed Reactions of Alkenes 8.1 Carbonylation 8.2 Hydroamination 8.3 Hydrometallation 8.4 Miscellaneous Reactions References

601 601 605 606 609 611

9

Pd(0)-Catalyzed Miscellaneous Reactions of Carbon Monoxide References

613 614

565 565 565 567

x

Contents

10 Miscellaneous Reactions Catalyzed by Chiral and Achiral Pd(II) Complexes References

615 621

Tables 1.1 to 1.18

623

Index

643

Preface

Organopalladium chemistry has changed remarkably since I wrote the book Palladium Reagents and Catalysts, Innovations in Organic Synthesis in 1995. This is the main reason why I undertook the difficult task of writing a new book on organopalladium chemistry. Several reactions which had long been regarded as impossible, are now known to proceed smoothly with Pd catalysts, and several dreams have become reality. For example, no one believed, only 5 years ago, that cyclohexanone could be arylated easily by a Pd-catalyzed reaction of chlorobenzene to afford 2-phenylcyclohexanone. Aryl chlorides, which had been regarded as totally inactive in catalytic reactions, are now known to undergo facile Pdcatalyzed reactions, giving a potentially big impact to practical applications. It is not an exaggeration to say that the recent development of organopalladium chemistry is revolutionary. It is widely recognized that palladium is the most versatile metal in promoting or catalyzing reactions, particularly those involving carbon–carbon bond formation, many of which are not always easy to achieve with other transition metal catalysts. In 1981, I wrote Organic Synthesis with Palladium Compounds citing about 1000 references which had appeared before 1978. I wrote a larger book (560 pages) in 1995, entitled Palladium Reagents and Catalysts, Innovations in Organic Synthesis. Mention should also be made of Handbook of Organopalladium Chemistry, edited by E. Negishi in 2002, which is 3279 pages long, and is an excellent encyclopedia covering all fields of organopalladium chemistry, and includes ample experimental data. Considering the explosive and remarkable growth in organopalladium chemistry, particularly in the last 5 years, I now feel that another comprehensive book is needed to summarize the newer aspects of organopalladium chemistry. My primary purpose in writing this book is to give new perspectives on the synthetic usefulness of contemporary organopalladium chemistry for synthetic organic chemists. I wrote this book on the assumption that my old book Palladium Reagents and Catalysts, Innovations in Organic Synthesis is accessible to readers, and I tried, as much as possible, to avoid repetitions or overlaps. I believe that, together, the two books cover the whole of organopalladium chemistry, from the past to the present. The proper classification of all Pd-catalyzed reactions is important, and there are several possibilities. The classification I chose tries to achieve easy understanding by synthetic organic chemists. It is different from the classification used by Negishi which is based mainly on organometallic chemistry. The many references that are given in this book were selected from a much larger number which I have collected over the years. I have tried to be as comprehensive

xii

Preface

as possible in selecting those references of evident synthetic utility in papers published before the middle of 2003. The overall task of selecting which references to include, based on my own interests, was very difficult. I can only hope that not too many researchers will feel that their important papers were not cited. It may be a hopeless venture for a single author to write a book covering the rapidly progressing field of modern organopalladium chemistry. I took great care writing this book. Many errors and incorrect citations must, however, inevitably be present. These are my sole responsibility, and readers are advised to keep in mind that statements, data, illustrations, or other items may, inadvertently, be inaccurate. I want to express my appreciation to Dr M. Miura (Associate Professor, Osaka University) for reading all chapters and correcting errors. I thank Professor H. Nozaki (Emeritus, Kyoto University) for his pertinent comments on the manuscript. The following chemists read various chapters of the crude manuscript and gave me valuable advice which I appreciated very much: M. Catellani (Professor, Parma University) T. Hiyama (Professor, Kyoto University), K. Mikami (Associate Professor, Tokyo Institute of Technology), M. Nishiyama (Tosoh Corporation), A. Suzuki (Emeritus Professor, Hokkaido University), Y. Tamaru (Professor, Nagasaki University), K. Yamamoto (Professor, Science University of Tokyo in Yamaguchi), and Y. Yamamoto (Professor, Tohoku University). Also, I want to thank T. Ikariya (Professor, Tokyo Institute of Technology) for designing the cover illustration. As one who has devoted most of his research life to the development of organopalladium chemistry, I will be very happy if this book stimulates, in any way, the further development of organopalladium chemistry. J. Tsuji October 2003 Kamakura, Japan

Abbreviations

Ac acac Ar atm BBEDA 9-BBN 9-BBNH Bn BINAP BPPFA bpy Boc BQ BSA Bz CDT COD Cp DBA DBU DCHPE DDQ DEAD DIPPP DIOP DMAD DMI DPMSPP DPPB DPPE DPPF DPPP EWG KHMDS LHMDS

acetyl acetylacetonato aryl atmospheric pressure N ,N
-bis(benzylidene)ethylenediamine 9-borabicyclo[3. 3. 1]nonanyl 9-borabicyclo[3. 3. 1]nonane benzyl 2,2
-bis(diphenylphosphino)-1,1
binaphthyl 1-[1,2-bis(diphenylphosphino)ferrocenyl]ethyldimethylamine 2,2
-bipyridyl t-butoxycarbonyl 1,4-benzoquinone N ,O-bis(trimethylsilyl)acetamide benzoyl 1,5,9-cyclododecatriene 1,5-cyclooctadiene cyclopentadienyl dibenzylideneacetone 1,8-diazabicyclo[5. 4. 0]undec-7-ene bis(dicyclohexylphosphino)ethane 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate bis(diisopropylphosphino)propane 2,3-O-isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane dimethyl acetylenedicarboxylate 1,3-dimethylimidazolidin-2-one diphenyl(m-sulfophenyl)phosphine bis(diphenylphosphino)butane bis(diphenylphosphino)ethane 1,1
-bis(diphenylphosphino)ferrocene bis(diphenylphosphino)propane electron-withdrawing group potassium hexamethyldisilazane, potassium bis(trimethylsilyl)amide lithium hexamethyldisilazane, lithium bis(trimethylsilyl)amide

xiv MA MOM MOP NaHMDS Nf Nu PEG phen PhMe PHMS PMP PPFA py TASF TBAC TBAF TBDMS TCPC TDMPP Tf TFA TFP TMG TMPP TMS Tol TON TOF TPPTS TPPMS

Ts TsOH TTMPP

Abbreviations maleic anhydride methoxymethyl monodentate optically active phosphine sodium hexamethyldisilazane, sodium bis(trimethylsilyl)amide nonaflate, nonafluorobutanesulfonate nucleophile poly(ethylene glycol) 1,10-phenanthroline toluene poly(hydromethylsiloxane) 1,2,2,6,6-pentamethylpiperidine N ,N -dimethyl-1,2-(diphenylphosphino)ferrocenylethylamine pyridine tris(diethylamino)sulfonium difluoro(trimethyl)silicate tetrabutylammonium chloride tetrabutylammonium fluoride t-butyldimethylsilyl 2,3,4,5-tetrakis(methoxycarbonyl)palladacyclopentadiene tri(2,6-dimethoxyphenyl)phosphine trifluoromethylsulfonyl (triflyl) trifluoroacetic acid tri(2-furyl)phosphine tetramethylguanidine trimethylolpropane phosphite or 4-ethyl-2,6,7-trioxa-1-phosphobicyclo[2. 2. 2]octane trimethylsilyl tolyl turnover numbers turnover frequencies (II-2) tri(m-sulfophenyl)phosphine; CA Index name, 3,3
,3

-phosphinidynetrisbenzenesulfonic acid (II-1) (m-sulfophenyl)diphenylphosphine, diphenyl(3-sulfophenyl)phosphine; CA Index name, 3-(diphenylphosphino)benzenesulfonic acid tosyl p-toluenesulfonic acid tri(2,4,6-trimethoxyphenyl)phosphine

Chapter 1 The Basic Chemistry of Organopalladium Compounds

1.1 Characteristic Features of Pd-Promoted or -Catalyzed Reactions There are several features which make reactions involving Pd catalysts and reagents particularly useful and versatile among many transition metals used for organic synthesis. Most importantly, Pd catalysts offer an abundance of possibilities of carbon–carbon bond formation. Importance of the carbon–carbon bond formation in organic synthesis needs no explanation. No other transition metals can offer such versatile methods of the carbon–carbon bond formations as Pd. Tolerance of Pd catalysts and reagents to many functional groups such as carbonyl and hydroxy groups is the second important feature. Pd-catalyzed reactions can be carried out without protection of these functional groups. Although reactions involving Pd should be carried out carefully, Pd reagents and catalysts are not very sensitive to oxygen and moisture, and even to acid in many reactions catalyzed by Pd–phosphine complexes. It is enough to apply precautions to avoid oxidation of coordinated phosphines, and this can be done easily. On the other hand, the Ni(0) complex is extremely sensitive to oxygen. Of course, Pd is a noble metal and expensive. Its price frequently fluctuates drastically. A few years ago, Pd was more expensive than Pt and Au but cheaper than Rh. As of October 2003, the comparative prices of the noble metals were: Pd (1), Au (1.8), Rh (2.8), Pt (3.3), Ru (0.2). Recently the price of Pd has dropped dramatically, and Pt is currently the most expensive noble metal. Also, the toxicity of Pd has posed no serious problem so far. The fact that a number of industrial processes, particularly for the production of fine chemicals based on Pd-catalyzed reactions, have been developed and are currently being operated, reflects the advantages of using Pd catalysts commercially.

1.2 Palladium Compounds, Complexes, and Ligands Widely Used in Organic Synthesis In organic synthesis, two kinds of Pd compounds, namely Pd(II) salts and Pd(0) complexes, are used. Pd(II) compounds are mainly used as oxidizing reagents, or catalysts for a few reactions. Pd(0) complexes are always used as catalysts. Pd(II) Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

2

The Basic Chemistry of Organopalladium Compounds

compounds such as PdCl2 and Pd(OAc)2 are stable, and commercially available. They can be used in two ways: as unique stoichiometric oxidizing agents; and as precursors of Pd(0) complexes. PdCl2 is stable, but its solubility in water and organic solvents is low. It is soluble in dilute HCl and becomes soluble in organic solvents by forming a PdCl2 (PhCN)2 complex. M2 PdCl4 (M = Li, Na, K) are soluble in water, lower alcohols and some organic solvents. Pd(OAc)2 is commercially available. It is stable and soluble in organic solvents. Pd(II) salts can be used as a source of Pd(0). Most conveniently phosphines can be used as reducing agents. For example, when Pd(OAc)2 is treated with PPh3 , Pd(0) species and phosphine oxide are formed slowly [1]. A highly active Pd(0) catalyst can be prepared by a rapid reaction of Pd(OAc)2 with P(n-Bu)3 in 1 : 1 ratio in THF or benzene [2]. P(n-Bu)3 is oxidized rapidly to phosphine oxide and a phosphine-free Pd(0) species is formed besides Ac2 O. This catalyst is very active, but not stable and must be used immediately; black Pd metal begins to precipitate after 30 min if no substrate is added. The in situ generation of Pd(0) species using n-PBu3 as a reducing agent is very convenient preparative method for Pd(0) catalysts. Pd(OAc)2 + PPh3 + H2O

Pd(0) + Ph3PO + 2 AcOH

Pd(OAc)2 + P(n-Bu3)

Pd(0)

O=PBu3 + Ac2O

Commercially available Pd(OAc)2 , PdCl2 (PPh3 )2 , Pd(PPh3 )4 , Pd2 (dba)3 -CHCl3 and (η3 -allyl-PdCl)2 are generally used as precursors of Pd(0) catalysts with or without addition of phosphine ligands. However, it should be mentioned that catalytic activities of Pd(0) catalysts generated in situ from these Pd compounds are not always the same, and it is advisable to test all of them in order to achieve efficient catalytic reactions. Pd(PPh3 )4 is light-sensitive, unstable in air, yellowish green crystals and a coordinatively saturated Pd(0) complex. Sometimes, Pd(PPh3 )4 is less active as a catalyst, because it is overligated and has too many ligands to allow the coordination of some reactants. Recently bulky and electron-rich P(t-Bu)3 has been attracting attention as an important ligand. Interestingly, highly coordinatively unsaturated Pd(t-Bu3 P)2 is a stable Pd(0) complex in solid state [3] and commercially available. The stability of this unsaturated phosphine complex is certainly due to bulkiness of the ligand. This complex is a very active catalyst in some reactions, particularly for aryl chlorides [4]. Pd2 (dba)3 -CHCl3 (dba = dibenzylideneacetone) is another commercially available Pd(0) complex in the form of purple needles which contain one molecule of CHCl3 when Pd(dba)2 , initially formed in the process of preparation, is recrystallized from CHCl3 , where Pd(dba)2 corresponds to Pd2 (dba)3 -dba. In literature, researchers use both Pd2 (dba)3 and Pd(dba)2 in their research papers. In this book both complexes are taken directly from original papers as complexes of the same nature. The molecule of dba is not a chelating ligand. One of the dba molecules in Pd2 (dba)3 -dba does not coordinate to Pd and is displaced by CHCl3 to form Pd2 (dba)3 -CHCl3 , when it is recrystallized from CHCl3 . In Pd2 (dba)3 , dba behaves as two monodentate ligands, but not one bidentate ligand, and each Pd

Palladium Compounds, Complexes, and Ligands

3

is coordinated with three double bonds of three molecules of dba, forming a 16electron complex. It is an air-stable complex, prepared by the reaction of PdCl2 with dba and recrystallization from CHCl3 [5]. Pd2 (dba)3 itself without phosphine is an active catalyst in some reactions. As a ligand, dba is comparable to, or better than monodentate phosphines. Pd on carbon in the presence of PPh3 may be used for reactive substrates as an active catalyst similar to Pd(PPh3 )n . Recently colloidal Pd nanoparticles protected with tetraalkylammonium salts have been attracting attention as active catalysts. They are used for Heck and Suzuki–Miyaura reactions without phosphine ligands [6,7]. Most simply, Pd(OAc)2 is used without a ligand, forming some kind of colloidal or soluble Pd(0) species in situ in reactions of active substrates such as aryl iodides and diazonium salts. Pd on carbon without phosphine is active for some Heck and other reactions, but not always. These Pd(0) catalysts without ligands are believed to behave as homogeneous catalysts [8]. A number of phosphine ligands are used. Phosphines used frequently in Pdcatalyzed reactions are listed in Tables 1.1–1.18. Most of them are commercially available [9]. Among them, PPh3 is by far the most widely used. Any contaminating phosphine oxide is readily removed by recrystallization from ethanol. Bulky tri(o-tolyl)phosphine is an especially effective ligand, and was used by Heck for the first time [10]. The Pd complex of this phosphine is not only active, but also its catalytic life is longer. This is explained by formation of the palladacycle 1, called the Herrmann complex, which is stable to air and moisture and commercially available [11]. It is an excellent precursor of underligated single phosphine Pd(0) catalyst. But this catalyst is not active at low temperature, and active above 110 ◦ C. Also a number of palladacycles (Table 1.18) are prepared as precursors of catalysts and show high catalytic activity and turnover numbers. Me

Me P + 2 Pd(OAc)2

2

O

O

O

o-tol

o-tol

o-tol P

Pd

Pd P

3

o-tol

O

+ 2 AcOH

Me 1

In some catalytic reactions, more electron-donating alkylphosphines such as P(n-Bu)3 and tricyclohexylphosphine, and arylphosphines such as tri(2,4,6-trimethoxyphenyl)phosphine (TTMPP) and tri(2,6-dimethoxyphenyl)phosphine (TDMPP), are used successfully. These electron-rich phosphines accelerate the ‘oxidative addition’ step. Furthermore, P(t-Bu)3 was found to be a very important ligand particularly for reactions of aryl chlorides. It is a very bulky and electron-rich phosphine, and has been neglected for a long time and has not been used as a ligand, because it is believed that the bulkiness inhibits coordination of reactants. Now it is understandable that strongly electron-donating t-Bu3 P accelerates the ‘oxidative addition’ step of aryl chlorides, because oxidative addition is nucleophilic in nature. Also, the bulkiness assists facile reductive elimination. The following pKa

4

The Basic Chemistry of Organopalladium Compounds

values of conjugate acids of phosphines support the high basicity of P(t-Bu)3 , which is more basic than P(n-Bu)3 : P(t-Bu)3 (11.4), PCy3 (9.7), P(n-Bu)3 (8.4), PPh3 (2.7) Since the first report on the use of P(t-Bu)3 in Pd-catalyzed amination of aryl chlorides by Koie and co-workers appeared in 1998 [12], syntheses and uses of a number of bulky and electron-rich phosphines related to P(t-Bu)3 (Tables 1.4–1.6) have been reported [13]. These di- and trialkylphosphines are somewhat air-sensitive. However, their phosphonium salts are air-stable, from which phosphines are liberated by the treatment with bases and conveniently used for catalytic processes [14]. Sulfonated triphenylphosphine [TPPTS (triphenylphosphine, m-trisulfonated); tri(m-sulfophenyl)phosphine] (II-1) and monosulfonated triphenylphosphine [TPPMS (triphenylphosphine, monosulfonated); 3-(diphenylphosphino)benzenesulfonic acid] (II-2) are commercially available ligands and their sodium salts are water-soluble [15]. The Na salt of the ligand TPPTS is very soluble and may be too soluble in water, hence moderately soluble TPPMS is preferred. Another water-soluble phosphine is 2-(diphenylphosphinoethyl)trimethyl ammonium halide (II-11) [16]. A number of other water-soluble phosphines are now known (Table 1.2). Pd complexes, coordinated by these phosphines, are soluble in water, and Pdcatalyzed reactions can be carried out in water, which is said to have an accelerating effect in some catalytic reactions. Bidentate phosphines such as DPPE, DPPP and DPPB1 play important roles in some reactions. Another bidentate phosphine is DPPF (XI-1), which is different from other bidentate phosphines, showing its own characteristic activity. The tetrapodal phosphine ligand, cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp) (X-1) was found to be a good ligand, and its Pd complex gives high turnover numbers [17]. Phosphites, such as triisopropyl phosphite and triphenyl phosphite, are weaker electron donors than the corresponding phosphines, but they are used in some reactions because of their greater π -acceptor ability. The cyclic phosphite [trimethylolpropane phosphite (TMPP) or 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]-octane] (III-2), which has a small cone angle and small steric hindrance, shows high catalytic activity in some reactions. It is not commercially available, but can be prepared easily [18]. Recently Li reported that air stable phosphine oxides 2a [RR
P(O)H] in the presence of transition metals undergo tautomerization to the less stable phosphinous acids 2b [RR
POH], which subsequently coordinate to Pd centers through phosphorus atoms to form Pd phosphinous acid complexes 2c, which behave as active catalysts for unactivated aryl chlorides [19]. Their Pd complexes XVIII-4 (POPd), -5 (POPd1) and -6 (POPd2) are commercially available (Table 1.18). R′ R

1

R′ P

O

Pd(0) P

OH

R′ R

P

H

R

HO

2a

2b

2c

Pd

According to IUPAC nomenclature, abbreviations of ligands themselves are written in capital letters, for example, DPPE, DPPF, BINAP, DBA are used, but the ligands in complexes are written with small letters like PdCl2 [dppe]Cl2 , Pd2 (dba)3 , although this rule is neglected in many cases.

Palladium Compounds, Complexes, and Ligands

5

Heterocyclic carbene ligands are now attracting attention as new ligands (Table 1.16). Carbenes are reactive and unstable species, which are difficult to isolate. It is well-known that they can be stabilized and isolated by coordinating to metal complexes of W, Mo and Cr. Recently Ardeuengo found that imidazol2-ylidenes with large substituents on nitrogens are stable carbenes and can be isolated [20,21]. They are good ligands of transition metal complexes, and called ‘phosphine mimics’, which are bulky and electron-rich, and hence active for the reactions of aryl chlorides [22]. The carbenes can be generated from dihydroimidazolium salts, which are prepared easily from glyoxal, primary amine and ortho-formate. Research on reactions catalyzed by Pd–carbene complexes is expanding rapidly including asymmetric catalysis. It should be mentioned that alkyl-substituted imidazolium salts are ionic liquids, used extensively as unique solvents for various reactions, including Pd-catalyzed reactions [23]. NH2 H

O +

H

2

+

HC(OEt)3

O

NaBH4

N + N C

NH4BF4

BF4

base N Ar

N C

Ar

dihydroimidazolium salt

Coordinated phosphines do not directly participate in catalytic reactions, and hence they are called ‘spectator’ or ‘innocent’ ligands. Roles of phosphines are not entirely understood and their performance is not always predictable [24]. Therefore, in surveying optimum conditions of catalytic reactions, it is advisable to test the activity of important types of phosphines and phosphites, which have both different steric effects and electron donating properties as much as possible. Ratios of Pd to ligands are also important. In the presence of an excess ligand, the concentration of active catalytic species is decreased, and hence the catalytic process may be inhibited. Some Pd(0)-catalyzed reactions proceed without phosphine ligands, and a phosphine-free catalyst is an ideal one, because phosphines are expensive and difficult to recover. Pd is an expensive metal. In Pd(0) or Pd(II)-catalyzed reactions, particularly in commercial processes, repeated uses of Pd catalysts are required. When products are low-boiling, they can be separated from the catalyst by distillation. The Wacker process for the production of acetaldehyde is an example. In order to separate from less volatile products, there are several approaches for the economical use of Pd catalysts. Active Pd complexes covalently bound to a polymer chain are frequently used. After the reaction, the supported catalyst can be recovered by filtration and reused several times. Polymers such as the Merrifield resin [25], amphiphilic poly(ethylene glycol)-polystyrene copolymer [26] and polyethylene [27] are typical examples. Also polymer-supported microencapsulated Pd is used as a reusable

6

The Basic Chemistry of Organopalladium Compounds

catalyst [28]. When a water-soluble phosphine is used, the Pd catalyst always stays in an aqueous phase and can be separated from products in an organic phase, and is used repeatedly. An N-containing 15-membered macrocyclic triolefin (XVII-1) is a good ligand for cross coupling [29]. Solid phase synthesis has been extensively applied to Pd-catalyzed reactions as an efficient synthetic method [30]. Recovery of Pd after reactions is important in commercial processes, but it is not always easy to collect Pd from solutions [31]. Pd can be recovered as insoluble complexes such as the dimethylglyoxime complex or PdCl2 (PPh3 )2 by treatment with HCl and PPh3 . Removal of a very small amount of Pd, remaining in a solution, or purification of reaction products contaminated with a trace of Pd, can be done by treating the solution with active charcoal, polyamines, polymeranchored phosphines and P(n-Bu)3 [32]. The Pd can be collected in solution by coordination or absorption. 3-(Diethylenetriamino)propyl-functionalized silica gel, commercially available from Aldrich, is used to scavenge Pd in a solution at a low concentration.

1.3 Fundamental Reactions of Pd Compounds The following six fundamental reactions of Pd complexes are briefly explained in order to understand how reactions either promoted or catalyzed by Pd proceed [32a]. In schemes used for explanation, ‘spectator’ or ‘innocent’ phosphine ligands are omitted for simplicity. First, a brief explanation of the chemical terms specific to organopalladium chemistry is given: 1. 2. 3. 4. 5. 6.

Oxidative addition (OA); Insertion (IS); Transmetallation (TM); Reductive elimination (RE); β-H elimination; Elimination of β-heteroatom groups and β-carbon.

It should be noted that sometimes different terms are used for the same process. This situation arises from the fact that chemical terms specific to organometallic chemistry originate from inorganic chemistry, and these terms differ from the ones originating from organic chemistry. 1.3.1 ‘Oxidative’ Addition The term ‘oxidative’ may sound strange for organic chemists who are not familiar with organometallic chemistry. The term ‘oxidative’ used in organometallic chemistry has a different meaning to ‘oxidation’ used in organic chemistry, such as oxidation of secondary alcohols to ketones. The ‘oxidative’ addition is the addition of a molecule X—Y to Pd(0) with cleavage of its covalent bond, forming two new bonds. Since the two previously nonbonding electrons of Pd are involved in bonding, the Pd increases its formal oxidation state by two units, namely, Pd(0) is oxidized to Pd(II). This process is similar to the formation of Grignard reagents from alkyl halides and Mg(0). In the preparation of Grignard reagents, Mg(0) is oxidized to Mg(II) by the ‘oxidative’ addition of alkyl halides to form two covalent

Fundamental Reactions of Pd Compounds

7

bonds. Another example, which clearly shows the difference between ‘oxidation’ in organic chemistry and ‘oxidative’ addition in organometallic chemistry, is the ‘oxidative’ addition of H2 to Pd(0) to form Pd(II) hydride. In other words, Pd(0) is ‘oxidized’ to Pd(II) by H2 . This sounds strange to organic chemists, because H2 is a reducing agent in organic chemistry.

Pd(0) + X-Y

oxidative addition

X-Pd(II)-Y

Mg(0) + CH3-I

CH3-Mg-I

Pd(0) + H-H

H-Pd(II)-H

According to the 18-electron rule, a stable Pd(0) complex with an electron configuration of the next highest noble gas is obtained when the sum of d electrons of Pd and electrons donated from ligands equals eighteen. Complexes which obey the 18-electron rule are said to be coordinatively saturated. Pd(0) forms complexes using d10 electrons (4d8 and 5s2 ). Coordinatively saturated complexes are formed by donation of electrons from the ligands until the total number of electrons reaches eighteen. This means that four ligands which donate two electrons each can coordinate Pd(0) to form a coordinatively saturated Pd(0) complex. In other words, the coordination number of Pd(0) is four. The oxidative addition occurs with coordinatively unsaturated complexes. As a typical example, the saturated Pd(0) complex, Pd(PPh3 )4 (four-coordinate, 18 electrons) undergoes reversible dissociation in situ in a solution to give the unsaturated 14-electron species Pd(PPh3 )2 , which is capable of undergoing oxidative addition. Various σ -bonded Pd complexes are formed by oxidative addition. In many cases, dissociation of ligands to supply vacant coordination sites is the first step of catalytic reactions. Ph-I Pd(PPh3)2

Pd((PPh3)4 18 electrons

14 electrons 2 PPh3

Ph-Pd-I(PPh3)2 16 electrons

Oxidative addition is facilitated by higher electron density of Pd, and in general, σ -donor ligands such as R3 P attached to Pd facilitate oxidative addition. On the other hand, π -acceptor ligands such as CO and alkenes tend to suppress oxidative addition. A number of different polar and nonpolar covalent bonds are capable of undergoing the oxidative addition to Pd(0). The widely known substrates are C—X (X = halogen and pseudohalogen). Most frequently observed is the oxidative addition of organic halides of sp2 carbons, and the rate of the addition decreases in the following order; C-I > C-Br >>> C-Cl >>> F. Aryl fluorides are almost inert [33]. For a long time this order has been thought to be correct. Recently a breakthrough has occurred in the discovery of facile oxidative addition of sp2 C-Cl bonds by using electron-rich ligands such as P(t-Bu)3 or N -heterocyclic carbene ligands. Alkenyl, aryl halides, acyl halides and sulfonyl halides undergo oxidative

8

The Basic Chemistry of Organopalladium Compounds

addition. Diazonium salts and triflates, which undergo facile oxidative addition, are treated as pseudohalides in this book. It should be pointed out that some Pd-catalyzed reactions of alkyl halides, and even alkyl chlorides are emerging, indicating that facile oxidative addition of alkyl halides is occurring. Substrates with halogen bonds O

X

X RSO2

R

X

X

X

X = halogen, pseudo-halogen RCO-Cl + Pd(0)

RCO-Pd-Cl

The following compounds with H-C and H-M
bonds undergo oxidative addition to form Pd hydrides. Reactions of terminal alkynes and aldehydes are known to start by the oxidative addition of their C-H bonds. The reaction, called ‘orthopalladation’, occurs on the aromatic C—H bond in 3 at an ortho position of such donor atoms as N, S, O and P to form a Pd—H bond and palladacycles. Formation of aromatic palladacycles is key in the C—H bond activation in a number of Pdcatalyzed reactions of aromatic compounds. Some reactions of carboxylic acids and active methylene compounds are described as starting by oxidative addition of their acidic O—H and C—H bonds. Hydrogen ligands on transition metals, formed by oxidative additions, are traditionally, and exclusively, called ‘hydrides’, whether they display any hydridic behavior or not. Thus Pd(0) is oxidized to H-Pd(II)-H by the oxidative addition of H2 . Substrates with hydride (hydrogen) bonds O H

H

R3Si

H

R3Sn

H

R2B

H

R R

H

H

H

Pd-H

PdLn

A

A 3 E R

C

H

PdLn

E R

C

Pd-H

RCO2

H

PdLn

RCO2

Pd-H

E

E E = EWG

Metal–metal bonds M
-M
, such as R2 B-BR2 and R3 Si-SiR3 , undergo oxidative addition by cleaving the M
-M
bond (where M
represents a main group metal).

Fundamental Reactions of Pd Compounds

9

Substrates with metal−metal bonds R3Si-SiR3 RM′

R2B-BR2

R3Sn-SnR3

M′R + Pd

R3Sn-SiR3

oxidative addition

etc.

RM′-Pd-M′R

An N-O bond in oxime derivatives undergoes oxidative addition to form a Pd-imino bond. New Pd-catalyzed reactions of oximes, such as the amino Heck reaction, have been discovered (see Chapter 3.2.10) [34]. O

N R

R′

+

N

Pd

O R′

Pd(0) R

R

R

Oxidative addition involves cleavage of the covalent bonds as described above. In addition, oxidative addition of a broader sense occurs without bond cleavage. For example, π -complexes of alkenes and alkynes are considered to form η2 complexes2 by oxidative addition. Two distinct Pd—C bonds are formed, and the resulting alkene complexes are more appropriately described as the palladacyclopropane 4 and the alkyne complex may be regarded as the palladacyclopropene 5. Thus the coordination of the alkene and alkyne results in formal oxidation of Pd. The palladacyclobutane 6 is formed by the oxidative addition of cyclopropane with bond cleavage. R R

R′

R′ R

+ Pd

R′ Pd

Pd

4 R

R

R

R′ + Pd

R′

R′

Pd

Pd 5

+ Pd Pd 6

Oxidative cyclization is another type of oxidative addition without bond cleavage. Two molecules of ethylene undergo Pd-catalyzed addition reactions. Intermolecular reaction is initiated by π -complexation of the two double bonds, followed by cyclization to form the palladacyclopentane 7. This is called oxidative cyclization. The oxidative cyclization of 1,6-diene affords the palladacyclopentane 8, which undergoes further transformations. Similarly, the oxidative cyclization of α,ω-enyne affords the palladacyclopentene 9. Formation of these five-membered rings occurs stepwise and can be understood in terms of the formation of either palladacyclopropene or palladacyclopropane. Then the inter- and intramolecular 2 The prefix ηn (hapto n) is used in front of the ligand formula to imply bonding to n carbons and to specify the number of carbon atoms that interact with the Pd center.

10

The Basic Chemistry of Organopalladium Compounds

insertions of alkene to the three-membered rings produces the palladacyclopentane 7 and palladacyclopentene 9. In the reaction of acetylene with Pd(0), palladacyclopropene 10 is generated and subsequent intermolecular insertion of acetylene provides palladacyclopentadiene 11. Oxidative cyclization Pd

+ Pd

Pd 7

+ Pd

Pd

Pd 8

+ Pd

Pd

Pd 9

+ Pd

Pd Pd 11

10

The term oxidative cyclization is based on the fact that two-electron oxidation of Pd(0) occurs by cyclization. The same reaction is sometimes called ‘reductive cyclization’, which may be a source of confusion. This term comes from organic chemistry and is based on the formal change in alkene or alkyne bonds, since the alkene double bond is ‘reduced’ to the alkane bond, and the alkyne bond is ‘reduced’ to the alkene bond by the cyclization. A number of Pd-catalyzed cyclizations of alkynes and alkenes are known and they proceed by oxidative cyclization. Thus both ‘oxidative’ and ‘reductive’ cyclizations are used for the same process. In cyclization of conjugated dienes, typically butadiene, coordination of two molecules of butadiene gives rise to the bis-π -allyl complexe 12. The distance between the terminals of two molecules of butadiene becomes closer by π -coordination to Pd(0), and the oxidative cyclization is thought to generate either the 1-pallada-2,5-divinylcyclopentane 13 or 1-pallada-3,7-cyclononadiene 14.

Pd(0)

oxidative cyclization

Pd

12

Pd

13

Pd

14

Similar to the formation of allylmagnesium halide, the oxidative addition of allyl halides to Pd(0) complexes generates allylpalladium complexes 15. However, in the latter case, the π -bond is formed by the donation of π -electrons of the double bond, and resonance of the σ -allyl and π -allyl bonds in 15 generates the π allyl complex 16 or η3 -allyl complex. The carbon–carbon bond in the π -allyl

Fundamental Reactions of Pd Compounds

11

complexes is the same length as that in benzene. The allyl Grignard reagent is prepared by reaction of an allyl halide with Mg metal. However, π -allylpalladium complexes are prepared by oxidative addition of not only allylic halides, but also esters of allylic alcohols (carboxylates, carbonates, phosphates), allyl aryl ethers and allyl nitro compounds. Typically, the π -allylpalladium complex is formed by the oxidative addition of allyl acetate to Pd(0) complex. Cl

+

MgCl

Mg(0) L

X

+

Pd

L

Pd

Ln

Pd X

X 15

16

X = Cl, Br, −OAc, −OCO2R, −OP(O)(OR)2, OPh, NO2 OAc

+

OAc

oxidative addition

Pd

Pd(PPh3)4

PPh3

+ 3 PPh3

1.3.2 Insertion Reaction of Grignard reagents with carbonyl groups can be understood as an insertion of an unsaturated C=O bond of the carbonyl groups into the Mg–carbon bond to form Mg alkoxide. Similarly, various unsaturated ligands such as alkenes, alkynes and CO formally insert into an adjacent Pd–ligand bond in Pd complexes to give 17. The term ‘insertion’ is somewhat misleading. The insertion should be understood as the migration of the adjacent ligand from the Pd to the Pd-bound unsaturated ligand. The reaction below is called ‘insertion’ of an alkene to a ArPdX bond mainly by inorganic chemists. Some organic chemists prefer to use the term ‘carbopalladation’ of alkenes. CH3 Mg-I CH3 C

CH3 Mg I

O

CH3 C

CH3 X

Pd Y

A

B

O

CH3 Insertion (migration)

X

Pd Y

A

B 17

Ar-Pd-X

+

R

carbopalladation or insertion

R X-Pd

Ar

The insertion is reversible. Two types of the insertion are known. They are α,β(or 1,2-) and α,α-(or 1,1-) insertions. Most widely observed is the α,β-insertion of unsaturated bonds such as alkenes and alkynes. The following unsaturated bonds undergo α,β-insertion: The insertion of alkene to Pd-H, which is called ‘hydropalladation’ of an alkene, affords the alkylpalladium complex 18, and insertion of alkyne to Pd-R bonds

12

The Basic Chemistry of Organopalladium Compounds C

O C

O

C

N

N

S C

O

S

forms the vinylpalladium complex 19. The reaction can be understood as the ‘ciscarbopalladation’ of alkynes. The π -allyl complex is formed by the reaction of conjugated dienes with Pd complexes. The insertion of one of the double bonds of butadiene to the Ph-Pd bond leads to the π -allylpalladium complex 20. R

+

Pd H

Pd CH2CH2-R 18

+

Pd R

R1

R1

R2

R

Pd

R2 19 Ph

Ph

Pd X

Ph

+ Pd-X

Pd X 20

Rates of insertion are controlled by several factors. Firstly, the insertion of an alkene to a Pd complex is faster when a cationic complex is used. The addition of a Ag salt to a chloro complex generates a cationic complex and hence the insertion is accelerated probably owing to facile coordination of the alkene. For insertion (migration), cis coordination is necessary. Thus the trans-acyl-alkene complex 21 must be isomerized to a rather unstable cis complex 22 to give the insertion product 23. Secondly coordination of a bidentate ligand forms the cis complex 24 L L

R′

R′

Pd COR

COR

Pd L R′

Pd L

L

L

21

22

O R 23

Ph

Ph

Ph P

COR Pd Ph

Ph P

COR Pd

NC-Me

P Ph

+

R′

Ph

Ph P

MeCN

R′

P Ph

Ph 24

R′ Pd

P Ph

O Ph

R

Fundamental Reactions of Pd Compounds

13

by chelation, and the insertion is possible without trans to cis isomerization. This effect explains partly an accelerating effect of bidentate ligands, which force the cis coordination of reacting molecules. CO is a representative species which undergoes the α,α-insertion. Its insertion to a Pd-carbon bond affords the acylpalladium complexes 25. The CO insertion is understood to occur by migration of an alkyl ligand in 26 to a coordinated CO. Mechanistically the CO insertion is regarded as 1,2-alkyl migration to the cis-bound CO (migratory insertion). The migration is reversible and an important step in carbonylation. SO2 , isonitriles and carbenes are other species that undergo α,α-insertion.

X Pd R

+

a a

C

O

:C

a,a-insertion

O:

(migration)

CO

R O

R LnPd

X Pd

25

R LnPd

C O

26

Both Mg and Pd complexes similarly undergo oxidative addition and insertion. Whereas the main reaction path of Grignard reagents is insertion of a carbonyl group, the Pd complexes can undergo both oxidative addition and insertion with a variety of π -bonds. In addition, it should be emphasized that the insertion can occur sequentially several times. For example, insertion of an alkene to a Pd-C or Pd-H bond affords the alkyl complex 27, and is followed by CO insertion to generate the acyl complex 28. Sometimes, further insertions of alkene and CO take place. Particularly useful is the formation of polycyclic compounds by sequential intramolecular insertions of several alkenyl and alkynyl bonds. Several C-C bonds are formed without adding other reagents and changing reaction conditions. These reactions are called either domino, cascade or tandem reactions. Among these terms, ‘domino’ is most common [35]. O X Pd H + RHC

CH2

alkene α,b-insertion

X Pd CH2CH2R 27

CO a,a-insertion

X Pd C

CH2CH2R

28

1.3.3 Transmetallation Organometallic compounds M
-R and hydrides M
-H of main group metals (M
= Mg, Zn, B, Al, Sn, Si, Hg) react with Pd complexes (A-Pd-X) formed by oxidative addition, and the organic group or hydride is transferred to Pd by substituting X with R or H. In other words, alkylation of Pd or hydride formation takes place and this process is called transmetallation. The driving force of transmetallation is ascribed to the difference in electronegativity of two metals, and the main group metal M
must be more electropositive than Pd for transmetallation to occur. The oxidative addition–transmetallation sequence is widely known. Reaction of benzoyl chloride with Pd(0) gives benzoylpalladium chloride (29), and subsequent

14

The Basic Chemistry of Organopalladium Compounds R A-Pd-X

+

Pd

Y-M-R

A

M = main group metal oxidative addition

O Ph

Cl

+ Pd(0)

Y M

A-Pd-R

+ Y-M-X

X MeSnBu3

O Ph

Pd Cl

Bu3SnCl

transmetallation

O Ph

29

Pd Me 30

O reductive elimination

Ph

Me

+ Pd(0)

transmetallation with methyltributyltin generates benzoylmethylpalladium (30). Formation of acetophenone by the reductive elimination of 30 is a typical example. 1.3.4 Reductive Elimination Similar to ‘oxidative’, the term ‘reductive’ used in organometallic chemistry has a different meaning from reduction in organic chemistry. Reductive elimination is a unimolecular decomposition pathway, and the reverse of oxidative addition. Reductive elimination (or reductive coupling) involves loss of two ligands of cis configuration from the Pd center in 31, and their combination gives rise to a single elimination product 32. In other words, coupling of two groups coordinated to Pd liberates the product 32 in the last step of a catalytic cycle. By reductive elimination, both the coordination number and the formal oxidation state of Pd(II) are reduced by two units to generate Pd(0), and hence the reaction is named ‘reductive’ elimination. The regenerated Pd(0) species undergo oxidative addition again. In this way, a catalytic cycle is completed by a reductive elimination step. No reductive elimination occurs in Grignard reactions. Without reductive elimination, the reaction ends as a stoichiometric one. This is a decisive difference between the reactions of Pd complexes and main group metal compounds. For example, in a carbonylation reaction, the acylpalladium complex 33, formed by the insertion of CO, undergoes reductive elimination to give ketone 34 as a product, and Pd(0) as a catalytic species is regenerated.

X

A

B 31

Pd(II)

reductive elimination

Y

X

A

B

+

Pd(0)

32 O

O RCH2CH2

Y

Pd(II) R

RCH2CH2

R + Pd(0)

34

33

The reductive elimination of A-B proceeds if A and B are mutually cis. In other words, reductive elimination is possible from cis-complexes. If groups to be eliminated are trans oriented, they must first rearrange to cis. The cis-diethyl complex

Fundamental Reactions of Pd Compounds

15

35 gives butane, whereas ethylene and ethane are formed from the trans-diethyl complex 36 via β-H elimination to generate the Pd hydride 37, and lead to its reductive elimination [36]. It is understandable that bidentate ligands of large bite angles help favor reductive elimination. Reductive elimination of the Pd-C(sp2 ) bond is faster than that of the Pd-C(sp3 ) bond. Thus the reductive elimination of cis-PdMe(Ph)(PEt2 Ph)2 (38) proceeds rapidly at room temperature, whereas heating is necessary for the generation of ethane from cis-PdMe2 (PEt2 Ph)2 (39). Reduced electron density of Pd promotes reductive elimination, and addition of strong π -accepter ligands, such as CO and electron deficient alkenes, promotes reductive elimination. Also bulky ligands facilitate reductive elimination. C2H5 L

Pd

C2H5

C2H5

C2H5-C2H5 L

Pd

L

−L L

C2H5

C2H5

35

36

37

Et2PhP

CH3

rt

Pd Et2PhP

Et2PhP Ph

CH3 Pd

CH3 Et2PhP

Ph 38

C2H4 + C2H6

H

Pd

L

heat H3C

CH3

CH3 39 Me

L2Pd

~ ~

L2Pd

L2Pd

E2

1.3.5 β-H Elimination (β-Elimination, Dehydropalladation) Another termination step in a catalytic cycle is syn elimination of hydrogen from carbon at β-position to Pd in alkylpalladium complexes to give rise to Pd hydride (H-Pd-X) and an alkene. This process is called either ‘β-hydride elimination’ or ‘βhydrogen elimination’. Most frequently used is ‘β-hydride elimination’, because the β-H is eliminated as the Pd-hydride (H-Pd-X). The proper and unambiguous term of this process is ‘dehydropalladation’ in a cis manner. This is somewhat similar to a E1 or E2 reaction in organic chemistry, althought it is anti elimination. Organic chemists, particularly synthetic organic chemists including myself, prefer to use arrows in mechanistic discussion of organic reactions to show formation and fission of bonds. When arrows are used, the direction of the arrow is important. An E1 or E2 reaction may be simply stated. Dehydropalladation may be explained similarly, because Pd-X is regarded as a leaving group. E2 base

H R

H

R

+

H-X

X

However, we must consider ‘dehydropalladation’ from a different point of view, although it may cause some confusion. The β-H is eliminated as a hydride by

16

The Basic Chemistry of Organopalladium Compounds

dehydropalladation to form H-Pd(II)-X (Pd hydride) and an alkene, the latter being in coordination to the Pd center to form 40. A hydrogen ligand on Pd is traditionally called a ‘hydride’. This is the reason why the reaction is called ‘β-hydride elimination’. Finally H-Pd(II)-X affords Pd(0) and HX by reductive elimination in the presence of a base. Thus the β-H elimination is expressed by an equation, in which arrows show different directions. If H-Pd-X is not scavenged quickly by a base, the reverse insertion of alkene to give alkylpalladium may occur. In this book, β-H elimination, or simply β-elimination is used. Insertion of alkene to a Pd hydride to form alkylpalladium and elimination of β-H from the alkylpalladium are reversible steps. The β-H elimination generates an alkene. Both the hydride and the alkene coordinate to Pd as shown by 40, increasing the coordination number of Pd by one. Therefore, the β-H elimination requires coordinative unsaturation of Pd complexes. The β-H to be eliminated should be cis to Pd. R H

R

H

Pd

R

+

H-Pd(II)-X

X H-Pd-X 40 Pd(0) + HX

H-Pd(II)-X

Alcohols are oxidized by Pd(II) species. In this case, carbonyl compounds are formed by the β-H elimination from the Pd alkoxides 41, and the reactions may be expressed by either 41 or 41a. R′ R H

R′ O

Pd X

O

+

Pd(0) + HX

O

+

H-Pd-X

R 41

R′ R H

R′ O

Pd X R

41a Pd + HX

H-Pd-X

The reductive elimination and the β-H elimination are competitive. The β-H elimination takes place with trans dialkylpalladium complexes such as 36. The reductive elimination is favored by coordination of bidentate phosphine ligands which have larger bite angles (for the effect of bite angles, see van Leeuwen et al. [24]) to force other mutually cis ligands closer. Thus bidentate ligands of Ph

Ph

Ph

P M

q

M

q

q = bite angle

P

P Ph

Ph P

Ph

Ph

Ph

Fundamental Reactions of Pd Compounds

17

large bite angles, such as DPPF and DPPB and very bulky P(t-Bu)3 , accelerate the reductive elimination more easily than the bidentate DPPE and monodentate PPh3 . 1.3.6 Elimination of β-Heteroatom Groups and β-Carbon In addition to β-H, β-heteroatoms and even β-carbon are eliminated, although they are observed less extensively. Elimination of β-heteroatoms seems to be specific to Pd(II) complexes. When heteroatom groups (Cl, Br, OAc, OH, etc.) are present on β-carbon to Pd, their elimination with PdX takes place. Most importantly the Pd(II) species is generated by the elimination of the heteroatom groups. Thus Pd(II)catalyzed oxidative reactions become possible. For example, HO-Pd-X, which is a Pd(II) species, is formed by the elimination of β-OH. No reductive elimination to give Pd(0) and HO-X occurs. Usually elimination of β-heteroatoms is faster than that of β-H. R

R + Pd(II)XY

Y = Cl, Br, OAc, OH

Pd-X

Y

Pd(0) + X-Y

Pd(II)XY

PdCl2 -catalyzed addition reaction of allyl chloride to alkynes is explained by chloropalladation of a triple bond, followed by insertion of the double bond of allyl chloride to generate 43. No π -allyl complex is formed from allyl chloride and PdCl2 . The final step is elimination of β-Cl to afford 1-chloro-1,4-diene 44 with regeneration of Pd(II) [37]. As another example, the Pd(0)-catalyzed Heck reaction of vinyl acetate affords stilbene; in this reaction, the primary product is β-phenylvinyl acetate (45), which reacts again with iodobenzene, and the last step is elimination of β-OAc to give stilbene. At the same time, Pd(II) is generated, which is reduced to Pd(0) in situ [38]. However, elimination of β-heteroatoms is not always faster than that of β-H. For example, the Heck reaction of allyl alcohol with iodobenzene proceeds by preferential elimination of β-H from the insertion product 46 to afford aldehyde 47, and no elimination of β-OH from the same carbon occurs to give the alkene 48 [39,40].

R

Cl

+

Cl

R

PdCl2

Cl

ClPd

R Cl

PdCl

Cl 43

R + PdCl2

Cl 44 OAc

Ph-I +

OAc

Pd(OAc)2 Et3N

Ph

Ph-Pd-I

45

Ph + Ph

I-Pd(II)OAc

Pd(0)

I-Pd

OAc

Ph

Ph

18

The Basic Chemistry of Organopalladium Compounds Ph-I

+

R

Pd(0)

OH Pd-X

R

R

OH Ph 46

R

OH

CHO + H-Pd(II)-X Ph

Ph

H

47

Pd-X R

R

OH Ph

+ X-Pd(II)-OH Ph

H

48

46

Elimination of β-carbon is less common, but its examples are increasing (see Chapter 3.8.2). β-Carbon elimination can be expressed by the following general scheme: R1 R2

C

Pd-X

b-carbon elimination

R2 A + R1 Pd-X

A R3

R3 A= C

,

N

,

further reactions

O

In the following, examples of β-carbon elimination when A = O are shown. The reaction is observed in the Pd-catalyzed reaction of tert-alcohols. Conversion of tert-alcohols to ketones occurs via their Pd-alkoxides 49 and the reaction can be understood by elimination of β-carbon. Fission of a carbon–carbon bond occurs. It should be noted that β-carbon elimination can be regarded as a reverse process of nucleophilic attack to the carbonyl group by R-Pd-X (see Chapter 3.7.2). As an example, Pd-catalyzed reaction of α,α-dimethylarylmethanol 50 with bromobenzene is explained by elimination of β-carbon of the arylpalladium alkoxide 51 to generate the diarylpalladium intermediate 52. Its reductive elimination affords 2-phenylbiphenyl (53) and acetone [41]. Similarly, Pd(II)promoted reaction of the cyclobutanol 54 to give the unsaturated ketone 56 can be understood by elimination of β-carbon from 55 and subsequent β-H elimination [42]. R1 R2

C

O

Pd-X b-carbon elimination

b-H elimination

R2 O +

R1 Pd-X

R3

R3

reductive elimination

49 R2 O + R3

R1 Pd-X

R1

nucleophilic attack to carbonyl group R2

C R3 49

Pd-X O

Fundamental Reactions of Pd Compounds

19

Br Pd(0)

+

Me

Me Me

OH

O

Me

Pd

51

50

b-carbon elimination

Me

Me Pd

+

O

53

52 O O

OH PdX2

Me

Me

Pd-X

b-carbon elimination

Me Pd-X

54

H

55

O

Pd(0) HX

56

1.3.7 Electrophilic Attack by Organopalladium Species Many useful reactions which are entirely different from ordinary organic reactions can be achieved by using Pd complexes. Effect of the coordination is remarkable. Unsaturated organic compounds such as CO, alkenes and alkynes are rather unreactive towards nucleophiles because they are electron rich. However, their reactivity is inverted when these unsaturated molecules coordinate to electron deficient Pd. This is a noteworthy effect of the coordination. Reaction of nucleophiles with the coordinated unsaturated bonds is one of the most characteristic and useful reactions of Pd complexes. Particularly complexes having strong π -acceptor ligands typically CO or cationic complexes are highly electrophilic and accept nucleophiles. Mechanistically, some nucleophiles attack the ligand after coordination to the metal, and the process is understood as the insertion of the ligand. Also, direct attack of nucleophiles on the ligand is possible. Various nucleophiles attack coordinated alkenes. Typically attack of the OH anion on ethylene coordinated to Pd(II), as shown by 57, takes place in the Wacker process to afford acetaldehyde [43]. Also, the COD complex of PdCl2 58 was

20

The Basic Chemistry of Organopalladium Compounds _ OH H2C

H2C

CH2

H2C +

H2O

O

H

Cl Cl

Cl

Cl

C H

Pd

Pd

Pd Cl

H

CH2

57 hydride shift

CH3CHO +

Pd(0)

+

HCl _ CH(CO2Et)2

CH(CO2Et)2

CH2(CO2Et)2 NaH

Pd

Pd Cl

Cl

Cl

Pd

Cl

Cl

58

59

shown to be attacked by carbon nucleophiles such as malonate anion to give 59. This reaction is the first example of carbopalladation of coordinated alkenes [44]. Attack of carbon nucleophiles such as malonate anion to π -allylpalladium 60 to give allylmalonate 61 is well-known [45]. Pd in the π -allyl complex 60 accepts two electrons by the nucleophilic attack, and is reduced to Pd(0) directly or indirectly. Generation of Pd(0) offers a chance to undergo oxidative addition again. The reduction of Pd(II) to Pd(0) is an essential step for catalytic cycles. Pd is a noble metal and Pd(0) is more stable than Pd(II). In this respect, Pd is very unique. In contrast, the attack of an electrophile such as aldehyde 63 on allyl compounds of Mg or Ni complex 62 proceeds to give homoallyl alcohol 64 and to generate oxidized metal ions Mg(II) or Ni(II), which cannot constitute catalytic cycles.

OAc

_ CH(CO2Me)2

OAc + Pd(0)

Pd

+ CH2(CO2Me)2

Pd OAc

60

CO2Me Pd(0) +

CO2Me 61

Recently Pd-catalyzed reactions of aryl halides, which can be formally understood as electrophilic attacks by arylpalladium halides 65, are rapidly emerging. Arylation of cyclohexanone to afford 2-phenylcyclohexanone (66) (see Chapter 3.7.1) and formation of arylamines 67 (see Chapter 3.7.2) are typical examples. One explanation of intramolecular attack on an aromatic ring in 68 to form biaryl 70 is electrophilic attack of 69 on an aromatic ring, although the mechanism may not be so simple. A detailed discussion is given in Chapter 3.3.

Fundamental Reactions of Pd Compounds

21

O Cl

Cl +

Ni(0)

R

RCHO

Ni

H Ni

62

Cl

63

OH + Ni(II)

R 64

O O

X

Pd-X

Pd(0)

66 NHR

RNH2 65 67 X Pd(0) A

B

R

68

Pd-X

A

B

R

R A

69

B

70

Recently Yamamoto reported Pd-catalyzed intramolecular nucleophilic addition of the arylpalladium bromide 72 formed from 71 to ketone to give the alcohol 73 using PCy3 as a ligand and an excess of 1-hexanol. This is the first example of a Pd-catalyzed Grignard-type reaction [46]. O O

Pd(OAc)2, PCy3 Na2CO3, DMF Ph

Br 71

1-hexanol 135 °C, 69%

Ph Pd Br

Ph

72

OH

73

1.3.8 Termination of Pd-Catalyzed or -Promoted Reactions and a Catalytic Cycle Grignard reactions proceed via oxidative addition and insertion. The reaction product 75 is isolated after hydrolysis of the insertion product 74 with dilute aqueous HCl, giving MgCl2 , and it is practically impossible to reduce the generated Mg(II)

22

The Basic Chemistry of Organopalladium Compounds

to Mg(0) in situ, and hence the Grignard reaction is stoichiometric. In other words, Mg(0) is oxidized to Mg(II) by the Grignard reaction. However, the reactions involving Pd(0) complexes proceed with a catalytic amount of Pd(0) compounds in many cases whenever they are attacked by nucleophiles. Me Me

HCl, H2O O-Mg-I

Me Me

OH

Me

Me

74

75

+

MgCl2

The catalytic reactions which can be carried out with a small amount of expensive Pd complexes is the most useful feature of synthetic reactions involving Pd complexes. In the catalytic reactions, an active catalytic species must be regenerated in the last step of the reactions. Reductive elimination and β-H elimination are two key reactions that regenerate the catalytic species, making the whole reaction catalytic. As shown in the following general scheme, the catalytic cycle of the Pd(0) catalyst is understood by a combination of the aforementioned unit reactions. The oxidative addition of R-X affords 76 which undergoes either transmetallation to give 77 or insertion to generate 78. The reductive elimination of the reaction product 79 from 77 occurs and regenerates Pd(0), which undergoes oxidative addition to afford 76 and starts the new catalytic cycle, then subsequent insertion gives 78 or transmetallation affords 77. The β-H elimination of the product 81 from 78 gives H-Pd-X 80, from which the Pd(0) catalytic species is formed. The Pd hydride 80 itself also serves as a catalytic species through insertion of alkenes. The ability of Pd to undergo facile shuttling between two oxidation states contributes to make the reactions catalytic. H-X

Pd(0)

Catalytic cycle

reductive elimination R-R′′

R′

H-Pd-X

79

A

80

B 81

R-X (H-X) reductive elimination

b-H elimination oxidative addition H A=B transmetallation

R-Pd-R′′

R-Pd-X

77

76 M′-X

M′-R′′

R-A-B-Pd-X insertion

H

78

As a typical example of the catalytic cycle, phenyldiazonium salt 82 undergoes oxidative addition, followed by CO insertion to afford the acylpalladium intermediate 83. Then transmetallation with triethylsilane generates 84 and benzaldehyde

Fundamental Reactions of Pd Compounds

23

is obtained by reductive elimination [47]. Another example is the reaction of iodobenzene with acrylate to give cinnamate via oxidative addition, insertion and β-H elimination (Heck reaction). O N2BF4 + Pd(0)

oxidative addition

Pd-X

Pd-X

CO insertion

82

83 O

O Et3SiX

Et3SiH

H

Pd

reductive elimination

C

H

+ Pd(0)

transmetallation 84

CO2Me

oxidative addition

Ph-I + Pd(0)

H

Pd-I

Ph-Pd-I insertion

b-H elimination

Ph

reductive elimination

Ph +

H-Pd

I

CO2Me

Pd(0) + HI

CO2Me

1.3.9 Reactions Involving Pd(II) Compounds and Pd(0) Complexes Organic reactions involving Pd are classified into oxidative reactions with Pd(II) salts and catalytic reactions with Pd(0) complexes. Pd(II) salts [PdCl2 , Pd(OAc)2 ] are unique oxidizing or dehydrogenating reagents. The reactions promoted by Oxidative (dehydrogenative) reactions with Pd(II) compounds A-H + B-H + PdX2

A-B + Pd(0) + 2 HX

Pd(0) + 2 HX + 1/2 O2 A-H + B-H + 1/2 O2

[OX]

PdX2 [OX]

PdX2 + H2O A-B + H2O

examples H H2C

+ AcOH + 1/2 O2

C

H

Pd(II) H2C

H

+

C

H2O

OAc

H + H

+ 1/2 O2

Pd(II)

+ H2O

24

The Basic Chemistry of Organopalladium Compounds Pd(0)-catalyzed reactions Pd(0)

Ar-X + B-H

Ar-B + HX

examples

R X

H

R

+

Pd(0)

+ HX

H

R

X

+ Pd(0)

Ar-X + RM′Y

Nu-H

Pd(0)

R

Nu

+ HX

Ar-R + M′XY

example X

Y2B +

Pd(0) R

R

+ BY2X

Pd(II) can be expressed by the following general schemes. As a whole, two hydrogens are abstracted from two substrates A-H and B-H, generating Pd(0) and the product A-B. This reaction is stoichiometric with Pd(II), but the reaction becomes catalytic when Pd(0) is oxidized in situ to Pd(II) with appropriate oxidants (OX), and the whole reaction can be summarized by a third equation. For example, formation of vinyl acetate from ethylene and oxidative coupling of benzene can be understood formally as dehydrogenation reactions. These oxidative reactions using Pd(II) are considered in Chapter 2. The Pd(0)-catalyzed reactions of Ar-X and B-H (or B-Y) can be expressed by the following general equations, which involve no oxidation. The Mizoroki–Heck reaction, allylation of nucleophiles, and cross-couplings are typical reactions of this type. They are treated in Chapters 3–8. A clear understanding that these two types of reactions involving Pd(II) and Pd(0) are mechanistically quite different is required before studying organopalladium chemistry.

References 1. F. Ozawa, A. Kubo, and T. Hayashi, Chem. Lett., 2177 (1992); T. Hayashi, A. Kubo, and F. Ozawa, Pure Appl. Chem., 64, 421 (1992). 2. T. Mandai, T. Matsumoto, J. Tsuji, and S. Saito, Tetrahedron Lett., 34, 2513 (1993). 3. S. Otsuka, T. Yoshida, M. Matsumoto, and K. Nakatsu, J. Am. Chem. Soc., 98, 5850 (1976); Inorg. Syn., 28, 113 (1990). 4. C. Dai and C. Fu, J. Am. Chem. Soc., 123, 2719 (2001). 5. T. Ukai, H. Kawazura, Y. Ishii, J. J. Bennett, and J. A. Ibers, J. Organomet. Chem., 65, 253 (1974). 6. M. Beller, H. Fischer, K. K¨uhlen, C. P. Reisinger, and W. A. Herrmann, J. Organomet. Chem., 520, 257 (1996). 7. M. T. Reetz and E. Westermann, Angew. Chem. Int. Ed., 39, 165 (2000). 8. I. W. Davies, L. Matty, D. L. Hughes, and P. J. Reider, J. Am Chem. Soc., 123, 10139 (2001). 9. ‘The Strem Chemiker’, Strem Chemicals, Inc., USA.

References

25

10. C. B. Ziegler and R. F. Heck, J. Org. Chem., 43, 2941 (1978). ¨ 11. W. A. Herrmann, C. Brossmer, K. Ofele, C. P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 34, 1844 (1995). 12. T. Yamamoto, M. Nishiyama, and Y. Koie, Tetrahedron Lett., 39, 617, 2367 (1998). 13. M. H. Ali and S. L. Buchwald, J. Org. Chem., 66, 2560 (2001) and references cited therein. 14. M. R. Netherton and G. C. Fu, Org. Lett., 3, 4295 (2001). 15. Reviews, W. A. Herrmann, and C. W. Kohlpaintner, Angew. Chem. Int. Ed. Engl., 32, 1524 (1993); J. P. Genet and M. Savignac, J. Organomet. Chem., 576, 305 (1999). 16. G. Peiffer, S. Chan, A. Bendayan, B. Waegell, and J. P. Zahra, J. Mol. Catal., 59, 1 (1990). 17. M. Feuerstein, D. Laurenti, H. Doucet, and M. Santelli, Synthesis, 2320 (2000). 18. Preparative method: T. J. Hutleman, J. Inorg. Chem., 4, 950 (1965). 19. G. Y. Li, Angew. Chem. Int. Ed. 40, 1513 (2001); J. Org. Chem., 67, 3643 (2002); G. Y. Li, G. Zhang, and A. F. Noonan, J. Org. Chem., 66, 8677 (2001). 20. A. J. Arduengo, Acc. Chem. Res., 32, 913 (1999). 21. D. Bourissou, O. Guerret, F. P. Gabbai, and G. Bertrand, Chem. Rev., 100, 39 (2000). 22. Review: W. A. Herrmann, Angew. Chem. Int. Ed., 41, 1290 (2002). 23. Reviews: T. Welton, Chem. Rev., 99, 2071 (1999); P. Wasserscheid and W. Keim, Angew. Chem. Int. Ed., 39, 3772 (2000). 24. P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, and P. Dierkes, Chem. Rev., 100, 2741 (2000). 25. C. A. Parrish and S. L. Buchwald, J. Org. Chem., 66, 3820 (2001). 26. Y. Uozumi and K. Shibatomi, J. Am. Chem. Soc., 123, 2919 (2001). 27. Commercially available from Johnson Matthey Chemicals as ‘FibreCat’. 28. R. Akiyama and S. Kobayashi, Angew. Chem. Int. Ed., 40, 3469 (2001). 29. J. Cortes, M. Moreno-Manas, and R. Pleixats, Eur. J. Org. Chem., 239 (2000). 30. Review on Pd-catalyzed reactions in solid phase synthesis: S. Br¨ose, J. H. Kirchhoff, and J. K¨obberling, Tetrahedron, 59, 885 (2003). 31. Review on recovery of catalysts: J. A. Gladysz (Ed.), Chem. Rev., 102, No. 10 (2002). 32. R. D. Larsen, A. O. King, C. Y. Chen, E. G. Corley, B. S. Foster, F. E. Roberts, C. Yang, D. R. Lieberman, R. A. Reamer, D. M. Tschaen, T. R. Verhoeven, and P. J. Reider, J. Org. Chem., 59, 6393 (1994). 32a. Review on mechanistic studies: C. Amatore and A. Jutand, J. Organomet. Chem., 576, 254 (1999). 33. V. C. Grushin, Chem. Eur. J., 8, 1007 (2002). 34. M. Kitamura, S. Zaman, and K. Narasaka, Synlett, 974 (2001). 35. L. F. Tietze, Chem. Rev., 96, 115 (1996). 36. F. Ozawa, T. Ito, and A. Yamamoto, J. Am. Chem. Soc., 102, 6457 (1980). 37. K. Kaneda, T. Uchiyama, Y. Fujiwara, T. Imanaka, and S. Teranishi, J. Org. Chem., 44, 55 (1979). 38 A. Kasahara, T. Izumi, and N. Fukuda, Bull. Chem. Soc. Jpn., 50, 551 (1977). 39. J. B. Melpolder and R. F. Heck, J. Org. Chem., 41, 265 (1976). 40. A. J. Chalk and S. A. Magennis, J. Org. Chem., 41, 273, 1206–(1976). 41. Y. Terao, H. Wakui, T. Satoh, M. Miura, and M. Nomura, J. Am. Chem. Soc., 123, 10407 (2001). 42. T. Nishimura, K. Ohe, and S. Uemura, J. Am. Chem. Soc., 121, 2645 (1999). 43. J. Smidt, W. Hafner, R. Jira, R. Sieber, and J. Sedlmeier, Angew. Chem. Int. Ed. Engl., 2, 80 (1962). 44. J. Tsuji and H. Takahashi, J. Am. Chem. Soc., 87, 3275 (1965); 90, 2387 (1968). 45. J. Tsuji, H. Takahashi, and M. Morikawa, Tetrahedron Lett., 4387 (1965). 46. L. G. Quo, M. Lamrani, and Y. Yamamoto, J. Am. Chem. Soc., 122, 4827 (2000). 47. K. Kikukawa, T. Totoki, F. Wada, and T. Matsuda, J. Organomet. Chem., 270, 283 (1984).

26

The Basic Chemistry of Organopalladium Compounds

Books3 A number of books and monographs treating organopalladium chemistry have been published as listed below. Particularly, there is an excellent encyclopedia of organopalladium chemistry, edited by E. Negishi, which was published in 2002 [9]. The book is 3279 pages long, covering all reactions either catalyzed or promoted by Pd(0) and Pd(II) compounds reported before 2000 and including ample experimental data and references. The Handbook is not only useful but also monumental in organopalladium chemistry. On Palladium Chemistry 1. P. M. Maitlis, The Organic Chemistry of Palladium, Vols 1 and 2, Academic Press, New York, 1971. 2. J. Tsuji, Organic Synthesis with Palladium Compounds, Springer, Berlin 1980. 3. P. M. Henry, Palladium Catalyzed Oxidation of Hydrocarbons, D. Reidel, Rordrecht 1980. 4. B. M. Trost and T. R. Verhoeven, Organopalladium Compounds in Organic Synthesis and in Catalysis, in Comprehensive Organometallic Chemistry, Pergamon Press, Oxford, 1982, Vol. 8, p. 799. 5. R. F. Heck, Palladium Reagents in Organic Syntheses, Academic Press, New York, 1985. 6. J. Tsuji, Palladium Reagents and Catalysts, Wiley, Chichester, 1995. 7. J. Tsuji (Ed.), Perspectives in Organopalladium Chemistry for the XXI Century, Elsevier, Amsterdam 1999; J. Organomet. Chem., 576 (1999). 8. J. J. Li and G. W. Gribble, Palladium in Heterocyclic Chemistry, Pergamon Press, Oxford, 1999. 9. E. Negishi (Ed.), Organopalladium Chemistry for Organic Synthesis, Wiley, New York, 2002, Vols I and II.

On Organometallic Chemistry Applied to Synthesis 1. J. P. Collman, L. S. Hegedus, J. R. Norton, and R. G. Finke, Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, CA, 1987. 2. P. J. Harrington, Transition Metals in Total Synthesis, Wiley, New York, 1990. 3. F. J. McQuillin, Transition Metals Organometallics for Organic Synthesis, Cambridge University Press, Cambridge, 1991. 4. H. M. Colquhoun, D. J. Thompson, and M. V. Twigg, Carbonylation, Plenum Press, New York, 1991. 5. L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules, 2nd Edn, University Science Books, Mill Valley, CA, 1999. 6. S. Murahashi and S. G. Davies (Eds), Transition Metal Catalyzed Reactions, Chemistry for the 21st Century, Blackwell Science, Oxford, 1999. 7. J. Tsuji, Transition Metal Reagents and Catalysts, Innovations in Organic Synthesis, Wiley, Chichester, 2000.

3 These book references are not cited in the text.

Chapter 2 Oxidative Reactions with Pd(II) Compounds

2.1 Introduction Pd(II) salts, typically PdCl2 and Pd(OAc)2 , are unique oxidizing reagents, and there are many useful oxidation reactions (dehydrogenation reactions) specific to Pd(II) salts. After the oxidation of organic substrates with Pd(II) is completed, Pd(II) is reduced to Pd(0). If a stoichiometric amount of expensive Pd(II) salts is consumed, the reaction can not be a truly useful synthetic method. It is possible to make the reaction catalytic with respect to Pd(II) by oxidizing Pd(0) efficiently in situ to Pd(II) with some oxidants. There are several ways to regenerate Pd(II) in situ. The first example of the oxidation of an organic compound catalyzed by Pd(II) was achieved in 1959 by the Wacker process [1]. This is a commercial process to oxidize ethylene to acetaldehyde using PdCl2 and CuCl2 as catalysts in aqueous HCl. The process involves three unit reactions (Equations 2.1–2.3). The essence of the Wacker process is the invention of an ingenious catalytic cycle, in which reduced Pd(0) is reoxidized in situ to Pd(II) with CuCl2 (Equation 2.2). It is ingenious because the oxidation of Pd(0), a noble metal, with CuCl2 , a base metal salt, is expected to be very difficult. The CuCl is easily reoxidized to CuCl2 with oxygen (Equation 2.3). CH3CHO + 2 HCl + Pd(0)

(2.1)

Pd(0) + 2 CuCl2

PdCl2 + 2 CuCl

(2.2)

2 CuCl + 2 HCl + 1/2 O2

2 CuCl2 + H2O

(2.3)

CH3CHO

(2.4)

CH2

CH2 + H2O + PdCl2

CH2

CH2 + 1/2 O2

PdCl2 CuCl2

In this way, ethylene (or other organic compounds) is oxidized indirectly with oxygen without consuming PdCl2 and CuCl2 by the combination of these redox reactions. The catalytic oxidation of organic compounds with Pd(II) and an oxidant can be regarded formally as a dehydrogenation reaction as summarized in the schemes shown in Equations (2.5–2.7). In this dehydrogenation reaction, two hydrogens are abstracted from ethylene and water in the Wacker reaction Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

28

Oxidative Reactions with Pd(II) Compounds A-H + B-H + PdX2

A-B + Pd(0) + 2 HX [Ox]

Pd(0) + 2 HX + 1/2 O2 PdX2

A-H + B-H + 1/2 O2

+

H-OH

+

PdX2 + H2O

(2.6) (2.7)

A-B + H2O

[Ox]

H CH2

(2.5)

H

PdX2

+

CH2

1/2 O2

A-H R

H2O

OH

H

B-H

CH3CHO

H +

+

H

PdX2

(2.8)

A-B

R + H2O

1/2 O2

H

A-H

(2.9)

A-B

B-H

(Equation 2.8). Similarly oxidative coupling of an alkene with benzene can be understood as the dehydrogenation reaction (Equation 2.9). In addition to CuCl2 , several inorganic compounds such as Cu(OAc)2 , HNO3 and MnO2 are used as oxidants of Pd(0). Also benzoquinone (BQ), hydrogen peroxide and some organic peroxides are used. Alkyl nitrites are unique oxidants which are used in some industrial processes [2]. Efficient reoxidation of Pd(0) in some oxidation reactions with O2 alone without other reoxidants is possible in DMSO [3–5]. It was found that Pd(0) species formed in situ from Pd(II) in the presence of O2 are stabilized by DMSO as a ligand and easily oxidized to Pd(II) with oxygen [6]. DMSO is a favorable ligand and ligand-promoted direct oxidation of Pd(0) with oxygen takes place [7]. Pd(OAc)2 –pyridine (1 : 2) is a simple and efficient catalyst system, and some oxidative reactions proceed under oxygen without using other oxidants [8]. The oxidation of Pd(0) is explained by the following mechanism [9]. Oxygenation of a pyridine–Pd(0) complex produces the peroxopalladium(II) complex, which is converted to a Pd(II) complex and hydrogen peroxide by protonation.

(py)2Pd(0)

O2

O (py)2Pd

O

2 H-X

H2O2 + (Py)2PdX2

An important Pd(II)-generation step in Pd(II)-catalyzed reactions is the elimination of heteroatom groups such as Cl, Br, OAc and OH at β-position to Pd, and Pd(II) species are generated after the elimination. Elimination of heteroatom groups is faster than that of hydrogen. No reoxidant is required for this efficient catalytic reaction. Based on this reaction, 1,2-dichloro- and dibromoethane derivatives [10], α-halo ketones such as chloroacetone and desyl chloride are used for Pd(II) generation [11,12]. Another important Pd(II)-generation step is protonolysis with acids. For example, alkenylpalladium intermediates formed by palladation of alkynes with

Reactions of Alkenes

29

b-Heteroatom elimination R Y

R

Pd-X

Cl

Cl

+ Pd0)

+ Pd(II)XY

ClPd

Cl

Y = Cl, Br, OAc, OH

PdCl2 + H2C

CH2

Pd(II) are living species, because there is no possibility of β-H elimination. So Pd(II)X2 is generated from these Pd intermediates by protonolysis with HX, or oxidative halogenation with CuX2 . In such a case, the reaction proceeds with a catalytic amount of Pd(II) salt without reoxidants.

R

H-Y

R

H

+ Pd(II)XY

2 CuCl2

R

Cl

+ PdClX + 2 CuCl

H-Y = HCl, AcOH

Pd-X

One important method for the oxidation reaction using Pd(II) is a gas phase reaction using a solid Pd catalyst supported on active carbon or alumina. Actually vinyl acetate and allyl acetate are produced commercially in a gas phase by using the supported Pd catalyst. It is assumed that Pd(0) is oxidized efficiently to Pd(II) with oxygen on the surface of the support. Oxidative reactions of various organic compounds with Pd(II) are surveyed by further subdivisions based on substrates.

2.2 Reactions of Alkenes 2.2.1 Introduction Alkenes coordinate to Pd(II) compounds to form π -complexes. Roughly speaking, a decrease in electron density of alkenes by the coordination to electrophilic Pd(II) permits attack by various nucleophiles to the coordinated alkenes. In contrast, electrophilic attack is commonly observed with uncomplexed alkenes. Pd(II) is highly electrophilic and behaves as a very expensive and selective proton equivalent toward alkenes. The attack of nucleophiles with concomitant formation of a carbon—palladium σ -bond 1 is called palladation of alkenes. This reaction is similar to the mercuration reaction. However, unlike the mercuration products, which are stable and isolable, the product 1 of the palladation is usually unstable and undergoes rapid decomposition. The palladation reaction is followed by three reactions. Pd-X in 1 is a good leaving group. The β-H elimination from 1 to form the vinyl compounds 2 is one reaction path, resulting in the nucleophilic substitution of olefinic proton (path a). When the displacement of Pd-X in 1 with another nucleophile takes place, the nucleophilic addition to alkenes occurs to give 3 (path b). Another possibility is 1,2-hydride shift. When the nucleophile is the OH anion, the carbonyl group 4 is generated via hydride shift (path c). Depending on

30

Oxidative Reactions with Pd(II) Compounds R R

palladation + A-H + PdX2

X

H A

Pd

HX

1

R path a X

Pd

B−

X

2

R

B−

R A H

Pd

+ Pd(0) + HX A

1

path b

R

b-H elimination

A H

displacement

+ Pd(0) + HX B

A 3

1

A = OH

O

H

path c

H X

Pd

hydride shift

O R

+ Pd(0) + HX H3C

R 4

AH, BH = nucleophiles, H2O, ROH, RCO 2H, RNH2, CH2E2 (E = electron-withdrawing group)

reactants and conditions, either nucleophilic substitution of alkenes or nucleophilic addition to alkenes takes place with or without hydride shift. The reactions of water, alcohols and carboxylic acids with alkenes are explained by these three reaction paths. Formation of acetaldehyde from ethylene, water and PdCl2 is understood by the sequence of hydroxypalladation to form 5, followed by hydride shift. It has been confirmed that no incorporation of deuterium occurs by the reaction of ethylene with PdCl2 carried out in D2 O, and the four hydrogens in ethylene are retained in acetaldehyde, indicating that hydride shift occurs (path c) [1]. Therefore, free vinyl alcohol (6), expected to be formed by β-H elimination (path a), is not an intermediate (path c). In the presence of LiCl, 2-chloroethanol (7) is obtained by path b. Oxidation of ethylene in alcohol with PdCl2 in the presence of a base gives the acetal of acetaldehyde as a major product and vinyl ether as a minor product. Methoxypalladation is the first step. Then hydride shift is followed by attack of methoxy anion to form the acetal of acetaldehyde. No deuterium incorporation is observed in the acetal formed from ethylene and MeOD, indicating that the hydride shift takes place as shown by 8 (path c). Formation of methyl vinyl ether can be understood by β-H elimination. The β-H elimination is a main path with higher alkenes. Formation of vinyl acetate by the reaction of ethylene with Pd(OAc)2 can be understood by the acetoxypalladation and β-H elimination (path a). No hydride shift occurs because the acetoxy group is electron-attracting. In addition, ethylene glycol monoacetate (9) is formed as a nucleophilic addition product in the presence of nitrate anion (path b) [13]. Formation of glycol monoacetate is explained by the displacement of Pd-OAc with a nitrate anion, followed by hydrolysis of the nitrate ester.

Reactions of Alkenes

31 H

oxypalladation

CH2 + H2O + PdCl2

CH2

C

CH2

H

OH

Pd-Cl 5 H H

hydride shift C

CH2

O

O + Pd(0) + HCl

H H3C

H

Pd Cl

H b-H elimination C

CH2 Pd-Cl

OH

H

CH2

C H

OH 6

Cl− H displacement C

CH2 Pd-Cl

H

+ Pd(0) + HCl

Cl OH

OH 7

OD CH2

CH2

R

CH2 +

MeOH +

H H Pd

hydride H3C shift

Me

OR

R

OR

Me

RO

+

+ Pd(0) + 2HCl

R

OMe

Cl-Pd

base H3C O

Me

O

H

Me

CH3CH(OMe)2

H

Pd(0), HCl

8

OMe H

b-H elimination CH2

CH3CHO + Pd(0) + 2 DCl

methoxypalladation PdCl2

O Cl

CH2DCHO

H

CH2 + D2O + PdCl2

+ 2 ROH + PdCl2

CH2

C

CH2 + 2 MeOD + PdCl2

+ Pd(0) + HCl OMe CH3CH(OMe)2 + 2 DCl + Pd(0)

Typical nucleophiles known to react with the coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines and active methylene compounds [14]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds [15,16]. CO and aromatics also react with alkenes.

32

Oxidative Reactions with Pd(II) Compounds CH2

CH2

+

acetoxypalladation Pd(OAc)2

OAc

AcO-Pd H b-H elimination OAc

AcO-Pd

OAc

+ AcOH + Pd(0)

−ONO 2

LiNO3

1. displacement 2. hydrolysis

OAc

AcO-Pd

OAc

HO

+ HNO3

9

2.2.2 Reaction with Water Formation of acetaldehyde and metallic Pd by passing ethylene into an aqueous solution of PdCl2 was reported by Phillips in 1894 [17] and used for a quantitative analysis of Pd(II) [18]. The reaction was highlighted after the industrial process of acetaldehyde production from ethylene based on this reaction had been developed [1]. The Wacker process is carried out in aqueous HCl solution and low-boiling acetaldehyde is removed continuously by distillation. However, the oxidation of higher alkenes is carried out in organic solvents which can mix both alkenes and water. DMF is widely used as a solvent for this purpose. The oxidation is a useful synthetic method of producing ketones from alkenes and is used extensively [19]. Some organic compounds are used as stoichiometric oxidants. Benzoquinone is most widely used. The oxidation of higher alkenes in organic solvents proceeds under almost neutral conditions, and hence many functional groups such as ester or lactone, sulfonate, aldehyde, acetal and MOM ether are tolerated. The attack of OH obeys the Markovnikov rule. Higher alkenes are oxidized to ketones and this unique oxidation of alkenes has extensive synthetic applications [19]. The oxidation of terminal alkenes affords methyl ketones, which have widespread uses in organic synthesis. Based on this reaction, the terminal alkenes, which are stable to acids, bases and nucleophiles, can be regarded as masked methyl ketones. Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 can be prepared by the allylation

R

+

O

PdCl2 H2 O

CuCl2

R

Br

O

Me

PdCl2, CuCl, O2 O

O

H2O, DMF, 68%

O 10

base 85%

O

Reactions of Alkenes

BnO

O

O

33

O

BnO

O

O

O

PdCl2, H2O DMF, 45 °C, 60% H OBn

EDMSO

H OBn

O EDMSO

11 O

BnO

O

O

H OBn

EDMSO 12

of ketones followed by oxidation [20]. The reaction was successfully applied to a multifunctionalized complex skeleton of a taxoid. Oxidation of the allyl group in 11 is followed by in situ aldol condensation to afford the cyclohexenone 12 in 60 % yield [21]. 3-Acetoxy-1,7-octadiene (13), obtained by Pd-catalyzed telomerization of butadiene (see Chapter 5.1), is converted to 1,7-octadien-3-one (14) by hydrolysis and oxidation. The compound 14 is a useful bis-annulation reagent. Bis-annulation to form two fused six-membered ketones is a synthetic application of the enone 14 [22]. The Michael addition of 2-methyl-1,3-cyclopentanedione (15) to 14 and asymmetric aldol condensation using (S)-phenylalanine afford the optically active diketone 16. The terminal double bond is oxidized with PdCl2 -CuCl-O2 to give the methyl ketone 17 (76 % optical purity) in 77 % yield. Finally reduction of the double bond and aldol condensation produce the important intermediate 18 of steroid synthesis in optically pure form after recrystallization several times. O

OH

OAc

H2O

13

14 O

O

14

1. Et 3N, 84%

+

O

2. ( S)-phenylalanine, 85% O

16

15 O

OH

PdCl2, CuCl H2O, DMF 77%

O O

17

O

18

34

Oxidative Reactions with Pd(II) Compounds Pd(0) HCO2H, Et3N

AcO

O

O

O

19

20

PdCl2 CuCl

O

O

O

21

22

CO2Me

CO2Me PdCl2, CuCl O

O2, H2O, DMF 65%

O

O

23

24 CO2Me LDA 58% O 25

The 1,5-diketone 21 is prepared by 3-butenylation of ketones to give 20 via Pd-catalyzed hydrogenolysis of the allylic acetate 19, followed by Pd-catalyzed oxidation, and is used for annulation to form the cyclohexenone 22 [19]. In this method, the 3-butenyl group is a masked methyl vinyl ketone. Preparation of the 1,7-diketone 24 was performed by oxidation of 23, and applied to the synthesis of dysidiolide (25) [23]. In some cases where there is a neighboring group participation, aldehydes are formed from terminal olefins. The aldehyde 27 was obtained cleanly by participation of the cyclic carbonate of allylic diol 26, but the normal oxidation to afford the methyl ketone 29 occurred with the unprotected diol 28 [24]. O

O MPMO O

O

O PdCl2, CuCl, O2

MPMO

CHO

H2O, DMF 95%

O 27

26 HO MPMO

O

HO

PdCl2, CuCl, O2 MPMO OH

28

H2O, DMF 93%

OH 29

Reactions of Alkenes

35

The oxidation of simple internal alkenes is very slow. Clean selective oxidation of the terminal double bond in 30 in the presence of an internal double bond to yield 31 is possible under normal conditions [25]. Oxidation of cyclic alkenes is difficult, but can be carried out under selected conditions. Addition of strong mineral acids such as HClO4 , H2 SO4 and HBF4 accelerates the oxidation of cyclohexene and cyclopentene [26]. Heteropoly acids (NPMoV) supported on carbon and Pd(OAc)2 are good catalyst systems to oxidize cyclopentene (32) in the presence of CH3 SO3 H to cycloptentanone [27]. Internal double bonds in methyl cinnamate (33) and stilbene (35) were oxidized to 34 and 36 using Pd(II) perfluorinated bis(diketonate) complex 37 as a catalyst in benzene using t-butyl hydroperoxide in fluorous biphasic system, which facilitates the isolation of products from the catalyst [28]. O PdCl2 OAc

OAc

CuCl, 70~83%

30

31

O

NPMoV/C, Pd(OAc) 2, O2 MeSO3H, MeCN, H2O 85%

32

O

[Pd], t-BuO2H CO2Me

Ph 33

C8F17Br, benzene 59%

CO2Me

Ph 34

Pd O

O Ph Ph

[Pd] 73%

35

Ph Ph

[Pd] =

36

C7F15

O F15C7 2

37

Ethylene chlorohydrin (38) is formed in the Wacker process as a byproduct. Chlorohydrins are obtained as main products when PdCl3 (pyridine)− is used [29]. The optically active chlorohydrin 40 with high ee was obtained without forming the regioisomer 41 from allyl phenyl ether (39) and other substituted alkenes when the bimetallic Pd complex 42 coordinated by water soluble chiral BINAP-based ligand 43 (II-9) was used [30]. 2.2.3 Reactions with Alcohols and Phenols Oxidation of ethylene in alcohol with PdCl2 in the presence of a base gives acetal and vinyl ether. Reaction of terminal alkenes in alcohols affords regioisomers of the acetals 44 and 45 and vinyl ethers 46 depending on the structure of the alkenes. Internal alkenes 47 and alcohols give allylic ethers 48 and 50 and vinyl ethers 49 and 51 depending on which hydrogen is eliminated. Oxidation of terminal alkenes bearing an EWG in alcohols or ethylene glycol affords acetals of aldehydes chemoselectively. 3,3-Dimethoxypropionitrile (53) is produced commercially in MeOH from acrylonitrile by use of methyl nitrite (52) as

36

Oxidative Reactions with Pd(II) Compounds CH2

PdCl2

CH2 + 2 CuCl2 + H2O

H2C

CH2

HO

+ 2 CuCl +

Cl

HCl

38 OH

[Pd], CuCl2

O Ph

25 °C, TON 170

40

X

*L

Pd O

O

Ph

PAr 2

O

PAr 2

Ph

* 41

93% ee

X

Pd

O

HO

*

39

*L

Cl O

Cl

Ar =

Me SO3Na

Me

Me 42

R1

+

43

ROH

OR

R1

PdX2

+

RO

OR

R1

OR

44

OR 46

45

PdX

R1

R1 R1

+

R1

R1 + OR

OR

+ ROH

OR

48

49

OR

47

OR

R1

R1 PdX

+

OR R1 51

50

a unique reoxidant of Pd(0). Methyl nitrite (52) is regenerated by oxidation of NO with oxygen in MeOH. Methyl nitrite is a gas, which can be separated easily from the water formed by the oxidation [2]. Ethyl acrylate was converted to the terminal acetal 55 in high yield using Pd(OAc)2 , combined with molybdovanadophosphate (NPMoV), supported on carbon, under oxygen atmosphere [31].

CN

+ 2 MeONO 52

2 NO + 2 MeOH + 1/2 O2

PdCl2

MeO

+ 2 NO CN

MeO 53

2 MeONO + H2O 52

CO2Et + EtOH

Pd(OAc)2, NPMoV/C

EtO

O2, MeSO3H 50 °C, 83%

EtO

CO2Et 55

Pd(OAc)2 -catalyzed cyclization of 56 gave the tetrahydrofurans 57 and 58 using molecular oxygen as reoxidant in DMSO [32]. Formation of the oxazole 60 from

Reactions of Alkenes

37

Pd(OAc)2, 5 mol % + DMSO, O 2 95%

OH 56

O 57

58

CO2Me BOC

N

O

95 : 5

CO2Me Pd(OAc)2, 2~10 mol%

OH

BOC

N

O

O2, DMSO, 70 °C

59

60

59 was carried out with a catalytic amount of Pd(OAc)2 in DMSO under oxygen (1 atm) [6]. A reaction of unsaturated diols, in which one of the OH groups is allylic, offers an example of elimination of β-heteroatom (in this case OH) and generation of Pd(II). For example, in the cyclization of the 2-cyclohexenol bearing the β-keto ester side chain 61, the enolate undergoes oxypalladation to form 62, and subsequent elimination of β-OH with PdCl in 62 gave the dihydrofuran 63 and the tricyclic spiroacetal 64 with generation of Pd(II) in one-pot using 5 mol% PdCl2 without reoxidant [33]. O PdCl2(MeCN)2

MeO2C

OTHP acetone, rt

61 HO

R CO2Me

MeO2C

OH OTHP O

HO PdCl

62

HO H H

CO2Me

CO2Me + OTHP O

Pd(II)

H

63

25%

O

O

64

75%

H

PdCl2(MeCN)2

A phenolic oxygen participates in facile oxypalladation [16]. Different chemoselectivity is observed depending on the catalytic species. The 2H-1-benzopyran 66 was formed cleanly from 2-allylphenol (65) by endo cyclization with Pd2 (dba)3 or

38

Oxidative Reactions with Pd(II) Compounds

Pd(OAc)2 , but the benzofuran 67 was obtained by exo cyclization with PdCl2 [34]. Catalytic asymmetric cyclization of 2-(2,3-dimethyl-2-butenyl)phenol (68) using the binaphthyl-based chiral ligand 70, called (S,S)-ip-boxax afforded the furan 69 with high ee (97 %) [35]. Pd2(dba)3 (5 mol%) DMSO, H 2O KHCO3, air, 80%

O 66

OH PdCl2, DMSO

65

KHCO3, H2O, air

O 67

Pd(MeCN)4(BF4)2 (1 mol%) (S,S)-70,BQ, MeOH, 90%

OH

O 69 97% ee

68 O N i-Pr

iPr

N O (S,S)-70

Asymmetric domino cyclization of the unsaturated alcohol 71 proceeded smoothly to give the bicyclic compound 72 with 82 % ee in 89 % yield as a single diastereomer using a spiro bis(oxazoline) ligand which has a chiral spiro skeleton and two oxazoline rings. The reaction proceeds via the formation of 73 and 74 as oxypalladation products. BQ was used as a reoxidant [36].

Pd(OCOCF3)2, L

H OBz

Cl2CH2, BQ, 0 °C 89%, 82% ee HO

O

OBz

72

71

XPd

H

H

XPd

OBz OBz

O

O

N

N

O

O 74 73

L = (M,S,S)-i-Pr-SPRIX

Reactions of Alkenes

39

2.2.4 Reactions with Carboxylic Acids Formation of vinyl acetate by the reaction of ethylene with Pd(OAc)2 via acetoxypalladation of ethylene and β-H elimination was discovered by Moiseev in 1960 [37]. Attempted industrial production of vinyl acetate from ethylene and AcOH using the Pd(II) and Cu(II) redox system in a liquid phase was abandoned due to corrosion of reactors by AcOH. Instead, an interesting commercial process in the gas phase using a supported Pd catalyst was developed by Kuraray in Japan [38]. At present, vinyl acetate is produced commercially from ethylene, AcOH and O2 in the gas phase using Pd supported on silica or alumina as a catalyst. It is assumed that rapid conversion of Pd(0) to Pd(OAc)2 with AcOH and O2 is repeated efficiently on the surface of the support at high temperature. Discovery of efficient conversion of Pd(0) to Pd(II) on the surface of the support is a big technical innovation and is applied to other processes. CH2

+ Pd(0) + AcOH

CH2 + Pd(OAc)2 OAc

CH2

CH2

Pd/SiO2

+ AcOH + 1/2 O2

OAc

Pd(OAc)2

H2O

+ H2O

CH2=CH2

SiO2

1/2 O2 AcOH

Pd(0) AcOH

OAc

1,2-Dioxygenation by nucleophilic addition to alkenes takes place in the presence of the nitrate anion. The reaction of ethylene with Pd(OAc)2 in the presence of LiNO3 affords ethylene glycol monoacetate (9) [13]. From higher alkenes, three kinds of products, namely alkenyl acetates, allylic acetates and dioxygenated products, are obtained. Reaction of propylene gives two propenyl acetates 77 and 78 and allyl acetate (79) by acetoxypalladation to form two intermediates 75 and 76, followed by elimination of different β-hydrogens.

AcOPd

+ Pd(OAc)2

acetoxypalladation

OAc

OAc

b-elimination 77

75 AcO

PdOAc

b-elimination AcO

76

78 +

+ AcOH + O2

Pd/SiO2

AcO + H2O 79

AcO

79

40

Oxidative Reactions with Pd(II) Compounds

The chemoselective formation of allyl acetate (79) by a gas phase reaction using a supported Pd catalyst has been developed as a commercial process by Showadenko Ltd in Japan. The oxidation of cycloalkenes to cyclic ketones with PdCl2 is difficult under usual conditions, but allylic oxidation proceeds smoothly. Reaction of cyclohexene with Pd(OAc)2 gives 3-acetoxycyclohexene (81); 1-acetoxycyclohexene (82) is not formed, because no β-H syn to Pd is available on the acetoxy-bearing carbon, and syn β-H elimination yields the allylic acetate 81 as shown by 80 [39]. H

OAc

OAc

81

82

AcOPd

Pd(OAc)2

AcO H 80

The intramolecular reaction of alkenes with various O and N functional groups offers useful synthetic methods for heterocycles [15,16,40]. Reaction of unsaturated carboxylic acids affords lactones by either exo or endo cyclization depending on the positions of the double bond. Both 5-hexenoic acid (83) and 4-hexenoic acid (84) were converted to five- or six-membered lactones depending on the solvents and bases [41,42]. Oxidative cyclization of the optically active 4-pentenoic acid derivative 85 (85 % ee) using O2 as an oxidant afforded the γ -lactone 86 with 86 % ee in 84 % yield [43]. 2-Vinylbenzoic acid (87) was converted to isocoumarin (88), but not to the five-membered lactone [41,44]. O PdCl2(MeCN)2

O

O

CO2H PdCl2(MeCN)2

83

DMSO, Na 2CO3 70%

CO2H

O

AcONa, MeCN 90%

84

PdCl2, CuCl2, O2

BnO

BnO

84% O 85

OH

O

85% ee

86

O 86% ee

PdCl2(MeCN)2 CO2H 87

O

Na2CO3 88

O

Treatment of an equimolar mixture of the sodium salts, derived from the lactones 89 and 91, with Pd(OAc)2 , Cu(OAc)2 , and O2 afforded two lactones 90 (60 %) and

Reactions of Alkenes

41

92 (39 %). Formation of the lactone 90 from 89 is explained by the intramolecular acyloxypalladation mechanism. On the other hand, the lactones 90 and 92 are formed by two paths. Two different mechanisms cooperate to form the desired lactone 90 in 60 % yield and 92 in 30 % yield. The formation of 90 and 92 can be rationalized by generation of the π -allylpalladium intermediates by allylic C—H bond activation as an alternative pathway [45]. O O

• •

O

Pd(OAc)2, Cu(OAc)2, O2

•

CO2Na

•

OH

•

• •

AcOH, MeOH, MeCN

89

O

• O

•

CO2Na

•

OH

OH 60%

90 X-Pd

•

O

•

CO2Na

•

CO2Na

•

OH

•

OH

X-Pd 91

O O 92

OH 30%

2.2.5 Reactions with Amines Formation of allylic amines 93 and enamines 94 is expected by oxidative amination of alkenes via aminopalladation and β-H elimination using Pd(II) salts. Formation of allylic amines is favored. NR2 R

R′ + PdX2 + R2NH

aminopalladation

R

R′ PdX

NR2 b-H elimination R

R′ 93

NR2 +

R

R′ 94

Aliphatic amines coordinate to electrophilic Pd(II) too strongly to undergo aminopalladation, and the aminopalladation is possible only in a special case. On the other hand, amides such as tosylamide, acetamide, and carbamates react more easily than free amines, because amidation reduces electron density and

42

Oxidative Reactions with Pd(II) Compounds

the complexing ability of amines. Intermolecular reactions are rather difficult, but intramolecular ones proceed smoothly and are extensively applied to syntheses of N-containing heterocycles [15,16,40]. For example, 5-exo cyclization of 4-hexenyltosylamide (95) using Pd(OAc)2 -pyridine (1 : 2) and oxygen gave the 2-vinylpyrrolidine (96) smoothly. No other oxidant is necessary [8]. Cyclization of the formamide 97 with a catalytic system of Pd(OAc)2 –DMSO-O2 afforded 98 [46]. Intramolecular aminopalladation of the allylic alcohol 99 is followed by elimination of β-OH to generate Pd(II) as shown by 100, and hence the cyclization proceeds with a catalytic amount of PdCl2 with no oxidant to give 101, and (+)-prosopinine was synthesized by this method [47]. Ts Pd(OAc)2, pyridine (1 : 2)

N

NHTs O2, 1 atm, xylene, 80 °C, 87%

95

96 BOC N

NHCHO

BOC Pd(OAc)2, O2

N

CHO

N

DMSO, 86%

97

98

OCOPh

OCOPh PdCl2(MeCN)2 (20 mol%) H HO

HN O 99

77%

H

H

HO

N PdX

O

O Pd(II)

O 100 OCOPh

H

H

OH steps EtCO(CH2)9

N

N H

OH

O O

(+)-prosopinine

101

Similarly, PdCl2 -catalyzed cyclization of the ureathane 102, derived from Dmannitol, proceeded with elimination of OH as shown by 103 to afford 104 with excellent diastereoselectivity, from which 1-deoxymannojirimycin was synthesized [48]. Treatment of the diallylic alcohol 105 with TsNCO gave the N -tosyldicarbamate 106. Interestingly, Pd-catalyzed cyclization of 106 gave the 4-vinyl-2oxazolidinone 108 (path a) regioselectively by elimination of the carbamate group as shown by 107 without forming the isomeric oxazolidinone 109 (path b). Addition of Li salt is essential, without which no reaction takes place. Cyclization of the chiral allylic alcohol 110 produced the highly optically pure 4-vinyl-2oxazolidinone 111, which was converted to 112 [49].

Reactions of Alkenes OBn

OBn MOMO

43

MOMO

PdCl2(MeCN)2 (15 mol%)

OBn

OBn

86%

NH BOC

PdCl

N BOC

OH

102

OH

103 OBn MOMO

OH HO

OBn

OH

steps

N Pd(II)

OH

N H

BOC

1-deoxymannojirimycin

104

HO

NHTs

TsNCO

OH

O

C5H11 105

TsHN

a O path b

O

b O

Pd(OAc)2

C5H11

LiBr path a

106

O

C5H11 O

O O

N Ts

OCONHTs

N Pd-X

Ts

C5H11

107

109 C5H11 O O

N Ts 108

O O O

O NHTs

110

O O

*

O *

Pd(OAc)2 OH 99% de

LiBr 97%

O

HO

OH

steps

* N

N H

Ts 111

99% de

OH

112

Oxidative amination of aromatic amines which are less basic than aliphatic amines proceeds smoothly without protection of amines. The intramolecular reaction of aniline derivatives offers good synthetic methods for heterocycles. 2Methylindole is obtained by 5-exo amination of 2-allylaniline [50]. As an application, N -methyl-2-methyl-3-siloxyindole 114 was prepared from N -methyl-2-(1siloxyallyl)aniline 113. Without silyl protection, no reaction occurred [51]. If there is another olefinic bond in the same molecule, the aminopalladation product 116 of the amide 115 undergoes olefin insertion to give the tricyclic compound 117 [50]. 2,2-Dimethyl-1,2-dihydroquinoline (119) was obtained by 6-endo cyclization of 2-(3,3-dimethylallyl)aniline (118).

44

Oxidative Reactions with Pd(II) Compounds OTBDMS

OTBDMS

+ PdCl2

PdCl2(MeCN)2 BQ, K2CO3, THF rt, 77%

NH

N Me

Me 113

114

Pd X N

N H

N

O

O 115

O 117

116

PdCl2(MeCN)2 BQ, 54% NH2

N H

118

119

2.2.6 Reactions with Carbon Nucleophiles When the stable complex of COD 120 was treated with malonate or acetoacetate in ether at room temperature in the presence of Na2 CO3 , a facile carbopalladation occurred to give the new and stable complex 121. This reaction is the first example of carbopalladation of alkenes in Pd chemistry. The Pd–carbon σ -bond in the carbopalladation product 121 is stabilized by coordination of π -olefin bond. By the treatment of the new complex 121 with a base, the generated malonate anion attacked the Pd–carbon σ -bond, affording the bicyclo[6.1.0]nonane 122. Also treatment of the complex 121 with another molecule of malonate afforded the bicyclo[3.3.0]octane 123 by transannulation to the π -olefin bond [14,52]. E E

+

Na2CO3

CO2R

r.t.

carbopalladation

CO2R Pd Cl

Pd E = COMe, CO2R

Cl

Cl

2

121

120 C(CO 2R)2 _

CO2R −

CH(CO2R)2

CO2R DMSO 122

Pd Cl

CH(CO2R)2 Pd

CH(CO2R)2

Cl 121

−

(RO2C)2CH Pd Cl

123

CH(CO2R)2

Reactions of Alkenes

45

Carbopalladation of the double bond of the benzyl N -vinylcarbamate 124 with benzyl acetoacetate, and subsequent carbonylation affords the amino ester 125, which was converted to a β-lactam [53]. O N H

O OBn

+

CO2Bn

+

CO

+ MeOH

PdCl2(MeCN)2 92%

124 O

O CO2Bn

R3SiO CO2Bn

CO2Me

CO ClPd NHCO2Bn

MeO2C

NH NHCO2Bn

O

125

Intramolecular carbopalladation of the unsaturated β-diketone 126 catalyzed by the combination of PdCl2 with CuCl2 at room temperature provided the cyclohexenone 127 in very high yield (97 %). In other words, facile oxidative alkylation of an unactivated alkene with a carbon nucleophile took place [54]. O

O

O

O

PdCl2(MeCN)2 PdCl

CuCl2, rt, 97% 126 O

O

O

O

127

2.2.7 Oxidative Carbonylation Oxidative carbonylation of alkenes is a unique reaction of Pd(II). Three types of oxidative carbonylation to give β-substituted acid derivatives 130, α,β-unsaturated esters 132 and succinate derivatives 134 are known, which can be understood by the following mechanism. Palladation of alkenes with PdX2 , followed by CO insertion, generates the acylpalladium intermediate 129 whose reductive elimination affords β-substituted carboxylic acid derivatives 130 (path a). Reaction in alcohol in the presence of a base starts by the formation of the alkoxycarbonylpalladium 128. Carbopalladation of alkene with 128 generates 131. Then β-H elimination of the intermediate 131 yields the α,β-unsaturated ester 132 (path b). Further CO insertion to 131 gives the acylpalladium intermediate 133 and its alcoholysis yields the succinate derivative 134 (path c). Formation of the β-alkoxy ester 130 (X-OR) is regarded as nucleophilic substitution of Pd-X in 131 with alcohols.

46

Oxidative Reactions with Pd(II) Compounds X-Pd-CO2R + HX

PdX2 + CO + ROH

128 R

path a

R R X

Pd-X

R

R

CO CO2R

X-Pd R

path c

131

O

CO2R

X-Pd

133

O

X

X 129

path b

Pd-X

b-H elimination

RO−

R

R + COX

X

R +

Pd(0)

Pd(0)

+ Pd(0) RO2C

CO2R

130

132

CO2R 134

X = Cl, OR, OH, OAc

The first report of the oxidative carbonylation is reaction of alkenes with CO in benzene in the presence of PdCl2 to afford the β-chloroacyl chloride 135 (path a) [14,55]. Hydrocarbonylation of alkenes to give the saturated esters 136 and 137 is catalyzed by Pd(0) (see Chapter 8.1) [56]. It should be pointed out that the hydrocarbonylation is clearly different mechanistically from the oxidative carbonylation, which is promoted by Pd(II) to produce 130, 132 and 134. path a R

R +

+ CO + PdCl2 Cl

Pd

COCl 135

R + CO + ROH

Pd(0)

R

R + H

RO2C 136

H

CO2R 137

Extensive studies have been carried out on oxidative carbonylation [57]. Oxidative dicarbonylation of cyclopentene to give the diester 138 and 139 (path c) proceeds with good yields using a catalytic amount of Pd(OAc)2 and heteropoly acid (NPMoV) under pressure of CO and air (5 atm each). Formation of the diester 139 is explained by dehydropalladation after monocarbonylation, followed by hydropalladation in a different direction [58]. Saigo and co-workers reported that phosphine sulfide (Ph3 PS) is an effective ligand for oxidative dicarbonylation of alkenes [59]. Aromatic alkenes such as p-methoystyrene and vinylsilane were converted to succinate derivatives in 82 % and 92 % yields, respectively, in the presence of Ph3 PS and CuCl at room temperature and under 1 atm of CO and O2 . The yield in carbonylation of styrene in the absence of phosphine sulfide was 36 %. Phosphine oxide is somewhat less effective (60 % yield) than Ph3 PS.

Reactions of Alkenes

47

Pd(OAc)2, NPMoV, O 2

+ CO + MeOH

MeSO3H, 60 °C, 81%

CO/air = 5/5 atm

Pd-X

Pd-X

CO2Me CO

H-PdX

MeOH CO2Me CO

CO2Me

CO2Me

H-PdX

CO2Me

139

MeOH CO2Me 138 : 139 = 54 : 46 CO2Me

138

CO2Me + CO + MeOH

CO2Me

PdCl2, Ph3PS, CuCl O2, 1 atm, rt 82%

MeO

MeO CO2Me

+ CO + MeOH

PhMe2Si

PdCl2, Ph3PS, CuCl

CO2Me PhMe2Si

O2, 1 atm, rt 90%

Carbonylation of alkenes having an amino or hydroxy group (AH or BH = OH or NHR) 140, 142 and 144 offers interesting synthetic methods for cyclic compounds. The 4-pentenylamine or alcohol 140 is converted to 141 via amino or oxypalladation, followed by carbonylation. The amino alcohol 142 gives 143 by palladation and carbonylation by path a. The homoallylic amine or alcohol 144 is converted to lactone or lactam ester 145 by path c [60]. Pd-X

path a

Pd-X PdX2

O CO

A

AH

ROH A

CO2R A

140

141 O

Pd-X BH

BH

BH

Pd-X

PdX2

O

CO A

AH

A

A

142

143

path c

Pd-X Pd-X

PdX2 CO A

AH 144

B

A, B = O, N

O

O

CO2R CO

O

ROH A

A 145

48

Oxidative Reactions with Pd(II) Compounds

Aminocarbonylation of N -4-pentenyl-N
-methylurea (146) gave 147 smoothly in the presence of PdCl2 , CuCl2 and O2 [61]. Aminocarbonylation of the unsaturated diamine derivative 148 is chemoselective. In the presence of sodium acetate and methyl orthoformate, aminopalladation of the tosylamide took place selectively to afford 150 via 149. On the other hand, selective reaction of the carbamate occurred to give 151 in the absence of sodium acetate [62]. PdCl

NHCONHMe

+ CO + MeOH

PdCl2, CuCl2 O2, 79%

O

CO N

N

NMe

CONHMe

146

O 147

NHCO2Me

TsNH

+ CO + MeOH PdX

O

O 148

Ts N

PdCl2, CuCl2, O2

NHCO2Me

O AcONa, MeC(OMe)3 aminopalladation

O 149 CO2Me Ts N

NHCO2Me

O O 150 CO2Me

PdCl2, CuCl2, O2 MeOH

74%

TsNH O

CO2Me N

O 151

The unsaturated hydroxy carboxylic acid 152 was converted to the dilactone 153 via domino oxypalladation and carbonylation [63]. The γ -lactone 156 was prepared by intramolecular oxycarbonylation of the alkenediol 154. The intermediate 155 is formed by the oxypalladation, and subsequent intramolecular carbonylation affords the lactone 156. The reaction was applied to the synthesis of tetronomycin [64]. The oxycarbonylations of alkenol and alkanediol can be carried out with a catalytic amount of PdCl2 and a stoichiometric amount of CuCl2 , and have been applied to syntheses of a number of natural products. Oxidative carbonylation of 3-penten-1-ol (157) in the presence of ethyl orthoformate gave the lactonic ester 158 smoothly by dicarbonylation under mild conditions (path c) [65]. Dicarbonylation of the homoallylic alcohol 159 carried out using the chiral bioxazolidine as a ligand 161 gave the chiral lactone 160 in 57 % yield with 65 % ee [66].

Reactions of Alkenes

49 Ph

OH Ph CO2H

H OH

PdCl2, CuCl2

+ CO

AcONa, AcOH, rt 86~95%

152

PdCl

O O Me

Ph H O O

O O Me 153

H OMe OH

OH

+ CO

HO

PdCl2, CuCl2

X-Pd

AcONa, AcOH 86~95%

H

154

O H 155

OMe

H O O O H H 156

OMe

Pd-Cl + CO + MeOH

PdCl2, CuCl2

Pd Cl

MeC(OEt)3

OH

O

O

O

O

157

CO2Me

O O 158

OH + CO

O

(h3-allyl-PdCl)2, CuOTf

CO2Me

rt, 1 atm 57%, 65% ee

159

160

Ph

O

O

N

N 161

O

Ph

50

Oxidative Reactions with Pd(II) Compounds

2.2.8 Reactions with Aromatic Compounds Similar to mercuration, Pd(OAc)2 undergoes facile palladation of aromatic compounds. The palladation product 162 is an unstable intermediate. It can be isolated only when stabilized by chelation. The palladation products of aromatics as reactive intermediates undergo three reactions. The reaction with alkenes to afford styrene derivatives 164 is the first one. Pd(II)-promoted alkenylation of aromatic compounds, discovered by Fujiwara, is a stoichiometric Heck reaction. The second one is homocoupling to form biaryls. The acetoxylation of aromatic rings is the third reaction. These latter two reactions are treated in Chapter 2.7. The Pd(II)-mediated reaction of benzene with alkenes affords styrene derivatives 164. The reaction can be understood by palladation, insertion of olefin to give 163, and β-H elimination [67,68]. In addition to benzene and naphthalene derivatives, electron-rich heteroaromatic compounds such as ferrocene, furan and thiophene react with alkenes to give vinyl heterocycles. The effect of substituents in this reaction is similar to that observed in the electrophilic aromatic substitution [69]. Oxidative coupling of arenes with alkenes consumes a stoichiometric amount of Pd(II). Efficient catalytic reaction of cinnamate (165) with benzene to afford 166 was carried out using BQ and t-butyl hydroperoxide as oxidant in AcOH [70]. The coupling proceeds smoothly in the presence of catalytic amounts of Pd(OAc)2 and molybdovanadophosphoric acid (HPMoV) under oxygen (1 atm) in AcOH [71]. R PdOAc

R PdOAc

+ Pd(OAc)2

insertion 162

163

R b-H elimination

+ Pd(0) + AcOH 164 CO2Et

+ Ph 165

Pd(OAc)2, BQ

Ph

t-BuOOH, AcOH 90 °C, 72%

Ph

CO2Et

166

Asymmetric oxidative coupling of benzene with cyclohexenecarbonitrile (167) using the chiral diamine 170 as a ligand is based on the expectation that β-H elimination from the opposite side to the phenyl group as shown by 168 should generate a chiral alkene. Pd(OAc)2 (10 mol %), the chiral sulfonylaminophenyloxazoline ligand 170 (1 : 1) and t-butyl perbenzoate as an oxidant were used, and 6-phenylcyclohexenecarbonitrile (169) with 30 % ee was obtained [72]. Intramolecular oxidative coupling of the benzene ring with 1,2-benzoquinone to yield 171 was applied to total synthesis of carbazoquinostatin A [73]. Cyclization of 2-arylamino-1,4-quinones was carried out using Pd(OAc)2 and Sn(OAc)2 (5 mol% each) in AcOH under oxygen [74]. In the enantioselective total synthesis of okaramine N, Corey carried out intramolecular oxidative coupling of congested trisubstituted alkene at C-2 of indole in a complex molecule to give 172 in 44 % yield using Pd(OAc)2 (1 equiv.) at room

Reactions of Alkenes

51 syn

anti CN

XPd Pd(OAc)2, L (1 : 1)

+

CN

CN

H

Ph

H

Ph

PhCO3H 167

168

169 30%, 30% ee

O

L= TfHN

N Bu

170

O O

N H

Me OAc

AcOH, 62%

Pd(OAc)2 (1.1 eq)

O

O

Me N H

OAc

171

Me

Me Me

N

N Pd(OAc)2, AcOH, dioxane

FmcNH MeO2C

H N

Me

O

H

O2, 25 °C, 70%

FmcNH H

MeO2C H

N

N H Me

Me

N H Me 172

Me

O

52

Oxidative Reactions with Pd(II) Compounds

temperature under O2 atmosphere. The reaction seems to occur via palladation at C-2 of the indole ring [75]. 2.2.9 Coupling of Alkenes with Organometallic Compounds Coupling of organometallic compounds of B, Sn and Si with alkenes as a halogenfree oxidative Heck-type reaction proceeds with Pd(II) compounds catalytically in the presence of oxidants. The reaction can be understood by alkylation (or arylation and alkenylation) of Pd(II)X2 with main group metal compounds M
Rn to generate R-Pd-X 173, which is a species similar to an intermediate formed in the Heck reaction. Subsequent alkene insertion and β-H elimination provide the coupling products and Pd(0). Reoxidation of Pd(0) with an oxidant to Pd(II) makes the reaction catalytic. Coupling of 1-hexenylboronic acid with acrylate promoted by Pd(OAc)2 to give methyl 2,4-nonadienoate (174) was reported by Dieck and Heck in 1975 [76]. Reaction of acrylate with phenylboronic acid in the presence of Pd(OAc)2 under O2 afforded cinnamate (175) in 87 % yield [77,78]. R′ R

PdX2 + MRn

+ Pd(0)

R-Pd-X oxidant

173

R′

Bu +

CO2Me

B(OH)2

+ Pd(OAc)2

Bu +

Pd(0)

+

AcOB(OH)2 +

AcOH

CO2Me 174 PhB(OH)2 +

Pd(OAc)2, O2, Na2CO3 CO2t-Bu

Ph

DMF, 50 °C, 87%

CO2t-Bu 175

Reaction of norbornene (176) with the organoborane 177 afforded the doubly alkenylated product 178. Although no mechanism was given, the first step seems to be the alkenylation of Pd(OAc)2 with 177, or transmetallation of 177 with Pd(OAc)2 to give 179 (which corresponds to 173). Then insertion of norbornene took place to afford 180. Since there is no β-H syn to Pd, β-H elimination is impossible. Therefore transmetallation with 177 and reductive elimination occur to give rise to the doubly alkenylated product 178. Chloroacetone was used as a good oxidant of Pd(0), since Cu(II) salts gave poor results in this reaction [11]. Reaction of phenylstannane with acrylate gave cinnamate (175) using Pd(OAc)2 and Cu(OAc)2 . The reaction is explained by phenylation of Pd(OAc)2 , insertion of alkene and β-H elimination. The generated Pd(0) is reoxidized to Pd(II) with Cu(II) salt [78,79]. Coupling of arylstannanes and alkenes proceeds smoothly using Pd(OAc)2 and pure O2 as an oxidant. Uses of DMF or NMP as a solvent and AcONa as a base are important [80]. Aryl and alkenyl silanols react smoothly with alkenes. The presence of the OH group on silicon is important and silanols are reactive without activation by

Reactions of Alkenes

53

fluorides. Phenyldimethylsilanol reacts with acrylate to give cinnamate (175) using Pd(OAc)2 and Cu(OAc)2 [79,81]. O +

t-Bu

t-Bu

ClCH2COCH3 K2CO3, 80%

O

176

t-Bu

Pd(PhCN)2Cl2

B 177

178

mechanism O

t-Bu

O

TM

+ Pd(OAc)2

B

PdOAc + AcO

t-Bu

B

O

O

177

179

t-Bu a. TM with 177

t-Bu

PdOAc

PdOAc

178

b. RE

insertion 180

179

Ph

Pd(OAc)2, Cu(OAc)2

PhSnBu3 +

CO2Bu

+

LiOAc, 84%

Ph-Ph

CO2Bu 77%

175

16%

mechanism PhSnBu3 + Pd(OAc)2

TM Ph-PdOAc

PdOAc

R insertion

Ph R

AcOSnBu3

Cu(OAc)2

b-H elimination Pd(0) + Ph

Pd(OAc)2, Cu(OAc)2

PhSiMe2OH +

CO2Bu

R

Ph

LiOAc, 69%

CO2Bu 175

π -Allylpalladium 181 is formed by a stoichiometric reaction of allylic trimethylsilane with PdCl2 , and undergoes intramolecular amination. Overall, Pd-catalyzed cyclization of allylsilanes by nucleophilic displacement of the silyl group occurred in the presence of CuCl2 [82]. Also oxidative arylation of alkenes can be carried out by the reaction of phenylphosphonic acid 182 with alkenes [83]. TsNH

SiMe3

Li2PdCl4, CuCl2

Ts N

t-BuOH, 74%

PdCl2 ClSiMe3 PdCl TsNH

PdCl

TsNH 181

O Ph

P OH 182

OH

+

Ph

Pd(OAc)2, Me3NO, TBAF Ph

THF, dioxane, 100 °C, 95%

Ph

54

Oxidative Reactions with Pd(II) Compounds

2.3 Stoichiometric Reactions of π -Allyl Complexes Reaction of π -allylpalladium chloride with a soft carbon nucleophile such as malonate and acetoacetate in DMSO as a coordinating solvent to give the allylated product 183 was reported in 1965 [14,84]. This reaction constitutes the basis of stoichiometric as well as catalytic π -allylpalladium chemistry. Depending on how π -allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of π -allyl complexes 185 from alkenes 184 requires Pd(II) salts, and subsequent reaction with a nucleophile generates Pd(0). The whole process consumes a stoichiometric amount of Pd(II), because in situ regeneration of Pd(II) is hardly attainable. These reactions are treated in this section. On the other hand, in situ formation of the π -allylpalladium complexes 185 by oxidative addition of Pd(0) to various allylic compounds (esters, carbonates, etc.), and their reactions with nucleophiles are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4.

+ Pd

CO2Et

DMSO

CO2Et

CO2Et

NaH

CO2Et 183

X R

R

+ Pd(0) + HCl

NuH

+ PdCl2

R

Nu

+ Pd(0)

Pd

184

Cl 185

R

X

+ Pd(0)

R

NuH

R

Nu

+ Pd(0)

Pd 185

X

X = OAc, OCO 2Me, etc.

Formation of π -allylpalladium complexes from alkenes and PdCl2 , and the reaction of the complexes with carbon nucleophiles constitutes alkylation of alkenes with carbon nucleophiles via π -allylpalladium complexes as a stoichiometric reaction, offering a method of oxidative functionalization of alkenes, and can be applied to syntheses of a number of natural products [85]. For example, functionalization of pinene (186) was carried out via the reaction of the π -allylpalladium 187 with a phenylsulfinyl group to give 188, and converted to the pinene derivative 189 [86]. π -Allyl complex formation takes place particularly easily from the α,β- or β,γ unsaturated carbonyl compounds. The reaction of the complex 191, formed from 3-penten-2-one (190), with a carbon nucleophile to lead to 192 is an example of γ -alkylation of α,β-unsaturated ketones or esters [87]. The enamine 193 as a carbon nucleophile reacts with π -allylpalladium chloride to give 2-allylcyclohexanone after hydrolysis [84]. Hard carbon nucleophiles of organometallic compounds also react with π -allylpalladium complexes. A steroidal side chain was introduced to 194 to afford 197 regio- and stereoselectively by the

Stoichiometric Reactions of π -Allyl Complexes CO2Me

CO2Me

Cl Pd

SOPh

CO2Me SOPh

PdCl2

HMPA 75 °C, 89%

Ph3P, DMSO 187

186

55

189

188

O

O

O CH2(CO2Me)2

+ PdCl2 Pd

190

CH(CO2Me)2

NaH 192

Cl

191

reaction of the steroidal π -allylpalladium complex 195 with the alkenylzirconium compound 196 [88].

O

N H2O

+

+ Pd(0)

Pd Cl 193

Pd Cl PdCl2 O O

194 195

Cp2ZrCl

196 78%

197

Interestingly, some nucleophiles attack the central carbon of the π -allyl system 198 to form the palladacyclobutane 199 and reductive elimination produces the cyclopropanes 200. Li enolates of carboxylic acids are such nucleophiles for the cyclopropanation [89,90]. The Li enolate of the ketone 201 reacts with π allylpalladium chloride to afford the α-cyclopropyl ketone 202 in the presence of TMEDA under CO atmosphere [91]. Treatment of π -allylpalladium chloride with CO in EtOH afforded ethyl 3butenoate (203) [92], which was easily converted to 1-carboethoxy-π -allylpalladium chloride (204) by treatment with Na2 PdCl4 in EtOH. Then the repeated

56

Oxidative Reactions with Pd(II) Compounds Cl

Nu

Nu

Pd 198

+ Pd(0)

Nu

Pd 199

200

O

O Cl +

LDA, TMEDA

Pd CO, 65%

201

202 CO2Et

Cl Pd

Na2PdCl4

CO2Et

+ CO + EtOH

Pd Cl

203

204 CO2Et

Na2PdCl4

CO EtOH

EtO2C

Pd

CO2Et

Cl

205

CO2Et 206

carbonylation of 204 gave ethyl 2-pentenedioate (205), which was converted further to the 1,3-dicarboethoxy-π -allylpalladium complex 206 [93]. Conjugated dienes are formed by β-H elimination of π -allylpalladium complexes. Catalytic oxidative dehydrogenation of ethyl 3-butenedicarboxylate (207) to afford butadienedicarboxylate (muconate) (209) proceeded in high yield using PdCl2 and CuCl2 under an oxygen atmosphere in AcOH containing sodium acetate [94]. The reaction proceeds via the π -allylpalladium complex 208 and subsequent β-H elimination. H PdCl2, CuCl2

EtO2C

CO2Et 207

O2, 78%

EtO2C

CO2Et Pd 208

b-H elimination

EtO2C

CO2Et

Cl

+ Pd(0) + HCl

209

2.4 Reactions of Conjugated Dienes When butadiene is treated with PdCl2 , the 1-chloromethyl-π -allylpalladium complex 210 (A = Cl) is formed by chloropalladation of one of the double bonds. In the presence of pronucleophiles AH, the substituted π -methallylpalladium complex 210 (A = nucleophile) is formed. In this way, the nucleophile can be introduced at the terminal carbon of conjugated diene systems. For example,

Reactions of Conjugated Dienes

57

a methoxy group is introduced at the terminal carbon of 3,7-dimethyl-1,3,6octatriene (212) to give the π -allylpalladium complex 213. The π -allylpalladium complexes formed from conjugated dienes are reactive and react further with nucleophiles to give the 1,4-difunctionalized products 211. Based on this reaction, various nucleophiles are introduced to conjugated dienes to form 1,4-difunctionalized 2-alkenes 211. In this way, acetoxy, alkoxy, halo, amino groups, carbon nucleophiles and CO are introduced to dienes. This is the basis of the synthetic application of Pd(II)-promoted oxidative difunctionalization of conjugated dienes [95]. The reaction itself is stoichiometric with respect to Pd(II) salts, but it can be made catalytic by the use of reoxidants of Pd(0). A + PdCl2 + A−

A B−

PdCl

B A

Pd Cl

211

210

A = Cl, OR, OAc

+ Na2PdCl4 + MeOH

OMe

212

Pd-Cl 213

The oxidative diacetoxylation of butadiene with Pd(OAc)2 affords 1,4-diacetoxy2-butene (214) and 3,4-diacetoxy-1-butene (215). The latter can be isomerized to the former. The commercial process for 1,4-diacetoxy-2-butene (214) was developed in AcOH using a Pd catalyst, which contains Te supported on carbon. Importantly, the Pd stays on carbon without dissolving into AcOH. 1,4-Butanediol (216) and THF are produced commercially from 214 [96]. OAc AcO Pd/Te/C + 2 AcOH + O2

214

AcONa AcO OAc 215 OH HO 216

O

Some synthetic applications of 1,4-difunctionalization of various 1,4-dienes are cited here. Stereoselective 1,4-difunctionalization of the 1,3-cyclohexadiene 217 using Pd(OAc)2 and O2 in DMSO afforded nearly equal amounts of 1,4-adduct 218 and addition–elimination product 219 [97]. Pd(II)-promoted intramolecular reaction of the allene-substituted 1,3-cyclohexadiene 220 gave the triene 223 regioand stereoselectively. The reaction may be explained by nucleophilic attack of the

58

Oxidative Reactions with Pd(II) Compounds

CO2Me 217 DMSO, O 2 80%

SO2Ph

Pd(OAc)2, LiOAc

H

H

AcO + H 218

SO2Ph CO2Me

H

SO2Ph CO2Me

219 45 : 55

allene to the 1,3-cyclohexadiene, followed by acetoxylation of the π -allylpalladium system as shown by 221 and 222 to give 223.

E

E

•

E Pd(OAc)2, BQ, O2 LiOAc, AcOH

E

•

67% Pd

220

E

E

AcO Pd

H 221

222 H AcO

E E

H 223

It is worth mentioning that the diene 225 was obtained by the Pd(0)-catalyzed reaction of the same substrate 220 by a different mechanism, namely oxidative cyclization of 220 to generate palladacyclopentane 224 and addition of AcO-H to 224 to give 225 [98]. Also reaction of the alkyne-substituted 1,3-cyclohexadiene 226 using Pd(OAc)2 and BQ in the presence of LiCl starts by chloropalladation of the triple bond, followed by attack to the diene as shown by 227 to give the dichloro compound 228 [99].

2.5 Reactions of Allenes Allenes react with Pd(II) salts in two ways, giving monomeric and dimeric π allylpalladium complexes 230 and 233 [100,101]. Chloropalladation of allene occurs in two directions depending on attack on the central carbon of allene either by Cl or PdCl. The complex 230 is obtained by the attack of PdCl on the terminal carbon

Reactions of Allenes E

E

E

59

E

Pd(dba)2, LiOAc •

AcOH, 65% Pd

220

224 E

H AcO

AcO-H

E + Pd(0) H 225

E

E

E

E

E

H Cl

Pd(OAc)2, BQ, O2

E

PdCl

LiCl, 65%

H 226

E = CO2Me

Cl

227

Cl

228

via 229. Chloropalladation in a different direction generates 231, and insertion of allene to 231 affords the dimeric complex 233 via 232. Cl

Cl

PdCl

PdCl

229 •

+

230

PdCl2

Pd-Cl

Pd-Cl

Pd-Cl • insertion Cl

Cl 231

Cl 232

233

Treatment of 232 with CuCl2 affords 2,3-bis(chloromethyl)-1,3-butadiene (234) and regenerates PdCl2 . Thus preparation of this interesting dimerization product 234 can be carried out with a catalytic amount of PdCl2 and 2 equivalents of CuCl2 in MeCN [102]. Pd-Cl •

+

CuCl2

PdCl2

+ PdCl2 Cl

Cl 234

Cl 232

60

Oxidative Reactions with Pd(II) Compounds

Intramolecular reaction of allenes is known to proceed mainly by palladation at the central carbon to generate alkenylpalladium 235, which undergoes further reactions. Also π -allylpalladium 236 is formed when a nucleophile attacks the central carbon. The intramolecular aminopalladation of the 6-aminoallene 237, followed by CO insertion, afforded the unsaturated amino ester 238. The reaction has been applied to the enantioselective synthesis of pumiliotoxin [103]. Oxycarbonylation of the allenyl alcohol 239 afforded the unsaturated ester 240 in 83 % yield using a catalytic amount of PdCl2 and 3 equivalents of CuCl2 in MeOH and is used for the synthesis of rhopaloic acid [104]. PdCl2

PdCl

PdCl

A AH

• Nu

NuH

Nu

Pd(0)

Nu

235

•

NH

+ CO + MeOH

236

aminopalladation

CO

PdCl2, CuCl2

MeOH

N

80%

N

Pd-X Ph

Ph

CO2Me Ph

237

238 OH

• + CO

PdCl2, CuCl2 MeOH 83%

geranyl

O CO2Me

geranyl 239

240

Aminopalladation of the carbamate 241 generates 242 and subsequent insertion of allylic chloride and dechloropalladation as shown by 243 as a Pd(II)-generation step affords the diene 244 and generates PdCl2 . Therefore the reaction proceeds with a catalytic amount of PdCl2 without a reoxidant [105]. Similarly, oxypalladation of the 2,3-allenol 245 generates 246. Reaction of allyl bromide and debromopalladation as shown by 247 produced 4-allyl-2,5-dihydrofuran 248 using 5 mol% of PdCl2 [106]. • O

PdCl2(PhCN)2

NHTs

76%

Cl

PdCl O

NTs O

O

242

241 PdCl Cl O

NTs

O

O

NTs O

243

244

+ PdCl2

Reaction of Alkynes Bu •

X-Pd

PdCl2, DMA

Br

+

61 Bu

Br

rt, 76%

Me HO

O

245

246

Me

Br Bu

Bu

X-Pd O

Me

Me

O 248

247

Intramolecular oxypalladation of the allenyl aldehyde 249 generates the intermediary alkenylpalladium complex 250, and subsequent carbonylation affords the unsaturated ester 251 in 88 % yield. Propylene oxide is added as a scavenger of HCl [107].

•

PdCl2

PdCl2, CuCl2 CH2Cl2, MeOH

O

O •

H propylene oxide 88%

TBDMSO

H OMe

TBDMSO

249 Pd-Cl

CO2Me O

OMe

O

CO

OMe

+ Pd(0)

MeOH TBDMSO

TBDMSO 250

O

251 OH

+ HCl Cl

Intramolecular oxypalladation of 5,6-dienoic acid 252 is followed by acrolein insertion to generate 254, which undergoes protonolysis to produce the aldehyde 253 without giving β-H elimination product as a Heck-type reaction. The reaction proceeds with a catalytic amount of Pd(OAc)2 in the presence of LiBr, which plays an important role in inhibiting β-H elimination in 254 [108]. Reaction of 252 in the presence of Pd(OAc)2 , Cu(OAc), LiBr and O2 in MeCN provided alkenyl bromide 255 [109].

2.6 Reaction of Alkynes Alkynes undergo several Pd(II)-promoted stoichiometric oxidative reactions via facile palladation. However, in some cases, reactions proceed with a catalytic amount of Pd(II) via in situ regeneration of Pd(II) by protonolysis. Various heterocyclic compounds can be synthesized by Pd(II)-catalyzed reaction of alkynoic alcohols, carboxylic acids and amines via oxy- or aminopalladation

62

Oxidative Reactions with Pd(II) Compounds

i-Pr

Pd(OAc)2, LiBr

CO2H +

•

CHO

THF, 89%

CHO O

O

252

253

i-Pr

protonolysis CHO CHO

PdX O

O

O

O

i-Pr

i-Pr

PdX i-Pr

254

Pd(OAc)2, Cu(OAc)2, LiBr

•

CO2H

O2, K2CO3, MeCN, 82%

252

O

O Br 255

of triple bonds. Intramolecular oxypalladation of 5-undecyn-1-ol with a catalytic amount of PdCl2 (PhCN)2 generates the vinylpalladium 256. The dihydropyran 257 and the keto alcohol 258 are produced by protonolysis of the oxypalladation product 256 as the Pd(II)-generation step. The reaction shows the possibility of regioselective hydration of alkynes [110]. γ -Lactone 262 was obtained by the treatment of 4-(trimethylsilyl)-3-butyn1-ol 259 with Pd(OAc)2 and CuCl2 under oxygen. Oxypalladation of 259 and protonolysis give 260. Then hydroxypalladation of 260, followed by desilylpalladation affords 262 and Pd(0), which is oxidized in situ to Pd(II) with CuCl2 [111]. The reaction shows that the silylacetylene is a synthetic equivalent of (—CH2 CO2 H). protonolysis HCl

oxypalladation C5H11

OH

PdCl2(PhCN)2 3mol%

Cl-Pd O C5H11

Pd(II)

256 + C6H13

OH

O

O

50%

45% H2 O

257 OH

259 HO

258 O

Pd(OAc)2, CuCl2 TMS

O

C6H13

TMS

260 O + Pd(0)

261

Pd-X

262

H2O Pd(II)

O2, MeCN, H2O, HCl, 72%

O

TMS

Reaction of Alkynes

63

Regioselective hydration of the alkynyl ketone 263 is also catalyzed by PdCl2 to afford the 1,5-diketone 265 under mild conditions. Protonolysis of the oxypalladation product 264 generates Pd(II), and the 1,5-diketone 265 is formed by hydration of the intermediate [112]. O

Me

Me

O

PdCl2(MeCN)2

oxypalladation

H2O, 92% PdCl2

263 H2O +

O

+

protonolysis HCl

Me

O

PdCl

OH

Me

Me

O

H PdCl2

264

O

O

265

PdCl2 -catalyzed oxypalladation of 4-pentynoic acid generates the γ -lactonic alkenylpalladium 266, and its protonolysis affords the γ -methylene-γ -lactone 267 with regeneration of Pd(II) [113]. A palladium cluster is a very active catalyst of the cyclization, and the δ-methylene-δ-lactone 268 was obtained from 5-hexynoic acid in high yield at 40 ◦ C in a few minutes [114]. protonolysis HCl

PdCl2(MeCN)2 CO2H

Cl-Pd THF reflux, Et3N, 1 h, 100%

O 266

O

O

O

267

PdCl2

[PdMo3S4(tacn)Cl](PF6), 0.3 mol% CO2H

40 °C, 3 min, 86% tacn = 1,4,7-triazacyclononane

O

O

268

The PdCl2 -catalyzed reaction of propargylic alcohol 269, CO2 and allyl chloride yields the cyclic carbonate 270 in the presence of BuLi. In this reaction, lithium 2-alkynyl carbonate 271 undergoes oxypalladation as shown by 272 to generate the cyclic carbonate 273. Insertion of allyl chloride gives 274, which undergoes dechloropalladation as shown by 274 to give the cyclic carbonate 270 and PdCl2 . Hydrolysis of the carbonate affords the 2-oxo-3-butyl-5-hexen-1-ol (275) [115]. Formation of the pyrrole 278 from 1-amino-3-alkyn-2-ol 276 is catalyzed by PdCl2 . The reaction can be understood as aminopalladation to generate 277, followed by protonolysis and dehydration [116]. Indoles are prepared from o-alkynyl aromatic amines. The required alkynyl amine 279 is prepared from o-iodoacetanilide. Aminopalladation of 279 and protonolysis affords 280 [117].

64

Oxidative Reactions with Pd(II) Compounds O Bu

1. BuLi

OH + CO2 +

Cl

Bu

91%

mechanism

O

CO2

O

O

2. PdCl 2(MeCN)2

269

270

PdCl2(MeCN)2

Bu

Bu

O

OLi

OLi

271 O

oxypalladation

Bu O

O

Cl

Cl-Pd

insertion

O

O

OPdCl Bu 273

272 O Cl

O

O Cl-Pd

O

dechloropalladation

O

O

Bu

Bu

PdCl2

274

270 Bu H2O OH O 275

OH Et

C6H13

PdCl2

OH

PdCl2(MeCN)2 Et

C6H13

84%

NH2 276

NH2

HX

Pd-Cl

Et

Et HO N H

C6H13

N H

277

278 R

I +

Pd-X PdCl2

Pd(0) R

C6H13

CuI

NHAc

NHAc

MeCN 84~93%

N Ac

R

279 H+ R N Ac 280

4-(1-Alkenyl)isoquinoline 282 was obtained by the reaction of 2-(1-alkynylphenyl)aldimine 281 with acrylate in DMSO. Cyclization of benzaldimine by PdBr2 generates 283, and insertion of acrylate, followed by β-H elimination gave 282 and Pd(0), which was oxidized to Pd(II) with CuCl2 and O2 . Finally the isoquinoline 282 was formed by fragmentation [118].

Reaction of Alkynes N

t-Bu

65

PdBr2,CuCl2,O2 +

CO2n-Bu

N

NaHCO3, DMSO 70 °C, 56%

Me + Me

Ph

Ph

281

n-BuO2C 282 fragmentation + N

t-Bu

+

CO2n-Bu

Pd(O)

PdBr

t-Bu

N O2

PdBr2

283 CO2n-Bu

Treatment of (Z)-pent-2-en-4-yn-1-ol 284 with PdI2 and KI afforded furan 286 via oxypalladation, followed by protonolysis to give 285 and regeneration of PdI2 . KI is added to make PdI2 soluble [119]. The corresponding thiol 287 undergoes a similar cyclization to form the thiophene 288 [120]. Me PdI2

DMA 92%

OH

Me

Me HI

PdI2, KI PdI

O

O

HI

PdI2

284

285

Me + PdI2 Me

O 286

Me

Me PdI2, KI

Et SH

DMA 80%

Me HI

PdI Et

S

287

Et PdI2

Me

Et

S

Me

S

+

PdI2

288

An enyne system 292, which can be generated by Pd-catalyzed domino reactions of the terminal alkyne 289 with the alkynoate 290, undergoes cyclization to give the furan 297 and the butenolide 295 under different conditions [121]. The reaction of the terminal alkyne 289 with Pd(OAc)2 using TDMPP (I-9) as a ligand

66

Oxidative Reactions with Pd(II) Compounds

generates alkynylpalladium 291. Insertion of 290 to 291 gives 292. The enyne system 293 is formed by protonolysis of 292. In the presence of triethylamine, lactonization of 293 takes place to afford the butenolide 295 in 81 % yield. On the other hand, the furan 297 is obtained in the presence of tributyltin acetate. In these reactions, protonolysis of 292 and 296 with AcOH generates Pd(OAc)2 and hence the oxidative reaction proceeds with a catalytic amount of Pd(OAc)2 . PdOAc

OH CO2Et OH

CO2Et

Pd(OAc)2 +

291

TDMPP(I-9) OH

289

OH 290

290 AcOPd

insertion

OH

H

CO2Et

CO2Et AcOH

OH

OH

OH + Pd(OAc)2

protonolysis 293

292 path b Bu3SnOAc Pd(OAc)2

path a THF, Et 3N lactonization

O

CO2Et O OH

OH OH 294

295

81%

oxypalladation AcOPd

OH

CO2Et

O

H

AcOH protonolysis OH

CO2Et

O

Pd(OAc)2

296 CO2Et

OH

O 297

56%

Oxidative carbonylation is another useful reaction. The following three types of oxidative carbonylation of alkynes are known. The first one is the synthesis of the acetylene carboxylates 299 via formation of the alkynylpalladium intermediate 298 from terminal alkynes (path a) [122].

Reaction of Alkynes

67

The second type of carbonylation starts by cis chloropalladation of triple bonds to generate 300 and 301, and CO insertion gives the unsaturated β-chloro esters 302 and 303 (path b). In the third type, oxidative dicarbonylation of alkyne gives maleate, fumarate and muconate derivatives 304 and 305 by dimerization and dicarbonylation, which are then converted to the corresponding esters 306 and 307 (path c) [123]. Methyl muconate was obtained as a main product in MeOH containing thiourea and a catalytic amount of PdCl2 by using acetylene and oxygen [124]. path a R

H

CO, ROH

+ PdCl2

R

PdCl

R

CO2R

298

299

HCl path b R R

H

R

+

+ PdCl2 Cl

Cl

Pd-Cl

Pd-Cl

300

301

R

R +

Cl

Cl

CO2R 302

CO2R 303

path c COCl HC

+

CH + CO + PdCl2 ClOC

COCl

304

305

CO2Et

EtOH

ClOC

EtO2C

+

CO2Et

EtO2C 306

307

Hydrocarbonylation of alkynes to give the unsaturated esters 308 and 309, catalyzed by Pd(0), is clearly different from the oxidative carbonylation, and this process is treated in Chapter 7.11.

R

H

+ CO + MeOH

Pd(0)

R

R +

MeO2C

CO2Me 308

309

Reaction of various terminal alkynes using PdCl2 and CuCl2 in the presence of a base affords the alkynic esters 310 in satisfactory yields (path a) [122]. Carbonylation of terminal alkynes proceeds smoothly using Pd(OAc)2 , hydroquinone and heteropolyacid (molybdovanadophosphate, NPMoV) in the presence of MeSO3 H under oxygen at room temperature. Different products are obtained depending on the solvents. In MeOH, the acetylenic ester 311 was obtained (path a), but α-alkylmaleic anhydride 312 was obtained in dioxane (path c) [125].

68

Oxidative Reactions with Pd(II) Compounds path a C5H11

H

Ph

H

PdCl2, CuCl2

+ CO + MeOH

+ CO + MeOH

C5H11

AcONa, 1 atm 74%

CO2Me 310

Pd(OAc)2, HQ, NPMoV Ph

MeSO3H, 25 °C 85%

CO2Me 311 t-Bu

path c t-Bu

Pd(OAc)2, HQ, NPMoV

+ CO

H

dioxane, MeSO 3H, 25 °C 70%

O

O

O 312

An example of path b-type reaction is regioselective chlorocarbonylation of phenylacetylene using PdCl2 and CuCl2 to give the 3-chloro-3-phenylacrylate (313). The reaction is understood by chloropalladation of alkynes, followed by CO insertion [126]. As a related reaction, oxidative carbonylation of the terminal propargylic acetate 314 gives γ -acetoxy-β-methoxy-α,β-unsaturated ester 317, which is hydrolyzed to give the β-keto ester 318. The reaction proceeds via regioselective methoxypalladation of the triple bond as shown by 315 and 316 [127]. It should be pointed out that these path b carbonylations of terminal alkynes are carried out without addition of bases, and no path a-type carbonylation to give acetylene carboxylates 319 is observed. 5-(Methoxycarbonyl)methylene-3oxazoline 321 is obtained by oxidative carbonylation of the benzamide 320 using path b H + CO + BuOH

Ph

PdCl

PdCl2, CuCl2

Cl

1 atm, rt 63%

Ph

CO2Bu

Cl Ph 313

OMe MeO PdCl2, CuCl2

AcO

MeOH, MeC(OMe)3 58% 314

PdCl2 O

PdCl OAc

O 315

316

O

MeO

CO2Me

AcO CO2Me

CO2Me OAc

OAc 317

HN + CO + MeOH

Ph O 320

318

319

N

Pd/C, KI CO 24 atm, O2 6 atm 83%

0%

Ph

CO2Me O 321

Reaction of Alkynes

69

Pd on carbon as a catalyst, and O2 and KI as oxidants. anti-Attack to the triple bond takes place to give the E-product stereoselectively [128]. Intramolecular path b-type reaction of (Z)-alk-2-en-4-yn-1-ols 322, catalyzed by PdI2 and KI, produced the furan-2-acetic ester 325 by efficient oxidative carbonylation. The reaction is explained by intramolecular oxypalladation of the triple bond to generate 323, followed by CO insertion to give 324 and double bond isomerization [129].

+ CO + MeOH + O2 OH

PdI2, KI 59%

Bu

322

Pd-X

oxypalladation O

CO MeOH

CO2Me O

Bu

Bu 324

323

CO2Me O Bu 325

Carbonylation of the 3-butyn-1-ols under mild conditions gives different products depending on substituents. The lactone 327 was obtained from 3-pentyn-1-ol (326) by path b-type reaction. The lactonic ester 329 was obtained by path c-type reaction from 328 which has a TMS group at the alkyne terminus [65]. Me

MeO Me + CO + MeOH

PdCl2, CuCl2 MeC(OEt)3

OH

O

326

O

327 TMS

TMS CO2Me + CO + MeOH

OH

PdCl2, CuCl2 MeC(OEt)3 O

328

O

329

Similarly, o-hydroxyphenylacetylene 330 underwent carbonylative cyclization to give benzofuran-3-carboxylate 333. As catalysts, PdI2 –thiourea–CBr4 [130] or PdCl2 –CuCl2 [131] are used. As a mechanistic explanation, the reaction proceeds by carbopalladation of methoxycarbonylpalladium as shown by 331 to give 332 and its reductive elimination. The reaction of o-hydroxyphenylacetylene 334 catalyzed by PdCl2 and BQ afforded the benzo[b]furan-3-carboxylate derivative 335 [132].

70

Oxidative Reactions with Pd(II) Compounds Ph

Ph

X-Pd-CO2Me PdI2, thiourea

+ CO + MeOH

CBr4, Cs2CO3 40 °C, 80%

OH 330

Pd CO2Me

OH 331 CO2Me

RE

Ph

O

Ph

O

332

333

EtO2C OMe OBn MeO

OH

+ CO

PdCl2, CuCl2 AcONa, MeOH 68%

334 CO2Me

OMe

EtO2C OBn O OMe 335

An efficient and selective dicarbonylation of terminal alkynes mainly to E form can be carried out under mild conditions using PdI2 and KI under pressure of CO and air. From 1-hexyne, dimethyl butylmaleate (336) was obtained as a main product and the acetal of butylmaleic anhydride 337 as a minor product [133]. Iodine is an oxidant. The usefulness of this reaction was demonstrated by the smooth preparation of a synthetic intermediate of CP-263,114 339 from the terminal alkyne 338 in high yield [134].

+ CO

Bu

PdI2/KI air, 20 °C 20 atm, 98%

Bu

Bu + CO2Me

MeO2C 336

AcO

MeO

337

65%

338

+ CO + MeOH

20%

CO2Me

AcO O

O

O

MeO

PdI2/KI

CO2Me O

air, 60 °C, 89%

339

In some cases, oxidative carbonylation proceeds even in the absence of any oxidant. As an example, diphenylcrotonolactone (340) was obtained unexpectedly

Reaction of Alkynes

71

as a major product by the carbonylation of diphenylacetylene in EtOH together with diethyl diphenylmaleate (341) using PdCl2 and HCl. In this oxidative carbonylation, reduction of an anhydride to a lactone occurred [135]. The unsaturated lactone [3-substituted furan-2(5H )-one] 342 was obtained from 1hexyne using PdI2 and KI under milder conditions. The presence of water is essential. Formation of CO2 was observed showing that the reduction occurred with H2 generated from CO and water [136]. Under similar conditions, oxidative dicarbonylation of the propargylamine 343 affords the β-lactam 344. Also γ lactams and oxazolines were obtained depending on the protecting groups of the amine [137].

Ph + CO + EtOH

Ph

PdCl2, HCl

Ph

Ph

Ph

Ph +

100 °C O

66%

340

CO2Et

EtO2C

O

341

26%

n-Bu + CO

n-Bu

PdI2/KI, 10 atm, 80 °C H2O (2 equiv), dioxane 65%

O

O

+ CO2

342 CO + H2O

Pd

CO2 + H2

RO2C + CO + ROH + O2

PdI2/KI 90%

NH-Bn

NBn O

343

344

Several products are obtained by Pd-catalyzed carbonylation of propargyl alcohol (345). As one example, aconitate is obtained as a minor product in the carbonylation of propargyl alcohol [138]. However, trimethyl aconitate (347) was obtained in 70 % overall yield from 345 in two steps. The first step is the oxidative carbonylation under CO and air using PdI2 and KI to give dimethyl hydroxymethylbutenedioate (346), which is carbonylated further to give 347 using [Pd(tu)4 ]I2 (tu = thiourea) as a catalyst [139]. HO + 2 CO + 2 MeOH

OH

PdI2, KI, air 90%

345

MeO2C

CO2Me 346 CO2Me

[Pd(tu)4]I2 73%

MeO2C

CO2Me 347

72

Oxidative Reactions with Pd(II) Compounds

Propargyl ester 348 undergoes an interesting oxidative rearrangement by using a catalytic amount of PdBr2 under an oxygen atmosphere to form the α-acetoxy-α,βunsaturated aldehyde 351 [140]. The first step is oxypalladation to form 349, and subsequent hydration as shown by 349 and 350 gives rise to the aldehyde 351. Interestingly, reoxidation of Pd(0) takes place smoothly under oxygen without using other reoxidants. Since it is known that the aldehyde 351 can be converted to 352 with a base, the reaction offers an efficient synthetic method for corticosteroids from 17-keto steroids [141,142]. The internal alkyne 353 undergoes similar rearrangement to give the α-acetoxy-α,β-unsaturated ketone 354. No reaction takes place in the absence of water and oxygen. The ketone 354 is hydrolyzed to give the α-diketone 355. The reaction offers a synthetic method for α-diketones [143]. Pd(0)-catalyzed hydrocarbonylation of propargyl alcohols is treated in Chapter 6.3. O Me Me

+

O O

O OH

K2PdBr4, O2

H

DME, 90% Pd-X O

349 348 Me

H

O O

AcO

O

CHO

Pd-X

+ Pd(0)

350

351 O OAc

DBU

H

O 352 AcO

OAc

PdCl2(MeCN)2 C6H13

Bu 353

THF, H 2O, O 2 72.5%

Bu

C6H13 O 354 O

H2O

C6H13

Bu O 355

Reaction of Alkynes

73

The chloroallylation of alkynes with allyl chlorides affords 1-chloro-1,4-dienes 358 using PdCl2 as a catalyst. The reaction can be understood by chloropalladation of alkyne to generate 356, followed by insertion of the double bond of allyl chloride to give 357. The last step is the well-established dechloropalladation to afford the chlorodiene 358 as the Pd(II)-generation step. In this case, no β-H elimination occurs. Interaction of Pd-Cl plays a role [144]. Pd(OAc)2 -catalyzed reaction of acetylene and allyl chloride in the presence of LiCl affords an E, Z-mixture of the 1-chloro-1,3,6-heptariene (360). In this case, first insertion of acetylene occurs to give 359, and then the insertion of allyl chloride follows [145].

R

R

PdCl2

Cl

+

R

chloropalladation

R

Cl

Cl

PdCl 356

R insertion

R

Cl

R

R

Pd

Cl

+ PdCl2

dechloropalladation Cl

Cl 357

2

HC

358 Pd(OAc)2

Cl

+

CH

Cl

LiCl, AcOH

Pd-Cl 359 Cl 360

The bromoallylation product 363 of the alkyne 361 was converted to the 1-aryl1,4-pentadiene 364 in 83 % yield by adding the the organoborane 362, P(t-Bu)3 and Cs2 CO3 . Thus the haloallylation products, obtained by the reaction shown above, are reactive alkenyl halides and further Pd-catalyzed conversion is possible as a two-step, one-pot reaction [146]. B(OH)2 CO2Me

+

Br

361

+

PdBr2(PhCN)2 DME, rt

MeO 362 B(OH)2 MeO2C

MeO2C

MeO Br

363

362

P(t-Bu)3, Cs2(CO)3 80 °C, 83%

364

OMe

The ketone 367 was obtained in one pot by oxidation of the terminal double bond of the bromoallylation product 366 of the alkyne 365 by adding CuCl and H2 O under O2 atmosphere [146].

74

Oxidative Reactions with Pd(II) Compounds n-Pr

n-Pr

n-Pr

PdBr2(PhCN)2

+

Br

n-Pr

DME, rt, 80%

Br

365

366

n-Pr

O

CuCl, O2

n-Pr Br

DME, H2O 367

Preparation of hepta-2,6-dien-2-yne 371 is possible by combination with the Sonogashira reaction. The dienyne 371 was obtained by Sonogashira coupling of the bromoallylation product 369 with the alkyne 370 at room temperature using CuI and P(t-Bu)3 [147]. Me OH

n-Bu

PdBr2(PhCN)2

n-Bu +

Br

370 Br

DME, rt

368

Me

P(t-Bu)3, CuI, HN(i-Pr)2, rt, 85%

369

n-Bu

Me Me

371

OH

γ ,δ-Unsaturated carbonyl compounds are obtained by the domino reaction of alkynes with acrolein or methyl vinyl ketone. Treatment of the alkyne 372 and acrolein (373) with Pd(OAc)2 (5 mol%) generates the acetoxylpalladation product 374, and insertion of acrolein to 374 gives 375, which is converted to the aldehyde 376 by protonolysis with AcOH, and Pd(OAc)2 is regenerated. The use of bpy (6 mol%) or phenanthroline as a ligand is important. The ligand plays a crucial role in inhibiting β-H elimination and assisting protonolysis [148]. Pd(OAc)2, bpy

CO2Bu +

Me 372 AcO

373 CO2Bu Pd-X

Me 375

CHO AcOH, MeCN, 78%

CHO

AcO

CO2Bu

CHO

Pd-X

Me 374

AcOH

AcO

protonolysis

Me

CO2Bu + Pd(OAc)2 376

CHO

An interesting and useful synthetic method of γ -lactones has been developed by Lu and co-workers based on an intramolecular version of the haloallylation reactions [149]. PdCl2 or Pd(OAc)2 -LiCl-catalyzed reaction of the 3
-(chloromethyl)-2
-alkenyl 2-alkynoates 377 affords the α-alkylidene-β-vinyl-γ -butyrolactones 379. The first step is chloropalladation of the triple bond, followed by

Reaction of Alkynes

75

insertion of the double bond to generate 378. The last step is dechloropalladation of the insertion product 378 to give the vinyl group 379 without undergoing β-H elimination. The reaction of the 2-alkynoate bearing an allylic acetate moiety 380 using Pd(OAc)2 and the chiral bisoxazoline ligand 383 afforded the β-vinylbutyrolactone 381 in 85 % ee. In this reaction, acetoxypalladation of the triple bond is followed by insertion of olefin bond, and deacetoxypalladation is the last step, and A-factor 382 (86 % ee) was synthesized from 381 [150]. The cyclization was extended to the allyl 2-alkynoates 384 without 4
-heteroatom [151]. In this case, the insertion products must be quenched by oxidative cleavage to generate Pd(II). Thus different products are obtained depending on methods of quenching the insertion products. In the presence of CuCl2 , oxidative chlorination of the insertion product 385 takes place to give the β-chloromethyllactones 386. Quenching is also possible by protonolysis and carbonylation [152]. Cl

H

PdX Cl

Pd(OAc)2, LiCl

Cl

AcOH O

O

O

O 378

377 Cl

+ Pd(II) O

O 379

C7H15

C7H15

C7H15 HO

AcO

OAc Pd(OAc)2/L*

OH

AcOH O

O

O 380 O L=

382

N

H

H

Ph

(S,S) 383

Me

Me Cl PdCl2, CuCl2

O

O

O

(3S)-(+)-A-factor 86% ee

381

O N

Ph

O

O 85% ee

86%

PdX

LiCl, MeCN 80%

O

384

O 385 Me

Cl CuCl2

Cl O

O 386

+ PdCl2

76

Oxidative Reactions with Pd(II) Compounds

Similarly, γ -lactams are prepared from 2-alkynamides bearing an allyl acetate moiety on nitrogen. The last step is deacetoxypalladation to generate Pd(II) [153]. The α-alkylidene-γ -butyrolactam 388 was obtained by cyclization of the N -allylic 2-alkynamide 387 using Pd(OAc)2 and LiBr, and the reaction has been applied to the synthesis of isocynometrine (389) [154]. The aldehyde 392 was obtained by cyclization of the alkynic α,β-unsaturated aldehyde 390, followed by protonolysis of the insertion product 391 with AcOH [155]. OAc

Ph

Ph

N

HO

Br

Pd(OAc)2, LiBr

Ph

N

AcOH, 92% O

Me O

N Me

O

N Me

387

388

N Me

isocynometrine 389

Me

Me

CHO

PdX

Br

Pd(OAc)2, LiBr

CHO

AcOH, 95% O

O

N Bn

N Bn

390

391 Me Br

protonation

CHO

Pd(II)

O

N Bn 392

In the reactions shown above, preferential β-heteroatom elimination occurs rather than β-H elimination. Lu reported that the presence of a halide ligand effectively blocks β-H elimination. Thus the different products were obtained depending on the amounts of added LiBr in the reaction of 3-heptynoic acid (393) with acrolein. In the presence of 200 mol% LiBr in AcOH, protonolysis occurs to give 395 and Pd(II), while the unsaturated aldehyde 394 was obtained by a O Pd-Br HO

Pd-Br +

CHO

CHO O

O

O

n-Pr

O

n-Pr

n-Pr 393

Pd(OAc)2 (5 mol%) LiBr (10 mol%)

AcOH 94% based on Pd

AcOH 85%

Pd(OAc)2 (5 mol%) LiBr (200 mol%)

CHO

CHO

+ Pd(0) O

O 394

n-Pr

+ Pd(II) O

O 395

n-Pr

Homocoupling and Oxidative Substitution Reactions

77

Heck-type reaction in 94 % yield based on Pd(OAc)2 when 10 mol% of LiBr was used [156].

2.7 Homocoupling and Oxidative Substitution Reactions of Aromatic Compounds Three oxidative reactions of benzene with Pd(OAc)2 via reactive phenylpalladium acetate (397) are known. The insertion of alkenes and β-H elimination afford arylalkenes 398. This topic is treated in Section 2.2.8. Two other reactions, oxidative homocoupling [157,158] and acetoxylation [159] are treated in this section. The palladation of aromatic compounds is possible only with Pd(OAc)2 . No reaction takes place with PdCl2 . The oxidative homocoupling of benzene with Pd(OAc)2 affords biphenyl (399). The scope of the homocoupling reaction has been studied [160,161]. The reaction was applied to commercial production of biphenyltetracarboxylate (400) by coupling of dimethyl phthalate using Pd(OAc)2 and Cu(OAc)2 . Addition of phenanthroline is important for the regioselective formation of the most important 3,4,3
4
-isomer [162]. R

398

R PdOAc + Pd(OAc)2 399

397

OAc

CO2R

RO2C CO2R

Pd(OAc)2 Cu(OAc)2

CO2R

RO2C

CO2R 400

In addition to benzene derivatives, the coupling can be extended to heteroaromatic compounds. Akermark found that preparation of carbazole (401) can be carried out using Pd(TFA)2 and Sn(OAc)2 under oxygen in AcOH [74]. Staurosporine aglycone 402 was prepared by the intramolecular coupling of indole rings [163]. The coupling of thiophene, furan and pyrrole [164,165] has been carried out. The oxidative crosscoupling of furans and thiophenes with benzene is possible. 4-Phenylfurfural (403) is a main product of the cross-coupling of furfural and benzene [166]. Biaryls are also prepared by oxidative coupling of organometallic compounds. Transmetallation of various organometallic compounds (Hg, Tl, Sn, B, Si, etc.) with Pd(II) generates in situ the reactive σ -arylpalladium intermediates 404, which undergo oxidative homocoupling to afford 405 (similar to formation of 399 from 397).

78

Oxidative Reactions with Pd(II) Compounds Pd(OCOCF3)2, Sn(OAc)2 O2, AcOH, 66% N H

N H 401 H N

O

O

H N

O

O

Pd(OAc)2 75% N H

N H

N H

N H 402

CHO

O

+

Pd(OAc)2 CHO

O

403 48% +

O

CHO 23%

R M

+ Pd(OAc)2

transmetallation

R PdOAc

+ MOAc

404 R

R

R

PdOAc M = HgY, BY 2, SnY3, SiY3

405

Biaryls are prepared also by homocoupling of arylmetal compounds using several oxidants. Arylbronic acids undergo efficient oxidative coupling [167]. 4,4
Dichlorobiphenyl (407) was obtained in 72 % yield from 4-chlorophenylboronic acid (406) using Cu(NO3 )2 as an oxidant [168]. Homocoupling of the alkenylstannane 408 was carried out with Pd(OAc)2 and O2 to give the conjugated diene 409 [169,170]. Alkyl–alkyl coupling of alkylboranes and alkylzinc compounds promoted by Pd(II) was carried out. Benzylzinc bromide (410) was coupled to give 411 in high yield by the treatment with PdCl2 (rac)-BINAP as a catalyst. In this reaction, desyl bromide (2-bromo-2-phenylacetophenone) or desyl chloride is used as an oxidant of Pd(0) [12]. Also N -chlorosuccinimde can be used as the oxidant in arylzinc coupling [171].

Regioselective Reactions Based on Chelation

79

Pd(PPh3)4 (0.1 equiv) Cu(NO3)2 (3 equiv) Cl

B(OH)2

AcONa, EtOH, rt, 72%

Cl

Cl

406

407 Pd(OAc)2

C6H13

SnEt3

C6H13

C6H13

O2, 79%

408

409

ZnBr

PdCl2(rac-BINAP) desyl bromide, 99%

410

411

Acetoxybenzene (412) is prepared by the reaction of benzene with Pd(OAc)2 [158,172]. This reaction is regarded as a potentially useful method for phenol production from benzene, if carried out with only a catalytic amount of Pd(OAc)2 . Further reaction of acetoxybenzene produces 1,3- and 1,4-diacetoxybenzenes. OAc OAc

OAc Pd(OAc)2

+

AcOH, O2

AcO

OAc 412

OH OH

OH + OH

HO

2.8 Regioselective Reactions Based on Chelation and Participation of Heteroatoms Unactivated aromatic and alkyl groups can be functionalized by formation of chelate Pd complexes and interesting applications have been published, although most of them are stoichiometric reactions. Aromatic compounds 413, bearing hetero atom-containing groups at positions suitable for forming mainly five-membered or sometimes six-membered chelating rings, undergo cyclopalladation at an ortho-position to form a σ -arylpalladium bond as in 414 by virtue of the stabilization due to the chelation of these hetero atoms. The ortho-palladation products 414 are stable and can be isolated [173]. After the first report on the preparation of the azobenzene and N ,N -dimethylbenzylamine complexes 415 and 416 [174], numerous complexes have been prepared.

80

Oxidative Reactions with Pd(II) Compounds

Cl Pd

Cl

N A

N

A

+ PdX2

Pd H 2C

Pd-X

413

N Me

Me

414

415

416

The σ -arylpalladium bonds in these complexes are reactive and undergo insertion and substitution reactions, and the reactions offer useful methods for the regiospecific functionalization of the aromatic rings. Alkenes, alkynes and CO insert under certain conditions. Some classical examples are cited in the following. The first example is insertion of styrene to N ,N -dimethylbenzylamine complex (416) to form the stilbene derivative 417, which takes place smoothly at room temperature in AcOH [14]. Alkynes insert smoothly. Two moles of diphenylacetylene insert into the benzyl methyl sulfide complex 418 to afford the eight-membered heterocycle 419 [175].

Pd

Cl

Ph +

AcOH

Ph

+ Pd + HCl

N

N

Me

Me

Me

Me 416

417

Ph

Ph Ph

PdOAc + Ph

Ph +

S Me 418

AcO-

S Me

Ph

419

Facile insertion of CO takes place, and the reaction offers a synthetic method of ortho-substituted benzoic acid derivatives. The 2-aryl-3-indazolone 421 was obtained in high yield by carbonylation of 4-methylazobenzene complex 420 in alcohol or water [176]. Cobalt-catalyzed carbonylation of 421 and subsequent hydrolysis afforded aniline and 5-methylanthranilic acid (422). The results show that the σ -bond formation is an electrophilic substitution of PdCl2 on the benzene ring [176,177]. The alkylation at the ortho carbon is possible by the reaction of chelate complexes with Grignard reagents, organolithium reagents in the presence of PPh3 , or alkyl halides. o-Methylbenzaldehyde was prepared via the formation of a Schiff base complex 423 and its reaction with MeLi [178]. The ortho alkylation is possible even with alkyl halides. Treatment of acetanilide (424) with 3 equivalents of

Regioselective Reactions Based on Chelation

81

Me

Me

Pd Cl

CO, EtOH C

84%

N

H N

CO O

NH

Co2(CO)8

N

N

O N

Me O

420

421

NH2

NH2 +

Me

CO2H 422

Pd(OAc)2 and an excess of MeI afforded 2,6-dimethylacetanilide (425) by stepwise ortho-palladation and methylation twice [179]. However, treatment of the Schiff base complex 426 with trifluoroacetic acid and alkyl iodide produced the 2,6-dialkylbenzaldehyde 427 after hydrolysis. This reaction can be made semicatalytic [180].

1. PhNH 2 2. Pd(OAc) 2

Pd-Cl

3. NaCl

HC N

MeLi

Me

Ph3P 90%

H2O

HC

Me

N

CHO

CHO

423 H N

H N O

+ Pd(OAc)2

MeI O

(3 equiv.)

O

AcO Pd

MeCN

N H

Pd

424

OAc

Me Me NHCOMe

MeI Me 425

C6H13 Ph N Pd AcO 426

CHO CF3CO2H

H2O

C6H13I

84%

C6H13 427

82

Oxidative Reactions with Pd(II) Compounds

Due to the chelating effect of nitrogen, facile cyclopalladation of allylamines occurs to form 428 which undergoes insertion reactions [180]. The first classical application is the ingenious synthesis by Holton of a prostaglandin derivative starting from 3-(dimethylamino)cyclopentene (429), utilizing facile palladation by the chelating effect of allylic amines [181]. The key steps in the synthesis are the facile and stereoselective introductions of a carbanion and an oxy anion into the cyclopentene ring by virtue of the stabilizing chelating effect of the amino group, and the alkene insertion to the Pd–carbon σ -bond. The first step is the stereo-defined carbopalladation with malonate and the subsequent β-H elimination to form the 3substituted 4-aminocyclopentene 430 in 92 % yield. The attack of the malonate is anti to the amino group. Further treatment of the amino ester 430 with Li2 PdCl4 , 2chloroethanol and diisopropylethylamine in DMSO gave rise to the oxypalladation product 431, which was immediately treated with pentyl vinyl ketone. Insertion of the alkene afforded the desired enone 432 in 50 % yield. The enone 432 was converted to an important intermediate 433 for prostaglandin synthesis. Cl MeO

NMe2 + MeOH + PdCl 2

Pd NMe2 428 N

N

N +

CO2Et CO2Et

+ Li2PdCl4

Pd

CO2Et

Cl

CO2Et

92%

CO2Et CO2Et

430

429 N

Cl Pd

Li2PdCl4 OH Cl

O

CO2Et CO2Et

O

50%

Cl 431 N CO2Et CO2Et

steps

Cl

O

O 432

O

O

RO 433

O

As a recent elegant application of coordination-directed C—H activation and subsequent C—C bond formation, Sames synthesized the core of teleocidin B4 [182].

Regioselective Reactions Based on Chelation

83

The key step is the selective C—H bond activation of two methyl groups of an ortho-tert-butyl in the Schiff base 434. Treatment of 434 with Pd(OAc)2 afforded the palladacycle 435 in 75 % yield by the help of rather strong coordination to N and O functions. The first functionalization was achieved by the reaction with the alkenylboronic acid to yield the alkylated product 436 in 86 % yield, which was converted to 437 by the Friedel-Crafts reaction. Then the second palladacycle formation from 437 provided two diastereomers 438, which were, without isolation, subjected to carbonylation (40 atm) at room temperature. Treatment of crude reaction mixture with silica gel cleaved the Schiff base and spontaneous lactonization occurred to give a mixture of the lactones 439 and 440 (6 : 1). The main product was N-alkylated to yield 441. Finally, the fourth ring was constructed by a Heck-type reaction on the aromatic ring to give the desired compound.

OMe

OMe

MeO OMe PdCl , AcONa 2

B(OH)2

AcOH, 75%

N

N Ag2O, DMF, 86%

Pd MeO

O

Cl

434

Me 435

OMe OMe MeSO3H

N

Friedel-Crafts MeO OMe 436

PdCl2, AcONa

N MeO 437 OMe OMe MeO 1. CO, MeOH N Pd Cl

2. SiO 2, CHCl3 O

65%

O Me

Me

439

438

+

NH

Me

OMe

NH

Me

O Me 440

84

Oxidative Reactions with Pd(II) Compounds OH Br Br

1. Br

Pd(OAc)2, P(t-Bu)3

t-BuOK

N

Me

Cs2CO3, DMA, 57% O

2. BBr 3

Me OH

441

N

Me

O Me teleocidin B4 core

Synthetic reactions utilizing the stable chelate complexes cited above are mostly stoichiometric. However, studies on catalytic reactions involving chelate complexes are attracting attention as more useful synthetic methods. The amide carbonyl of acetanilide (442) is capable of forming a six-membered chelate ring 443, and undergoes alkene insertion [183]. Importantly, the reaction of the acetanilide 442 with butyl acrylate via the complex 443 can be carried out in AcOH with a catalytic amount of Pd(OAc)2 (2 mol%) and BQ as an oxidant to give the coupling product in 85 % yield [184]. H N

H N + O 442

Pd(OAc)2 (2 mol %) CO2Bu

BQ, AcOH, 85%

Pd

O

OAc 443 H N O

CO2Bu

Similarly, the catalytic functionalization t-butyl group has been investigated. Using 2-thiobenzylidene Schiff base 444, phenylation of the methyl group with Ph2 Si(OH)Me was carried out in the presence of Pd(OAc) 2 (2.5 mol%) and Cu(OAc)2 (2 equiv.) in DMF, and the phenylated product was obtained in 51 % yield with TON 20. Although the reaction is not efficient, further improvement is expected [185]. Recently, regioselective oxidative coupling of alkenes with aromatics as useful synthetic methods has been developed based on participation of some functional groups such as OH and amino present in suitable positions of aromatic rings, even though no stable chelate complex is isolated. Oxidative coupling of 2phenylphenol (445) with acrylate using Pd(OAc)2 and Cu(OAc)2 in the presence of MS 4A under air occurred regioselectively at the 2
carbon due to coordination

Regioselective Reactions Based on Chelation

85

Pd(OAc)2, Cu(OAc)2

N

+ Ph2Si(OH)Me

DMF, 100 °C, 51% TON 20

S Me 444

N S Me

of phenolic oxygen to Pd(II) species as shown by 446 to give 447 as a primary product. Subsequent Michael-type addition afforded 6H -dibenzo[b,d]pyran6-acetate 448 in 69 % yield [186]. Sulfonamide in biphenyl 449 is a good coordinating group, and regioselective coupling of acrylate at 2
carbon occurred to give 450, and subsequent Michael-type addition afforded ethyl 5,6-dihydro-5(benzenesulfonyl)phenanthridine-6-acetate (451).

+

Pd(OAc)2, Cu(OAc)2 CO2Bu

MS 4A, air, DMF, 79% PdOAc

OH

O

445

446

CO2Bu

O

OH CO2Bu

448

447

Pd(OAc)2 , Cu(OAc)2

+

CO2Et AcONa, MS 4A, air

PhO2SHN

DMF, 84%

449 EtO2C PhO2SHN 450 CO2Et

PhO2S N

451

86

Oxidative Reactions with Pd(II) Compounds

Furthermore, regioselective reaction of styrene at the ortho position of p-methoxybenzoic acid (452) gave 453 as a primary product. Subsequent oxypalladation of 453 to give 454 and 455, and β-H elimination produced two lactones 456 and 457 [187]. Clean regiocontrol by weak coordination of Pd to OH, NHR and COOH groups is remarkable. CO2H

CO2H

Ph

Pd(OAc)2 , Cu(OAc)2

+

Pd(OAc)2

AcONa, MS 4A, air

Ph

Cu(OAc)2

DMF OMe

OMe

453

452 O

O +

O

MeO

Ph

MeO

O

PdX 455 O

O +

O

Ph

MeO 456

Ph

XPd

454

26%

O MeO Ph 14%

457

2.9 Oxidative Carbonylation of Alcohols and Amines Oxidative carbonylation of alcohols using PdCl2 affords the carbonate 458 and the oxalate 459 [188,189]. Selectivity of the mono- and dicarbonylation depends on CO pressure and reaction conditions. OR CO + 2 ROH + PdCl2

O

C OR

+ Pd + 2 HCl

458 2 CO + 2 ROH + PdCl2

CO2R CO2R

+ Pd + 2 HCl

459

Industrial processes for dialkyl oxalate and dimethyl carbonate from CO, alcohol and oxygen catalyzed by Pd have been developed by Ube Industries in Japan [2].

Oxidative Carbonylation of Alcohols and Amines

87

Production of n-butyl oxalate (461) is carried out in 1-butanol containing n-butyl nitrite (460) using Pd on carbon as a catalyst under CO pressure. The most ingenious invention in this process is the use of n-butyl nitrite as an efficient oxidant of Pd(0). Formally Pd(0) is oxidized to Pd(II) easily with n-butyl nitrite 460, then oxidative carbonylation proceeds to give di-n-butyl oxalate (461) and Pd(0). NO gas is generated after oxalate formation. In turn, NO is reconverted to 460 by the reaction with oxygen and 1-butanol. Most important from the standpoint of a commercial process is easy azeotropic separation of H2 O, formed by the oxidation, from 1-butanol. Otherwise water reacts with CO to produce CO2 in the presence of a Pd catalyst. The mechanism of this interesting catalytic cycle is explained in the following. Oxidative addition of alkyl nitrite 460 to Pd(0) is followed by CO insertion to generate 462, which is converted to 463 by the reaction of CO and butyl nitrite. Finally, reductive elimination of 463 affords the oxalate 461 and Pd(0). 2 CO + 2 BuONO

CO2Bu

Pd/C 90 °C, 60 atm

460

CO2Bu

+ 2 NO

461 2 NO + 2 BuOH + 1/2 O2

2 BuONO + H2O CO2Bu

2 CO + 2 BuOH + 1/2 O2

CO2Bu

+ H2O

461

CO2Bu CO2Bu Pd(0)

461

BuONO 460

O2 Pd(CO2Bu)2

BuOH

463

2 NO

ON-Pd-OBu

H2O CO BuONO 460

CO, BuONO

ON-Pd-CO2Bu 462

As an application, the polyoxalate 465 has been synthesized from dinitrite 464 using Pd-phosphine complex as a catalyst [190]. O ONO ONO 464

+ CO

PdCl2 O 465

O

n

88

Oxidative Reactions with Pd(II) Compounds

Dimethyl carbonate (467) is produced under low pressure CO. Dimethyl carbonate is now produced commercially by Ube industries based on the oxidative carbonylation of MeOH in the gas phase using methyl nitrite (466) as an oxidant as shown below. Another promising reaction is the preparation of commercially important diphenyl carbonate (468) by the oxidative carbonylation of phenol. So far the technology developed in many industrial laboratories is far from commercialization [191].

CO + 2 MeONO

PdCl2-CuCl2/C

MeO O + 2 NO

120 °C

MeO

466

467

2 NO + 2 MeOH + 1/2 O2

2 MeONO + H2O MeO

CO + 2 MeOH + 1/2 O2

O + H2O MeO 467

OH

O Pd/C, PbO, NMe 4Br, air + CO

OPh

PhO

60 atm,100 °C

TON = 1273 468

Oxidative carbonylation of amines affords alkylurea 469 and oxamide 470 [192]. Substituted ureas were prepared efficiently in the presence of PdI2 and KI under CO and CO2 pressure (total 60 atm) [193]. Synthesis of 2-oxazolidinone (471) by the carbonylation of 2-aminoethanol was carried out efficiently using a catalytic system of PdI2 –KI [194]. CO + RNH2

Pd/C

RNHCONHR +

CONHR CONHR

469

HO

NH2

+ CO

470

PdI2, KI, O2, air 20 atm, 100 °C, MeOH

O

NH O 471

Carbamates are produced by the oxidative carbonylation of amines in alcohol, and active research on the commercial production of alkyl carbamate as a precursor of isocyanates based on this reaction has been carried out. As an example, ethyl phenylcarbamate (472) was produced in a high yield (95 %) with a selectivity higher than 97 % by the reaction of aniline with CO in EtOH at 150 ◦ C

Oxidative Carbonylation of Alcohols and Amines

89

and 50 atm. Pd on carbon is the catalyst and KI is added as a promoter [195]. Furthermore, methyl phenylcarbamate (473) is obtained by reductive carbonylation of nitrobenzene directly. Pd(II) coordinated by phenanthroline is used as a catalyst [196]. Pd/C

PhNH2 + CO + EtOH + 1/2 O2

PhNHCO2Et + H2O

KI

472

NO2 + CO + MeOH

Pd(1,10-phenanthroline)2(OTf) 2 NHCO2Me

135 °C, 60 bar CO2

473

Interestingly ketones can be carbonylated. Reaction of cyclohexanone with CO in MeOH using PdCl2 and CuCl2 as catalysts under mild conditions afforded dimethyl pimelate (474) and methyl 6-chlorohexanoate (475) in good yields. Mechanism of the carbonylation is not clear. Dimethyl pimelate (474) is formed by methanolysis (retro-Dieckmann reaction) of methyl cyclohexanonecarboxylate (478) promoted by CuCl2 and acid. Methyl cyclohexanonecarboxylate (478) may be formed by methoxypalladation of the enolate 476 to form Pd enolate 477, followed by CO insertion. Chlorination of cyclohexanone with CuCl2 gives 2-chlorocyclohexanone 480 which is converted to 475 [197]. O

PdCl2 (0.56 mmol) CuCl2 (15 mmol)

+ CO + MeOH

1 atm, rt, 62%

MeO2C

CO2Me 474

Cl

CO2Me

5 mmol 475 OH

OMe Pd-X

HO PdCl2

HO

O

OMe CO-PdCl

CO2Me

CO MeOH

MeOH

476

478

477

MeO2C O

O

479 Cl

CuCl2

CuCl2

Cl

CO2Me

MeOH 475 480

CO2Me

90

Oxidative Reactions with Pd(II) Compounds

2.10 Oxidation of Alcohols Alcohols are oxidized slowly with PdCl2 or Pd(OAc)2 . The reaction is explained by formation of Pd-alkoxide 481, followed by β-H elimination. More efficient methods of oxidation using palladium catalysts and O2 as an oxidant have been reported by several groups. Primary alcohols are oxidized to carboxylic acids using Pd-phenanthroline 482 as a catalyst, which can be recycled [198].

H

H OH + PdX2

R

R

O

Pd

R

X

R

R

R

481

O + Pd(0) + HX

[Ox] O

0.05 mol% PhenS-Pd(OAc)2 OH

OH

H2O, AcONa, air, 100 °C 90% yield 90% selectivity

NaO3S N Pd(OAc)2 N

PhenS

NaO3S

482

Primary and secondary alcohols such as benzyl alcohol (483) and 1phenylethanol (484) are oxidized with O2 efficiently to benzaldehyde and acetophenone using Pd(OAc)2 , complexed with pyridine, as a catalyst in the presence of a molecular sieve [199] or supported on hydrotalcite [200]. Also, the palladacycle of 4,5-dihydro-1,3-oxazole 485 is a good catalyst for oxidation of alcohols in DMSO under oxygen [201].

OH

Pd(OAc), (5mol%), O2

CHO

pyridine, toluene, MS3A 80 °C, 100%

483 OH

O

O palladacycle (485), O2

Pd N AcO

DMSO, NaHCO 3, 89% 484

485

Oxidation of Alcohols

91

More importantly, asymmetric synthesis is possible using an optically active alkaloid as a ligand. Pd-catalyzed oxidative kinetic resolution of secondary alcohols with molecular oxygen was achieved using Pd(OAc)2 -(−)-sparteine complex. Optically enriched (−)-1-(2-naphthyl)ethanol (99 % ee) (487) was recovered in 44 % yield by the oxidation of a racemic mixture of 1-(2-naphthyl)ethanol. Quantitative reduction of the ketone provides an opportunity for the preparation of chiral alcohols in >50 % overall yield from the racemic mixture via multistep oxidative kinetic resolution [202]. Pd(MeCN)2 Cl2 complexed with (−)-sparteine (486) can be used similarly. It is concluded that (−)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on Pd and an exogenous base [203,204]. Efficient enantio-selective oxidation of 1,3-meso-diol 488 resulted in an oxidative desymmetrization to provide 489 with 82 % ee in 69 % yield [204,205]. tert-Butyl alcohol was found to be a good solvent for the oxidation of benzylic, allylic and aliphatic alcohols [204]. OH

O

OH

Pd(nbd)Cl2, O2 (−)-sparteine MS3A, PhMe, 80 °C

+

55% conversion 55% conversion

1st cycle, 5 g 2nd cycle, 2.7 g

487 2.2 g, 99% ee 1.2 g, 99% ee

2.7 g 1.4 g

NaBH4, 99%

H N

OH

OH

(−)-sparteine, 60 °C 69% yield, 82% ee

Ph

Ph

OH

PdCl2(MeCN)2, O2

488

O

N H

Ph

Ph

(−)-sparteine

489

486

Oxidative rearrangement and ring expansion of strained molecules of tert-cyclobutanols are known [206]. Recently it has been claimed that the reaction can be explained more reasonably by elimination of β-carbon (see Chapter 3.8.2) [207]. Conversion of the vinylcyclobutanol 490 to the ring-opened product 493 by relief of the ring strain under oxidative conditions is explained by β-carbon elimination as shown by 491 to generate 492, followed by β-H elimination. In this case, OH a

Pd(OAc)2 (10 mol%) b

O

Pd

X

O2, pyridine, MS3A 56%

490 491 O

O + Pd(0) O2

Pd-X H

Pd(II) 492

493

b-carbon elimination

92

Oxidative Reactions with Pd(II) Compounds

formation of the alkoxypalladium 491, instead of pre-coordination of π -bond with Pd, is a crucial step. Also the β-carbon elimination occurs selectively from the less substituted bond (bond b). Similarly cleavage of the tert-cyclobutanol ring 494 occurs to generate 495, and β-H elimination affords 496. Finally, 497 is obtained after isomerization [207]. OH PdX2

Ph

O

b-carbon elimination

O-PdX Ph

Ph

52% H13C6

Pd-X

R

R 494

495 O

O H13C6

H13C6

Ph

Ph 497

496

The presence of an angular methyl as in 498 makes a difference. Bond cleavage occurs in two ways (a and b). The cleavage of bond a as shown by 499 is followed by 5-exo cyclization of the intermediate 500 and β-H elimination to afford the cyclopentanone 501 and then 502 [205]. Using Pd(OAc)2 (10 mol%), pyridine and molecular sieve under oxygen, the different cyclopentanone 506 was obtained selectively by cleavage of bond b in 498 as shown by 503 [207]. Unlike 502, the β-H elimination in 504 is impossible in the presence of the angular methyl, and 5-exo cyclization occurs to generate 505, and then 506 is formed. Pd-X a

O

OH

Pd-X

PdCl2(PhCN)2 b

a-breaking

BQ,THF, 67%

498

O 499

500

Pd-X b-H elimination

insertion O

O

501 O + Pd(0)

502

Pd(II)

As another possibility, the reaction is explained by precoordination of PdX2 to the double bond. Then palladation occurs with concomitant rearrangement and ring expansion as shown by 507 to generate 505 and then 506.

Oxidation of Alcohols

a

93 Pd-X

OH

O Pd(OAc)2 (10 mol%)

b

b-breaking

O2, pyridine, MS3A 67% 503

498 O

O 5-exo cyclization Pd-X

Pd-X

504

505 O b-H elimination

+ Pd(0)

506

OH

H

PdX2

O Pd-X

+

PdX2

rearrangement

507

498 O

O Pd-X + Pd(0)

505

506

Treatment of the 1-isopropenyl-2-(3-butenyl)cyclobutanol 508 with Pd(II) afforded the bicyclo[4.3.0]nonane 512. The reaction can be understood by domino β-carbon elimination as shown by 509, followed by 5-exo and 6-exo cyclizations of 510 to give 511, and β-H elimination and isomerization afforded 512 [208]. A different mechanism based on ring expansion was given before. The vinylcyclobutanol 513, bearing a β-methoxy group, was converted to two products 514 and 515 with or without elimination of the methyl group when PdCl2 and BQ, or Pd(OAc)2 and DDQ were used [209]. Palladation of alkyne 516 and ring expansion occurred as shown by 518 to give the cyclopentanone 517 in 91 % yield at room temperature using Pd(TFA)2 [210].

94

Oxidative Reactions with Pd(II) Compounds X-Pd O

HO

b-carbon elimination

PdCl2(MeCN)2

TBSO

TBSO

509

508

O

O

O 5-exo

6-exo

Pd-X

Pd-X

Pd-X TBSO

TBSO

TBSO

511

510 O b-H elimination isomerization TBSO 512

29%

O

PdCl2(MeCN)2, BQ X

OH

514 X

68%

N X=

O

O

Ph O

OMe

Ph Pd(OAc)2, DDQ

513

67% X

OMe 515

O

O

n-Bu

CH2Cl2, rt, 91%

OH 516

O

Pd(OCOCF3)2

O

O Pd(OCOCF3)2

ring expansion protonolysis

O O O H 518

n-Bu XPd-X

517

n-Bu

Enone Formation from Ketones and Cycloalkenylation

95

2.11 Enone Formation from Ketones and Cycloalkenylation Preparation of enones from saturated ketones by Pd(II)-promoted dehydrosilylation via silyl enol ethers was reported by Ito. Transmetallation of the silyl enol ether of cyclohexanone 519 with Pd(OAc)2 gives the oxo-π -allylpalladium complex 520 (Pd enolate), which undergoes β-H elimination to afford cyclohexenone. BQ is used as an oxidant of Pd(0) [211]. However, the enone formation can be carried out using a catalytic amount of Pd(OAc)2 in DMSO under oxygen without other oxidants at room temperature. Also aldehyde 521 is converted to unsaturated aldehyde 522 via silyl ether in DMSO [4]. AcOH

BQ O

OTMS

O

O-PdOAc

Pd-X

O

Pd(OAc)2

Me3SiCl

+ Pd(0)

base

CHO C8H17

H

520

519

Pd(OAc)2

OTMS

C8H17

CHO C8H17

DMSO, O 2 25 °C, 86%

521

522

The enone formation has been applied to a number of natural product syntheses. The enone 524 was prepared from the complex molecule 523 and successfully applied to the total synthesis of pallescensin [212]. Even the phenolic OH in 525 was converted to the conjugated ketone. The reaction was utilized as a key step in hypoxyxylerone synthesis [213]. In the total synthesis of galbulimima alkaloid GB 13, Mander converted a cyclohexanone in the complicated molecule 526 to the corresponding cyclohexenone via silyl enol ether in 82 % yield [214].

O

O

OMe TMSCl

O

O

OSiMe3

THPO

Pd(OAc)2

OMe

MeCN, 78%

O

OMe

THPO

THPO

523

524

MeO MeO

OMe

O 1. TMSOTf, 2,6-lutidine OMe

OH 525

2. Pd(OAc) 2, MeCN, reflux OMe 56%

MeO

MeO

OMe

O

OMe

O OMe

96

Oxidative Reactions with Pd(II) Compounds

F3C

F3C

O

O H

H

N

N H

H

1) LDA, TMSCl, THF H

2) Pd(OAc)2, DMSO MeCN, 82%

H MOMO

H

H

H H

MOMO

H

O

O

526

In the presence of a double bond, its intramolecular insertion to Pd enolate in 528 takes place. For example, the silyl enol ether 527 undergoes transmetallation with Pd(OAc)2 to give the Pd enolate 528, or the oxy-π -allylpalladium, which undergoes 6-exo cyclization to generate 529. The subsequent β-H elimination gives the 3-methylcyclohexenone (530) [215]. The reaction is called ‘cycloalkenylation’ [216]. O

O-SiMe3 + Pd(OAc)2

TM

6-exo cyclization

PdOAc

527

528

O

O

O

PdOAc 529

530

Five- and six-membered rings can be prepared by this reaction [217], and the reaction has been applied to syntheses of natural products. Now the cycloalkenylation can be carried out with a catalytic amount of Pd(OAc)2 in DMSO under O2 . The bicyclo[3.2.1]octenone 532, a partial skeleton of gibberellin, was obtained in 81 % yield by the cycloalkenylation of the silyl dienol ether 531 in DMSO using OTBDMS

O Pd(OAc)2 (3 mol%) O2 (1 atm), DMSO 81%

MOMO

MOMO 532

531 H O steps

H HO2C

CO2H

gibberellin A12

References

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3 mol% of Pd(OAc)2 under O2 . Use of TBDMS gave higher yields than TMS group [218,219]. Furthermore, the reaction has been extended to coupling with an aromatic ring. Treatment of 533 with Pd(OAc)2 in DMSO under O2 generates the Pd enolate 534, which has no possibility of β-H elimination and attacks the aromatic ring to afford the benzo-fused bicyclo[3.3.0]octane 535 [220].

O

Me2SiO Me

Me 533

PdOAc

Me

Pd(OAc)2 (10 mol%) O2 (1 atm), DMSO 45 °C, 70%

Me 534 O

Me

H

Me 535

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Chapter 3 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

3.1 Introduction Among many substrates used for Pd(0)-catalyzed reactions, organic halides are most widely used. In Grignard reactions, Mg(0) metal reacts with organic halides of sp3 carbons (alkyl halides) more easily than halides of sp2 carbons (aryl and alkenyl halides). On the other hand, Pd(0) complexes react more easily with halides attached to sp2 carbons, namely aryl and alkenyl halides. In addition, several pseudohalides are used as well. They undergo facile oxidative addition to Pd(0) to form Pd complexes which have σ -Pd–carbon bonds. Scheme 3.1 summarizes the oxidative addition of phenyl halides and pseudohalides to form phenylpalladium halides. Aryl iodides and bromides have been used widely. Until recently use of aryl chlorides for catalytic reactions has been neglected due to low reactivity, despite the fact that chlorides are cheaply and easily available. Remarkable progress has been achieved since 1998 in developing Pd-catalyzed reactions of aryl chlorides. A review of Pd-catalyzed reactions of aryl chlorides has been published by Littke and Fu [1]. Facile Pd-catalyzed reactions of aryl chlorides occur by using electron-rich and bulky ligands and proper bases. P(t-Bu)3 , biphenylyl(di-t-butyl)phosphine and heterocyclic carbenes are the most effective ligands. As measures of basicity and bulkiness, the pKa and cone angles of some phosphines are cited: pKa :

P(t-Bu)3 = 11.40,

Cone angle :

PCy3 = 9.7, ◦

P(t-Bu)3 = 182 ,

P(2, 4, 6-(OMe)3 C6 H3 )3 = 11.0 ◦

PCy3 = 170 , ◦

P(2, 4, 6-(OMe)3 C6 H3 )3 = 184

It is instructive to compare these values with those of PPh3 and P(n-Bu)3 : PPh3 :

pKa = 2.73,

◦

cone angle = 145 ;

P(n-Bu)3 ,

pKa = 8.4

Consideration of the order of reactivity of several kinds of chlorides is also important: heteroaryl chlorides > electron-deficient chlorides (activated chlorides) > neutral or electron-rich chlorides Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

106 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Br

Cl

I

NO2

N2X

NH2

2 OH

OTf Pd-X

Pd(0) 3 CO2H

1

COCl

4

CO

O O 2 5 SO3H

CO

SO2Cl

SO2

6

X

X-Pd Pd(0) A

A

X

Pd-X Pd(0) A

A A = N, O, S

Scheme 3.1 Formation of phenylpalladium intermediates from organic halides and pseudohalides by oxidative addition.

Many papers reporting ‘best ligand’ or ‘most active catalyst for the coupling of aryl chlorides’ have appeared, but some of them are active only for activated aryl chlorides, and not necessarily effective for electron-rich chlorides, sometimes poor catalysts. Chlorides of some nitrogen-containing heterocycles are reactive under

Introduction

107 R

R 7

Pd-X X

8

Pd(0)Ln

Pd-X

9

Pd-X

R1 R1

R2

R2

Pd-X 10

1

CO2R ROH O CO

CHO

H−

Pd-X

11

COR M′-R

Scheme 3.2 Insertion to phenylpalladium intermediates.

usual conditions. For example, Pd-catalyzed reactions of 2- and 4-chloropyridines, 4- and 6-chloropyrimidines, 2-chloroquinolines, and 2- and 3-chloropyrazines proceed in the presence of PPh3 and are extensively applied to their functionalization. Cl

Cl 4

4

N

3

Cl

N 2

N

Cl

6

Cl

2

2

N

Cl

N

Cl

N

Cl

Several reactive pseudohalides are available for catalytic reactions. Diazonium salts 2 derived from anilines, and phenyl triflates 3 and nonaflates (nonafluorobutanesulfonates) derived from phenols are highly reactive substrates. In addition, acyl chlorides 4, anhydrides 5, and sulfonyl chlorides 6 are also used. The phenylpalladium halides 1 are ‘living’ species and undergo several further transformations before termination. Insertion of unsaturated bonds is one of them, as summarized in Scheme 3.2. Alkene insertion is followed by β-H elimination to yield arylalkenes 7. Insertion of 1,2- and 1,3-dienes generates the π -allylpalladium

108 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Pd-X

R

Pd-R

R-M′Y transmetallation

reductive elimination

1

12 M′= MgX, ZnX, BY2, SnR3, SiR3 Ar-M′Y

Ar R

R-M′Y R

R

Pd-X XM′ R 1 XM′

R

H

R CuI

R′-M′-M′-R′

M′R′

Scheme 3.3 Transmetallation of phenylpalladium intermediates 1.

intermediates 8 and 9. Alkyne insertion gives rise to the alkenylpalladiums 10. These species 8, 9 and 10 undergo further reactions before termination. The acylpalladium 11 is formed by CO insertion, from which esters, aldehydes and ketones are produced. Cross-coupling proceeds by transmetallation of 1 with organometallic compounds of main group metals (Mg, Zn, B, Al, Sn, Si) and reductive elimination to give 12 as summarized in Scheme 3.3. Trapping of phenylpalladium 1 with several anions or nucleophiles produces a variety of aromatic substitution products as shown in Scheme 3.4. By considering Schemes 3.1–3.4, we can easily see the wide versatility and high synthetic value of the new and rich aromatic chemistry involving Pd-catalyzed reactions of aryl halides. These reactions offer unique methods for carbon–carbon bond formation, which are impossible or difficult to achieve by conventional means. A revolution and large expansion occurred in aromatic substitution reactions on the discovery of these aryl halide reactions. Alkenyl halides undergo similar transformations. In addition to alkenyl halides 13, alkenyl triflates 15 and phosphates 16, derived from aldehydes and ketones, are useful pseudohalides, that undergo oxidative addition to form alkenylpalladium intermediates 14. Typical examples of insertion of unsaturated bonds to 14 are shown in Scheme 3.5. Transformations of the alkenylpalladium 11 via transmetallation and trapping with anions are summarized in Scheme 3.6. All the reactions summarized in Schemes 3.1–3.6 are treated in this chapter.

Reactions with Alkenes (Mizoroki–Heck Reaction)

109

NHR

NH2R

OR ROH

SR RSH

Pd-X

P(O)Ph2

HP(O)Ph2

H

H−

1

CN

CN−

E′ −

E′ E

E O O

R −

R

Scheme 3.4 Trapping of phenylpalladium intermediate 1 with anions and nucleophiles.

3.2 Reactions with Alkenes (Mizoroki–Heck Reaction) 3.2.1 Introduction Direct alkenylation of benzene derivatives with alkenes was reported by Fujiwara in 1967 and via mercuration by Heck in 1968 using a stoichiometric amount of Pd(II) salts [2]. Then, inspired by the discovery of oxidative addition of iodobenzene to Pd(PPh3 )4 to generate Ph-Pd-I by Fitton in 1968 [3], Mizoroki and Heck independently reported the alkenylation of benzene derivatives by the reaction of Mizoroki, 1971 Ph-I

+

Ph

Ph

Pd/C, AcOK PhH, AcOH 125 °C, 93%

Ph +

Ph

10 : 1

Heck, 1972 Ph-I

+

Ph

Ph

Pd(OAc)2, 1 mol% Bu3N 100 °C, 2 h, 75%

Ph

Ph

110 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides R R

X 1

R

R2

R1

R2 13 Pd(0)Ln

R1 R2

Pd-X

Pd-X R3

R2

1R

R3

R

R4

4

Pd-X

14

R1

R2

Pd(0)Ln

CO2R

ROH OTf

OP(O)(OR)2 R1

R1

15

R2

CHO

R2 CO

H−

Pd-X

16

R1

R2

R2

1R

COR

M′-R

O

R1

R2

R1 O

R1

R2

R2

Scheme 3.5 Insertion to alkenylpalladium intermediates 14. R2

R

R

CuI

R1 Ar

M′-Ar R1

R

M′-R R1

R2

R M′ R1

14

R2

R

Pd-X R1

R2

M′R′

R′M′-M′R′ R1 H−

R2 H

R1 CN− − E′

R2

R2 CN

R1

R2

R1

R2

E M′ = MgX, ZnX, BY2, SnR3, SiR3

E′ E

Scheme 3.6 Transmetallation and trapping of alkenylpalladium intermediates 14 with anions.

Reactions with Alkenes (Mizoroki–Heck Reaction)

111

aryl iodides with various alkenes, typically acrylate and styrene using Pd on carbon or Pd(OAc)2 as a catalyst without a phosphine in the presence of bases. Sadly Mizoroki died after publishing only a few papers on the reaction [4,5]. This hitherto unknown reaction has attracted attention as a potentially important method for carbon–carbon bond formation. Now all reactions which proceed via insertion of alkenes and also alkynes to the arylpalladium intermediates 1 (Scheme 3.1) and the alkenylpalladium 14 (Scheme 3.5) are called Mizoroki–Heck reactions or Heck reactions (abbreviated to HR in this chapter). A number of reviews have already been published [6]. The reaction is certainly the most useful and versatile method of carbon–carbon bond formation involving sp2 carbons. HR consists of three elemental reactions: (1) oxidative addition of an organic halide to form arylpalladium halides; (2) insertion of an alkene to form the alkylpalladium 17 (or carbopalladation of alkene); and (3) dehydropalladation (β-H elimination) to give the arylalkenes 18 or conjugated dienes. The stereochemistry of the insertion (carbopalladation) is syn addition. The syn addition of Ar-PdX to an alkene generates σ -(β-aryl)alkylpalladiums 17. Then internal rotation around the former double bond occurs, making the syn β-H elimination possible to give the trans-alkenes 18. H

R Ar-X +

Pd(0)

OA Ar-Pd-X

R

H H syn addition

H

H X-Pd

H Ar 17

R

H

H X-Pd

H Ar

rotation

X-Pd

H

R H

Ar

H

R

syn elimination H

b-H elimination

Ar

H 18

As supporting evidence of the syn addition, the syn elimination mechanism, Fu obtained only the E-isomer 19 as a kinetic product of the reaction of methyl transcinnamate with deuterated bromobenzene at room temperature using Pd2 (dba)3 and P(t-Bu)3 . Under thermodynamic control at 120 ◦ C, an E, Z-mixture (1 : 1) was formed [7]. Br D

+ D

D D

D

Pd2(dba)3 (1.5%)

D

P(t-Bu)3 (3.0%) Cy2NMe (1.1 equiv) dioxane, r.t. 94% CO2Me

D CO2Me

D D

D

one isomer

19

The syn addition, rotation, and syn elimination rule is valid even for reaction of congested molecules. Hirama applied HR of 20 to the stereocontrolled synthesis of the northern part of a potent proteasome inhibitor TMC-95A, and found that the Z isomer of the cyclized product 21 was obtained selectively in 86 % yield

112 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

BocN

Br

PdBr Pd2(dba)3, NEt3

O

trans

THF-NMP, r.t, 86% N Br

O

N

O BocN

Boc

O

Boc

Br

20 O BocN

BrPd O

PdBr

H

syn addition

H BocN O

rotation

O N Br

N

Boc

Boc

Br

O BocN O

syn b-H eliminatioin N Br

Boc 21

using Pd2 (dba)3 without phosphine ligand in the presence of Et3 N [8]. Selective formation of the Z isomer can be understood by the syn addition, rotation, and syn elimination rule. The selection of conditions is critical for effective cyclization. Under different conditions, the yield of the cyclized product was low [9]. On the other hand, rotation of the intermediate 22 formed from cyclic alkenes is impossible and the syn β-H elimination from carbon C3 gives 3-arylalkene 23, rather than 1-substituted alkene 24, because β-H at carbon 1 is anti to PdX.

H

syn elimination

X-Pd 2

Ar-Pd-X +

syn addition

2

Ar

3

23

1

1

Ar

anti elimination

H 22

Ar 24

Furthermore, attention should be paid to the fact that direct syn β-H elimination is not possible in an intramolecular reaction. For example, syn carbopalladation of 25 generates the intermediate 26 and formal anti β-H elimination occurs to afford the cyclic alkene 27. As one explanation, stereomutation may occur to allow syn

Reactions with Alkenes (Mizoroki–Heck Reaction) Pd-I H

syn addition Pd(OAc)2, PPh3

I O O

MeCN, Et3N 58%

113

O

H O

25

26

anti elimination ? O O 27

elimination, because Pd is on a benzylic carbon [10]. There are a number of examples of formal anti elimination, and there is no definite answer at present as to whether this is direct anti elimination or syn elimination after stereomutation. The following factors are variable in HR, and careful qualitative and quantitative optimization of these factors are essential to achieve successful reactions: halides; alkenes; ligands; solvents; bases; additives; and temperature. In order to find optimum conditions of reactions, a careful survey of these factors is crucial. In the literature, numerous recipes of optimum reactions have been reported, in which high turnover numbers (TON) and TOF have been reported. However, in many cases, these results have been obtained under a narrow range of conditions from specific reactants in small scale experiments, and the results can not always be retraced. At present, it is difficult to find clear-cut recipes for many kinds of reactions from data reported in the literature. In the following sections, some controlling factors are surveyed. 3.2.2 Catalysts and Ligands HR are catalyzed by Pd(0) complexes of phosphines. Mainly commercially available Pd(PPh3 )4 , Pd2 (dba)3 and Pd(OAc)2 are used as precursors of Pd(0) catalysts with or without phosphines. When overligated Pd(PPh3 )4 is used, reactions of congested molecules may be slow due to the presence of too many ligands, which inhibit coordination of reactants. Pd(OAc)2 , Pd(dba)2 and even Pd on carbon are used with phosphines. Bulky tri(o-tolyl)phosphine was used first by Heck [11]. A palladacycle obtained from it is known as the Herrmann complex (XVIII-1) and is used extensively in HR [12]. Also, palladacycles XVIII-7 [13] and XVIII-2 [14] are high performance catalysts. Turnover numbers as high as 630–8900 were achieved by tetraphosphine Tedicyp (X-1) [15]. Recently, the remarkable effect of electron-rich and bulky phosphines, typically P(t-Bu)3 and other phosphines shown in Tables 1.4, 1.5 and 1.6, have been unveiled. Smooth reactions of aryl chlorides using these ligands are treated later. Electron-rich ligands accelerate oxidative addition of aryl chlorides, and reductive elimination is accelerated by bulky ligands. HR can be carried out in an aqueous solution by use of a water-soluble sulfonated phosphine (TPPMS, II-2) [16].

114 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Sometimes, AsPh3 shows better effect than PPh3 . In the synthesis of epibatidine (30) by hydroarylation of the azabicyclic alkene 28 with 2-chloro-5-iodopyridine (29) in the presence of formic acid, the best result was obtained using AsPh3 [17]. CO2Me

CO2Me N

N

Cl

+

N

Cl

N

Pd(OAc)2, AsPh3 Et3N, HCO2H DMSO, 81%

I 28

29

30

In addition, electron-rich and bulky heterocyclic carbenes are attracting attention as effective phosphine mimics [18]. Using carbene ligand XVI-6, HR of aryl bromides proceeds at 120 ◦ C [19] and that of diazonium salts 31 at room temperature [20]. A new phosphine-imidazolium salt (XVI-14) was found to catalyze HR efficiently [21]. Br CO2Bu

Me

Cs2CO3, DMAC 120 °C, 66%

Me Ph

N2BF4

Pd(OAc)2, IMes•HCl(XVI-6)

+ Ph

MeO

CO2Bu

Pd(OAc)2, IMes•HCl(XVI-6)

+

THF, r.t. 88%

MeO

31

Occasionally reactions proceed with phosphine-free Pd(0) catalysts. Some phosphines are more expensive than Pd and more difficult to recover than Pd. Therefore, an ideal catalyst is a phosphine-free Pd(0) catalyst. Reactions of reactive halides and pseudohalides such as aryl iodides, diazonium salts and acyl chlorides proceed under phosphine-free conditions. Supported heterogeneous Pd catalyst can be used with or without phosphine. K¨ohler reported that ligandless Pd/C (product of Degusa AG) is highly active; TON up to 36 000 was obtained in the reaction of bromobenzene with styrene in NMP at 140 ◦ C [22]. Some reactions catalyzed by ligand-free Pd catalysts in the presence of various additives proceed smoothly, and are treated in the next section. 3.2.3 Reaction Conditions (Bases, Solvents, and Additives) Since strong acids are formed, the reaction must be carried out in the presence of bases. Coordinating and polar solvents, such as DMF, MeCN, NMP and DMSO, are preferable solvents. DMF is the most widely used. Water, a highly polar liquid, has been found to accelerate some reactions, which are carried out smoothly in aqueous solvents using water-soluble ligands. Poly(ethylene glycol) (PEG) having molecular weight 2000 (or lower) has been used as a good biphasic solvent for regioselective reaction of n-butyl vinyl ether

Reactions with Alkenes (Mizoroki–Heck Reaction)

115

to give a single isomer 32 cleanly. It is known that a mixture of regioisomers is formed in other solvents. Furthermore, after the reaction, products can be isolated with dry ether. Pd catalyst always stays in the PEG layer and is recycled easily [22a]. HR proceeds rapidly in ionic liquids and catalysts can be recycled [18,23,24]. Double HR of bromobenzene with butyl acrylate occurred rapidly under microwave irradiation in bmim PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) to give β,β-diphenylacrylate (33) [24]. In addition to the use of the ionic solvent, addition of 1,2,2,6,6-pentamethylpiperidine (PMP) as a base is important for the double HR. Br +

n-Bu O

O

Pd(OAc)2, Et3N PEG, 80 °C, 82%

n-Bu

32

MeO

E:Z=7:3

Ph-Br

+

CO2Bu

PdCl2, P(o-Tol) 3 bmimPF6, PMP, 45 min 220 °C, 50%

CO2Bu

Ph Ph 33

Uses of some additives are recommended. Addition of Ag2 CO3 cleanly suppresses double bond isomerization in products. In addition, Ag salts accelerate reactions, possibly by removing halide ions strongly attached to Pd from a coordination sphere to generate a cationic Pd catalyst, making the insertion easier. Thallium salts also accelerate reactions, and suppress the double bond isomerization. A favorable effect of some alkali halides, such as LiCl and KBr, on the reaction is known [25]. Selection of bases is also important. Trialkylamines and inorganic bases such as K2 CO3 and KOAc are commonly used. An unusually good effect of Cs2 CO3 in some reactions is now well-known. It behaves as a base better than K2 CO3 due to partly better solubility in organic solvents and higher basicity, and is used frequently. Buchwald reported that a bulky amine, Cy2 NMe, is a very effective base [26]. Larock found that the reaction of 2-iodo-4-methylbiphenyl (34) with acrylate provided two products 35 and 36 in equal amounts using cesium pivalate as a base. Of course, 35 is an expected product [27]. Also the reaction of 37 afforded the mixture of 35 and 36. Gallagher also discovered a similar migration using 3bromo-4-phenylpyridine (38) and acrylate to afford 39 and 40 [28]. Although the mechanism of the migration process to form the crossover products is not clear, certainly a reversible 1,4-Pd shift of arylpalladium intermediates 41 and 43 via the palladacycle 42 is occurring. Reetz reported that a highly active ligandless Pd catalyst for HR of aryl bromides can be generated by combining Pd(OAc)2 or PdCl2 (PhCN)2 with N ,N dimethylglycine (DMG), and TON 106 700 was obtained with this catalyst in the reaction of bromobenzene with styrene, although the reaction was slow [29,30]. Jeffery made the important observation that a large rate acceleration in HR of aryl iodides occurs by addition of more than equimolar amounts of tetraalkylammonium salts as a phase-transfer catalyst and solid bases without ligands. The

116 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Me

Me

I

Me

CO2Et

Pd(OAc)2, PPh3

+

CO2Et

+

CsPiv, DMF 100 °C, 87%

CO2Et 50 : 50

34

35

36

Me

I

+

Pd(OAc)2, PPh3 CO2Et

CsPiv, DMF 100 °C, 86%

35

+

36

49 : 51

37

Br

Pd(OAc)2, P(o-Tol) 3

+

CO2Et

CO2Et +

Et3N, MeCN 125 °C, 89%

N

CO2Et N

38

N 2:1

39 A

A

A

Br

40 A

Pd-Br

Pd(0)

Pd

41

42

Pd-Br

43

conditions are called ‘Jeffery’s ligandless conditions’. Reactions of aryl and alkenyl iodides proceed smoothly by the addition of KHCO3 and Bu4 NCl in DMF at room temperature [31]. Detailed studies have shown that careful selection of the kinds and amounts of Pd catalysts, bases, solvents, water and particularly tetraalkylammonium salts, are important to find optimum conditions [32]. As one explanation of the effect of tetraalkylammonium salts, Reetz found using transmission electron microscopy that R4 N+ X− -stabilized Pd colloids are formed under Jeffery’s ligandless conditions and function as active catalysts [33].

Reactions with Alkenes (Mizoroki–Heck Reaction)

117

As a recent example, HR of the disubstituted alkenes 44 gave 45 with high stereoselectivity using a ligandless catalyst. In this case, selection of bases is crucial and combined use of methyl(dicyclohexyl)amine and a phase transfer catalyst gave the best results [26]. CO2Me

MeO2C

Br CO2Me MeO2C

+

44

OMe

Pd(OAc)2 Me(Cy)2N (1.5 equiv) Et4NCl (1 equiv) 95 °C, 72%

MeO 45

E:Z = 11 : 1

It is known that HR of vinyltrimethylsilane with aryl halides affords styrene derivatives by desilylation–arylation. In the presence of Ag salt, normal products are obtained [34]. Jeffery reported that either the normal product 46 or styrene, the desilylation product, from iodobenzene and vinyltrimethylsilane are obtained selectively under mild conditions by slight modification of conditions. In the presence of Bu4 NOAc and molecular sieve in DMF, 2-trimethylsilylstyrene (46) is obtained as expected. On the other hand, styrene is obtained selectively as an abnormal product in toluene in the presence of 3 equivalents of KF. Formation of styrene is explained by the combination of three reactions, namely β-H elimination, reverse readdition of H-Pd-X, and subsequent desilylpalladation. Whatever the mechanism, the presence of a large amount of KF, which strongly activates the TMS group, must play an important role [35]. Pd(OAc)2 n-Bu4N(OAc) (2.5 equiv) MS 4A, DMF, r.t., 99% I + SiMe3

Pd2(dba)3, KF (3 equiv) n-Bu4NCl (2 equiv)

46

SiMe3

toluene, r.t., 94%

As another example of a delicate effect of tetraalkylammonium salts, either 2-phenyl-2,5-dihydrofuran (47) or 2-phenyl-2,3-dihydrofuran (48) was obtained selectively in the arylation of 2,3-dihydrofuran with a slight change of additives [36]. Pd(OAc)2 n-Bu4N(OAc) (2.5 equiv)

O

4 A MS, DMF, r.t., 94% I

O +

47 Pd(OAc)2, KOAc (2.5 equiv) n-Bu4NCl (2.5 equiv) O

DMF, r.t., 92% 48

118 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Jeffery’s conditions are so mild that reaction of an alkenyl iodide containing a very unstable peroxide group 49 proceeded smoothly without decomposition of the peroxide under the conditions at room temperature [37]. Cyclization of the quinoxaline chloride 50 to prepare pyrrolo[2,3-b]quinoxaline under usual conditions is slow and the yield is low, because the aminoquinoxalines are strong chelating agents and poison Pd catalysts. However, the locked Pd catalyst is released and the reaction proceeds smoothly under Jeffery’s ligandless conditions to give the pyrrolo[2,3-b]quinoxaline 51 in 67 % yield [38]. O

OMe

O

CO2Me

+

excess

I

O

Pd(OAc)2,K2CO3 Bu4NBr, rt 86%

OMe

O CO2Me

49 N

Cl

N

N H

Pd(OAc)2,K2CO3 Bu4NBr, DMF 100 °C, 67%

N

N

N H

51

50

Many successful applications of Jeffery’s conditions have been reported. However, Rawal reported in his alkaloid synthesis that Jeffery’s conditions were not suitable for the attempted cyclization of the iodide corresponding to 52 (Br → I), and the cyclization of the vinyl bromide 52 proceeded cleanly under a ‘nonpolar’ set of conditions; Pd(OAc)2 , PPh3 , proton sponge in toluene at 100 ◦ C to give 53 in 82 % yield [39]. O

N N

Pd(OAc)2 (5 mol%) PPh3 (20 mol%) proton sponge K2CO3, PhMe, 110 °C, 82%

Br

H

N O

N

H

52

53

A remarkable effect on rate enhancement under high pressure is known [40]. The enantiomerically pure isoquinoline 55 was obtained from the bromide 54 in 70 % yield and with high diastereoselectivity (16 : 1) under pressure (10 kbar). The yield was lower than 10 % under normal pressure and even under Jeffery’s conditions [41]. N-Boc Br

Et

Pd(PPh3)4, Et3N,

N-Boc

MeCN, DMF 60 °C, 10 kbar, 70%

Et

diastereoselectivity = 16 : 1 54

55

Also acceleration is observed by microwave irradiation in a solvent-free reaction [24,42]. HR of the steroidal triflate 57 with alkene 56 is a key reaction in practical synthesis of the complex bis-steroidal diene intermediate 58. The best yield

Reactions with Alkenes (Mizoroki–Heck Reaction)

O

O

O

O

O

O O

H H

O

O

H

+ H

H TfO

O

119

56

H

57 Pd(OAc)2, Bu4NCl, Cs2CO3

microwave (20 min), 77%

O

O

O O H

O

H H

O

O

H H

O H

H

O O 58

(77 %) was obtained under Jeffery’s ligandless conditions and microwave irradiation. Cs2 CO3 was found to be more effective than K2 CO3 [43]. 3.2.4 Halides and Pseudohalides The halides and pseudohalides given in Scheme 3.1 show different reactivities, which are summarized briefly in the following. 3.2.4.1 Diazonium Salts Diazonium salts are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature using Pd2 (dba)3 as a catalyst in the absence of both phosphine ligand and base [44]. The reaction of diazonium salts means indirect substitution reaction of an amino group of anilines or aromatic nitro group with an alkene. The use of diazonium salts is synthetically more convenient than the use of aryl halides, because many aryl halides, particularly iodides, are prepared from diazonium salts. Ph NO2

NH2

N2BF4 NaNO2 HBF4

Pd-BF4 Ph

Pd2(dba)3 MeCN, r.t.

R

R

R

90%~ R

R

120 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides p-Methoxystyrene (60) and other styrene derivatives are prepared from pmethoxyaniline (59) via diazotization with butyl nitrite in AcOH and reaction under ethylene [45]. The highly reactive diazonium group in the iodoaryldiazonium salt 61 was selectively displaced with styrene at 80 ◦ C in EtOH using Pd(OAc)2 to give 62 and then the remaining iodo group was displaced with acrylonitrile in the presence of Bu4 NCl in DMF at 80 ◦ C to afford 63 [46]. NH2 +

H2C

1. BuONO

CH2

2. Pd(OAc) 2, AcOH 20 °C, 64%

MeO

MeO

59

60 Ph

Ph Me N2BF4

Ph

CN Pd(OAc)2, NaHCO3, Bu4NCl, DMF, 80 °C

Pd(OAc)2, EtOH, 80 °C I

I

Me

Me

61

63

62

61%

NC

Usually the reaction of diazonium salts is carried out in the absence of bases, and the reaction medium becomes acidic with progress of the reaction, and some undesirable reactions may occur. This problem can be solved by adding CaCO3 as a heterogeneous base. The α-benzylidene-γ -butyrolactone 65 was prepared by arylation of the very labile α-methylenebutyrolactone (64) using Pd on CaCO3 as a catalyst and CaCO3 as the solid base in MeOH [47]. Vinylphosphonates such as 67 are prepared by the reaction of aryldiazonium salts with diethyl vinylphosphonate (66) using CaCO3 as the base. The reaction, followed by hydrogenation, offers a good synthetic method for Wadsworth–Emmons reagents [48]. The Pd(0) complex of 15-membered macrocyclic triolefins containing different aryl units (XVII-1) is an air- and moisture-stable phosphine-free complex, and can be used as a highly active catalyst for HR of diazonium tetrafluoroborates at room temperature [49]. O

N2BF4

O

O

O

Pd/CaCO3, CaCO3

+

MeOH, 88%

MeO

OMe

64

65 MeO O

N2BF4 + MeO

P EtO

OEt

Pd(OAc)2, CaCO3 MeOH, 98%

O P

66 67

EtO CO2Et

N2BF4 +

CO2Et

Pd(XVII-I) EtOH, rt, 95%

OEt

Reactions with Alkenes (Mizoroki–Heck Reaction)

121

3.2.4.2 Halides The oxidative addition of aryl halides to Pd(0) is a disfavored step when powerful electron donors such as OH and NH2 reside on aromatic rings. Iodides react smoothly even in the absence of a ligand, and bromides in the presence or absence of a phosphine ligand. For a long time, iodides and bromides have been used as reactive halides. Recently remarkably smooth reactions of aryl chlorides have been achieved by proper selection of ligands and bases; electron-rich and bulky phosphines, typically P(t-Bu)3 , are effective. Littke and Fu reported that HR of aryl chlorides proceeds smoothly using Pd2 (dba)3 /P(t-Bu)3 /Cs2 CO3 [50]. Furthermore, the combination of Pd2 (dba)3 /P(t-Bu)3 /Cy2 NMe gives a versatile catalyst for reactions of aryl chlorides under mild conditions [7]. The unusual effectiveness of Cy2 NMe was reported by G¨urtler and Buchwald [26]. Reactions of aryl chlorides 68 and 69 activated by EWGs proceed at room temperature. A higher temperature (120 ◦ C) is required for the reaction of p-chloroanisole (70) under these conditions. Reetz et al. reported that the combination of Pd(OAc)2 or PdCl2 with Ph4 PX(X = Cl, Br, I) in a ratio of 1 : 6 generates an active catalyst for HR of aryl chlorides in the presence of sodium acetate in DMF or NMP at 120–150 ◦ C. In addition, N ,N -dimethylglycine is an excellent additive to improve regioselectivity [30]. Me

Ph

Cl + O

Pd2(dba)3 (1.5%) P(t-Bu)3 (3.0%)

Me

Cy2NMe (1.1 equiv) dioxane, r.t. 78%

O

Ph

68 CO2Me CO2Me

Cl

69

+

CO2Me

Pd2(dba)3 (1.5%) P(t-Bu)3 (6.0%)

Ph

Cl +

MeO

Me

Cy2NMe (1.1 equiv) dioxane, r.t. 90%

Me

CO2Me

Pd2(dba)3 (1.5%) P(t-Bu)3 (3.0%)

Cy2NMe (1.1 equiv) dioxane, 120 °C, 72%

MeO

Ph

70

HR of electron-rich aryl bromides with 1,1- or 1,2-disubstituted alkenes such as methyl methacrylate (71) and crotonate (72) proceeds at room temperature in dioxane with the same catalyst to provide 73 and 74 [26].

CO2Me Me2N

Br + Me 71

Me2N

Br +

73 CO2Me

Me

Pd2(dba)3 (0.5%) P(t-Bu)3 (1.0%) Cy2NMe (1.1 equiv) dioxane, r.t. 68%

72

Me

Cy2NMe (1.1 equiv) dioxane, r.t. 94% Me2N

CO2Me

Me

CO2Me

Pd2(dba)3 (0.5%) P(t-Bu)3 (1.0%)

Me2N

74

122 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Unlike aryl chlorides, unactivated alkenyl chlorides react more smoothly. It is generally recognized that alkenyl chlorides are much more reactive than aryl chlorides. However, curiously somewhat higher reactivity of chlorobenzene than the alkenyl chloride 75 was observed by the use of this catalyst in the following competitive reaction. The yield of 76 was higher than that of 77. Ph Cl

Ph

Cl +

Ph

+

Pd2(dba)3 (1.5%) P(t-Bu)3 (6.0%)

+

Cy2NMe (1.1 equiv) dioxane, 110 °C, 72%

76

t-Bu

t-Bu 77 40%

57%

75 1:1:1

Littke and Fu reported an interesting and important suggestion that commercially available Pd[P(t-Bu)3 ]2 is a resting state of the system in the HR, and not a catalytically active species. Change of the ratio of Pd to phosphine from 1 : 1 to 1 : 2 leads to a marked decrease in the rate of reactions, and the Pd monophosphine adduct PdP(t-Bu)3 is the active catalyst. The combination of Pd[P(t-Bu)3 ]2 and a phosphine-free Pd complex generates in situ the active 1 : 1 adduct [7]. Also diadamantyl(t-butyl)phosphine (I-20) is a good ligand for HR of aryl bromides at room temperature [51]. Benzyl chlorides are reactive partners of HR. For example, intra- and intermolecular reactions of the benzyl chloride 78 with methyl acrylate afford the indane ester 79 [52]. CO2Me +

Pd(OAc)2, PPh3

CO2Me

Ag2CO3, MeCN, 55% 79

Cl 78

3.2.4.3 Triflates Aryl and alkenyl triflates prepared from phenols and carbonyl compounds are reactive substrates which undergo facile oxidative addition. Reactivity of triflates is between that of iodides and bromides. Pd-catalyzed reactions of triflates mean indirect displacement of the phenolic OH group to afford 80 and transformation of carbonyl compounds 81 to the substituted alkenes 82. In classical organic chemR OH

OTf

R

80 R′ O R

OTf R

81

R′ R 82

Reactions with Alkenes (Mizoroki–Heck Reaction)

123

istry, displacement of the phenolic OH group is practically impossible. Nonaflates (nonafluorobutanesulfonates) are also active reaction partners. 3.2.4.4 Acyl Halides, Carboxylic Acid Anhydrides, and Aldehydes The acylpalladium halide complex 84 is an intermediate of catalytic decarbonylation of aroyl halides 83 [53]. The decarbonylation of 84 generates the arylpalladium intermediate 85 at higher temperature which undergoes facile alkene insertion. Therefore, similar to aryl halides, acyl halides can be used for the alkene insertion. The reaction is carried out with a phosphine-free Pd catalyst in the presence of tertiary amines [54]. Higher yields were obtained by using a mixture of K2 CO3 and benzyltrioctylammonium chloride [55]. O Cl

Ar

R

O

Pd(0)

Pd-Cl

Ar

83

Ar Ar-Pd-Cl R

85

CO

84

Cl

Cl PdCl2(PhCN)2, K2CO3

+

CO2Bu

Bn(Oct)3NCl, 140 °C, 93%

COCl

CO2Bu

Anhydrides of aromatic acids undergo facile oxidative addition, followed by decarbonylation to generate arylpalladium intermediates 86. HR of anhydrides was carried out using catalytic amounts of PdCl2 and NaBr in NMP at 160 ◦ C in the absence of ligands. Higher temperature is required for the decarbonylation. It should be mentioned that addition of bases is not necessary (of course, bases react with anhydrides). In this base-free reaction, only the free acid 87 is formed as a byproduct [56]. Also the reaction proceeds in an ionic liquid (N -hexylpyridinium chloride) using PdCl2 as a catalyst at 160 ◦ C. Facile recycle of the catalyst and the ionic liquid is possible [57]. O

O

Ph

PdCl2, NaBr

O +

NMP, 160 °C 1.5 h, 77%

CO2Bu

Ph O

CO2Bu

H Ph

Pd-OCOPh

Ph

Ph

Pd

Ph

Pd

Ph

O

O O

O

CO

86

Ph CO2Bu

CO2Bu

+

PhCO2H 87

O Ph O + Ph

PdCl2, [C6py]Cl CO2Bu

160 °C, 90%

O [C6py]Cl = N-hexylpyridinium chloride

Ph CO2Bu

+ PhCO2H + CO

124 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Meyers et al. reported that arylpalladium intermediates are generated from electron-rich aromatic acids 88 by decarboxylation and undergo HR in 5 % DMSO–DMF when palladium trifluoroacetate was used. However, addition of 3 equivalents of Ag2 CO3 , which may accelerate the decarboxylation, is necessary [58].

MeO

Pd(O2CCF3)2 MeO Ag2CO3 (3 equiv)

CO2H +

MeO

DMSO-DMF, 120 °C, 90%

OMe

MeO

OMe

88

Esters are usually inert for oxidative addition. Exceptionally, p-nitrophenyl esters of aromatic acids 89 undergo oxidative addition to generate the acylpalladium 90, and its decarbonylation generates the arylpalladium intermediate 91. Insertion of alkene and β-H elimination give the coupled product 92. The basefree HR of the esters proceeds by using PdCl2 as a catalyst and isoquinoline as a ligand in the presence of LiCl at 160 ◦ C in NMP. Phosphine inhibits the reaction [59]. NO2 O

O PdCl2, LiCl isoquinoline

O NC

NMP, 160 °C 16 h, 83%

89

Pd

O NO2

NC

CO

90 NO2 Pd

H

O Pd

NC

NC

91

NO2 O

HO + NC

92

+ Pd(0) NO2

Interestingly, HR of o-bromobenzaldehyde (93) with acrylate gave the doubly substituted product 94 and the expected product 95 under Jeffery’s ligandless conditions [60]. Formation of 94 is explained by the following mechanism. Insertion of acrylate to 93, followed by oxidative addition of aldehyde generates 96. The palladacycle 97 is formed by decarbonylation, and its reductive elimination gives 98. The final product 94 is obtained by HR of 98 with acrylate.

Reactions with Alkenes (Mizoroki–Heck Reaction)

125

CHO

CHO

CO2Me

Pd(OAc)2, Bu4NCl

CO2Me

95

+

K2CO3, DMF 65 °C, 78%

Br

CO2Me

93

CO2Me

CO2Me

94 CO2Me

O

X

X Pd

PdX H

Pd H

H

CO2Me

CO2Me CO

CO2Me

96

97

98

Oxidative addition of the sulfonyl chlorides 99 is followed by facile generation of SO2 to form the arylpalladium complexes, which undergo alkene insertion and β-H elimination to give 100 [55]. Cl-Pd SO2Cl

SO2 PdCl2(PhCN)2

+

CO2Bu

K2CO3, Bn(C8H17)3NCl 140 °C, 95%

99

CO2Bu Pd-X CO2Bu SO2

100

3.2.5 Alkenes Characteristic behaviors of several functionalized alkenes in HR are summarized as follows. HR of monosubstituted alkenes usually proceeds satisfactorily. Intermolecular HR is sensitive to steric factors of alkenes, and reactions of 1,1- and 1,2disubstituted alkenes are slower than those of monosubstituted alkenes. Although intermolecular reactions of congested double bonds are slow, intramolecular reactions of even very hindered double bonds proceed smoothly. Although examples are few, stereospecific HR of 1,2-disubstituted alkenes such as cinnamate under controlled conditions is known [7,26]. As another example, (E)-3,3-diarylacrylonitrile 101 was obtained selectively by the reaction of (E)3-phenylacrylonitrile with p-iodoanisole [61]. HR of methyl o-hydroxycinnamate with p-iodotoluene afforded the coumarin 102, showing that the tolyl and ester groups are trans as expected [62]. Alkenes bearing EWGs are most reactive. Reactivity of alkenes bearing electrondonating groups such as vinyl ethers, vinyl esters, enamides, and enamines, is lower

126 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

I

CN +

CN

Pd(OAc)2, AcOK Bu4NBr, DMF, 84%

MeO 101

MeO Me

CO2Me

I +

OH

Pd(OAc)2, AcOK DMF, 84%

Me O

O 102

than that of alkenes with EWGs. In addition, their reactions give two regioisomers depending on substrates and reaction conditions. As a recent example, reaction of n-butyl vinyl ether with p-N ,N -dimethylaminophenyl bromide afforded the isomers 103 as a major product together with 104. The reaction occurs at room temperature when electron-rich P(t-Bu)3 is used as a ligand [7]. Aryl or vinyl methyl ketones are prepared by α-selective reaction of methyl or ethyl vinyl ethers with aryl or vinyl halides, followed by hydrolysis [63]. Also HR of ethyl vinyl ether with the vinyl iodide 105 proceeded regioselectively in the presence of Ag2 CO3 , and the product 106 was converted to the bromomethyl ketone 107 [64]. O-n-Bu Br +

Me2N

Pd2(dba)3 (0.5%) P(t-Bu)3 (1.0%) Cy2NMe (1.1 equiv) dioxane, r.t. 97% O-n-Bu

O-n-Bu

O

+ Me2N

103

NMe2

104 E : Z = 3 : 1

4:1

O

I

OTIPS

Pd(OAc)2, PPh3

+

O

OTIPS

Ag2CO3, 73%

105 O TMSOTf

106

Br OTIPS

Et3N, NBS 107

Reactions with Alkenes (Mizoroki–Heck Reaction)

127

The protected indanone 109 was obtained by the Pd-catalyzed one-pot reaction of the triflate of salicylic aldehyde 108 with 2-hydroxyethyl vinyl ether and addition of AcOH [65]. In this case, selective α-arylation is followed by annulation promoted by Pd and AcOH to give 109. OTf

MeO

1. Pd(OAc) 2, DPPP, 120 °C

OH

+

O

2. AcOH, 78%

CHO 108 O

O O

OH MeO

O

MeO

OH

109

H

Cinnamaldehydes 111 are prepared by the reaction of acrolein diethyl acetal (110) with aryl halides and hydrolysis of the coupling product. Formation of saturated esters (3-arylpropionates) is competitive, and cinnamaldehydes were obtained with high selectivity in the presence of Pd(OAc)2 , Bu4 NOAc, K2 CO3 , and KCl in DMF at 90 ◦ C [66].

OEt

Br +

MeO

Pd(OAc)2, n-Bu4NOAc K2CO3, KCl, DMF

CHO MeO

70 °C, 81% OEt

111

110 PdX OEt

Ar

b-H elimination

Ar

OEt OEt

OEt b-H elimination hydrolysis

OEt

Ar

Ar CO2Et

OEt

Reaction of ethylene with aryl iodide can be carried out under pressure. The vinylpyridone was prepared in 80 % yield from the 3-iodopyridone 112 under pressure (7 atm) [67]. EtO2C

I + N H 112

O

H2C

CH2

Pd(OAc)2, PPh3 Et3N, MeCN 100 °C, 7 atm 80%

EtO2C

N H

O

128 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides When allylic alcohols are used as an alkene component in HR, β-H elimination occurs from an oxygen-bearing carbon, and aldehydes or ketones are obtained, rather than β-arylated allylic alcohols [68,69]. The reaction of methallyl alcohol (113) with a halobenzene is a good synthetic method for dihydro-2methylcinnamaldehyde, an important fragrant compound 114. The allylic alcohol 115 is not formed. An intramolecular version of the aldehyde formation was applied to the preparation of the key intermediate 117 from 116 in the total synthesis of saponaceolide [70]. Me Me

OH Ph-X + Pd(0)

OH

Ph

113

H

Ph-Pd-X

Pd-X H

b-H elimination

O

Me OH

Ph

Me

Me Ph

H

Ph

OH

CHO 114

115

O

H

Pd2(dba)3, DPPB Br

O

OH 116

Ag2PO4, CaCO3, DMA, 79%

CHO

O

H 117

Arylation of the easily available Baylis–Hillman adduct 118 under Jeffery’s conditions gave the keto ester (119) in good yield [71]. On the other hand, some allylic alcohols behave differently. The β-substituted butenolide 123 was obtained by the reaction of the steroidal vinyl triflate 120 with methyl 4-hydroxy-2-butenoate (121). In this case, 3-substituted 4-hydroxy-2-butenoate 122 is a primary product, rather than an aldehyde [72]. In addition to allylic alcohols, other unsaturated alcohols react with aryl halides to give carbonyl compounds. For example, although the reaction was slow (3 days), undecen-1-ol (124) reacted with iodobenzene to afford the aldehydes 125 and126. In this reaction, reversible and efficient elimination of H-Pd-I and its readdition (reinsertion) in reverse regiochemistry are repeated several times until irreversible elimination of H-Pd-I from the oxygen-bearing carbon in 124 occurs, finally giving 125 as a main product in a surprisingly high yield and 126 as a minor product. Efficient Pd migration occurs [73]. In the reaction of allylic ethers with aryl halides, elimination of β-alkoxy group occurs in some cases. Intramolecular reaction of the glycal 127 afforded the cisfused pyrano[2,3-c]pyran 129 via deoxypalladation as shown by 128 [74]. On the other hand, ring cleavage of 130 occurs by deoxypalladation to give 132 via 131 [75]. Furthermore, the bis-annulated pyranoside 134 was obtained by domino HR without elimination of the allyl ether group in 133 [76].

Reactions with Alkenes (Mizoroki–Heck Reaction) OH

O CO2Me

Ph

129

Pd(OAc)2

+ Ph-Br

118

n-Bu4NBr, NaHCO 3 THF reflux, 81%

CO2Me

Ph

Ph

119

OTf

Pd(OAc)2, PPh3

+

HO

CO2Me 121

MeO

KOAc, 74%

120 HO

OH H

CO2Me

Pd-X CO2Me

O

O

122

MeO 123

OH

+

Ph-I

124 Ph

CHO + 125

Pd(OAc)2, n-Bu4NCl LiOAc, LiCl, DMF, 50 °C, 3 days, 91%

Ph

CHO 126

88 : 12

OTBDMS O Br OTBDMS O

127

Pd(OAc)2, PPh3,

O OAr

Et3N, Bu4NHSO4 DMF, 55%

O

OAr

Pd-Br

Ar = p-C6H4-t-Bu

128 OTBDMS O O + Pd(II)

129

130 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides TBDMSO

TBDMSO O

Pd(OAc)2, PPh3

O

Br

OEt

O O

Et3N, Bu4NHSO4, MeCN, H2O, 67%

OEt Pd-Br

130 131 TBDMSO H O

OH

OEt

H 132

TBDMSO

TBDMSO O

O

O

Pd(OAc)2, PPh3, Et3N O

Bu4NBr, MeCN, 75%

O

O Pd-X

Br

TBDMSO

133

O O

O

134

Single products are obtained by the HR of unsaturated esters such as acrylate. On the other hand, two reactions occur in HR of α,β-unsaturated ketones depending on substrates and reaction conditions. One of them is normal HR to give substituted products 135 formed via β-H elimination. In addition, 1,4-conjugated addition to give the Michael addition-type products 136 by reduction of alkylpalladium R Ar-X

+

Pd(0)

R

Ar

R

Ar +

O

O 135

O 136

intermediates is observed. Intramolecular reaction of the enone 137 afforded the reduced product 138 under usual conditions and the unsaturated ketone 139 in the presence of AgNO3 [77]. Chemoselectivity of the reaction of the aryl triflate 140 with methyl vinyl ketone depends on bases. The unsaturated product 141 was obtained in the presence of NaHCO3 , and the saturated ketone 142 was obtained when Et3 N was used as the base [78].

Reactions with Alkenes (Mizoroki–Heck Reaction)

131 OBn

O

OBn

Pd(OAc)2, PPh3 OBn O

O

Et3N, MeCN, 56% O

OBn

138 O

I

OBn O

O

O

OBn

Pd(OAc)2, PPh3

O

137

Et3N, MeCN, AgNO3, 70%

O O 139

O

PdCl2(PPh3)2, DPPP Me Me

NaHCO3, DMF, 86%

Me

O

Me

OTf Me

+ O

141

Me

Me

140

PdCl2(PPh3)2, DPPP

O

Me

Et3N, DMF, 75% Me 142

As an example of 1,4-conjugated addition, the intramolecular reaction of 143, carried out in the total synthesis of strychnine by Bonjoch, gave the unexpected reduced product 144. Et3 N may be a hydride source [79]. In the stereocontrolled synthesis of zoanthenol by the Hirama group, the benzylic quaternary center was constructed in 84 % yield by HR of the very congested β,β-disubstituted enone 145 using DPPB as a ligand in the presence of Et3 N. The Pd-enolate 146, formed by intramolecular insertion, is an intermediate, and the saturated ketone 147 was obtained by attack of the hydride supplied possibly from Et3 N or protonolysis of the enolate. Direct hydrogenolysis of the triflate group in 145 occurred before olefin insertion when HCO2 H was added as a hydride source [80]. OTBDMS N I

NO2 O 143

Pd(OAc)2, PPh3

N

NEt3, THF, 90 °C 53% NO2 O H 144

OTBDMS

132 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Me

Me

OMOM

Pd2(dba)3, DPPB DMAC, NEt 3

OBOM

120 °C, 12 h, 84%

TfO

X-Pd

OBOM

Me

Me

OMOM

OH

OH

H

O

Me

Me

H

O

145 OMOM

OMOM OBOM

Me

OBOM hydride

Me

Me

Me

Me

Me OH

OH

XPd H

H

O

O

146

147

Bicyclopropylidene (148) undergoes HR with ring cleavage. Carbopalladation of 148 generates 150. Then 151 is formed by β-carbon elimination. This intermediate undergoes several transformations with other substrates. In one case, it is converted to 1,3-diene 152, and its Diels-Alder reaction with acrylate affords the spirocyclopropane 149 [81].

I +

CO2Me

+

Pd(OAc)2, PPh3 Bu4NCl, K2CO3 MeCN, 2 d, 95%

CO2Me

148

149

CO2Me

Pd-I I-Pd

150

151

152

Reactions with Alkenes (Mizoroki–Heck Reaction)

133

3.2.6 Formation of Neopentylpalladium and its Termination by Anion Capture The carbopalladation of the 1,1-disubstituted alkenes 153 generates the neopentylpalladium 154 which is a living species, because there is no β-H to be eliminated in 154, and the reactions are terminated only by exchanging Pd—X with anions or nucleophiles to afford 155, and the product 156 is formed by reductive elimination. As an intramolecular version, the cyclized product 161 was obtained from halo dienes 158 by exchange of the neopentylpalladium intermediate 159 with anions to give 160. As a side reaction, direct displacement of Ar—X with anions occurs to give 157 or 162. Usually carbopalladation is faster than the direct anion exchange process to give 162. −

Anionic : Neutral :

H, − OAc, − N3 , − CH(CO2 R)2 , − SO2 Ph, RCO2 − .

NHR2 , ROH, CO-ROH.

Organometallic RM :

M = Mg, Zn, B, Sn.

Ar-X

Pd-Y

Pd-X

Pd(0) Ar-Pd-X

R

R

+

Ar

R Ar

154

153

Y

Y anion exchange

155 RE

Ar-Y

Ar-Pd-Y

Y

157 R Ar 156

Pd(0)

X

Y

insertion

Pd-X 159

Pd-Y 160

158

Y Y 162

161

134 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Some examples of termination by anion capture are as follows. Reactions are terminated by carbonylation. Domino carbopalladation and carbonylation of the iododiene 163 under 1 atm of CO via a neopentylpalladium intermediate gave the cyclized ester 164 with high yield and diastereoselectivity [82]. The iodide 165 underwent 5-exo cyclization to generate the neopentylpalladium 166 and its carbonylation gave the acylpalladium 167. Intramolecular attack by malonate anion affords 168 [83].

I

PdCl2(PPh3)2,

+ CO + MeOH H

ZO 163

CO2Me

Et3N, DMF, 91% 94% diastereoselectivity

ZO 164

Z = t-BuMe2Si

CH(CO2Me)2

CH(CO2Me)2 I Pd(OAc)2, PPh3

+

CO

Pd-X

TlOAc, MeCN 50%

N SO2Ph

N SO2Ph

165

166 CO2Me

MeO2C

MeO2C

CO2Me O

Pd-X O CO N SO2Ph

N SO2Ph

167

168

Total synthesis of capnellene has been achieved by bis-cyclization of the cyclopentene 169. The tricyclic compounds 170 and 171 were prepared by the attack of malonate anion using TFP as a ligand, and capnellene was synthesized from 170 [84]. CO2Me CO2Me Pd(OAc)2, TFP I 169

KH, THF, 25 °C, 70% 170

CO2Me

CO2Me

CO2Me +

CO2Me

93 : 7

171

capnellene

Termination occurs by transmetallation with organometallic compounds of B and Sn, followed by reductive elimination. The aryl iodide 172 underwent 5-exo cyclization. Transmetallation of the alkylpalladium with vinyltin reagent, followed by reductive elimination, afforded 173 [85]. The anion trap is not limited to the

Reactions with Alkenes (Mizoroki–Heck Reaction)

135

Bn N

O

Pd(OAc)2, PPh3

+

SnBu3

I

MeCN, 80 °C, 60%

O

N Bn

172

173

neopentylpalladium intermediate. The domino reaction of the bromodiene 174 was terminated with phenylboronic acid to afford 176. In this case, transmetallation occurs preferentially in 175 with suppression of β-H elimination [86]. Similarly the domino Heck–Suzuki coupling of norbornadiene, iodobenzene and phenylboronic acid afforded the diphenylnorbornene 178. In this case, syn β-H elimination from 177 is not possible on steric grounds [87]. Br

Pd-X + PhB(OH)2

N Ts

Ph

Pd(PPh3)4 Na2CO3, THF 75%

N Ts

174

N Ts 175

+ Ph-I + Ph-B(OH)2

176

Ph

Pd(OAc)2

Ph

Ph-B(OH)2

Pd-I

PPh3, 76% 177

Ph 178

Hydroarylation of olefins by attack of hydride derived from formic acid is frequently used. Cyclization of 179 generates the neopentylpalladium 180, which is trapped with the hydride to yield the hydroarylation product 181 [88].

I

Ph

N Bn

Pd(OAc)2, PPh3 Et4NCl, DMF, 55%

O 179

Ph

Ph Pd-X N O

180

Me

HCO2Na

N

Bn

Bn

O 181

3.2.7 Intramolecular Reactions 3.2.7.1 Introduction Many intramolecular versions and domino reactions involving halides as a starter and alkenes and alkynes as a relay offer a variety of useful synthetic methods of unique heterocycles and carbocycles. Few other methods can compete with

136 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides these Pd-catalyzed cyclizations. Negishi et al. gave a review of cyclic carbopalladation [6f]. Although many reports and a number of excellent reviews have been published [6], an understanding of the high potentiality of these somewhat complicated cyclization methods in organic synthesis is becoming increasingly difficult. Also complete coverage of the chemistry is nearly impossible. Therefore, in order to improve understanding, the cyclization methods are classified into several patterns and the types and are explained with pertinent examples. There are two modes of cyclization, namely exo and endo. Extensive studies on the selectivity between exo and endo cyclizations have been carried out by Grigg et al. [89]. Exo cyclization is the favored path, and endo cyclization is less likely for the formation of smaller than six-membered rings. Endo cyclization becomes the main path when carbon chains are more flexible in forming rings of larger sizes. Cyclization of 2-halo-1,6-heptadiene 182 gives rise to the fivemembered ring 184 by 5-exo-trig cyclization, and the six-membered rings 185 and 186 by endo cyclization. Although formation of the six-membered ring 185 may be understood by direct 6-endo-trig cyclization, an accepted explanation for its formation is 5-exo-trig to generate 183 and its 3-exo-trig cyclization to give the cyclopropane 187. Subsequent cyclopropylcarbinyl-homoallyl rearrangement, which is β-carbon elimination, to afford 188 and β-H elimination afford the sixmembered rings 185 and 186. Ratios of exo and endo cyclizations may change by size and conformation of rings, substituents, and reaction conditions as shown in following examples. Pd-X 5-exo -trig

Pd(0) Pd-X

X

182

183

184 3-exo-trig

6-endo b-carbon elimination

+ Pd-X

Pd-X 185

186

188

187

The total synthesis of xestoquinone 192 was carried out based on domino 6exo-trig and 6-endo-trig cyclizations of 189. In this case, the selective 6-endo-trig cyclization of 190 to give 191 seems to be favored by smaller ring strain of the six-membered ring than that of the five-membered ring presumably formed by 5-exo-trig cyclization [90]. Similarly, exclusive endo cyclization of N -allylindole 193 to give 194 is understandable by smaller ring strain of the product [91]. The following example shows that ratio of 6-endo to 5-exo in the cyclization of 195 changes dramatically from 99 : 1 to 4 : 96 by slight modification of the catalyst systems [89,92,93]. The effect of the addition of HCO2 H as a hydride source to afford the 5-exo product 198 is understandable. The exo cyclization generates

Reactions with Alkenes (Mizoroki–Heck Reaction)

137

XPd OMe

OMe

H

H

OTf

Pd2(dba)3, (S)-BINAP PMP, 78%, 68% ee 6-exo -trig O

OMe

O OMe

O 189

O 190

OMe

Pd-X H b-H elimination

6-endo O OMe

O 191

OMe

O H

H

O OMe

O O

O

O 192

OMe

OMe Ph

MeO N

Ph

Ph

6-endo Pd(OAc)2, P(o-Tol) 3 Et3N, MeCN, 96%

N

MeO

Ph

Br 193

194

the neopentylpalladium 197, and termination by itself is difficult. The reaction can be terminated smoothly to give 198 by hydride capture in the presence of HCO2 Na. Exclusive endo cyclization occurs to give 196 in the absence of anions. Thus generally speaking, exo cyclization is more favored than endo cyclization whenever the situation allows in five- and six-membered ring formations. Yields of endo cyclization products of the iodo enamine 199 to give the heterocycles 200 steadily increase with longer chain lengths under Jeffery’s conditions. It is surprising that the medium-sized (eight- and nine-membered) rings were obtained in high yields [94]. 3.2.7.2 Formation of Three- and Four-Membered Rings Intramolecular HR has been utilized as a simple construction method for complex skeletons of natural products. Many elegant and efficient total syntheses of natural products with interesting structures have been achieved, showing that HR is a

138 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides MeO

MeO 6-endo Pd(OAc)2, PPh3

S N

55%

MeO O

N

MeO

O

Br 6-endo : 5- exo 99 : 1

195

S 196

5-exo MeCN, HCO2Na Pd(OAc)2, PPh3 Et4NCl, MeCN

MeO

MeO N

MeO

HCO2H (H−)

O

N

MeO

X-Pd

O

Me S 197

S

198 b-H elimination

6-endo : 5- exo 4 : 96

BOC ( )n

N

CO2Me

( )n

Pd(OAc)2, NaHCO3

N

MS 3A, Bu4NCl, 105 °C I

n 1 2 3

199

yield 41% 63 89

200

BOC

CO2Me

powerful tool for the cyclization based on carbon–carbon bond formation. Some examples are shown in the following. Numerous carbo- and heterocyclic compounds of various sizes have been prepared by HR-type monocyclization. Cyclopropanes are formed only when neopentylpalladium intermediates are formed in the absence of anions. Intramolecular carbopalladation of the alkenyl triflate 201 generates the neopentylpalladium 202, and its 3-exo cyclization and β-H elimination afford the cyclopropane 203 [95]. Intermolecular carbopalladation of the alkyne 204 generates 205. Its 5-exo cyclization provides the neopentylpalladium 206, which undergoes 3-exo cyclization to construct the three-membered ring 207. Finally β-H elimination gives rise to the cyclopropane 208 [96].

X-Pd TfO

Pd(OAc)2, PPh3

3-exo-trig

Et4NCl, Na2CO3 CO2Me

CO2Me 201

202

CO2Me 203

Reactions with Alkenes (Mizoroki–Heck Reaction) Me

Me

139

Ph

I Pd(OAc)2, PPh3

+ E

5-exo PdX

TlOAc, DMF E = CO2Me

E

E

204 Ph

Me

Pd-X

Ph

Me 3-exo E

E 205

Me Me

Me

X-Pd

b-H elimination E

E

Ph

E

E

207

206

E

208

Formation of cyclobutanes is not common. As a rare example, Overman reported that bis-cyclization of the triflate 209 afforded the spirocycle 211 as a major product via 210. At the same time, construction of the cyclobutane 213 by 4-exo cyclization of 210 occurred and 214 was detected in 5 % yield [97]. XPd OTf

Pd(OAc)2, PPh3 Et3N, MeCN

O

O

209

O

210

211 53%

4-exo XPd

O

O

214

213

3.2.7.3 Formation of Five- and Six-Membered Rings in Natural Product Syntheses Facile formation of five- and six-membered rings has wide application in natural product syntheses. The tricyclic synthetic intermediate of the galantamine alkaloid 216 was prepared by intramolecular HR of 215. A single double bond isomer was obtained in the presence of Ag2 CO3 as a weak base [98,99]. MeO

MeO

CHO

O I

Pd(OAc)2, Ag2CO3 DPPE, DMF, 75%

CHO

O

CONMe2

Me2NOC

215

216

140 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides An interesting example which shows different catalysts are required for HR of a vinyl bromide and an aryl bromide was observed in enantiopure synthesis of estrone by double HR [100]. The vinyl bromide in 217 preferentially reacted with 218 to give 219 selectively in 61 % yield without giving a double bond isomer using Pd(OAc)2 and PPh3 . Then 219 was converted to 220 in 99 % yield under Jeffery’s conditions using the Herrmann complex (XVIII-1) as a catalyst. On the other hand, the one-pot domino reaction of 217 with 218 under the same conditions afforded 220 in 35 % yield. O-t-Bu

O-t-Bu Br Br

Pd(OAc)2, PPh3

+

Br

61%

MeO 218

217

H

H MeO 219

XVIII-1, Bu4NOAc 35% 60 °C, 168 h

99% O-t-Bu

XVIII-1, Bu4NOAc, 115 °C, 4.5 h

H H

H

MeO 220

A practical six-step synthesis of (S)-camptothecin has been achieved utilizing HR as a key reaction. Intramolecular reaction of the optically pure quinoline chloride 221 with the enamide moiety gave pure (S)-camptothecin (222) after recrystallization in 64 % yield under usual conditions [101]. It should be added that chlorides of heterocyclic compounds such as pyridines and quinolines are activated by electron-attracting nitrogens and react smoothly without using electron-rich ligands.

HO N

HO O

Cl

Pd(OAc)2(PPh3)2 N

221

O O

N

KOAc, MeCN 100 °C, 64%

O O

N 222

O

In the enantioselective synthesis of a cardenolide precursor, the congested quaternary carbon center and the cis-AB ring fusion in the steroid skeleton 224 were constructed by cyclization of the alkenyl triflate 223 [102]. Similarly critical quaternary carbon–aryl bond formation took place by the cyclization of the bromopyridine 225 to afford the pyridinomorphinan 226 using 60 mol% Pd trifluoroacetate and PPh3 [103].

Reactions with Alkenes (Mizoroki–Heck Reaction)

141

CN

CN

PhS

PhS Pd(dppb), KOAc

TfO OH

O

DMA, 70%

OH

PdX O

O

CN

O PhS O

223

O

A

B

OH

224

N

N DBS

H

Pd(OCOCF3)2(PPh3)2

i-Pr2EtN, xylene, 51% NDBS

N

Br 225

226

In the total synthesis of gelsemine achieved by Overman, carbopalladation of a very congested tetrasubstituted double bond of a vinylogous carbamate in 227 was successfully carried out under cationic Heck conditions adding silver phosphate to give the spirooxindole 228 as the major product in 61–78 % yield, which had the opposite configuration of the spirooxindole as that found in gelsemine. After epimerization, total synthesis of gelsemine (229) has been completed [104]. I O MOM RN

NMOM

Pd2(dba)3,

N

Ag2PO4, Et3N THF, 78%

OMe

O RN

OMe

Br

Br

228

227

H N

O steps MeN O

gelsemine 229

142 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides In the studies of gelsemine synthesis, Danishefsky studied stereochemical control in intramolecular HR of 230 [105]. In this case, carbopalladation of C3—C7 double bond occurs preferentially from the α face due to coordination of Pd to both double bonds as shown by 233 using a ligandless catalyst and AgOTf to give the desired oxindole 231 as a major isomer (7 : 1), which has the correct configuration for gelsemine synthesis. When Pd(PPh3 )4 is used, both isomers were obtained in 4 : 3 ratio, because a few molecules of PPh3 coordinate to Pd, inhibiting coordination of Pd to the C5—C6 double bond. When the C5—C6 double bond is reduced as 234, there is no possibility of fixing Pd species in the α side, and hence the carbopalladation occurs from the less congested β side to give the major isomer 235 and the minor product 236 in a ratio of 7 : 1. O

tBuO 7

Me N

O

Me N

tBuO

tBuO

NMe

+ 3

I

5

O

6

230

231

conditions

Pd2(dba)3, AgOTf, Et 3N, dioxane 50−70%

7 : 1 4 : 3

Pd(PPh3)4, MeCN

OtBu

O

232

Me N

O

tBuO

Me N

I Pd

X 233

234 O

Pd2(dba)3, AgOTf

tBuO

tBuO

NMe

Me N

+

Et3N, dioxane

O

235

7:1

236

Total syntheses of the complex molecule of strychnine have been carried out by several groups applying intramolecular HR as key reactions. The first elegant Pd-based total synthesis of strychnine (237) has been achieved by Rawal. An intramolecular Diels-Alder reaction and HR were key reactions. The Pd-catalyzed cyclization of the pentacyclic lactam 238 under Jeffery’s conditions gave isostrychnine 239 in 74 % yield. Conversion of 239 to 237 is known [106].

Reactions with Alkenes (Mizoroki–Heck Reaction)

143

N

H N

H

H O

O strychnine 237

Rawal

OTBS N

N I

Pd(OAc)2, Bu4NCl

steps

K2CO3, DMF, 70 °C 74%

N H

N

H

H

O

O 238

237

OTBS

239

The Vollhardt’s synthesis utilizes [2 + 2 + 2]cycloaddition of 240 with acetylene mediated by a Co–acetylene complex to yield 241 and an intramolecular HR of 243 to afford 244 as the key reactions. The intramolecular HR of the conjugated dienone 243 under usual conditions affords the pyridone 244 via β-H elimination from C8 [107]. Vollhardt

NHAc NHAc + HC N

CpCo(C2H4)2 CH

steps

H

THF, 0 °C, 46%

N

O

CoCp

O 240

241

N

NH H N

H

C8

N

Pd(OAc)2, PPh3 I

C-8

Et3N, 70 °C, 46%

TBSO O

O 242

243 N

steps

237

N TBSO

O 244

HR of a similar type is utilized in the total synthesis of optically active strychnine by Mori’s group [108]. Their method can be said to be a truly Pd-based

144 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides synthesis because the total synthesis has been achieved by applying six-different Pd-catalyzed reactions. At first asymmetric allylation of 246 with the allylic phosphate 245 using (S)-BINAPO (XV-4) afforded 247 with 84 % ee. Intramolecular HR of 248 using Me2 PPh as a ligand yielded 249 with 99 % ee after recrystallization. Pd(OAc)2 -promoted intramolecular aminopalladation of 250 in the presence of BQ and MnO2 as oxidants of Pd(0) gave 251. The ketone 252 was converted to an enol triflate, which was subjected to Pd-catalyzed hydrogenolysis with HCO2 H to give the olefin 253. Again, intramolecular HR of 254 gave 255, and subsequent Mori

OTBS TsHN

OPO(OEt)2

Pd2(dba)3, (S)-BINAPO (XV-4)

+

NaH, DMF, 0 °C, 44 h 80%, 84% ee

Br 245

246 CN

OTBS

Pd(OAc)2, Me2PPh

steps N Ts

Br

Br

247

Ag2CO3, DMSO 90 °C, 87%

N Ts 248

CN

NHBoc Pd(OAc)2, BQ MnO2, AcOH, 87%

N Ts H

N Ts H

249

250 NBoc

NBoc 1. PhNTf 2, KHMDS

steps N Ts H

N Ts H

O

2. Pd(OAc) 2, PPh3 HCO2H, i-Pr2NEt 64%

252

251 NBoc

NBoc Pd(OAc)2, PPh3

N Ts H

i-Pr2NEt, DMSO 46%

N H

253

Br

O 254 NBoc

H N O 255

NaO-i-Pr

242

239

237 (−) strychnine

Reactions with Alkenes (Mizoroki–Heck Reaction)

145

isomerization of the double bond in 255 gave the conjugated dienone 242, which is the same intermediate in Vollhardt’s synthesis, thus completing the chiral total synthesis of strychnine (237). 3.2.7.4 Syntheses of Medium to Large Rings and Applications to Natural Product Syntheses Two Pd-catalyzed cyclizations were used for the enantioselective synthesis of (−)-cephalotoxine [109]. One-pot Pd-catalyzed domino reactions, namely intramolecular allylation of amine and HR of 256, seem to be the best path for the desired synthesis. However, attempted direct conversion of 256 to 258 with the Herrmann complex was unsuccessful. Then selective intramolecular aminoallylation with the chiral cyclopentyl acetate occurred smoothly to give the spiro amine 257 in 88 % yield when Pd(PPh3 )4 and TMG (tetramethylguanidine) as a base were used. The cyclization proceeded with retention of stereochemistry without racemization. The next HR reaction of 257 gave the seven-membered compound 258 in 81 % yield under Jeffery’s conditions using the Herrmann complex as a catalyst. No transformation of 257 to 258 occurred when Pd(PPh3 )4 was used. The results show that the best catalysts for the allylation and HR are different. H N

O

Pd(PPh3)4 , TMG MeCN, 88%

O

Br

N

O O

Br

256

257

Bu4NOAc

XVIII-1

OAc XVIII-1 Bu4NOAc

O

MeCN, DMF

81% N

O H 258

steps cephalotoxine

The bis-Heck cyclization of trienyl iodides has been applied as a key reaction by Overman to total syntheses of stemodane diterpenes and scopadulcic acid. Treatment of the 6R, 8R epimer of the trienyl iodide intermediate 259 with Pd(dppb) in the presence of Ag2 CO3 in DMA provided two tricyclic products 260 (40 %) and 261 (25 %). The major product 260 has the stemodane skeleton [110]. On the other hand, bis-cyclization of the 6S, 8R epimer of the trienyl iodide 262 proceeded with complete stereo- and regioselectivity as shown by 263 and 264 to afford the tricycle of the scopadulan skeleton 266, from which total synthesis of scopadulcic acid A (267) was achieved. In the second cyclization as shown by 264, generation of the cyclohexylpalladium intermediate 265, having Pd attached to the secondary carbon center is favored to give 266 selectively. Formation of a stemodane skeleton is expected from the 6R, 8R epimer [111].

146 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

I H 6R

Pd(dppb)

8R

MOMO

H

Ag2CO3, KOAc DMA steps

259

MOMO

H

+ MOMO

40%

260

stemodinone

25%

261

I

O O

Pd(OAc)2, Ag2CO3

8R

R

H

Pd

H 6S

8R

TBDMSO

6S

OTBDMS

Ph3P, THF, 65 °C 90%

R 263

262 X-Pd

Pd-X

R

R H

H

OTBDMS

O

Bu4NF

H O 266

OTBDMS 265

264

OH

HO

O H steps

O H

260 H

H

HO2C

OCOPh stemodinone

HO 267

For the total synthesis of macrocyclic compound ‘diazonamide A’, Harran’s group tried intramolecular HR of highly functionalized iodide 268, although they found the proposed structure to be wrong. Selective endo cyclization took place to give the macrocycle 269 in 82 % yield when Pd2 (dba)3 , Ag3 CO3 , and biphenylylH

BOC

H N

N

HN O

CN

H

THF, 82% I

H

endo-trig Pd2(dba)3, Ag2CO3

O

BOC

H N H

O

CN

O

HO

OBn 268

N

HN

OBn OH

OMe, 6%

269

RO

Reactions with Alkenes (Mizoroki–Heck Reaction)

147

(di-t-butyl)phosphine (IV-1) were used [112]. Participation of the phenolic OH group near the double bond by forming Pd phenoxide seems to be crucial for the smooth cyclization. When OH was methylated, the yield of the cyclization was only 6 %. The eight-membered ring of baccatin III skeleton 271 was constructed by 8exo HR of the enol triflate 270 [113]. The 21-membered ring 273 was obtained in surprisingly high yield (66 %) from 272. In similar cyclizations, rings larger than 13 members are obtained under high dilution conditions [114]. Interestingly, exclusive endo cyclizations occur in the formation of large rings.

OTBS

OTf OTBS Pd(PPh3)4, K2CO3 O O

MeCN, 85 °C, 49%

H

O

O OBn

O

OBn

O

270

271 E

I E

O

H

O

E E 12

E

Pd(OAc)2, PPh3

21

Ag2CO3, 66% E

272

E

E

273

3.2.7.5 Domino cyclization to form polycycles Polycyclic compounds are prepared by domino polycyclization of suitably designed polyenynes, in which a starter (halide), a relay (alkene or alkyne), and a terminator (alkene or alkyne) are tethered in such a way to induce efficient domino reactions. The alkyne insertion produces the thermally stable alkenylpalladium species as living species, which can not be terminated by themselves, and further transformations are required in order to terminate reactions and to regenerate Pd(0) species for catalytic recycling. While alkynes play the role of the relay to pass the ability of carbon–carbon bond formation to other groups, alkene insertion is followed by facile dehydropalladation whenever there is a β-H, and generation of Pd(0) catalytic species. In order to play the role of the relay, the alkenes must be 1,1-disubstituted, and its insertion generates neopentylpalladiums as the living species. These living species undergo further insertion of alkenes and alkynes, and the reactions are terminated by capturing the anionic species as described before. Grigg has shown a number of possibilities of polycyclizations. As an early example, the 1,6-diene 274 underwent 5-exo cyclization to generate the neopentylpalladium 275, and 6-exo cyclization of 275 yields the neopentylpalladium 276, which was captured by NaBPh4 to afford the spiro compound 277 as a single diastereomer [115].

148 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides SO2Ph N

PhO2SN 5-exo-trig Pd(OAc)2, PPh3

I

Pd-X

NaBPh4, DMF, 63%

N SO2Ph

6-exo-trig

N SO2Ph

274

275 PhO2SN

PhO2SN Pd-X

Ph NaBPh4 N SO2Ph

N SO2Ph 276

277

3.2.8. Asymmetric Reactions Compared to very extensive studies on Heck reactions, examples of successful asymmetric Heck reactions (abbreviated to AHR in this section) are rather limited, showing that AHRs are not easy to carry out, and careful tuning of conditions is crucial. Most of the HRs proceed by using monodentate ligands. On the other hand, chiral bidentate ligands are mainly required for AHRs. This may be a reason for the difficulty in achieving efficient AHRs. The ligands most extensively used are BINAP, its derivatives, and phosphinooxazolines [116]. Construction of racemic tertiary and quaternary carbon centers by HR has been studied extensively, suggesting the potential of asymmetric syntheses. Actually AHRs have been achieved by constructing quaternary and tertiary carbon centers. The quaternary carbon centers 279 are introduced at β-carbons by H elimination from β
-carbon in 278. On the other hand, construction of tertiary carbon centers 281 is more challenging, because there is a possibility of β-H elimination to provide 282 as a competitive path, which destroys the newly formed carbon center in 280. Thus Construction of quaternary carbon R4 b Ar-X +

Pd(0)

a b′

R1

R2

Ar

Pd-X

R4

b′

R1

b′-H elimination

Ar R4

R2

R2

R1 3

R3

3

R

R

278

279 Ar

Construction of tertiary carbon

R1

R2 R

b Ar-X +

a b′

R1 R3

Pd(0) R2

Ar

Pd-X

b

b′

R1 R3 280

R2

3

b′-H elimination product

281

R1 Ar

R2

R3 b-H elimination product

282

Reactions with Alkenes (Mizoroki–Heck Reaction)

149

how to achieve β
-H elimination selectively, rather than β-H elimination, is a crucial problem for successful AHR, and several methods have been reported. As one solution, Ag or Tl salts are added in order to generate cationic Pd catalysts. It is generally accepted that double bond migration is suppressed by the use of the cationic Pd catalysts. 3.2.8.1 Intermolecular AHR Successful intermolecular AHR has been studied much less than intramolecular AHR. After pioneering work by Hayashi et al. on intermolecular AHR of 2,3dihydrofuran (286) with phenyl triflate using (R)-BINAP to afford 2-phenyl-2,3dihydrofuran (288) with 96 % ee [117], a number of AHR using related substrates have been reported. Pfaltz carried out successful AHR of cyclopentene with cyclohexenyl triflate (283) using phosphinooxazoline (VII-3) as a ligand and obtained selectively the coupled product 284 with 89 % ee in 70 % yield. A small amount of the isomer 285 was formed [118]. This ligand is effective to suppress double bond migration. Under similar conditions using BINAP, a mixture of double bond isomers was obtained. OTf

Pd2(dba)3, VII-3

+

i-Pr2NEt, benzene 70 °C,

283

+ 70%, 89% ee 284

98 : 2

285

Further studies on AHR of 2,3-dihydrofuran (286) with phenyl triflate afforded different products with high % ee depending on the ligands used. The isomer 287 with 96 % ee was obtained selectively when the phosphine—oxazoline ligand 291 was used [119]. On the other hand, the isomer (288) with 98 % ee was the major product when (S)-MeO-BIPHEP (292) was used [120]. AHR of 283 with 289 using (R)-BITIANP (293, XV-7) in the presence of proton sponge afforded the coupling product 290 with 91 % ee selectively [121]. OTf O

+

O

+

O 286

287

288

Pd2(dba)3, 291

i-Pr2NEt, benzene 70 °C, Pd(OAc)2, (S)-292 40 °C OTf + 283

100% conv. 96% ee

3%, 98% ee

65%, 98% ee

Pd2(dba)3, (R)-BITIANP N CO2Me 289

proton sponge, DMF 90 °C, 73%, 91% ee

N MeO2C 290

150 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides S

O

PPh2

MeO

PAr 2

PPh2

MeO

PAr 2

PPh2

N S H

t-Bu Ar = 3,5(t-Bu)2C6H3

291

293 (R)-BITIANP

292

(XV-7)

O N

t-Bu

PPh2 VII-3

According to Hayashi et al. [117], formation of 287 and 288 can be understood by the following mechanism; carbopalladation to form the intermediate 294, followed by β-H elimination gives the primary product 287. Inverse addition of the resulting H-Pd-X to 287 gives another intermediate 295, and β-H elimination affords the dihydrofuran 288 [117]. It should be noted that the β-H elimination from 294 to give 2-phenyl-4,5-dihydrofuran (296) is not possible because there is no H at C-1 syn to Pd, and H at C-4 is eliminated to give 287. This situation is one reason why AHR by creating tert-carbon centers is possible in rigid cyclic systems. H Ph-OTf +

(R)-BINAP, C 6H6

O

H

X-Pd

H

295

O H-Pd-X

Ph

(S)-287 7%, 67% ee

b-H elimination

H-Pd-X O

b-H elimination

Ph

O 294

286

addition

Pd-X

Pd(OAc)2, base

Ph

O

Ph

(R)-288

O

Ph

296

71%, 93% ee

3.2.8.2 Construction of Tertiary Carbon Centers by Intramolecular AHR Intramolecular AHR is a useful tool for total syntheses of optically active natural products [121a]. Tietze has shown that regiochemistry of β-H elimination can be controlled by employing an allyltrimethylsilane moiety in directing the elimination as in 297, and the product 298 with 92 % ee was obtained from 297 in 92 % yield. Then 298 was converted to the calamenene derivative 299 [122].

Reactions with Alkenes (Mizoroki–Heck Reaction)

151

SiMe3 Me

I

Me

Pd2(dba)3, (R)-BINAP Ag3PO4, DMF, 80 °C 91%, 92% ee

MeO

MeO

297

298 Me

MeO 299

The first examples of intramolecular AHRs were reported by Shibasaki et al. [123] and Overman et al. [124] in 1989. The Shibasaki group carried out cyclization of achiral alkenyl iodide or triflate 300 to give the chiral tetrahydronaphthalene system 301 by differentiation of enantiotopic C=C double bonds using (R)-BINAP without using a silver salt [123]. Subsequently, the reaction has been improved [125]. The chiral hexahydronaphthalene system 304 with 86 % ee was obtained by AHR of the bisallylic alcohol 302 via syn β-H elimination from the intermediate 303, and 304 was converted to the key intermediate 305 in the synthesis of vernolepin (306). Use of a mixed solvent of 1,2-dichloroethane and t-BuOH is important [126]. CO2Me

CO2Me Pd(OAc)2, (R)-BINAP, K 2CO3 ClCH2CH2Cl, t-BuOH OTf

78%, 95% ee

H

300

301 OPiv

OPiv Pd2(dba)3, (R)-BINAP ClCH2CH2Cl, t-BuOH

HO

TfO

K2CO3, 76%, 86% ee

HO H Pd

302

P

H P

* 303 OPiv

O H 304

152 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O O OH O

steps O

O H

H

305

306

O O

In the total synthesis of (−)-eptazocine (309), the benzylic quaternary center with 90 % ee in 308 was constructed by AHR of the triflate 307 using (R)-BINAP [127]. Pd(OAc)2, (R)-BINAP K2CO3, 90%, 90% ee OTf

MeO

MeO OTBDPS

Me

OTBDPS

307

308 Me N

steps HO Me 309

Differentiation of the prochiral cyclopentadienyl system in 310 by intramolecular AHR generates π -allylpalladium 312, which was trapped intermolecularly with the malonate 311 in regio- and stereoselective manner to provide the bicyclic system 313 with 87 % ee in the presence of NaBr in DMSO. The regio- and stereoselective anion capture can be understood by considering the steric effect as shown by 312. The total synthesis of capnellene 314 has been achieved from 313 [128]. OTf [Pd(allyl)Cl]2, (S)-BINAP CH(CO2Et)2 NaBr, DMSO, 77%, 87% ee

+ TBDPSO 311

310

EtO2C Nu

CO2Et

H OTBDPS steps

Me Me

H H

H

Pd-X Me 312

Me

Me

313

314

3.2.8.3 Construction of Quaternary Carbon Centers by Intramolecular AHR Overman and co-workers have carried out pioneering and extensive studies on AHR to synthesize quaternary carbons bearing two aryl substituents. Aiming at the

Reactions with Alkenes (Mizoroki–Heck Reaction)

153

enantioselective syntheses of naturally occurring indole alkaloides, they obtained 3-alkyl-3-aryloxindole moiety, and several related indole alkaloids [129]. Construction of the quaternary carbon in 316 was achieved with high enantioselectivity (98 % ee) in high yield (91 %) by AHR of the triflate 315 using (R)-BINAP as a ligand and PMP as a base. OMe

OTf O

NHBoc Pd(OAc)2, (R)-BINAP

N Bn

OMe

PMP, THF, 80 °C 91%, 98% ee

NHBoc

O N Bn 316

315

High % ee was obtained by domino AHR of the diene 317. The AHR of the diene 317 (R = Me) afforded the tetracyclic compound 318 in 91 % yield with high ee (90 % ee). Unexpected 6-endo cyclization, rather than 5-exo cyclization occurred to produce the six-membered ring in the second cyclization. It was found that ee was 71 % when R = H. The results show that the remote substituent gave a profound effect on the ee in the polyene cyclization [130]. R OTf R

O O 317

6-exo, 6-endo Pd2(dba)3, (R)-BINAP

R = Me, H

PMP, 110 °C 78%, 90% ee

O O (R)-318

Elegant enantioselective total syntheses of quadrigemine C (321) and psycholeine have been achieved by Overman [131]. The key step is the desymmetrization of the meso intermediate 319 by asymmetric double Heck cyclization using (R)-Tol-BINAP as a chiral ligand and PMP as a base to provide the C1 -symmetric dioxindole 320 in 62 % yield with 90 % ee, installing the two peripheral quaternary stereocenters. A highly enantioselective intramolecular AHR of the cyclohexadienone 322 to give 324 with 96 % ee in 100 % conversion was carried out using the chiral phosphoamidite-type ligand (III-10), which is monodentate. The stereogenic center was not created at the site of C—C bond formation, but instead the cyclohexadienone was desymmetrized. The use of Cy2 MeN as a base gave the best result. It should be added that the carbopalladation product 323 has no β-H syn to Pd, and hence the cyclized product 324 was formed by syn β-H elimination after epimerization [132]. As another approach to AHR, an efficient AHR can be achieved based on the remarkable diastereoselectivity, which is caused by chiral auxiliaries. Coupling of the chiral prolinol vinyl ether 325, which contains a prochiral double bond, with o-iodoanisole using ligandless Pd(OAc)2 in aqueous DMF, afforded the product

154 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Bn N

NMeTs

O

O NMeTs

N Bn

H H Me N N

H H Me N N

OTf

Pd(OAc)2 (R)-Tol-BINAP ( XV-2) PMP, MeCN 62%, 90% ee OTf

N N H H Me

N N H H Me

Bn N

NMeTs N Bn

O NMeTs 319

O

320 Bn H CH3 N N

H H Me N N steps

N N H H Me

N N Bn H CH3 321

O O H

re

si MeO

O

I

Pd(OAc)2, III-10 CHCl3, Cy2MeN 100% conv., 96% ee

322

O 323

O

* MeO

MeO

O 324

Pd-I

1. enolization/ epimerization

H

2. b-H elimination

Reactions with Alkenes (Mizoroki–Heck Reaction)

155

326, creating the quaternary carbon with 98 % ee. Effect of the chiral auxiliary amine is remarkable [133]. Hydrolysis of 326 provided the chiral 2,2-disubstituted cyclopentanone 327. In this way, asymmetric α-arylation of cyclopentanones can be achieved in three steps.

OMe

O

N Me

I Me

+

Pd(OAc)2, DMF, H 2O

O

N Me

Me

67%, 98% ee

325

326

MeO

O Me +

H3 O

MeO 327

Also HR of 4,5-dihydrofuran, attached to the chiral o-dimethylaminophenylsulfoxide 328, with iodobenzene afforded the coupling product 329 with 94 % diastereoselectivity [134]. The efficient asymmetric induction occurred by the coordination of Ph-Pd-I to the amino group. A similar effect of the chiral sulfoxide was observed in the intramolecular HR [135].

O O

S

I

S

Pd(OAc)2, DPPF

+ NMe2

NMe2

AgNO3, DMF, 94% diastereselectivity

O

O 328 329

3.2.9 Reactions with 1,2-, 1,3-, and 1,4-Dienes 3.2.9.1 Reactions of 1,3- and 1,4-Dienes Reaction of conjugated dienes with aryl and alkenyl halides can be explained by the following mechanism. Insertion of a conjugated 1,3-diene into an aryl or alkenylpalladium bond gives the π -allylpalladium complex 330 as an intermediate, which reacts further in two ways. As expected, nucleophiles such as carbon nucleophiles, amines, and alcohols attack the π -allylpalladium intermediate to form the 1,4-addition product 331 and 1,2-addition product 332. In the absence of the nucleophiles, β-H elimination occurs to afford the substituted 1,3-diene 333. In some cases, the substituted 1,3-diene 333 reacts again with aryl halide to form the π -allylpalladium 334. Subsequent elimination affords the 1,4-diarylated 1,3-diene 335.

156 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Ar-X

insertion

Ar-PdX +

Ar

Ar PdX

Nu

NuH

PdX

Ar

+

Ar

path A

330

Nu

331

332 PdX

b-H Elim.

Ar-PdX Ar

path B

Ar

insertion

333

Ar 334

b-H Elim.

Ar Ar 335

As early examples, Heck prepared the arylated conjugated dienes 333 and the 1,4-diarylated dienes 335. Also reaction of 2-phenylvinyl bromide with hexatriene afforded 1,10-diphenyl-1,3,5,7,9-decapentaene (336), although yield was low [136]. + Ar-I

Pd(OAc)2, P(o-tol)3 Ar

Et3N 333

Ar-I

Ar

Ar Ar = 4-C6H4OH

Pd(OAc)2, P(o-tol)3 335

60%

Pd(OAc)2, P(o-tol)3

Ph

+

Br

Ph

Ph

Et3N, 15% 336

Dieck reported preparation of the tetrahydrocarbazole 337 by heteroannulation of o-iodoaniline with 1,3-cyclohexadiene [137]. As a recent example, heteroannulation of the o-iodoaniline derivative 338 with the conjugate dienyl sulfone 339 afforded the vinylogous 2-sulfonylindoline 340, which was converted to the indole derivative 341 by oxidative dehydrogenation [138]. Pd-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumain 342 offers a synthetic method for dihydrofurocoumarins. The dihydrofurocoumarin 343 was obtained by the reaction of 342 with 1-phenylbutadiene in 80 % yield. After optimization, the uses of Pd(OAc)2 , I + NH2

Pd(OAc)2, PPh3 Et3N, 70% NH2

Pd-X

N H 337

Reactions with Alkenes (Mizoroki–Heck Reaction)

157

DPPE, Ag2 CO3 in a mixture of dioxane and water provided good results [139]. Carboannulation of diethyl o-iodophenylmalonate (344) with isoprene afforded 345 by 1,2-addition [140]. Me

I

Pd(OAc)2, K2CO3 +

Ts

NH 338

DMF, H 2O, 81%

339

Cbz

Me

Me DDQ Ts

N

Ts

N

Cbz

Cbz

340

341

Me Me Pd2(dba)3, DPPE AcO

+ Ph

O

O

O

O

Ag2CO3, dioxane, H 2O 100 °C, 80%

O

I Ph

342

343

E CHE2

E

Pd(OAc)2, K2CO3

+

Bu4NCl, DMF, 82%

I 344

E = CO2Et

345

γ -Lactams are prepared by the reaction of α-bromoacrylamides with dienes. The bicyclic lactam 348 was obtained by treatment of 1,3-cyclohexadiene with 346. The reaction is considered to proceed via the π -allylpalladium intermediate 347 [141]. O

O CONHAr Ph

+ Br

346 Ar = 4-methoxyphenyl

PdCl2(PPh3)2 Na2CO3

Ph

N H

Ar

Ar N

Ph

NMP, 53% PdX 347

348

Unconjugated 1,4-cyclohexadiene (350) undergoes heteroannulation. Reaction of 350 with 349 is explained by carbopalladation to give 351. Dehydropalladation

158 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides and readdition of H-Pd-X in the opposite direction generate the π -allylpalladium 352, and intramolecular nucleophilic attack of the malonate provides 353 [142].

CHE2

CHE2

Pd(OAc)2, Bu4NCl, AcONa

+

DMF, 5 days, 64%

I 350

349

XPd 351

CHE2

CHE2

E

E

H-Pd-X PdX 352

E = CO2Et

353

Intramolecular reaction is useful for construction of complex molecules. Annulation of the congested 1,3-diene system to construct a quaternary carbon was applied to several total syntheses of natural products. In the total synthesis of tabersonine 356, the key step is the intramolecular reaction of the vinylpalladium to the conjugated diene in 354 to generate π -allylpalladium intermediate 355, which is trapped by hydride from formic acid to afford 356 [143]. I

Pd-X

N

N Pd(OAc)2, PPh3

6-exo

HCO2H, Et3N 43%

N

CO2Me

N

CO2Me 354

N

N HCO2H, Et3N

N 355

Pd-X CO2Me

H N 356

CO2Me

Among several possibilities in the cyclization of the 1,3-cyclohexadiene 357, 6-exo cyclization to the olefin moiety to generate 358 is expected to be the most favorable, and asymmetric cyclization of the 1,3-diene 357 using BINAP as a chiral ligand constructed a quaternary carbon, and subsequent β-H elimination gives a mixture of the 1,4- and 1,3-dienes 359 and 360. The best results were obtained at

Reactions with Alkenes (Mizoroki–Heck Reaction)

159

50 ◦ C. The 1,4-diene 359 was converted to the 1,3-diene 360 using naphthaleneCr(CO)3 as a catalyst, and then to the synthetic intermediate of diterpene 361 [144]. OMe X

OMe

Pd Me

TfO

Pd(OAc)2, (R)-BINAP K2CO3, toluene, 50 °C, 62% Me

Me

Me 358 357 OMe

OMe

Me

OMe

Me

Me steps

O Me

Me

3:1

359

Me 360

NaphCr(CO)3

361

95% ee

Interestingly, reaction of aryl halides with long chain α,ω-dienes proceeds efficiently via Pd migration and formation of π -allylpalladium intermediates, which are trapped by nucleophiles. Treatment of 3-iodopyridine (362) with 1,12-tridecadiene (363) in the presence of amine 364 produced a mixture of 365 (62 %) and 366 (13 %). The reaction took 4 days showing that the elimination and readdition of H-Pd-X occurred back and forth many times along the long carbon chain, and was terminated by the formation of the π -allylpalladium intermediate [145]. I

Pd(dba)2, Bu4NCl

+ 9

+

2 PhCH2NHTs

N 362

363

Na2CO3, DMF 100 °C, 4 d

364 CH3 N

9

Ph

+

8

N

Ph

Ts

Ts N

N 365

62%

13%

366

3.2.9.2 Reactions of 1,2-Dienes Allenes undergo facile carbopalladation and are used extensively in organic synthesis. The general reaction patterns of allenes with aryl halides are as follows. In carbopalladation of allene, an Ar group attacks the central sp carbon of the allene system to generate 367 and then the π -allylpalladium 368 as an intermediate. Then the attack of a nucleophile mainly on a less substituted terminus yields the alkene 369. Thus 1,2-addition to one of the double bonds in the allene occurs. In the absence of nucleophiles, β-H elimination gives 2-substituted 1,3-dienes

160 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 370. As an early example, reaction of 1,2-hexadiene (371) with iodobenzene and pyrrolidine afforded the allylic amine 372 [146]. Ar Ar

R Ar-PdX +

R

insertion R

•

Ar NuH R

PdX

Nu

PdX

367

369

368 Ar Ar-PdX +

•

Ar

b-H elimination

R

R

R

PdX

n-Bu •

+

Ph-I

+

370 Ph

Pd(OAc)2, DPPE N

82%

N H 371

Bu 372

Allenes are extensively used for synthetic purposes due to high reactivity for carbopalladation. They are more reactive than alkenes. Ma and Negishi have shown that common, medium, and large ring compounds can be prepared efficiently by cyclization of ω-(2-halophenyl)allenes, 373, 375, and 377. Carbon–carbon bond formation takes place at the central carbon of the allenes to give exo-methylene groups under Jeffery conditions. In addition to efficient formation of eight- and nine-membered rings 374 and 376, the 20-membered ring 378 was constructed from 377 in 86 % yield in 5 h. This is a remarkably high yield for such a large ring achieved in a short reaction time [147]. I PdCl2(PPh3)2, K2CO3 O

8

EtOH, DMF, 100 °C 2 h, 74%

•

373

O 374

Br

PdCl2(PPh3)2, K2CO3

9

Bu4NCl, DMF, 120 °C 12 h, 55%

• 375

376

I E

E

E

•

(C12) 377 E

20

E

PdCl2(PPh3)2, K2CO3

E

E 378

E

Bu4NCl, DMF, 120 °C 5 h, 86%

Reactions with Alkenes (Mizoroki–Heck Reaction)

161

A main reaction path of the 2,3-butadien-1-ols 379 with aryl and alkenyl halides in DMSO using DPPE is β-H elimination, and β,γ -unsaturated aldehyde 380 or ketones are obtained [148]. However, allenes bearing nucleophilic centers undergo heterocyclization under different conditions and numerous applications have been reported.

OH •

Pd(OAc)2, DPPE, H

+ Ph-I

OH

Ph

N Me

OH

Ph H

DMSO, 110 °C, 88%

379

Pd

X

Ph CHO 380

For example, allenyl alcohols are extensively used for heteroannulation. The alkenyloxirane 382 was obtained with high ee and in high yield by the cyclization of the chiral 1-substituted 2,3-butadien-1-ol 381. The reaction is highly diastereoselective and the trans-alkenyloxirane was obtained with no racemization and without forming a dihydrofuran [149]. Ar •

Ar

Pd(PPh3)4, K2CO3 Oct + Ar-I

DMF, 95%

HO 381 95% ee

X

Oct

Pd

O

HO

Oct

382

Ar = p-MeC6H4

98% ee

The remarkable effect of substituents on regioselectivity was observed in the intermolecular reaction of 1-substituted 2,3-butadien-1-ols with nucleophiles giving different regioisomers depending on the kind of 1-substituents. 1-Phenyl-2,3butadien-1-ol (383) reacts with diethylamine to afford 2-amino-1,3-diphenyl-3buten-1-ol 384 regio- and stereoselectively. On the other hand, reaction of 1-alkyl2,3-butadien-1-ol 385 yields the 4-amino-2(E)-alken-1-ol 386. These reactions offer efficient synthetic methods for 2- or 4-amino alken-1-ols with high regioand stereoselectivity [150]. NuH b • Ph + Ph-I HO 383

Ph

a a

reflux, 82%

Ph

Pd

X

Ph 384

HO

Ph •

n-Bu + Ph-I HO 385

H OH H Ph

Et2N

Pd(PPh3)4, Et2NH

b

Pd(PPh3)4, BnNH2 reflux, 92% X

Ph

n-Bu

BnNH

n-Bu

Pd HO

OH 386

162 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Different regioselectivities were observed in the reaction of 3,4-pentadien-1ols 387 with aryl iodides. The expected products 390 and 391 from the π allylpalladium intermediates 389 were not formed [151]. Exclusive formation of the dihydrofuran 388 is explained by concerted inter- and intramolecular exooxypalladation as shown by 392 to give π -allylpalladium 393, and reductive elimination gives rise to the dihydrofuran 394, showing that the intramolecular oxypalladation is faster than the intermolecular carbopalladation with Ar-Pd-I. Ar

n-Bu

•

Me

n-Bu + Ar-I

Pd(PPh3)4, Cs2CO3 DMF, 70 °C, 68%

HO

O

387 Ar

Ar

Ar

n-Bu

n-Bu

Me

O 391

Me

Me 390

389

n-Bu

+

O

XPd HO

Ar-Pd-I •

Me 388

Pd-Ar

n-Bu

Pd-Ar n-Bu

n-Bu

RE

exo oxypalladation Me

O

O

HO 392

Me

Me

Ar - p-ClC6H4

393 Ar

n-Bu O

Me 394

Unusual Pd-catalyzed fragmentation occurred in the reaction of 1-phenyl-2,2dimethyl-3,4-pentadien-1-ol (395) with iodobenzene. The arylated diene 397 and benzaldehyde were obtained in high yields. In this reaction, phenylpalladium attacked the central carbon to generate the π -allylpalladium intermediate 396. Then decarbopalladation (β-carbon elimination) occurred to provide the arylated diene 397 and α-hydroxybenzylpalladium 398, which collapsed to benzaldehyde and Pd(0) [152]. PdX • + Ph-I Ph

Pd(PPh3)4 K2CO3, dioxane

β-carbon elimination

Ph HO Ph

OH 395

Ph

396

397

Ph PdX HO 398

87% PhCHO 82%

Reactions with Alkenes (Mizoroki–Heck Reaction)

163

In the presence of CO, insertion of CO is faster than that of allenes. In the reaction of o-iodophenol (399) with 1,2-nonadiene (400) under CO pressure (20 atm) by use of DPPB as a ligand, CO insertion generates the acylpalladium 401, to which insertion of the allene occurs to give the π -allylpalladium intermediate 402, and nucleophilic attack of phenolic OH yields 403 in high yield [153]. I +

+ CO

•

OH

400

399

Pd(OAc)2, DPPB (i-Pr)2NEt, 20 atm, 100 °C, 93% O

O

O Pd-I

OH

OH 401

PD-X n-hex

O

402

403

Butenolides are obtained by the reaction of 2,3-alkadienoic acids catalyzed by Pd(0) in the presence of Ag2 CO3 as shown by the transformation of 404 to 405 [154]. The butenolide formation proceeds even in the absence of Ag salt [155]. The furan 407 was obtained directly by the reaction of methyl 2,3-alkadienoate 406 [156]. Ph

n-Bu •

Pd(PPh3)4, Ag2CO3 OH + Ph-I

K2CO3, MeCN, 79%

n-Bu

O

O

O 404

405 MeO2C

n-Bu CO2Me

• OMe + O

I

406

n-Bu

OMe

O

407

Unexpected O-attack, rather than N-attack, occurred in the cyclization of 2,4,4trisubstituted 2,3-butadienamide 408 to afford the iminolactone 409 in high yield [157]. Me Me

Bn O BnNH 408

Bn

Ph

• + Ph-I

Pd(PPh3)4, Bu4NBr K2CO3, toluene, 96%

Me Me

O 409

N Bn

164 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The 2,3-disubstituted 3,4-pentadienylamine derivative 410 underwent exocyclization to produce the dihydropyrrole 411 as a major product [158]. Ph

n-Bu • Me + Ph-I HN

n-Bu

Pd(PPh3)4, K2CO3 DMF, 70 °C, 55% Ns

N

Me

Ns 410

411

Formation of azetidines and tetrahydropyridines is expected by the reaction of 3,4-pentadienylamines with alkenyl halides. The ratio of the two products was found to change depending on the substrates. The reaction of the amino acid ester 412 with the triflate 413 afforded the azetidine 414 with high selectivity and the six-membered ring 415 as the minor product. On the other hand, the pipecolic ester 416 was obtained as the sole product of the reaction of 412 with iodobenzene [159]. t-Bu

•

Pd(PPh3)4, K2CO3

+

DMF, 96%

CO2Me

HN

OTf

Ts 412

413

t-Bu

+ N

t-Bu

Ts

88 : 12

414

• + Ph-I HN

CO2Me

Ts

N

CO2Me

Pd(PPh3)4, K2CO3

CO2Me

Ts 415

Ph

DMF, 78% N

CO2Me

Ts 412

416

Reaction of the 2,3-butadienylamine 417 with aryl iodides affords three- and five-membered rings. The regioselectivity depends on reaction conditions. Particularly solvents play an important role. Dioxane is a solvent of choice for the aziridine formation. The chiral aziridine 418 as a main product and 419 as the minor product were obtained from 2,3-butadenylamine 417 without racemization in dioxane. The five-membered ring 420 was not obtained in this case [160]. The 2,5-dihydropyrrole 422 was obtained by the reaction of the 2,3-pentadienylamine 421 under Jeffery conditions. In the absence of Bu4 NCl, the pyrrole 423 was the sole product [161].

Reactions with Alkenes (Mizoroki–Heck Reaction)

165

H •

Pd(PPh3)4, K2CO3

+ Ph-I

Me

dioxane reflux, 80%

HN Mts

H

417 Ph Ph

Me

Ph

Me

+ H H

N

H H

H

N

Mts

Mts

Mts 82 : 18

418

Me

419

420

n-Bu

n-Bu

•

+ Ph-I Me

Me

N

H

NH

n-Bu

Ph

Ph

Pd(PPh3)4, K2CO3 Bu4NCl, DMF, 25 °C, 50%

Me

N

Me

N

Me

Me

422

423

421

Unexpected nucleophilic attack of the amino group in the β-lactam 424 at the central carbon of the allene system occurred in the intramolecular reaction of the β-lactam bearing the terminal allene to give the carbapenem 425 under Jeffery conditions without giving an expected six-membered ring [162]. The cyclization of the γ -lactam 426 afforded again the unexpected product 429 as the main product, and 430 as the minor product formed by the attack of the amino group at the central carbon. Formation of 429 can be understood by generation of a different type of π -allylpalladium intermediate 427 by aminopalladation of 426. Deoxypalladation (β-acetoxy elimination) as shown by 428 gives rise to the diene 429 [163]. The unexpected reaction shows that the aminopalladation is more favorable and faster than the intermolecular carbopalladation. TBSO

TBSO H

H

H + Ph-I NH

O

•

H

Pd(PPh3)4, K2CO3 Bu4NCl, MeCN, 79%

N

O 425

424

Ph OAr

OAr NH O

Pd(PPh3)4, K2CO3 + Ph-I

•

Ph

N

Bu4NCl, MeCN, 50% O

Pd

427

426

OAr

OAr N

N Pd O

428

+

Ph

O

N O

429

50%

430

Ph 7%

166 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Reaction of the o-iodoaniline derivative 431 with 1,2-decadiene in the presence of the chiral bisoxazoline 433 as a ligand and Ag salt provided the indoline 432 with 80 % ee [164]. Construction of indole skeletons was carried out by intramolecular carbopalladation of allenes followed by amination. The π -allylpalladium intermediate 435 was formed from o-iodoaniline derivative 434, and intramolecular amination afforded the indole 436 in 89 % yield [165]. Ts NHTs

n-C8H17

DMF, 94%, 82% ee

n-C8H17

I

N

Pd(OAc)2, L, Ag3PO4

•

+ 431

432 O

O L=

N

N Ph

Ph

433

Me Pd X

Me

• I

Me

Pd(dba)2, PPh3 THF, 89% N

N

N H 434

H 435

436

The intermediate formed by the reaction of the vinyl iodide 437 with the allene 438 was trapped by the malonate as shown by 439 to yield 440 [166].

Me

EtO2C

CO2Et + I 437

CO2Et

PdX

Pd(OAc)2, PPh3

•

Bu4NCl, Na2CO3 DMF, 75%

CO2Et

Me

438

439 EtO2C

Me

CO2Et

440

Efficient asymmetric carbopalladation occurred in the reaction of the racemic allene 441 with iodobenzene and malonate using BPPFOAc (XI-14) as a chiral ligand. The chiral malonate derivative 442 with 95 % ee was obtained in 77 % yield [167]. Cyclization of dimethyl 2,3-butadienylmalonate (443) yielded mainly the five-membered ring, rather than the three-membered ring via the intermediate

Reactions with Alkenes (Mizoroki–Heck Reaction)

167

444 [168]. Recently however, Ma found that regioselectivity to give the threemembered ring 445 and the five-membered ring 446 can be controlled; while the three-membered ring 445 was obtained selectively by the addition of a catalytic amount of Bu4 NCl, the five-membered ring 446 was the main product when NaOH was used as a base [169]. Ph

Me •

+

Pd(dba)2 (R)-(S)-BPPPFOAc

E

DMSO, 77%, 95% ee

Ph-I +

H

H

E

Ph

E

Ph E H

441

442 E = CO2Me

Ph Pd(PPh3)4, K2CO3 PdX

Bu4NCl, MeCN, 80%

E

•

E

+ Ph-I

445 E Ph

Ph

443

Pd(PPh3)4, NaOH

E

E

E

DMF, 85 °C, 66%

444

446

E

E

In the presence of an imine, a three-component cyclization occurred to produce pyrrolidine. Reaction of the allene 443, the imine 447, and iodobenzene catalyzed by Pd(PPh3 )4 in the presence of Bu4 NBr gave the cis-pyrrolidine 448 in 92 % yield. The pyrrolidine 448 was formed by the reaction of the intermediate 444 with the imine before the cyclization. The product 449, obtained by the two-component reaction, was the minor product [170]. Ts E

•

E

N

+ Ph-I +

Pd(PPh3)4, Bu4NBr K2CO3,THF

Ph 447

443 E

Ph E +

Ph N

Ph E

Ts 448

92%

449

E 6%

Interestingly, the four-membered ring 451 was obtained from allenylmalonate 450 as the major product, and the six-membered ring 452 was the minor product [171]. E

E •

E E

Pd(PPh3)4, K2CO3 +

Ph-I

E

DMF, 100 °C,74%

Ph

E

+

450

Ph 451

2:1

452

168 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Efficient domino reactions of the alkenyl iodide 453 with CO, allene, and piperidine proceeded to give 456 in very high yield (80 %) after six-step reactions [172]. CO is the most reactive, and CO insertion is followed by olefin insertion to generate 454. Then allene insertion occurs after the second CO insertion. Finally, the π -allylpalladium intermediate 455 is trapped by the amine to yield 456. I +

•

Pd(OAc)2, PPh3

+ CO + N H

453

K2CO3, Et4NCl toluene, 80% O

O •

O

+ CO

Pd-X Pd-X 454

455 O O

amine

N 456

Reactions of allenes with halides are terminated by attack of organometallic compounds. The reaction of the 2-(2,3-butadienyl)iodobenzene (457) was terminated with alkenyl borane to give 458 [173]. 3-Methyl-1,2-butadiene (459) reacts with ary iodide, and the reaction is terminated by the attack of arylboronic acid 460 to afford 461 [174]. Ph

I

O

•

+

Pd(OAc)2, PPh3 B Ph

O

Na2CO3, toluene, 61%

457 OMe • 459

O 458

+

Pd(dba)2. CsF

+ MeO

B(OH)2

I 460 OMe

OMe 461

DMF, 78%

Reactions with Alkenes (Mizoroki–Heck Reaction)

169

‘Umpolung’ occurs by transmetallation of the π -allylpalladium intermediate, formed from the allene 462 and iodobenzene, with hexabutyldistannane, and the generated the allylstannane intermediate 463 reacts with aldehyde intramolecularly to yield the cyclopentanols 464 and 465 [175]. A similar ‘umpolung’ reaction was carried out using indium [176,177]. Ph • Ts

N

Pd2(dba)3

+ Ph-I + Bu3SnSnBu3

CHO

N

Ts

PdX CHO

462 Ph

Ph transmetallation

Ts

N

Ts

SnBu3

Ph

+ Ts

N

N

OH

CHO

H

H

463

OH

464

465

53%

22%

3.2.10 Amino Heck Reactions of Oximes Narasaka found that an N—O bond in oxime undergoes oxidative addition to Pd(0). Based on this reaction, his group developed a new synthetic method of Nheterocycles. Oxidative addition of some unsaturated ketone oximes 466 generates 467, which undergoes intramolecular aminopalladation. Particularly, facile oxidative addition of O-pentafluorobenzoyloxime 468 occurs to provide 470. When the oxime of γ , δ-unsaturated ketone 468 is treated with Pd(PPh3 )4 in the presence of a base in DMF, intramolecular Heck-type amination of alkene takes place to give rise to the the pyrrole 469. The reaction can be understood by sequences of oxidative addition to give alkylideneaminopalladium 470, double bond insertion to form the cyclized intermediate 471, β-H elimination to form the cyclic imine 472, and double bond isomerization [178]. N

OCOAr

Pd OCOAr

N

+ Pd(0)

intramoleculkar aminopalladation product

R

R 466

467 Me N

OCOC6F5

Pd(PPh3)4, Et3N

HN

DMF, 80 °C, 81% Ph(CH2)2

Ph(CH2)2 468

469

Pd(0) OCOC6F5 N

Pd-X

Pd

N Ph(CH2)2

Ph(CH2)2 470

471

N Ph(CH2)2 472

170 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Pyridines and quinolines are similarly prepared. The pyrrole 474 was obtained by 5-exo cyclization of 3-methoxy-1-phenyl-4-penten-1-one (E)-O-pentarfluorobenzoyloxime 473 under usual conditions. On the other hand, 2-phenylpyridine (475) was obtained by 6-endo cyclization as the main product in the presence of n-Bu4 NCl. Isoquinoline 477 was prepared in 77 % yield by 6-exo cyclization of the oxime 476 [179]. Me

OCOC6F5 OMe N

HN

Pd(PPh3)4, Et3N DMF, 80 °C

Ph

N

OMe +

Ph

473

Ph 474 69%

475 7%

11%

58%

in the presence of n-Bu4NCl

Me

Me N

OCOC6F5

Pd(PPh3)4, Et3N, n-Bu4NCl,

N

DMF, 80 °C, 77%

Me 476

477

Substituted azaazulene 479 was prepared from cycloheptatrienylmethyl ketone O-pentafluorobenzyloxime 478 by Pd-P(t-Bu)3 -catalyzed cyclization, followed by treatment with MnO2 [180]. As observed in the Heck reaction, the domino insertion of olefins occurred to produce the polycyclic imine 481 when the trienyloxime 480 was subjected to the Pd-catalyzed reaction [181]. Ph

Ph

OCOC6F5 N

N

1. Pd 2(dba)3, P(t-Bu)3 Et3N, MS 4A, DMF,

478

N

2. MnO 2, CH2Cl2 reflux, 78%

479

OCOC6F5 Pd(PPh3)4, Et3N

Ph

N

DMF, MS 4A 110 °C, 74%

Ph

481 480

As a related reaction, an N-Cl bond in unsaturated N -chloroamine undergoes oxidative addition to Pd(0) and cyclization. In the treatment of N -chloro-2,2dimethyl-4-pentenylamine 482 with Pd(PPh3 )4 in the absence of a base, oxidative

References

171

addition is followed by double bond insertion to give the alkylpalladium chloride 484, which is converted to the 2-chloromethylpyrroridine 485 by reductive elimination, without undergoing β-H elimination in the absence of a base. Then isomerization of the less stable 485 to the more stable 3-chloropiperidine 483 occurs. The presence of 2,2-dimethyl groups is important for the smooth reaction; the yield was low without them [182]. Bu Cl N

N

Pd(PPh3)4, THF Bu

rt, 85% Cl

482

483 Bu

Cl Pd N

Bu

N Cl-Pd

N Cl

Bu 484

485

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3.3 Reactions of Aromatics and Heteroaromatics Aryl–aryl coupling is an important synthetic reaction. Efficient aryl–aryl coupling is possible by Pd-catalyzed cross couplings of aryl halides with aryl metal (Mg, Zn, B, Sn, Si) compounds, and the methods have wide applications. On the other hand, a simple Pd-catalyzed arylation of arenes with aryl halides has been known. Although less attention has been paid, the importance of the reaction is increasing as more efficient methods of aryl–aryl bond formation become available. The arylation of arenes with aryl halides is treated in this section. In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as furans, thiophenes, pyrroles, oxazoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called ‘heteroaryl Heck reactions’ [2].

Reactions of Aromatics and Heteroaromatics

177

3.3.1 Arylation of Heterocycles Some heterocycles undergo facile inter- and intramolecular arylations. Two mechanistic explanations of the arylation are possible. The Heck-type reaction is one of them. Carbopalladation of one of two double bonds with Ar-Pd-X gives 1a, which is stabilized by π -allylpalladium formation. Pd and β-H is anti in 1a and hence syn β-H elimination is not possible. Therefore, in stereoisomerization from anti 1a to syn 1b a relationship between Pd and β-hydrogen occurs, and syn β-H elimination from 1b affords the arylation product (path a). Another explanation is electrophilic substitution with Ar-Pd-X. Since arylations occur mainly at electron-rich carbons of heterocycles, they can be understood as electrophilic substitutions (path b). In some cases, a Heck-type mechanism seems to be more reasonable. Certainly arylations proceed by one of these mechanisms depending on the electronic nature of the substrates and reaction conditions, and hence further mechanistic studies are necessary. Furans, thiophenes, and pyrroles are arylated at the electron-rich C-2 positions. Further arylation occurs at C-5. Similarly, arylations at C-2 positions of benzofurans, benzothiophenes, and indoles take place preferentially. Ohta and co-workers carried out extensive studies on intermolecular arylation of various heterocycles (furan, thiophene, pyrrole, oxazole, thiazole, N -methylimidazole, benz[b]oxazole, benzo[b]furan, and benzo[b]thiophene) with mainly chloropyrazines as heteroaryl halides using Pd(PPh3 )4 and AcOK [3]. Y-Pd

Y-Pd

path a

Pd-Y Ar

Ar-Pd-Y

H

Ar

X

H

Ar

X

1a

Ar

X

H

X

1b

X path b Ar-Pd

RE

+ H

Ar-Pd

X

5

Ar

X

X

2 X

X = O. S, NR

X

2

3.3.1.1 Furan and Benzofuran Reaction of the chloropyrazine 2 with furan afforded the 2-arylfuran. 2-Arylation of benzo[b]furan (4) occurs with o-bromonitrobenzene (3) [3b]. Regioselective 2arylation of ethyl 3-furancarboxylate with 3 occurred to give 5 in 80 % yield when Pd(PPh3 )4 and AcOK were used in toluene. 5-Arylation was the main path when ligandless Pd/C was used in the polar solvent NMP. The furo[3,2-c]quinolinone 6 was obtained after hydrogenation of the nitro group [4].

178 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides N

Me

N

+ Me

AcOK, 75%

O

Cl

N

Me

Pd(PPh3)4 Me

O

N

2 Br NO2

Pd(PPh3)4

+

AcOK, 50%

NO2

O

O

3

4

CO2Et

CO2Et

NO2

Pd(PPh3)4, AcOK

+

toluene, 80%

Br

O

O

NO2

3

H N

5 O

H2-Pd/C 75% O 6

Intramolecular reaction of the vinyl triflate with benzo[b]furan in 7 is a key step in the preparation of the synthetic intermediate 8 of (−)-frondosin A [5]. Intramolecular reaction of the iodide with furan in 9 gave the tetracyclic βlactam 10 containing furan ring in the presence of Tl2 CO3 as a base. The rather unusual C-3 substitution occurs in the reactions of 7 and 9, because the C-2
positions are blocked [6]. If the cyclizations of 7 and 9 proceed similar to Heck-type carbopalladation and β-H elimination, direct syn β-H elimination is not possible, and isomerization from anti to syn, followed by syn β-H elimination should occur. Therefore, direct electrophilic substitution may be a better explanation. MeO OMe OTf

Pd(PPh3)4, Cul Et3N, MeCN, 94%

O O

O Me

Me O 7

PhCH2O

H

8

H

N

Pd(OAc)2, PPh3 I

O

PhCH2O

Tl2CO3, toluene 110 °C, 52%

H

H

N O

O

O 9

10

Reactions of Aromatics and Heteroaromatics

179

Arylation is not limited to aryl halides. Alkenylpalladium intermediates, formed in situ in domino reactions of polyenynes, attack aromatic rings. The intermediate 11 is generated by 5-exo cyclization of the iodide 10a. Then cyclization occurs to give 12 by attack of the alkylpalladium species on furan in 11, because the alkylpalladium has no possibility of β-H elimination [7]. I

Pd-l

Pd(OAc)2

N

PPh3

N

O

O

O

O 10a

11 O N O 12

3.3.1.2 Thiophene and Benzothiophene 5-Arylation of 2-thiophenecarbaldehyde, catalyzed by Pd(OAc)2 and CuI, took place with iodobenzene to give 5-phenyl-2-thiophenecarbaldehyde in high yield. Although the role of CuI is not clear, coordination of sulfur to CuI may enhance the deprotonation at C-2 [8]. Reaction of an excess of bromobenzene with 2thiophenecarboxamide 13 afforded 2,3,5-triphenylthiophene (14) in 96 % yield. (Biphenyl-2-yl)(di-t-butyl)phosphine (IV-1) and Cs2 CO3 were used in the reaction. The reaction involves unusual decarbamoylation and C—C bond cleavage via 3phenyl- and 3,5-diphenyl-2-thiophenecarboxamides. Ph3 N was obtained in 82 % yield as the byproduct. Reaction of phenyl triflate with the thiophene 13 afforded the 3-phenyl and 3,5-diphenylthiophenes 15 and 16, showing that the phenylation proceeds successively at the C-3 and C-5 positions. The C-3 substitution is rather unusual [9]. I

Pd(OAc)2 , CuI, PPh3

+ S

CHO

Br

Cs2CO3, DMF, 82%

Ph

Ph

Pd(OAc)2 , IV-1

+ S

CONHPh

Cs2CO3, xylene S

6 equiv

Ph +

S

CONHPh

13 Ph

Ph

CHO

S

CONHPh

Ph 14

Ph3N

Ph

S 96%

82%

180 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides OTf

Pd(OAc)2 , IV-1

+

Cs2CO3, toluene

CONHPh

S 13

6 equiv

Ph

Ph +

CONHPh

S 15

Ph

CONHPh

S

71%

16

8%

Benzo[b]thiophene (18) is arylated with the aryl bromide 17 as expected at C-2 to afford 19 [3b]. Intramolecular 3-arylation of the thiophene in 20 gave the tetracyclic β-lactam 21 containing thiophene in the presence of Tl2 CO3 as a base [6].

CHO Pd(PPh3)4, AcOK

+

DMA, 40%

Br

S

S 17

PhCH2O

18

H

H I

O

H

PhCH2O

Pd(OAc)2 , PPh3 N

CHO

19

Tl2CO3, toluene 110 °C, 65%

H

N O S

S 20

21

3.3.1.3 Pyrrole and indole The 2- and 3-substitution products 24 and 25 were obtained in 1 : 1 ratio by the reaction of the chloropyrazine 2 with N -phenylsulfonylpyrrole (23). Since reaction of 2 with pyrrole itself occurs only at the C-2 position, the PhSO2 group seems to enhance the reactivity at C-3. Indole (27) is intermolecularly arylated with 26 at C-2 as expected [3a]. Me

Me

Pd(PPh3)4 +

Me

N 2

Cl

N

KOAc, DMA reflux, 41%

Me

+

N

SO2Ph 23

N N

N

Me N

N

SO2Ph

N 24

SO2Ph 1:1

Me 25

Reactions of Aromatics and Heteroaromatics Et

N

Et Pd(PPh3)4

+ Et

181

N

Cl

AcOK, DMA reflux, 62%

N

N

Me

Me 26

N

N

27

Et

C-arylations of azoles proceed smoothly when N-protected azoles (pyrrole, indole, and imidazole) are used. N-free pyrrole, imidazole, and indole are poor substrates for C-arylation. However, Sezen and Sames reported an interesting effect of MgO as an additive [10]. 2-Phenylpyrrole was obtained cleanly in 86 % yield by the reaction of unprotected pyrrole with iodobenzene in the presence of MgO (1.2 equiv.). No N-arylation occurred. MgO seems to be bound to nitrogen strongly, and not only protects the nitrogen, but also increases the nucleophilicity of heteroarene nucleus.

+ PhI

N H

Pd(OAc)2, PPh3, MgO dioxane, 150 °C, 86%

1.2 equiv

Ph

N H

Intramolecular arylation of 28 and 29 occurred at either C-2 or C-3 to give 30 and 31 when the C-3 or C-2 position is substituted [11]. The alkenylpalladium intermediate 33, generated by the reaction of the bis-indole 32 with an alkyne as a relay, attacks the indole to give 34 [12]. O

O

i-Pr2N

i-Pr2N Pd(PPh3)4, AcOK

2

DMA, 160 °C, 81% N

N Br 28

30

Br Pd(PPh3)4, KOAc

3

DMA, 130 °C, 95%

N Me

O 29

N Me 31

O

182 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides I Pd(PPh3)4, Tl 2CO3

+ N Me

Bu

CO2Me

toluene, 56%

N Me 32 CO2Me

CO2Me

Bu

Pd-I

Bu

N Me

N Me

N Me

N Me 33

34

3.3.1.4 Thiazole and Benzo[b]thiazole Most reactive sites in thiazoles, oxazoles, and imidazoles are electron-rich C-5 positions. If C-5 positions are blocked, less reactive C-2 positions are arylated. Also arylation of their benzo derivatives occurs at C-2. Phenylation of thiazole with iodobenzene at C-5 gave 5-phenylthiazole and further reaction afforded 2,5-diphenylthiazole (35) when Pd(OAc)2 , PPh3 , and Cs2 CO3 were used. Addition of CuI gives a favorable effect [8]. Regioselectivity of mono- and diarylation of thiazole can be controlled. 2-Arylation with 4-iodoanisole took place cleanly when PdCl2 (PPh3 )2 and CuI were used in the presence of TBAF in DMSO at 60 ◦ C. Further arylation in the presence of Pd(OAc)2 (PPh3 )2 and Cs2 CO3 in DMF at 140 ◦ C afforded 2,5-diarylthiazole 36 [13]. Arylation of benzothiazole (37) with the 2-chloropyrazine 26 occurred regioselectively at C-2 [3]. N 5

N

2

2

X

X

X = O, S, NR I

N +

Cs2CO3, DMF, 140 °C 66%

S

N

Pd(OAc)2, CuI Ph

N Ph

S

S

Ph

35

OMe

N + S

N PdCl2(PPh3)2, CuI, TBAF DMSO, 60 °C, 82%

S

I

OMe Me

I Pd(OAc)2, PPh3 Cs2CO3, 94%

N S

36

CHO

Reactions of Aromatics and Heteroaromatics Et

N

N

+ Et

N

183 Et

N

Pd(PPh3)4, AcOK 59%

Cl

26

S

N

Et

S

N

37

3.3.1.5 Oxazole and Benz[b]oxazole 2-Phenyloxazole (38) is regioselectively phenylated at C-5 to afford 2,5-diphenyloxazole with bromobenzene, and arylation of benz[b]oxazole (39) with 26 gives the C-2 arylation product 40 as expected [3]. N

Br

N

Pd(OAc)2, PPh3

+

Ph

O

K2CO3, 17 h, 90%

Ph

Ph

O

38

N

Et

N

N

+ N

Et

Pd(PPh3)4, AcOK

Cl

O

O

26

Et

N

DMA, 65%

Et

39

N

40

3.3.1.6 Imidazole and 1H-benzimidazole Phenylation of 1-methylimidazole with bromobenzene occurred at the most electron-rich C-5. Weak bases such as K2 CO3 were used. At the same time, the electron-poor C-2 position is also phenylated further to give 41. The results suggest different mechanisms for the phenylations at C-5 and C-2 [9]. 1,5Dimethylimidazole (42) is arylated at C-2 with chloropyrazine 26 [3]. Sezen and Sames found that the regiochemistry of C-phenylation of N-unprotected imidazole can be controlled by additives without giving the N-phenylation product. 4Phenylimidazole 43 was obtained from imidazole in 72 % yield by the addition of MgO (1.2 equiv.). Furthermore, exclusive 2-phenylation occurred to provide 44 in 83 % yield when CuI (2 equiv.) was added to the Pd–PPh3 –MgO system [10]. N

Br +

K2CO3, DMF, 20 h

N

N

Pd(OAc)2, PPh3 Ph

Me

2 equiv.

N +

N

Ph

N

Me

Me

53%

33%

Ph

41

N

N

Et +

Et

N 26

Cl

N

Et

Pd(PPh3)4, AcOK Me

N Me 42

DMA, 43%

Me N

Et

N N

Me

184 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Ph N

N

Pd(OAc)2 , PPh3

+

PhI

N H

N

MgO, dioxane, 72%

N H 43

N

Pd(OAc)2 , PPh3 , MgO

+

PhI

N H

CuI, dioxane, 83%

Ph

N H 44

1H-Benz[b]imidazole (45) is phenylated at the electron-poor C-2 in very low yield (2 %). However, the reaction proceeds effectively in the presence of CuI as a promoter [8]. Intramolecular arylation of the 1-methylimidazole moiety 46 gave the C-5 arylation product 47 under ligandless Jeffery conditions [14]. I N

+

Cs2CO3, DMF 8 h, 91%

N 2 equiv.

N

Pd(OAc)2, CuI, PPh3 N

Me

Me 45

Me N Me N

Br

N

N

n-Bu

N Pd(OAc)2, n-Bu4NCl NaHCO3, DMA, 150 °C 83%

N

O

n-Bu

O 46

47

3.3.2 Intermolecular Arylation of Phenols Intermolecular arylation of carbocyclic arenes are rare. Exceptionally, phenols are easily arylated. As treated in Chapter 3.7.4, the aryl ether 48 is formed by reaction of aryl halides with hydroquinone monomethyl ether when bulky and electron-rich phosphines are used, which accelerate reductive elimination. Miura and co-workers found new completely different reactions of phenol with bromobenzene by using Pd(OAc)2 , PPh3 and Cs2 CO3 to give the unexpected pentaphenylated product 49 in 58 % yield [1b,15]. Me

NaO

Cl

Me

Me

O

Pd2(dba)3, L-6

+ OMe

toluene, 92% Me 48

OMe

Reactions of Aromatics and Heteroaromatics

Br

OH

185

HO Pd(OAc)2 , PPh3

+

Cs2CO3, o-xylene 58%

49

The first product of the interesting pentaphenylation is o-phenylphenol (50). It was found that o-phenylphenol (50) undergoes not only monophenylation, but also diphenylation on treatment with iodobenzene at the C-2
positions to give 51 and 52 by the use of PdCl2 and Cs2 CO3 . The fact that the monoarylated product 51 (25 %) and the diarylated product 52 (62 %) were obtained by the treatment of 2-phenylphenol (50) with 4 equivalents of iodobenzene shows that the arylation of benzene ring is faster than the arylation of ortho carbon of phenol under these conditions [16]. Similarly, when the reaction of bromobenzene with 50 in xylene was stopped after a short time, 2-(biphenyl-2-yl)phenol (51) was obtained in high yield, but 2,6-diphenylphenol was not formed [15].

I

PdCl2

+

+

Cs2CO3, xylene

OH

OH OH

50 51

Br

25%

52

PdCl2

+ OH

Cs2CO3, xylene 1 h, 75%

OH

50

51

OH

not formed

62%

186 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Formation of 50 may be understood in terms of arylation of phenol via the keto form 54 which is stabilized as the oxa-π -allylpalladium 55 as one possibility. This reaction path is similar to arylation of cyclohexanone. Electrophilic attack of 53 at ortho carbon to give 56 and reductive elimination are another explanation. O

O

Br

Pd

H

Pd-Br RE

55

Pd(0) O

Pd O

OH

Pd H

base 54 53

OH

OH Pd

RE

50

56

Formation of 2(biphenyl-2-yl)phenol (51) from 50 is explained by electrophilic attack of 57 to form 59 and its reductive elimination. As another explanation, oxidative addition of aromatic ortho C—H bond to 57 generates the palladacycle 58 and its reductive elimination affords 59. Domino arylations by a similar sequence of the reactions via 60 finally give rise to the pentaphenylated product 49 in 58 % yield. Certainly the reaction occurs by strong participation of OH group. It is surprising that efficient polyarylation of phenol with bromobenzene proceeds smoothly in the presence of Cs2 CO3 which is sparingly soluble in xylene and since it is difficult to abstract protons from phenol. Ph Pd OH

Ph

O

H Pd

O

Ph-Pd-Br base

50

57

OH

58

OH

Ph-Pd OH

59

steps

51

60

49

Reactions of Aromatics and Heteroaromatics

187

Phenylation of o-(2-nitrophenyl)phenol (61) with iodobenzene occurred at C-6
of the electron-deficient nitrobenzene to give 62 in 87 % yield, suggesting that the phenylation is not a simple electrophilic substitution [17]. NO2 NO2 OH I

Pd(OAc)2 +

Cs2CO3, DMF 87%

OH 61

62

Interestingly 2,6-di-t-butylphenol (63), which has no possibility of oxaπ -allylpalladium formation, undergoes p-phenylation with bromobenzene as shown by 64 to afford 65 when PPh3 and Cs2 CO3 are used [18]. The reaction is understandable as electrophilic substitution. Commercially important 4-hydroxybiphenyl (66) is produced from 65 by removal of the t-butyl groups. Reaction of the phenol 63 with 1,3,5-tribromobenzene afforded the 1,3,5-tri(4hydroxyphenyl)benzene 67. Br

t-Bu

t-Bu Pd(OAc)2, PPh3

+

OH

t-Bu

Ph

Cs2CO3, xylene 75%

H

Pd

O

Br

t-Bu

63

64

t-Bu

t-Bu

H+ PhPd

OH

OH

t-Bu

65

OH

t-Bu

66

OH

t-Bu

t-Bu Br

t-Bu Pd(OAc)2 , PPh3

+ Br

OH

Br

t-Bu 63

Cs2CO3, xylene 36%

t-Bu

t-Bu

OH

HO

t-Bu

t-Bu 67

188 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Arylation of 1-naphthol (68) with iodobenzene, catalyzed by ligandless Pd(OAc)2 , gave 8-phenyl-1-naphthol (69). The expected 2-phenylnaphthol was not obtained. Iodobenzene gave better results than bromobenzene. On the other hand, 1-(biphenyl-2-yl)-2-naphthol (71) was obtained by the reaction of 2-naphthol (70) with bromobenzene by the use of Pd(OAc)2 , PPh3 and Cs2 CO3 [16,17].

I

OH

PhPd

Ph-Pd-O

OH Pd(OAc)2

+

Cs2CO3, DMF 73% 68

OH

69

I

OH +

Pd(OAc)2 , PPh3 Cs2CO3, DMF 74%

OH

70 71

As a related reaction, Rawal carried out intramolecular vinylation of 2-bromoallyl ether of electron-rich resorcinol 72 and obtained the benzofurans 73 and 74 in equal amounts by ortho and para substitutions when the Herrmann catalyst (XVIII-1) was used. Cleavage of the allyl ether to give resorcinol (75) is a side reaction, whose amount increases when Pd(PPh3 )4 is used as a catalyst. Similarly the indoles 77 and 78 were synthesized in 1 : 1 ratio from 76 [19]. OH

OH Br

O

Me

XVIII-1, Cs2CO3 O 73

OH Br

N

74

OH 75

Me

XVIII-1, Cs2CO3

Me +

DMA, 78 °C 1 day, 79%

N

N

HO

CO2Me

CO2Me

CO2Me 76

O

HO 1:1

OH

OH

+

+

DMA, 70 °C 3 days, 82%

72

Me

77

1:1

78

Reactions of Aromatics and Heteroaromatics

189

3.3.3 Intermolecular Polyarylation of Ketones An interesting arylation (aryl–aryl coupling) was discovered by Miura’s group during their studies on arylation of ketones as described in Chapter 3.7.1.2 [1b]. An attempted arylation of benzyl phenyl ketone (79) with bromobenzene produced the α-monoarylated ketone 80 in high yield when K2 CO3 was used as a base and Pd(OAc)2 -PPh3 as a catalyst. Unexpectedly they obtained the polyarylated product 81 when Cs2 CO3 and Pd(PPh3 )4 were used. Different effects of K2 CO3 and Cs2 CO3 on the reaction path are noteworthy [20,21]. This interesting polyarylated product 81 was obtained by ortho–ortho’ diarylation of the phenyl ring of 80. It is difficult to stop the reaction after α-monoarylation to form 80 when Cs2 CO3 is used as the base. Br

O

O

Pd(OAc)2, PPh3

+

K2CO3, xylene 96%

79 Pd(PPh3)4

80 Cs2CO3, xylene 61%

O

81

This reaction is explained by the following mechanism. The first step is αarylation of the ketone to give 80. Then stepwise mono- and diarylations of both ortho carbons in the phenyl ring in 80 take place by neighboring carbonyl group participation. Transmetallation of Cs enolate 82 with Ph-Pd-Br generates the Pd-Oenolate 83, and the phenyl-Pd-aryl species 84 is generated by electrophilic attack at the ortho carbon. Finally reductive elimination affords the diarylated product 85. The triarylated product 81 is obtained from 85 by a similar sequence of reactions. Anthrone (86) was triphenylated at C-1, C-8, and C-10 positions to give 87. The mechanism of the unexpected hydroxylation at the C-10 position is unknown. O

OCs Cs2CO3

80

Ph-Pd-Br

82

190 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Ph Pd

PhPd

O

O

83

84

O

81

85

O

Br

O Pd(OAc)2, PPh3

+

Cs2CO3, toluene 47%

OH

86

87

A similar efficient ortho–ortho diarylation of the N -phenylbenzanilide 88 with phenyl triflate took place to give 89 in 95 % yield in the presence of PPh3 as a ligand and Cs2 CO3 as a base. Certainly, participation of the amide carbonyl group plays an important role [22].

OTf

HN

HN O

+

Pd(OAc)2, PPh3 Cs2CO3, toluene 110 °C, 93%

Cl

O Cl

88 89

3.3.4 Intramolecular Arylation of Aromatics Pd-catalyzed intramolecular arylation of some aromatics proceeds smoothly, offering a useful method of aryl–aryl coupling. However, the reaction is not mechanistically simple [1a], and several mechanisms (paths a, b, c, and d) for the arylation

Reactions of Aromatics and Heteroaromatics

191

of aromatics 90 to give 91 are possible. Intramolecular electrophilic substitution via 93 generates the palladacycle 94 and its reductive elimination affords 91. This mechanism is applicable to arylation of electron-rich aromatics (path a). Oxidative addition of an ortho C—H bond in 92 affords the Pd(IV) species 96, which is converted to 94 (path b). Similar to a Heck-type reaction, carbopalladation of 92 to give 97 and the π -allylpalladium 98 is another possibility. After stereoisomerization via the π -allylpalladium intermediate 98, syn β-H elimination affords 91 (path c). Carbopalladation to form the spiro ring 99 and rearrangement as shown by 100 gives 101, and subsequent syn β-H elimination yields 91 (path d). X

Pd(0)

A B 90

A B 91 X H

Pd

X

Pd(0) OA

A B

A B 92

electrophilic Path b aromatic substitution oxidative addition

Path a

X

carbopalladation

carbopalladation

X Pd

Path d

Path c

H X Pd

Pd

H

H

A B

A B 97

A B 96

93

B

Pd-X

A 99

− HX Pd X

H Pd

A B

A B

94

Pd-X

98

reductive elimination

B A 100

b-H elimination Pd-X

H-Pd-X H

A B 91

H-Pd-X

A B 101

192 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The Pd-catalyzed intramolecular coupling of aryl halides or triflates with aromatic rings to give biaryl compounds offers useful synthetic methods. Intramolecular arylation of benzene derivatives was reported first by Ames. Cyclization of 102, catalyzed by Pd(OAc)2 in the presence of DBU, is an example [23]. Pyrimido[4,5-b]indole was prepared by intramolecular arylation of 4-anilino-5-iodopyrimidine 103 in 86 % yield in the presence of Pd(OAc)2 , PPh3 and AcONa in DMF [24]. Cyclization of the monobrominated diarylpyrazole 104 afforded pyrazolo[1,5-f ]phenanthridine in 65 % yield in the presence of phosphine-free Pd(OAc)2 , Bu4 NBr, LiCl and K2 CO3 in DMF at 110 ◦ C [25]. I Pd(OAc)2, DBU

O

O

102

Et

I

Et

N N H

N

Pd(OAc)2, PPh3, AcONa DMF, 80 °C, 86%

N

N H

N

103

Pd(OAc)2, Bu4NBr, LiCl Br

N

K2CO3, DMF, 110 °C, 65%

N

N

N

Me Me 104

In intramolecular arylation of the indole 105, the C-2 arylation product of the pyrrole ring was obtained preferentially without attacking the benzene ring. On the other hand, when the C-2 position is blocked, arylation of 106 occurs in the benzene ring to give 107, showing that pyrrole is more reactive than benzene [26]. CHO

CHO Pd(PPh3)4, AcOK

N

105

Br

DMF, 87%

N

Reactions of Aromatics and Heteroaromatics

193

CHO

CHO Pd(PPh3)4, AcOK

Me

N

Me

N

DMF, 97%

Br 107

106

The alkenylpalladium 109 formed as an intermediate of two domino 6-exo-dig cyclizations of 108 undergoes vinylation to the benzene ring to give the naphthalene ring 110. This type of reaction is observed frequently as a termination step of domino cyclization of polyenynes [27]. NEt3 Et3N

N

Pd(OAc)2, PPh3

I

N

SO2Ph

SO2Ph

I-Pd

Ag2CO3, MeCN 80 °C, 50%

E

E

6-exo-dig, 6-exo-dig

E

E 109

108

SO2Ph N Et3N

E E

110

A number of synthetic applications have been published. The synthesis of the naphthylisoquinoline alkaloid 112 from 111 is an early example [28]. The reaction has been applied to the synthesis of gilvocarcin M [29,30]. A recent example is the synthesis of benzo[c]phenanthridine alkaloids 114 by cyclization of the triflate 113. High yields were obtained by combined use of DPPP and n-Bu3 P [31]. Me Br MeO

N O

MeO 111

PdCl2(Ph3P)2, AcONa Bn

DMA, 130 °C, 75%

Me

Me

O N

MeO

Bn O

MeO O

Me 112

194 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O Pd(OAc)2, DPPP, PBu 3

OTf O MeO

i-Pr2NEt, DMF, 93%

NMe O

MeO

O

113

MeO

O NMe

MeO O 114

Dibenzo[a, g]corannulene (116), a fullerene fragment, was obtained by cyclization of 7,10-di(2-bromophenyl)fluoranthene (115). A Herrmann palladacycle (XVIII-1) as a catalyst and excess DBU as a base were used under rather severe conditions (150 ◦ C, 72 h) [32]. Also the as-indaceneo[3.2.1.8.7.6-pqrstuv]picene derivative 118 was prepared from the dichloride 117 in 91 % yield. PCy3 and DBU were used for activation of the less reactive dichloride 117 [33].

XIII-1, DBU DMF, 150 °C, 57% Br

Br

116

115 Me

Me

Me

Me

Pd(PCy3)Cl2, DBU DMAc, 140 °C, 91% Cl

Cl 117

118

The spiro-polycyclic aromatic compound 120 was prepared from the nitro dibromide 119 under ligandless Jeffery conditions. In addition, reaction of the nitro monobromide 121 under similar conditions afforded 122 and 123 in a ratio of

NO2 Br

Br

NO2 Pd(OAc)2, BnMe3NBr DMF, 70 °C, 53%

120 119

Reactions of Aromatics and Heteroaromatics

195

2 : 1. The fact that the arylation occurs on the deactivated nitro group-bearing benzene rings in 119 and 121 indicates that the reaction is not a simple electrophilic substitution [34].

NO2

Pd(OAc)2, BnMe3NBr DMF, 100 °C, 62%

Me

Br

121 NO2

NO2

+

Me

Me 2:1

122

123

Reaction of the alkenyl bromide 124 with diphenylacetylene generates the alkenylpalladium intermediate 125, which undergoes intramolecular alkenylation to give 126 by using a ligandless catalyst [35]. Br

+

Ph

Ph

Pd(OAc)2, Bu4NBr K2CO3, DMF, 57%

124

Pd-Br

125

126

Dyker has developed novel domino reactions, which involve facile formation of palladacycles. He reported very interesting domino reactions of three molecules of 2-iodoanisole (127) to give the 6H-dibenzo[b, d]pyran 128 in high yield (90 %) after several steps in one pot under ligandless Jeffery conditions [36]. The key step of the reaction is the formation of the five-membered palladacycles 129 and 132 by ortho-palladation (cyclopalladation) involving sp3 C—H activation of the methoxy group. The oxidative addition of 127 to the palladacycle 129 generates 130, and its reductive elimination gives the arylated product 131. Then the palladacycle 132 is formed from 131. A similar sequence of reactions from 132 via 133 yields

196 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 128. It is important to mention that no reductive elimination of the five-membered palladacycle 129 to form four-membered ether occurs. Instead, oxidative addition of 127 to 129 takes place to form 130. MeO

I

Pd(OAc)2, Bu4NBr K2CO3, DMF, 90%

O

OMe MeO

127

128

H3CO I

Pd

Pd(o)

127 I

OCH3

O

HI

127

OCH3

Pd

O 129

O

H3CO

H3CO

H3CO

Pd-I

131

130

127 O

HI O

H3CO

Pd

O

HI Pd-I

H3CO

132 133

128

Domino reactions of two molecules of 1-iodo-2,3-dimethoxybenzene (134), in which the position for the second cyclopalladation is blocked, gave 135. The reaction proceeds via formation of the palladacycle 136. Oxidative addition of 134 to 136 generates 137. Reductive elimination of 137 gives 138. Then cyclopalladation of 138 and reductive elimination afford the ether ring 135. OCH3

I H3CO

Pd(OAc)2, Bu4NBr K2CO3, DMF, 87%

H3CO

O H3CO

134 H3CO 135

Reactions of Aromatics and Heteroaromatics

197

H3CO OCH3

H3CO PdX Pd

Pd

O

O

OCH3

I O

134

135 H3CO

H3CO 136

H3CO 137

138

Intermolecular reaction of 1-iodo-2,3-dimethoxybenzene (134) with the vinyl bromide 140 (10 equiv.) gave a mixture of 141 and 142 [37]. In this reaction, oxidative addition of 140 to the palladacycle 143 generates 144, and the coupled product 145 is formed by reductive elimination. Finally 5-exo cyclization of 145 and β-H elimination afford 141.

Br

I +

Pd(OAc)2, Bu4NBr, K 2CO3 +

DMF, 100 °C, 82%

OCH3 OCH3 134

OCH3

140 excess

Pd 134

O

O 1:2

OCH3 142

141

Pd Br

140

O

O

OCH3

OCH3

143

144

O

Pd-Br

OCH3 145

Pd-Br 141 O OCH3

Furthermore, Dyker reported the Pd-catalyzed reaction of 2-t-butyliodobenzene (147) gave the benzocyclobutane 148 and the trimer 149 [38]. Key steps are facile formation of the palladacycles 150, 153, and 156 by C—H activation of the methyl group. Oxidative addition of 147 to the five-membered palladacycle 150 to generate 151 and reductive elimination gives 152. In this case, the palladacycle 153 undergoes very unusual reductive elimination to give the strained benzocyclobutane 148 in 75 % yield. Further reaction of 153 via 154 and 155 yields again the

198 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides unusual seven-membered palladacycle 156. The cyclohexane 149 is obtained by its reductive elimination, although yield was low (7 %).

I

Pd(OAc)2, Bu4NBr, K 2CO3

+

DMF, 100 °C, 82%

147

147

148

Pd-X

Pd(0)

Pd

149

7%

Pd

147

X

150

Pd X

75%

151

Pd 152

153

148

149

Pd

Pd

Pd-X

X

155

156

154

Unexpected annulation occurred in an attempted Heck reaction of the α,βunsaturated sulfone 157 with an excess of iodobenzene to give 158 in high yield. The use of Ag2 CO3 as a base is important [39]. The expected Heck product 159

Reactions of Aromatics and Heteroaromatics

199

was a minor one under the conditions. The reaction is explained by the following mechanism. Formation of the Heck product 159 by carbopalladation to generate 160, followed by β-H elimination is understandable. However, formation of the palladacycle 161 from 160 occurs as the main path. Oxidative addition of Ph—I to 161 affords 162, and its reductive elimination gives the o-phenylated product 163. Similar sequences via 164 and 165 yield the palladacycle 166, and 158 is obtained by reductive elimination. Ph

PhSO2

Ph + Ph-I 157

Ph Ph

PhSO2

Pd(OAc)2, Ag2CO3

+ PhSO2

DMF, 120 °C, 82%

Ph 159

97 : 3

158

Ph PhSO2

syn b-H elimination

Ph 159 Ph

Ph-Ph-I carbopalladation PhSO2

H PhSO2

H Ph

PhSO2

Ph

Pd HX

PdX

161

160 PhSO2

Ph Ph-I

H

PhSO2

Pd

Ph

Ph

Pd

HX

X 162

PhSO2

163

Ph

Ph

Ph

Ph

X-Pd

PhSO2

Ph-I

Ph

PhSO2

Ph

164 Ph

Ph

Ph

PhSO2

X-Pd H

Pd HX

165

166

158

It seems likely that facile formation of palladacycles as intermediates will play an important role in developing new Pd-catalyzed reactions of aromatic compounds.

200 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

References 1. Reviews: (a) G. Dyker, Chem. Ber./Recueil, 130, 1567 (1997); Angew. Chem. Int. Ed., 38, 1698 (1999); (b) M. Miura and M. Nomura in ‘Cross-Coupling Reactions’, Ed. N. Miyaura, Springer Verlag, Berlin, 2002, p. 211; (c) T. Satoh, M. Miura, and M. Nomura, J. Organomet. Chem., 653, 161 (2002). 2. J. J. Li and G. W. Gribble, Palladium in Heterocyclic Chemistry, Pergamon, Oxford, 2000, p. 14. 3. (a) Y. Akita, Y. Itagaki, S. Takizawa, and A. Ohta, Chem. Pharm. Bull., 37, 1477 (1989); (b) A. Ohta, Y. Akita, T. Ohkuma, M. Chiba, R. Fukunaga, A. Miyafuji, T. Nakata, N. Tani, and Y. Aoyagi, Heterocycles, 31, 1951 (1990); (c) Y. Aoyagi, A. Inoue, I. Koizumi, R. Hashimoto, K. Tokunaga, K. Gohma, J. Komatsu, K. Sekine, A. Miyafuji, J. Kunoh, R. Honma, Y. Akita, and A. Ohta, Heterocycles, 33, 257 (1992). 4. B. Glover, K. A. Harvey, B. Liu, M. J. Sharp, and M. F. Tymoschenko, Org. Lett., 5, 301 (2003). 5. C. C. Hughes and D. Trauner, Angew. Chem. Int. Ed., 41, 1569 (2002). 6. M. Burwood, B. Davies, I. Diaz, R. Grigg, P. Molina, V. Sridharan, and M. Hughes, Tetrahedron Lett., 36, 9053 (1995). 7. D. Brown, R. Grigg, V. Sridharan, and V. Tambyrajah, Tetrahedron Lett., 36, 8137 (1995). 8. S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, and M. Nomura, Bull. Chem. Soc. Jpn., 71, 467 (1998). 9. T. Okazawa, T. Satoh, M. Miura, and M. Nomura, J. Am. Chem. Soc., 124, 5286 (2002). 10. B. Sezen and D. Sames, J. Am. Chem. Soc., 125, 5274 (2003). 11. A. P. Kozikowaki and D. Ma, Tetrahedron Lett., 32, 3317 (1991). 12. C. A. Merlic and D. M. McInnes, Tetrahedron Lett., 38, 7661 (1997). 13. A. Mori, A. Sekiguchi, K. Masui, T. Shimada, M. Horie, K. Osakada, M. Kawamoto, and T. Ikeda, J. Am. Chem. Soc., 125, 1700 (2003). 14. T. Kuroda and F. Suzuki, Tetrahedron Lett., 32, 6915 (1991). 15. Y. Kawamura, T. Satoh, Y. Kametani, M. Miura, and M. Nomura, Chem. Lett., 961 (1999). 16. T. Satoh, J. Inoh, Y. Kawamura, Y. Kawamura, M. Miura, and M. Nomura, Bull. Chem. Soc. Jpn., 71, 2239 (1998). 17. T. Satoh, Y. Kawamura, M. Miura, and M. Nomura, Angew. Chem. Int. Ed. Engl., 36, 1740 (1997). 18. Y. Kawamura, T. Satoh, M. Miura, and M. Nomura, Chem. Lett., 931 (1998). 19. D. D. Hennings, S. Iwasa, and V. H. Rawal, Tetrahedron Lett., 38, 6379 (1997). 20. T. Satoh, Y. Kametani, Y. Terao, M. Miura, and M. Nomura, Tetrahedron Lett., 40, 5345 (1999). 21. Y. Terao, Y. Kametani, H. Wakui, T. Satoh, M. Miura, and M. Nomura, Tetrahedron, 57, 5967 (2001). 22. Y. Kametani, T. Satoh, M. Miura, and M. Nomura, Tetrahedron Lett., 41, 2655 (2000). 23. D. E. Ames and A. Opalko, Tetrahedron, 40, 1919 (1984); Synthesis, 234 (1983). 24. Y. M. Zhang, T. Razler, and P. F. Jackson, Tetrahedron Lett., 43, 8235 (2002). 25. S. Hernandez, R. SanMartin, I. Tellitu, and E. Dominiguez, Org. Lett., 5, 1095 (2003). 26. E. Desarbre and J. Y. Merour, Heterocycles, 41, 1987 (1995). 27. R. Grigg, L. Loganathanm, and V. Sridharan, Tetrahedron Lett., 37, 3399 (1996). 28. G. Bringmann, J. R. Jansen, and H. P. Rink, Angew. Chem. Int. Ed. Engl., 25, 913 (1986). G. Bringmann, J. R. Jansen, H. Reuscher, M. Rubenacker, K. Peters, and H. G. von Schnering, Tetrahedron Lett., 30, 5249 (1989); 31, 643 (1990). 29. P. P. Deshpande and O. R. Martin, Tetrahedron Lett., 31, 6313 (1990). 30. T. Hosoya, E. Takashiro, T. Matsumoto, and K. Suzuki, J. Am. Chem. Soc., 116, 1004 (1994). 31. T. Harayama, T. Akiyama, Y. Nakano, K. Shibaike, H. Akamatsu, A. Hori, H. Abe, and Y. Takeuchi, Synthesis, 237 (2002).

Reactions with Alkynes

201

32. H. A. Reisch, M. S. Bratcher, and L. T. Scott, Org. Lett., 2, 1427 (2000). 33. L. Wang and P. B. Shevlin, Org. Lett., 2, 3703 (2000). 34. J. J. Gonzalez, N. Gartcia, B. Gomez-Lor, and A. M. Echavarren, J. Org. Chem., 62, 1286 (1997). 35. G. Dyker, P. Siemsen, S. Sostmann, A. Wiegand, I. Dix, and P. G. Jones, Chem. Ber./Recueil, 130, 261 (1997). 36. G. Dyker, Chem. Ber., 127, 739 (1994). 37. G. Dyker, J. Org. Chem., 58, 6426 (1993). 38. G. Dyker, Angew. Chem. Int. Ed. Engl., 31, 1023 (1992). 39. P. Mauleon, I. Alonso, and J. C. Carretero, Angew. Chem. Int. Ed., 40, 1291 (2001).

3.4 Reactions with Alkynes 3.4.1 Introduction Pd-catalyzed coupling reactions of terminal and internal alkynes 1 and 4 with halides are surveyed in this section. Reactions of alkynes with aryl and alkenyl halides are classified in to two types. The first one is the preparation of arylalkynes 2 and alkenylalkynes (1,3-enynes) 3 by the reactions of terminal alkynes 1 with aryl and alkenyl halides in the presence of Pd(0) and CuI as catalysts (section 3.4.2). The second one is insertion of internal alkynes 4 to aryl- and alkenylpalladium bonds formed by oxidative addition of halides, generating alkenylpalladiums 5, which are living species and undergo further transformations before termination. Terminal alkynes also undergo the insertion in the absence of CuI catalyst (section 3.4.3)

R

H

+

Pd(0) R

Ar-X

1 R1

Pd(0)

H +

R

R′ 4

R

X

1

R

Ar 2

+

R′

R Ar-Pd-Br Pd(0)

R1

3

insertion

R′

Pd-Br 5

Ar-Br

3.4.2 Reactions of Terminal Alkynes to Form Aryl- and Alkenylalkynes (Sonogashira Coupling) Direct introduction of sp2 carbon to alkynes by the reaction of Cu acetylides with aryl and alkenyl halides to form arylalkynes and alkenylalkynes is known as the Castro reaction [1]. Later it was found that coupling of terminal alkynes (1-alkynes) with halides proceeds more smoothly by using Pd catalysts. There are two methods of Pd-catalyzed coupling. In 1975 direct coupling of 1-alkynes catalyzed by a phosphine-Pd(0) complex in the presence of amines was reported by Heck and Cassar as an extension of the Heck reaction to 1-alkynes [2,3]. In the same year, Sonogashira and Hagihara found that the addition of CuI as a co-catalyst gave better results, and the Pd(0)-CuI-catalyzed reaction is called the

202 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Sonogashira reaction [4,5]. A comprehensive review on Pd-catalyzed alkynylation was published recently by Negishi and Anastasia [6]. Facile Pd(0)-CuI-catalyzed coupling of aryl and alkenyl halides with 1-alkynes is used extensively for the preparation of arylalkynes or enynes. The reaction is explained by the following mechanism. At first, CuI activates 1-alkynes 1 by forming the Cu acetylides 6, which undergo transmetallation with arylpalladium halides to form the alkynylarylpalladium species 7, and reductive elimination to give 2 is the final step. However, the coupling proceeds even in the absence of CuI under certain conditions, and it may be possible to form the alkynylarylpalladium species 7 directly from 1-alkynes. As another less likely possibility, carbopalladation of a triple bond with Ar-Pd-X (or insertion of the triple bond to Ar-Pd-X) generates the alkenylpalladium 8 which undergoes dehydropalladation to afford disubstituted alkynes 2. In this mechanism, CuI plays no role. The mechanism of β-H elimination of alkenylpalladium to form alkynes is not clearly known.

H + CuI

R

Cu + HI

R

1

6

CuI + HX + R

Pd-Ar 7

Ar-X + Pd(0)

Ar-Pd-X Pd(0) + R

Ar 2

R

H 1

Ar-X + Pd(0)

Ar-Pd-X

R

H

X-Pd

Ar

?

Ar + Pd(0)

R 2

8

Coupling catalyzed by Pd(0) and CuI proceeds via in situ generation of Cu acetylides 6. Later acetylides of main group metals such as Mg, Zn, Sn, and B have been found to be good partners of the coupling. This is the second preparative method of arylalkynes. Coupling of metal acetylides 9 of 1-alkynes with halides proceeds without CuI. In an exact sense, Pd-catalyzed couplings of metal acetylides with halides are different from the Sonogashira reaction. Coupling of Zn acetylides is regarded as a Negishi reaction, and that of Sn acetylides may be called a Kosugi–Migita–Stille reaction. These couplings with metal acetylides are treated in this section for the sake of convenience, rather than in section 3.6, because the same products are obtained by this method and the Sonogashira reaction.

R

MX

+

Ar-X

Pd(0) R

9

Ar 2

M = Mg, Zn, B, Sn, Si

+

MX2

Reactions with Alkynes

203

3.4.2.1 Aryl–Alkynyl Coupling (Sonogashira Reaction): Reaction Conditions and Catalysts Various results are obtained in Sonogashira coupling depending on the substrates used and the reaction conditions. Homocoupling and decomposition of alkynes are serious competitive reactions, and poor results are obtained sometimes due to these side reactions in the Sonogashira reaction particularly when less reactive electron-rich aryl halides are used. It is well known that CuI catalyzes oxidative homocoupling of 1-alkynes in O2 atmosphere (Glaser reaction). Also Pd(II) promotes the homocoupling. Therefore the reaction should be carried out with strict exclusion of O2 . Homocoupling in the Sonogashira reaction can be decreased by slow addition of alkynes in THF [7] and use of phase-transfer agent (n-Bu4 NI) in H2 O–toluene [8]. Ho et al. reported that the homocoupling of phenylacetylene with 4-iodoanisole (10) can be reduced drastically by carrying out the reaction in an atmosphere of H2 diluted with N2 or argon [9]. I

PdCl2(PPh3)2, CuI, Et3N

+ Ph

DMF, 100 °C, N2 + H2

MeO 10 +

MeO

without N2 + H2

Ph

Ph

98%

1.9%

70%

23%

Phenylacetylene is an exceptionally reactive alkyne, and it is true that coupling of some electron-rich aryl halides proceeds smoothly only with phenylacetylene. In many papers, the coupling of phenylacetylene alone is reported. Good results are not always obtained in reactions of other alkynes with electron-rich aryl halides under similar conditions. Aryl iodides, bromides, and triflates are used for the coupling. Curiously, it is generally believed that Sonogashira coupling of aryl chlorides is difficult, and only a few reports on Sonogashira coupling of activated chlorides have been published. Plenio found a versatile catalyst for the Sonogashira coupling of various aryl chlorides. As a ligand, bulky and electron-rich P(t-Bu)3 or (1-Ad)2 P(n-Bu) is the most effective. Na2 PdCl4 /PR3 /CuI was found to be a precursor of the efficient catalyst system, and the coupling proceeds in toluene or DMSO at 100 ◦ C [10]. Na2PdCl4, P(t-Bu)3, CuI

Cl + MeO

n-C6H13

Na2CO3, toluene 100 °C, 78%

MeO

n-C6H13

Alkynes with EWGs such as propiolate are poor substrates for the coupling with halides. Therefore, instead of inactive propiolate, triethyl orthopropiolate (11) is used for the coupling with aryl halides to prepare the arylpropiolate 12. The

204 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides coupling product 14 obtained from 3,3-diethoxy-1-propyne (13) and aryl halides is a precursor of the arylalkynal 15 [11]. I

1. PdCl 2(PPh3)2, CuI, Et3N

OEt +

OEt

2. TsOH, 83%

Me

CO2Et

OEt

Me

12

11 OEt OEt I

CHO

OEt PdCl2(PPh3)2, CuI

+ 13

OEt

Et3N, DMF, 64% 14

15

The Sonogashira reaction is usually carried out at about 80 ◦ C. Pd(OAc)2 , PdCl2 (PPh3 )2 or Pd(PPh3 )4 are used in the presence of excess amine in most cases. It should be added that these Pd compounds as precursors do not always show the same behavior and sometimes show different activity. At this temperature, decomposition of some labile alkynes tends to occur. Therefore, the reaction should be carried out under milder conditions as far as possible to prevent the side reaction. Pd on charcoal acts as an efficient catalyst for the coupling of aryl bromides such as 3-bromopyridine in the presence of CuI, PPh3 , and i-Pr2 NH in DMA–H2 O [12]. Br +

Pd/C, PPh3, CuI, i-Pr2NH

n-Bu

n-Bu

DMF, reflux, 81%

N

N

Thorand and Krause claimed that THF is a very good solvent [7], but Ho et al. reported that THF is a poor solvent in their reaction [9]. One drawback of the Sonogashira reaction is the use of a large excess of amines almost as a solvent. Buchwald and Fu et al. reported that coupling of inactivated 4-bromoanisole (16) can be carried out at room temperature by using Pd(PhCN)2 Cl2 as a catalyst, P(t-Bu)3 as a ligand, and only 1.2 equivalents of diisopropylamine. Poor results are obtained when PPh3 , PCy3 , P(o-Tol)3 and DPPF are used instead of P(t-Bu)3 under similar conditions [13]. Br + H MeO 16

Me OH Me

Pd(PhCN)2Cl2, CuI, P(t-Bu)3

i-Pr2NH (1.2 equiv), dioxane r.t, 2 h, 95%

MeO

Me OH Me

Reactions with Alkynes

205

Beletskaya et al. reported that the reaction of arylalkynes proceeds smoothly at room temperature in water using only 10 mol% of Bu3 N and excess K2 CO3 . PdCl2 (PPh3 )2 and CuI are catalysts [14]. Mori and co-workers discovered a convenient and useful procedure for Sonogashira coupling. They found that the coupling of aryl iodides such as electron-rich p-iodoanisole (10) can be carried out smoothly at room temperature using only 2 equivalents of aq. NH3 (0.5 M) in THF [15]. Room temperature coupling of aryl iodides 10 is possible in the presence of carbamoyl-substituted N-heterocyclic carbene complex (XVI-12) with the coexistence of PPh3 (1 mol%) and Et3 N (1.2 equiv.) in DMF. Reaction of electron-rich aryl bromide 16 proceeds at 80 ◦ C with the same catalyst and Cs2 CO3 as the best base [16]. Reaction of the reactive aromatic alkyne 18 with the reactive electron-deficient aryl iodide 17 proceeds even at −20 ◦ C in a quantitative yield. Tri(2,4,6-trimethylphenyl)phosphine (I-8) was used as a ligand [17]. PdCl2(PPh3)2, CuI

I +

n-C6H13

H

MeO 10 I

THF, aq. NH 3 (2 equiv) r.t, 81%

MeO

n-C6H13

MeO

t-Bu

MeO

t-Bu

XVI-12, CuI, PPh3

+ H

t-Bu

+ H

t-Bu

MeO

NEt3 (1.2 equiv), DMF r.t, 2 h 93%

10

Br

XVI-12, CuI, PPh3

MeO 16

Cs2CO3 (1.2 equiv), DMF 80 °C, 5 h, 97% OMe

I +

Pd2(dba)3, CuI, L ( I-8) H 18

MeO2C 17

i-Pr2NEt, n-Bu4NI, DMF −20 °C, 20 min, 100%

OMe

MeO2C

Room temperature reaction of p-iodoanisole (10) also takes place in the presence of Bu4 NF (TBAF) or hydroxide (TBAOH) without addition of other amines. PdCl2 (PPh3 )2 and CuI are catalysts [18]. Ag2 O, instead of CuI, can be used for the coupling at 60 ◦ C [19]. Furthermore, the coupling proceeds without CuI or Ag2 O in the presence of a stoichiometric amount of TBAF [20]. Sonogashira reaction proceeds in aqueous media (MeCN/H2 O) at room temperature by the use of the water-soluble sulfonated phosphine ligand II-2 without CuI [21]. Also coupling of triple bonds in peptides with aryl iodides was carried out in water in the presence

206 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides of II-2 as a ligand [22]. Synthesis of the 65-membered cyclic peptide containing triple bonds was achieved via ‘on resin’ Sonogashira coupling [23].

MeO

PdCl2(PPh3)2, CuI

I+H

C6H13

I +H

SiMe3

I +H

C6H13

TBAOH (1.2equiv) THF, r.t, 6 h, 98%

MeO

C6H13

MeO

SiMe3

MeO

C6H13

10

MeO

Pd(PPh)4, Ag2O THF, 60 °C, 60%

10

MeO 10

Pd2(dba)3, PPh3 TBAF (1 equiv) THF, 60 °C, 83%

SiMe3 I

OHC

+

Pd(OAc)2, L (II-2) H

SiMe3

OHC

Et3N, MeCN/H2O 25° C, 80%

The coupling proceeds in an ionic liquid BMim (1-butyl-3-methylimidazolium hexafluorophosphate) in the absence of CuI. In this medium, the facile separation and recycling of the catalyst are possible [24]. I

PdCl2(PPh3)2, [BMim][PF6]

+ H

C6H13

Me

Bu

i-Pr2NH, 80°C, 4 h, 87%

C6H13

[PF6]−

[BMim]

Isomerization of the coupling products of 1-arylpropargyl alcohols with electrondeficient halides generate α,β-unsaturated aryl ketones, which undergo further condensation to afford heterocycles such as pyrroles and pyrimidines [25]. For example, domino coupling–isomerization–condensation reactions of 1phenylpropargyl alcohol (17), 2-bromothiazole, and methylhydrazine generated the enone 18, and the pyrazoline 19 was obtained by the reaction of methylhydrazine [25]. Pd on carbon and CuI, combined with phosphine ligands, are used as good catalysts in some cases. The coupling of N -propargylamino acid 20 with 3bromopyridine proceeded in an aqueous phase to give 21. Pd on carbon and water-soluble diphenylphosphinobenzoic acid (II-3) were used [26].

Reactions with Alkynes

207 N

OH

N

+ MeNHNH2

+ H Br

S

PdCl2(PPh3)2, CuI

17

S

Et3N, 69%

Ph

Ph OH

N

N

MeNHNH2

Ph

Me N N

S

S O

18

19

Ph Me

Boc

Boc

Br

Me CO2H

N

CO2H

N

Pd/C, CuI, L (II-3)

+

DME/H2O 75%

N

N

20

21

Aryl and alkenyl triflates are reactive partners. Coupling of ditriflate of catechol (22) with the alkyne 23 gave the 1,2-dialkynylbenzene 24 in good yield in the presence of n-Bu4 NI (300 mol %) [27]. Functionalization of some heterocycles is possible by the reaction of their triflates. Coupling of the 5-acetyl-4-thiazolyl triflate 25 proceeded at room temperature in the presence of Pd(PPh3 )4 and CuI, and the product 26 was converted to the pyrido[3.4-c]thiazole 27 by treatment with ammonia [28]. The triflate 29 was prepared from the corresponding oxazolone, and its Sonogashira reaction with methyl N -propargylcarbamate (28) afforded the 2-alkynyloxazole 30 in 84 % yield [29]. SiMe3 OTf PdCl2(PPh3)2, CuI

+

H

SiMe3

Bu4NI, Et3N, DMF 70 °C, 91%

23

OTf 22

SiMe3

24 OTf

F

HO

N +

S

Pd(PPh)4, CuI

H

Et3N, DME, r.t 67%

O

F 25

HO

F

HO F

NH3

N

N

N

75% S

S O

F 26

F 27

208 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides OSiR3 HN

+

H

CO2Me

TfO

N

O SiR3 = TBDMS

28

2,6-lutidine dioxane, rt, 84%

29

OSiR3

Pd(PPh3)4, HN CuI N

CO2Me O 30

3.4.2.2 Alkenyl–Alkynyl Coupling (Sonogashira Reaction) Aryl iodides, bromides, and triflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pdcatalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cis-1,2-dichloroethylene (31) can be coupled with 1alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric (E)-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with trans-1,2-dichloroethylene 35. 2) H Cl

Cl

+ H

(CH2)4OH 32

31

C5H11

C5H11

1) Pd(PPh3)4, CuI

33

BuNH2, rt

PdCl2(PhCN)2 piperidine, rt

(CH2)4OH 34

73%

2) H

Cl +

H

Cl

C5H11 33

35

SiMe3

1) Pd(PPh3)4, CuI

23

piperidine, rt

PdCl2(PhCN)2 piperidine, rt

SiMe3

C5H11

37

75%

The novel [6.6]metacyclophane 40 was prepared by coupling 31 with 1-alkynes as a key reaction. The shortest way to 40 is the coupling of m-diethynylbenzene (41)

Reactions with Alkynes

209

with 31. The yield of the attempted reaction was only 2 %. Then 39 was prepared in 67 % yield by coupling 38 with 31, from which 40 was obtained by Ti-mediated intramolecular coupling of aldehydes [33].

O Cl +

Pd(PPh3)4, CuI

O

BuNH2, rt, 67%

O

Cl O 31

O 38

O

39

Cl Pd(PPh3)4, CuI

+ Cl

BuNH2, rt 2%

31 41 40

Both chlorines of 1,1-dichloroethylene (42) react stepwise with different 1alkynes 43 and 44 to form the asymmetric enediyne 45 [34]. The enediyne system 48 was prepared by Pd-catalyzed stereoselective hydrogenolysis of the 1,1dibromo-1-alkene 46 with tin hydride to give 47, followed by coupling with 1-alkyne 23 in a one-pot reaction [35]. C5H11 C3H7 Cl + C5H11 Cl 42

Pd(PPh3)4

44

CuI, 81%

75%

Cl

43 C5H11

Br Br

+

Pd(PPh3)4

HSnBu3

63%

Ph 46

45 C3H7 H Br Ph

47

TMS 23 Pd(PPh3)4/CuI i-Pr2NEt, 70%

Ph

TMS 48

210 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Alkenyl triflates are reactive partners. In the total synthesis of (−)-tricholomenyn (52b), coupling of the vinyl triflate 49 with 23 gave the enyne 50a, and reaction of the vinyl iodide 51 with the deprotected 1-alkyne 50b afforded 52a. Combined use of PdCl2 (PPh3 )2 , CuI, and i-Pr2 NH gave the best results in this case. The reaction in THF and di-isopropylamine at 0 ◦ C is important. Under usual conditions of the Sonogashira reaction, no product was obtained [36]. Coupling of ethynyloxirane 53 with alkenyl triflate afforded the epoxyenediyne 54 in high yield without attacking the labile epoxyalkyne system. AgI is a better cocatalyst than CuI in this reaction [37]. R

OTf PdCl2(PPh3)2, CuI

+ TMS

i-Pr2NH, 85% 23

49

50a 50b

O

R = TMS R=H

I O O

OTBS 51 PdCl2(PPh3)2, CuI

O

i-Pr2NH, 0 °C 54%

52a, R = TBS 52b, R = H, tricholomenyn

OR

SiPh2t-Bu

OTf +

t-Bu O 53 SiPh2t-Bu Pd(PPh3)4, AgI

t-Bu

i-Pr2NH, DMF 90%

O 54

Vinyl tosylates are also used. Coupling of the vinyl tosylate 55 with an 1-alkyne afforded the enyne 56. Only the use of PdCl2 (PPh3 )2 , CuI, and i-Pr2 NH gave satisfactory results [38]. Ph

SPh OTs

H 55

PdCl2(PPh3)2, CuI + H

CH2OMe

i-Pr2NH, THF rt, 90%

Ph

SPh

H 56

CH2OMe

Reactions with Alkynes

211

3.4.2.3 Coupling and cyclization Coupling of 1-alkynes with aryl halides having a nucleophilic group at an ortho position and subsequent cyclization offer useful synthetic methods of heterocycles [39]. Two types are known. In type 1, the halides 57 react with 1-alkynes to generate 58, which undergo cyclization to afford 2-substituted heterocycles 59. β-Substituted alkenyl halides 60 behave similarly to give 2-substituted heterocycles 61. R

Type 1 X +

R

Pd(0), CuI R

Sonogashira

Y

YH

YH

59

58

57

R X +

R

Pd(0), CuI Sonogashira YH

61

YH = OH, NH2

60

R

Y

YH

In type 2, the ethynyl derivatives 62 and 63 react with aryl halides to generate disubstituted alkynes, which cyclize to afford 59 and 61. These reactions are used extensively for the preparation of heterocycles 59 and 61 such as benzo[b]furans, butenolides, and indoles. In some cases, cyclization proceeds spontaneously to give 59 in a one-pot reaction. Type 2

Ar

+ Ar-X

Ar

YH

Y

YH

62

59 Ar

R

R

R

+ Ar-X R

YH 63

Ar R

YH

R

Y 61

Furan derivatives are prepared by reaction of o-iodophenols. 2-Phenylbenzo[b]furan was prepared by the reaction of o-iodophenol (64) with 1-alkyne in one step [40]. It should be noted that similar 2-arylbenzo[b]furan formation occurred by the use of Pd-free, copper-phosphine complex [41]. Similarly 2-substituted furo[3.2-b]pyridine 66 was prepared from 2-iodo-3-pyridinol (65) in a one-pot reaction [42]. Naturally occurring ailanthoidol was synthesized by the reaction of 67 and 68 to give the cyclized product 69 [43]. The deoxynucleoside 72 was prepared in two steps by coupling the 5-iodo nucleoside 70 with 1-dodecyne, and CuI-catalyzed cyclization of 71 [44].

212 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides I

Pd(OAc)2(PPh3)2

Ph

+

Ph

piperidine,CuI, 80%

O

OH 64 N

I + OH

N

OEt

Pd(OAc)2(PPh3)2, CuI

OEt

piperidine, DMF, 82 %

OEt O

65

66

MeO2C

I

PdCl2(PPh3)2, CuI OBn

+

Et3N, MeCN, 68%

OH 67

OMe

OMe

68

MeO2C OBn O OMe

OMe 69 HO

OH O OMe

OMe ailanthoidol

O I

HN N

O

+

Pd(PPh3)4, CuI

C10H21

i-Pr2EtN, DMF, 57%

HO

HO

O 70 C10H21 O

C10H21

O

HN

N N

O

CuI, Et3N MeOH, 58%

HO

HO

OEt

O 71

N

O HO

HO

O 72

Reactions with Alkynes

213

Sonogashira coupling of o-iodothioanisole (73) with phenylacetylene affords o-(1-alkynyl)thioanisole 74, which cyclizes to give 2-substituted 3-iodobenzothiophene 75 by the treatment with iodine. Furthermore, Suzuki coupling of 75 affords the 2,3-disubstituted benzothiophene 76 [45]. The iminoalkyne 78 is prepared by Sonogashira coupling of the alkenyl iodide 77, and the substituted pyridine 79 is obtained by the CuI-catalyzed cyclization [46]. Ph I +

Ph

PdCl2(PPh3)2, CuI

I2, CH2Cl2

Et3N, 25 °C, 100%

25 °C,100%

SMe

SMe 74

73 I

Ph NaBPh4 Pd(OAc)2, Na2CO3,

Ph S

DMF, 92%

75

H

76

H

t-Bu N

Ph

Ph

S

+

Ph

t-Bu N

PdCl2(PPh3)2, CuI (1 mol%) Et3N, 55 °C, 57%

Ph

I

Ph 77

78 N

CuI (10 mol%) DMF, 100 °C

Ph

Ph 79

As an alternative procedure (type 2 reaction), coupling of the o-ethynylphenol 80 with the alkenyl triflate 81 proceeds smoothly to yield the benzofuran 82 [40]. Coupling of 2-bromothiazole with an enolate of 1,3-dicarbonyl compound was used for preparation of 2,5-disubstituted furan 83 [47]. Coupling of 2-iodoanisole OTf

Me

Pd(OAc)2(PPh3)2, CuI

+

Et3N, DMF, 50%

OH

Ph

O

80

81 Ph

Me O O

N

+ Me

Br

O O

82 O

Pd(Ph3P)4 K2CO3, DMF, 73%

Me

N O 83

S

S

214 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides with N -propargylbenzamide (84) generated the coupling product in the presence of t-BuONa, which underwent base-catalyzed in situ cyclization to yield 2,5disubstituted oxazole 85 [48]. OMe +

Pd2(dba)3, TFP (I-3) HN

O

t-BuONa, MeCN 83%

I Ph 84

MeO MeO

HN

O

N

O

Ph

Ph

85

The coupling of the o-iodoaniline derivative 86 with 1-alkynes in aqueous media at room temperature by the use of the water soluble ligand II-2, followed by intramolecular amination gave the indoles 87a and 87b [49]. As a type 2 reaction, the indole 91 was obtained by coupling 2-ethynylaniline (88) with the triflate 89 and cyclization [50]. I +

Pd(OAc)2, L (II-2) H

Bu

Et3N, MeCN/H2O rt, 70%

NHCOCF3 86

Bu +

Bu

N H

N COCF3

87a

87b OTf Pd(PPh3)4

+

CuI

NH2 88

89

Pd(II) 64% NH2

N H 91

Reactions with Alkynes

215

The γ -alkylidenebutenolide 93 was prepared by domino coupling of (Z)-3bromoacrylic acid (92) with 1-alkynes to generate an enyne acid, followed by lactonization [51]. Negishi synthesized γ -alkylidenebutenolide 98 by the coupling–lactonization reaction [52]. The 3-aryl-3-iodocinnamic acid 96, a coupling partner, was prepared by the coupling of Zn acetylide of ethyl propiolate with 95, followed by hydroiodination. As described earlier, Sonogashira coupling of propiolate itself is very difficult. The coupling–lactonization of 96 with the 1-alkyne 97 afforded the acetate of rubrolide (98) in 70 % yield via lactonization.

O

Pd(PPh3)4, CuI H

Ph

+

CO2H

Br

HO

Et3N, 80% Ph

92

O

O Ph 93

AcO

Br +

Br

94

Pd(PPh3)4 BrZn

CO2Et

I Br AcO

Br AcO

Br

AcO

Br

CO2Et

Br

97

Pd(Ph3P)4, CuI Br

I 95 AcO

CO2H 96

Et3N, MeCN 25 °C, 70%

AcO

Br

Br

Br

Br

CO2H O Br

O

Br

AcO Br

AcO

Br 98

Stereoselective preparation of (E)-5-stannyl-γ -alkylidenebutenolide 100 was achieved by the reaction of tin acetylide with tributylstannyl 3-iodopropenoate derivative 99, and the arylbutenolide 101 was obtained by the Migita–Kosugi– Stille reaction of 100 [53].

216 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O

+

MeO I

H

SnBu3

OSnBu3 99 O MeO

Pd(PPh3)4 DMF, 70%

OSnBu3

SnBu3 MeO

MeO I

S PdCl2(MeCN)2

Bu3Sn

O

O

S O

O

70%

100

101

3.4.2.4 Acetylene Surrogates Selective monosubstitution of acetylene to prepare 1-alkynes is not easy. It can be done by the use of protected acetylenes. As one method, trimethylsilylacetylene (TMS-acetylene) (23) is used. After its coupling with halides, the TMS group is removed by treatment with a base or fluoride anion to give 1-alkynes. Among numerous examples, an application to synthesize a rigid macrocycle with two exotopic phenanthroline binding sites is cited. In this synthesis, TMS-acetylene (23) and triisopropylsilylacetylene (102) are used as protected acetylenes [54]. At first the dialkynes 103, protected with TMS and triisopropylsilyl groups, were prepared from p-bromoiodobenzene in high yield, and the TMS group in 103 was selectively removed to give 104, which undergoes coupling with the dibromophenanthroline Ar-X + H

SiMe3

Pd(0), CuI

Ar

SiMe3

F−

Ar

H

23

Br

I

+

H

SiMe3 23

PdCl2(PPh3)2 CuI, Et3N rt, 98%

Br

SiMe3

Si(i-Pr)3

H 102

(i-Pr)3Si

PdCl2(PPh3)2

SiMe3

CuI, Et3N rt, 98%

KOH MeOH

103

(i-Pr)3Si

H 104

105 to give 106a in 91 % yield. Deprotection of 106a afforded the diyne 106b. Coupling of 106b with two molecules of the 1,3-diiodobenzene 107 afforded 108 in 84 % yield. Finally the macrocycle 109 was obtained by the coupling of 108 with 106b in 16 % yield.

Reactions with Alkynes

217 R OMe

C6H13

C6H13

Br N + 104

t-Bu 107

N

PdCl2(PPh3)2

N

I

I

CuI, Et3N rt, 91%

Pd(PPh3)4 84% N

Br C6H13

C6H13

105

106a R = -Si(i-Pr)3 106b R = H

R

t-Bu

I OMe C6H13 106b N

Pd(PPh3)4 Et3N, benzene reflux 40 h, 16%

N C6H13

OMe I 108

t-Bu

t-Bu

OMe C6H13

C6H13

N

N

N N C6H13

OMe

t-Bu 109

C6H13

218 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides One-pot synthesis of symmetric and asymmetric biarylacetylenes was carried out from 23 at room temperature. The TMS group in the coupling product 110 of p-chloroiodobenzene was removed in situ by addition of DBU (6 equiv.) and water (40 mol%). Then m-bromoiodobenzene was added to give asymmetric diarylacetylene in 90 % yield [55]. I +

TMS 23

Cl

PdCl2(PPh3)2, CuI

Cl

TMS

Et3N, benzene, rt 110

I

Br DBU, H 2O, rt

Cl

90%

Br

Another protected acetylene is propargyl alcohol and 2-methyl-3-butyn-2-ol (111). After coupling with halides, deprotection by alkaline hydrolysis gives 1-alkynes. Dehydro[12]annulenes 114 was synthesized from 111 as the protected acetylene. Monocoupling of o-dibromobenzene with 111 afforded the protected alkyne 112. Treatment of 112 with Pd(0)-CuI catalyst, NaOH, and quaternary ammonium chloride generates the deprotected 1-alkyne 113 in situ. Subsequent homocoupling of three molecules of 113 afforded the annulene 114 in 36 % OH Pd(0), CuI

Ar-X +

Ar

OH base

Ar

H

OH Br +

OH

Pd(PPh3)4, CuI

Pd(PPh3)4, CuI Et3N, 63%

BnEt3NCl, aq. NaOH benzene, 36%

Br Br

111

112

Br 113

114

yield [56]. Deprotection of the diyne 115 in situ, followed by coupling with 2bromothiophene in a basic solution, provided the coupled product 116 [57]. As an improved procedure of the deprotection, the coupled products were heated

Reactions with Alkynes HO

219 PdCl2(PPh3)2, CuI

+

OH

Br

S 115

S

NaOH, BnEt3NCl dioxane-H 2O, 45%

S 116

in paraffin oil with a catalytic amount of powdered KOH in vacuo and volatile 1-alkynes were collected by distillation [58]. The protected acetylene 111 was used for the synthesis of the oligoenynes 121. Coupling of 111 with alkenyl iodide 117 afforded 118 which was deprotected to give 119. The conjugated dienetriyne 120 was obtained by further coupling of the terminal alkyne 119 with 117. After repeating the same sequence of reactions, namely deprotection and Sonogashira coupling, the oligoenyne 121 was obtained [59].

OH Pr

Pr

Pd(PPh3)4, CuI

Pr

OH + 111

Pr

Et2NH, THF, 67%

TMS

OH

I

Pr

Pr

117 TMS

118

H

119

OH Ph Pr

Pr 117 Pd(PPh3)4, CuI Et2NH, THF, 64%

Pr Pr

Pr

n Ph

Pr TMS

121 120

Ethynyl Grignard reagent 122 and ethynylzinc halide 123 are good protected acetylenes as described in the next section. 3.4.2.5 Coupling of Metal Acetylides In addition to Sonogashira coupling via Cu acetylides generated in situ as mentioned in sections 3.4.2.2–3.4.2.4, coupling of 1-alkynes has been carried out smoothly using acetylides of main group metals as an alternative method of

220 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides arylation and alkenylation of 1-alkynes. Mg, Zn, and Sn acetylides are used frequently as activated alkynes and the coupling with aryl and alkenyl halides proceeds without using CuI. This method often gives better results than the Pd(0)/CuIcatalyzed Sonogashira coupling of free 1-alkynes, but not always. Mg acetylides are easily prepared and used for coupling. A good preparative method of 1-alkynes is the coupling of commercially available ethynylmagnesium chloride (122) or ethynylzinc chloride (123) as acetylene surrogates with aryl or alkenyl halides. Their couplings with halides directly afford the 1-alkynes 124. No deprotection is necessary [60]. ClMg Pd(PPh)4

122

THF, 1 h, 95% MeO

ClZn

I

MeO Pd(PPh)4

123

124

Smooth chemoselective coupling of triflate group in p-bromophenyl triflate (125) with the Mg acetylide 126 at room temperature in the presence of an aminophosphine named alaphos (VII-6) and PdCl2 gave 127 [61]. This aminophosphine ligand is superior to DPPF, DPPP and PPh3 . On the other hand, the bromo group in 125 reacted chemoselectively with free phenylacetylene to afford the triflate 128 when PdCl2 (PPh3 )2 and CuI were used. Asymmetric monocoupling of the prochiral biaryl ditriflate 129 with the Mg acetylide 130 in the presence of LiBr and chiral PdCl2 (alaphos) gave the axially chiral monoalkynylated product 131 with 99 % ee. In this reaction, addition of LiBr is essential [62]. ClMg OTf

Ph 126

Br

PdCl2(alaphos) 92% H Br 125

TfO

127

Ph

PdCl2(PPh3)2, CuI Et3N, THF 73%

TfO

Ph 128

PdCl2((S)-alaphos)

OTf + ClMg

SiPh3 130

129

Ph

OTf

Ph3Si

131 >99% ee

Zn acetylides, prepared in situ by the treatment of Li acetylides with ZnCl2 , are widely used. Both trans- and cis-1,2-dibromo-ethylenes react with metal acetylides

Reactions with Alkynes

221

with different reactivity. Competitive reactions of trans- and cis-1, 2-dibromoethylenes with the Zn acetylide 132 showed that the trans isomer is more reactive than the cis isomer to give 133 with high selectivity [63,64]. Also the competitive reactions of trans-(134) and cis-vinyl bromides (135) with the Zn acetylide 136 showed that the trans-vinyl bromide 134 is more reactive than the cis isomer 135, giving 137 selectively and keeping the cis-bromide 135 intact [65]. Negishi and coworkers have demonstrated that the coupling of alkynylzincs is more satisfactory than the Sonogashira reaction under various conditions, as shown by the following examples. The coupling of the alkynylzinc 138, formed from methyl propiolate which is an EWG, with alkenyl iodides proceeded well at room temperature to give conjugated enyne 139 in 87 % yield. The yield of 139 by the corresponding Sonogashira reaction was 53 % [66]. Br

SiMe3 Br + Me3Si

Br

ZnCl 132

Br

Pd(PPh3)4 rt., THF, 87% Me3Si

Br

Br

Me3Si

Br

+ 133

Me3Si Me3Si 134 Br Me3Si

+ ClZn

Pd(PPh3)4

C5H11

THF, 78%

136

Br

+ 137

C5H11

135

135

M 1. LDA n-C6H13

+

CO2Me 2. ZnBr 2

BrZn

I

CO2Me 138

Pd(PPh3)4

n-C6H13

THF, 23 °C, 87%

CO2Me 139

n-C6H13

+ H I

CO2Me

PdCl2(PPh3)4, CuI

n-C6H13

K2CO3, THF, 53%

CO2Me 139

Differently substituted hexaethynylbenzenes were prepared by domino Sonogashira and Negishi couplings of trichlorotriiodobenzene 140 [67]. The Sonogashira coupling of 140 with phenylacetylene afforded 141 chemoselectively in 47 % yield. Then Negishi coupling of 141 with the Zn acetylide 132 catalyzed by Pd(PPh3 )4 yielded the differently substituted hexaethynylbenzene 142 in 81 % yield. It is surprising that 142 was obtained in such a high yield by the coupling of less reactive chlorides. This is a rare example of the coupling of 1-alkynes with aryl

222 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides chlorides. In this case, electron-attracting ethynyl groups activate (though weakly) the C—Cl bonds toward oxidative addition to Pd(0). Ph

Cl I

Cl

Ph

I +

Cl

H

Ph

Cl I

Pd(PPh3)4, CuI

i-Pr2NH, THF 2 days, 47%

Cl

Cl

TMS

140 Ph

Ph TMS

Ph

ZnCl

141

132 Pd(PPh3)4 THF, 2 days, 81% TMS

TMS

Ph 142

Negishi reported improved procedures (A and B) of coupling with aryl halides by generating Zn acetylide derivatives in situ [68]. In procedure A, alkynylzinc halides are generated by the treatment of 1-alkynes with LDA and then ZnX2 , and are directly used for the coupling with aryl halides. This method is valuable for electron-deficient alkynes, and methyl propiolate (143) can be coupled via the Zn acetylide 144 to afford 145 in 89 % yield. As described earlier in this section, coupling of propiolate is less satisfactory under Sonogashira conditions. An amine as a base and ZnBr2 are used in procedure B to generate the Zn acetylide 147 from 146, and its reaction with aryl bromide gives 148. Therefore procedure B is operationally simple. Procedure A

R

H

1. LDA 2. ZnX 2 3. Ar-X, PdL n

R

Ar

H + LDA + ZnCl2

MeO2C

MeO2C 144

143 Me I

Me OMe

Pd(PPh3)4 23 °C, 89%

ZnCl

MeO2C

OMe 145

Reactions with Alkynes

223

Procedure B R

1. NEt 3 / ZnX2 (4 : 1)

H

2. Ar-X, PdL n

R

Ar

H + NEt3 + ZnBr2

C6H13

C6H13

ZnBr 147

146 MeO

MeO

I C6H13

Pd(PPh3)4, 23 °C, 89%

148

Sn acetylides are frequently used for coupling. Coupling of Mn tricarbonyl complex of pentaiodocyclopentadiene (149) with trimethylpropynyltin afforded the pentapropynyl derivative 150 at room temperature [69]. Symmetrically disubstituted alkynes can be prepared by coupling of bis(tributylstannyl)ethyne (152). The bis(binaphthol) derivative 153 was prepared by the reaction of 152 with the iodide 151 [70]. Me

I I

I

+ Me3Sn I

Me

Me

Me

PdCl2(MeCN)2 DMF, 20 °C, 38%

I Mn(CO)3

Me

149

Mn(CO)3 150

I

MeO MeO

OMe OMe

+ Bu3Sn

SnBu3

Pd(OAc)2, PPh3 66%

152

151

OMe OMe 153

Me

224 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides In the synthesis of tricholomenyn (52b), Sonogashira coupling of vinyl iodide was carried out in 54 % yield under the carefully controlled conditions as described before [36]. Ogasawara and Taylor reported that the reaction gave poor yields under usual conditions of Sonogashira coupling. They obtained the model compound 156 in 74 % yield by coupling the Sn acetylide 155 with the iodide 154 [71].

O

O I

PdCl2(PPh3)2, CuI

+ Bu3Sn

O

THF, rt, 74%

O

155 OH 154

OH 156

A few studies have been carried out on coupling of alkynyl borones. The stable methoxy(alkynyl)borate complex 158 was prepared in situ by the treatment of B-methoxy-9-borabicyclo[3.3.1]nonane (157) with alkynyllithiums or potassium reagents, and used directly for the coupling with halides to afford a variety of the disubstituted alkynes such as 159 [72,73].

B

+

OMe

M B

M = K, Li

157

M+ OMe 158

OHC

Br OHC OMe PdCl2(dppf) 60%

OMe

159

As an efficient coupling partner, the alkynylboronate 160 was generated in situ from alkynyllithium and triisopropoxyborane, and used for the coupling as a onepot reaction [74]. The method is simple and particularly useful for the coupling of C6H13

Li + B(O-i-Pr)3 (1.3 equiv)

160

MeO MeO Br Pd(PPh3)4, DME/THF reflux, 5 h, 98%

C6H13

B(O-i-Pr)3

C6H13

Reactions with Alkynes

225

unactivated and ortho-substituted aryl halides such as o-bromoanisole to give the arylalkyne in high yield. Air- and moisture-stable potassium alkynyltrifluoroborate 161 is a convenient coupling partner with aryl halides or triflates [75].

TfO 1. BuLi, B(OMe) 3

n-Bu

H

2. KHF 2

n-Bu

n-Bu

BF3K 161

OMe

PdCl2(dppf), Cs2CO3 THF, 78%

OMe

Sodium tetralkynylaluminates 162, prepared from NaAlH4 and terminal alkynes, are used for the coupling with aryl halides such as 3-bromofuran (163) to give the coupled product 164 cleanly in high yield. Most importantly, all four alkynyl moieties can be utilized for the coupling [76]. 4 TMS

H

+ NaAlH4

NaAl(

TMS)4 162 TMS

Br NaAl(

TMS)4

+

4

PdCl2(PPh3)2

O

162

+ AlBr3 + NaBr

THF, 83% O 164

163

As described before, trimethylsilylacetylene (23) is used as a protected acetylene, because no Pd-catalyzed coupling reaction occurs with the TMS group. Interestingly, however, Hiyama discovered that alkynylsilanes can be used for the coupling with aryl and alkenyl triflates using Pd(0)-CuCl as catalysts [77,78]. For example, coupling of the trimethylsilylalkyne 165 with the alkenyl triflate 166 using Pd(0)CuCl as the catalyst in DMF gave the diarylalkyne 167 in nearly quantitative yield. The asymmetric diarylalkyne 170 was prepared in one pot from 23 and two different aryl triflates. The first coupling of the aryl triflate 168 with 23 produced the silylalkyne 169 using Pd(0) and Et3 N. Without isolation, the silylalkyne 169 was coupled with another aryl triflate by addition of CuCl as the cocatalyst to afford OTf

MeO

SiMe3

Pd(PPh3)4 / CuCl

+

DMF, 80 °C, 99%

165

t-Bu 166

t-Bu

MeO 167

226 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides the asymmetric diarylalkyne 170. Aryl chlorides bearing an EWG 171 can be coupled with trimethylsilylalkyne 165 to give 172. PdCl2 (dppb) is a good catalyst. No efficient coupling takes place with electron-rich aryl chlorides. Coupling of 4bromoanisole (173) with alkynylsilane 174 to give 175 occurred when Pd(OAc)2 , carbene ligand XVI-1, and Cs2 CO3 with or without CuI are used [79]. Pd(PPh3)4

SiMe3 + TfO

H

OMe

23 168

TfO

MeO

Et3N, DMF, 60 °C, 6 h

SiMe3 169

CN

CuCl, 80 °C, 12h

MeO

CN 170

94%

Cl PdCl2(dppb), CuCl

SiMe3 +

MeO 165

DMF, 120 °C, 56% COCH3 171

MeO

COCH3 172

Br

MeO 173

Pd(OAc)2, XVI-1

+ TMS 174

Cs2CO3, DMA 80 °C, 82% MeO 175

3.4.2.6 Homo- and Cross-couplings of 1-Haloalkynes 1-Haloalkynes 176 behave as reactive halides and palladium acetylides 177 are generated by oxidative addition, which undergo various coupling reactions as expected. Coupling of 1-haloalkynes 176 with 1-alkynes catalyzed by CuI in the presence of aliphatic amines to give asymmetric 1,4-diynes 178 is known as the Cadiot–Chodkiewicz reaction. Efficient coupling takes place with 1-iodoalkynes. Better results are obtained by the addition of a Pd complex [80]. The 1,3-diyne 180 was obtained by the coupling of the 1-bromoalkyne 179 in 91 % yield when both PdCl2 (PPh3 )2 and CuI were used. The yield was 74 % when CuI alone was used [81]. Coupling of 1-iodoalkyne 181 with 1-alkyne in aqueous media using water-soluble phosphine ligand gave 182 smoothly. Pd(OAc)2 and ligand (II-2) are used in the absence of CuI [21].

Reactions with Alkynes

227

Pd-catalyzed Reaction of Alkynyl Halides R′ R

X

R′

M

Pd(0)

R

R

insertion

176

R′ transmetallation M

Pd-X

R R′

177 X = Br, I

R

transmetallation R′

R

X

R′

CuI

+

H

R′

176

C5H11

R

R

R′ 178

CuI, PdCl2(PPh3)2

+

Br

pyrrolidine

H

CH2CH2OH

179

pyrrolidine, 20 °C 91% C5H11

CH2CH2OH 180

Et H2N

+

I

C5H11

Pd(OAc)2, L (II-2)

OH

NEt3, MeCN / H2O 35 °C, 65%

H

Et 181

Et

C5H11

H2 N Et

OH 182

As an alternative preparative method of enynes, the highly strained cyclic enediyne moiety 185 was constructed by coupling the dialkynyl diiodide 183 with (Z)-1,2-distannylethylene (184) in 80 % yield in the total synthesis of dyenemicin A [82]. The presence of the epoxide in 183 is important. No coupling took place I

MeO2C

N

I

OAc OAc

OTBS 183

Pd(PPh3)4

+ Me3Sn

O

SnMe3

DMF, 80%

MeO2C

N

OAc O OAc

184

OTBS 185

228 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides when there is a double bond instead of the epoxide. By a similar method, the cyclic enediyne structure 187 was constructed by coupling the dialkynyl diiodide 186 with 184 as a key step in the total synthesis of calicheamicinone [83].

O

O

O

O

NHCO2Me

NHCO2Me Pd(PPh3)4

+ Me3Sn

TBDMSO O

I I

TBDMSO

SnMe3

O

184

O

O

186 187

3.4.2.7 Miscellaneous Reactions Although no halides are involved, homocoupling of alkynes are cited here as a related reaction. Homocoupling (oxidative coupling) of 1-alkynes is catalyzed by CuCl in pyridine under oxygen, and is called Glaser coupling. The coupling also proceeds in the presence of PdCl2 (PPh3 )2 and CuI in aliphatic amines. This oxidative coupling requires Pd(II), which is reduced to Pd(0), and some oxidizing agents are necessary to regenerate Pd(II). For this purpose, chloroacetone [84], bromoacetate [85], and iodine [86] are added as shown by the following examples. It is known that Pd(0) is oxidized to Pd(II) by oxidative addition to these halides. PdCl2(PPh3)2, CuI

n-Bu

H

i-Pr2NH, I2 (0.5 eq) rt, 86%

n-Bu

n-Bu

OH OH

HO

PdCl2(PPh3)2, CuI BrCH2CO2Et, THF, rt, 99%

Henkelmann and co-workers found that chloroformates are good coupling partners of 1-alkynes, and the reaction offers a useful synthetic method for arylpropiolates [87]. Reaction of n-butyl chloroformate with phenylacetylene in the presence of 1,2,2,6,6-pentamethylpiperidine as a hindered base and a small amount of N ,N -dimethylaminopyridine afforded n-butyl phenylpropiolate (188) in 98 % yield within 25 min in refluxing dichloromethane.

+

Pd(PPh3)4, amine ClCO2-n-Bu

CO2-n-Bu

CH2Cl2, 25 min, 98% 188

amine = 1,2,2,6,6-pentamethylpiperidine, dimethylaminopyridine

References

229

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33.

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3.4.3 Reactions of Internal and Terminal Alkynes with Aryl and Alkenyl Halides via Insertion 3.4.3.1 Classification of Reactions Alkynes are more reactive than alkenes in carbopalladation. Facile insertion of internal alkynes to some Pd—C bonds (carbopalladation of alkynes) generates the alkenylpalladiums 2 and 7 by mainly selective syn addition of organopalladium species 1 and 6 to alkynes. Formally the species 2 can be generated by oxidative addition of appropriately substituted alkenyl halides 3 to Pd(0). Terminal alkynes react with aryl halides to form arylalkynes and enynes in the presence of CuI as described in section 3.4.2. Insertion of terminal alkynes also occurs in the absence of CuI, and the alkenylpalladium species 2 and 7 are formed and undergo further reactions (Scheme 3.6). The reactions of internal and terminal alkynes via insertion are treated in this section. R1

R2

X

X 3 Pd(0)

oxid. addn. Pd(0) R1 Pd-X

1

Pd-X

R R insertion or cis-carbopalladation

1 direct nucleophilic YH attack

R1

YH

products

anion capture R1

R2 Pd-Y

5

insertion of CO, alkenes, alkynes

2

R2 = H or alkyl

Y

R2

2

R2 Y

reductive elimination 4

232 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides X

Pd-X

Pd(0)

R3

R3

6

R1 R1 R2 R = aryl, alkenyl

R2 products

Pd-X R3

7

Scheme 3.6 Reactions of alkynes with aryl and alkenyl halides and further transformation.

Whereas alkene insertion is followed by facile dehydropalladation whenever there is a β-hydrogen to afford alkenes and Pd(0) catalytic species, the alkyne insertion produces the thermally stable alkenylpalladium species 2 and 7, which can not be terminated by themselves and further transformations are required in order to terminate the reactions and to regenerate Pd(0) species for catalytic recycling. In other words, it is generally believed that the reaction of generated alkenylpalladium species 2 and 7 can not be terminated, because the β-H elimination (formation of alkynes or allenes) even in the presence of a β-hydrogen is not possible. Therefore the carbopalladation of alkynes is a ‘living’ process, in which alkynes play a role of ‘relay’ to pass the ability of carbon–carbon bond formation to other reactants. However, there have appeared a few reports on the formation of allenes 9 from 8 by the reaction of alkynes with halides. As one example, clean and selective formation of the allene 13 in good yield by the reaction of the aryl bromide 10 with 4-octyne (11) was reported. It is important to use ortho-substituted bromides for the allene formation [1]. The reaction can be understood by β-H elimination from the alkenylpalladium species 12. Similar allene forming reactions have been reported [2–4]. At present, the allene formation has been observed only in reactions using dialkylacetylenes, and should be regarded as an exceptional process. R1

CH2R2 Pd-X

R2

R1 •

b-H elimination

H

?

8

+ Pd(0) + HX

9 Me

Me + Me

Pd(OAc)2, PPh3

n-Pr

CH2Et

Cs2CO3, DMF 130 °C, 80%

Br

Pd-Br Me

11

10

CH2Et

n-Pr 12

Me b-H elimination

Et

+ Pd(0) + HBr

•

Me

H

n-Pr 13

In this section, transformations of 2 and 7 are classified and explained by citing proper examples. The formation of 2 is competitive with direct coupling of aryl halides with anions or nucleophiles as a side reaction to give 5. Yields of desired

Reactions with Alkynes

233

products of domino coupling reaction formed via 2 and 7 are sometimes low due to this side reaction. 3.4.3.2 Intermolecular Reactions The alkenylpalladium species 2 and 7 are capable of undergoing further insertion or anion trap before termination as summarized in Scheme 3.7. The following species trap the alkenylpalladium species 2 and 7. Anionic: H, OAc, N3 , CH(CO2 R)2 , SO2 Ph, RCO2 Neutral: NHR2 , ROH, CO-ROH Organometallic RM: M = Zn, B, Sn.

R

R1

R2

R1

2

Arylalkenylation R

M'-R R' = Ar, vinyl, alkyl Arylarylation Arylalkenylation

CO2R

R1 R2

R3

R3 H Arylalkynylation

R1

R3

R

R2

R3

M'R

R R1

R2 Nu

R3

NuH

anion capture H− Hydroarylation

R4 Nu

R1 R1

R4 R'

R1

NuH

R4

R

7 R1

R4

CO, ROH

Arylcarbonylation

2

R R3

CO2R R1

R4

R1

R

CO, ROH

R3

R

2

R H

R3

H− R1

R4 H

Scheme 3.7 Intermolecular transformations of aryl- and alkenylpalladium intermediates 2 and 7.

As a typical intermolecular carbopalladation and termination, hydroarylation of alkynes are carried out extensively in the presence of HCO2 H as a hydride source. Formation of regioisomers is observed in the reaction of asymmetric alkynes, and ratios depend on the nature of the substituents. High regioselectivity was observed in the reaction of the tertiary propargylic alcohol 14 to give 15 as a major product [5]. The (Z)-2-arylcinnamates 17, rather than 3-arylcinnamate 18, was obtained by the hydroarylation of methyl phenylpropiolate (16) [6]. 3-Substituted quinoline 21 was prepared by the regioselective hydroarylation of 19, followed by treatment of 20 with an acid without isolation [6].

234 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides OMe + HCO2H

+

MeO HO 14

Pd(OAc)2(PPh3)2 piperidine, DMF, 60 °C

I

MeO

OMe + OH

OH

MeO

MeO 15

80%

5%

OMe

CO2Me

16

Pd(OAc)2

+ HCO2K

+

DMF, 40 °C

I OMe

MeO

+ CO2Me

17

CO2Me

53%

18

9%

OEt OEt

OH +

NHAc

+ HCO2K I

19

OH OH

Pd(OAc)2

OEt

DMF, 40 °C, 63% NHAc 20

OEt

TsOH, EtOH N 21

Fulvenes are obtained by the Pd-catalyzed reaction of alkenyl iodides with two alkynes [7,8]. The pentasubstituted fulvene 23 was obtained in good yield from two molecules of 3-hexyne and the alkenyl iodide 22 in the presence of an equimolar amount of silver carbonate without phosphine [9]. In this reaction,

Reactions with Alkynes

235 Et

Et 2 Et

Et

CO2Me

+

CO2Me

Pd(OAc)2, Ag2CO3 (100 mol%) MeCN, 20 °C, 3 h, 97%

I

Et Et

22

23 CO2Me CO2Me Et

CO2Me Pd(0) I

X-Pd

22

Et

Et

Et

Pd-X

Et

CO2Me insertion

Et

Pd-X

Et Et

Et

Et

Et

Et

Et

CO2Me

Et

Pd-X

Et

Et CO2Me

Et Et 23

the alkenylpalladium undergoes intermolecular insertion of 3-hexyne twice, and intramolecular Heck-type reaction affords the fulvene 23. 3.4.3.3 Intramolecular Reactions; General Patterns of Cyclization Intramolecular versions and domino reactions involving appropriately functionalized aryl halides and alkynes offer useful synthetic methods for a variety of heterocycles and carbocycles. Few other methods can compete with these Pdcatalyzed cyclizations in versatility. Numerous reports and a number of excellent reviews covering the carbo- and heteroannulations have been published [10]. In order to aid understanding of this somewhat complex chemistry, the cyclizations are classified in to three types (Scheme 3.8). R1

Type 1 X +

type 1a

R1

R2

Pd(0) R2 Y

YH

R1 X +

type 1b

R1

R2

Pd(0) R2 Y

YH

R2 R2

X +

type 1c A

R1

R2

Pd(0) Y

YH

A R2 R2

X +

type 1d A

R1

R2

YH

Pd(0) Y A

Scheme 3.8

236 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Type 2

Ar

type 2a

+

R

Ar-X

Pd(0) R Y

YH R

+

type 2b

Ar-X

Ar

Pd(0)

R

Y

YH

Ar

R

R type 2c

+

YH

Ar-X

Pd(0) Y Ar

R +

type 2d

Ar-X

Pd(0) R

Y

YH A type 2e R

YH A

+

+

type 2f

Ar-X

Ar-X

Pd(0)

Pd(0)

Ar

Y

R

A

R

YH

A

Ar

Y R

Scheme 3.8

Type 3

R

R Y

X +

type 3a

YH

Pd(0) A

A R

R X

type 3b

+

YH

Y

Pd(0) A

A

Scheme 3.8 Types of Cyclization Reactions.

3.4.3.4 Cyclization Type 1 At first, syntheses of heterocycles and carbocycles by the reaction of internal alkynes with ortho-functionalized aryl halides 24 are surveyed (Scheme 3.9). The

Reactions with Alkynes

237

cyclization proceeds by carbopalladation of alkyne to generate the alkenylpalladium 25, followed by attack of a nucleophile YH to form the palladacycle 26. Reductive elimination produces the cyclic compound 27. Overall cis addition to alkyne occurs. R1 X

Pd-X

R2

R1

Pd(0)

R2 Pd-X

insertion YH

YH

R

1

HX

25

R1 R2

reductive elimination R2

Pd

E

+ Pd(0)

YH = OH, NHR, HC E

Y

Y

26

YH

R2 = H, or alkyl

24

27

Scheme 3.9

Pd-catalyzed reaction of o-iodophenol (26) with alkynes offers a good synthetic method of functionalized benzofurans 27. The silyl group in the benzofuran 27, obtained from tri-isopropylsilylalkyne, can be used for electrophilic substitution or desilylation to yield 28 [11]. In the reaction of 26 under CO atmosphere (1 atm), the insertion of 4-octyne occurs in preference to the insertion of CO to generate the alkenylpalladium 29, to which CO insertion occurs to afford the acylpalladium 30. Finally, intramolecular reaction of 30 yields the coumarin 31. The chromone 32 is not obtained [12]. Me I +

Si(i-Pr)3

Me

OH

Pd(OAc)2, n-Bu4NCl LiCl, Na2CO3 DMF, 90%

Si(i -Pr)3

O

26

27

Me KF H

87%

O 28

Pr I + Pr

Pr + CO

OH

Pd(OAc)2, n-Bu4NCl

Pr

pyridine, DMF 120 °C, 63%

OH

26

Pd-X

29 O

Pr

Pr

Pr

Pr CO

Pr OH 30

COPd-X

O 31

O

O 32

Pr

238 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Reaction of o-iodoaniline (33) with internal alkynes offers a good synthetic method of substituted indoles [13]. A practical synthesis of psilocin was carried out by utilizing the reaction of the iodoaniline derivative 34 with internal alkyne to form an indole derivative as a key reaction [14]. The thieno[3.2-b]pyrrole 37 was obtained by the reaction of 2-iodo-3-aminothiophene (35) with the alkyne 36 [15]. These reactions of aryl iodides proceed in the absence of phosphine ligands. The isocoumarin 39 was obtained by the reaction of methyl o-iodobenzoate (38). Poor yield was obtained when the free acid was used [11]. OMe I + R

R

NH2

R

Pd(OAc)2, n-Bu4NCl, DMF

+

K2CO3, 100 °C, 50~98%

NH 34

OMe

BOC

OH

Pd(OAc)2 PPh3

NMe2

NMe2

Steps

Et4NCl i-Pr2EtN DMF, 69%

TMS

R

N H

33 NMe2

I

TMS

N

N H

BOC

psilocin Boc NHBoc + t-BuMe2Si I

S

CH2OH 36

Pd(OAc)2, Bu4NCl, DMF AcOK, 100 ˚C, 67%

35

N SiMe2-t-Bu S CH2OH 37 Et

HO

I + CO2Me 38

Et

Pd(0) 63%

OH O O 39

MeCN is a good and inert solvent used in various Pd-catalyzed reactions. However, nitriles participate in Pd-catalyzed intramolecular reactions. The indenone 43 was obtained by the reaction of o-iodobenzonitrile (40) with alkynes. The reaction can be understood by insertion of a nitrile bond to alkenylpalladium intermediate 41 or 5-exo cyclization to give the iminopalladium 42, hydrolysis of which affords the indenone 43 and Pd(II), which is reduced to Pd(0) [4]. Similarly, the six-membered ketone 45 was obtained from 2-(o-iodophenyl)-2methylpropanenitrile (44). However, the reaction of o-iodophenylacetonitrile (46) afforded the β-naphthylamine 49, not a ketone. Presumably, 6-exo cyclization of 47 yields the iminopalladium 48. Tautomerization (aromatization) of 48 occurs

Reactions with Alkynes

239

to form the amino group 49 in the final step, rather than hydrolysis to give the ketone [16,17]. Ph I

Ph Pd-X

Pd(dba)2, Et3N

+ Ph

Ph

insertion

DMF -H2O 130 ˚C, 96%

CN

C

40

N

41 Ph

Ph H2O

Ph

Ph N-PdI

42

43

+

Pd(0)

Pd(II)

O

Ph I + Ph

Ph

CN

Ph

Pd(dba)2, Et3N DMF - H2O, 96%

O

Me

Me

Me

Me

44

45 Ph I +

Ph

Ph

CN

Ph

Pd(OAc)2, n-Bu4NCl

Pd-X

Et3N, DMF, 83%

C

N

insertion

47

46 Ph

Ph Ph

Ph

H2O

+

N-PdX H 48

Pd(II)

Pd(0)

NH2 49

Reaction of the imine 50, derived from o-iodoaniline and benzaldehyde, with diphenylacetylene afforded a mixture of the quinoline 53 and the isoindolo[2.1a]indole 56. Formation of the quinoline can be understood by insertion of the C=N bond in 51, which is regarded as 6-endo cyclization of the intermediate 51 to generate 52, followed by β-H elimination to yield the quinoline 53. On the other hand, the isoindolo[2.1-a]indole 56 is formed by 5-exo cyclization of 51 to produce 54. The final step is the electrophilic palladation of the σ -palladium intermediate 54 to the adjacent aromatic ring to give 55, and reductive elimination gives rise to 56 [18]. The isoindolo[2.1-a]indole 59 was obtained in high yield from alkylarylacetylene 58 and the imine 50 [19].

240 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Ph

N

Ph

N

+ Ph

Pd(OAc)2, n-Bu4NCl

Ph

PdX

AcONa, DMF

I Ph

50

51

Ph

PdX N

Ph

6-endo

N

Ph

Ph

Ph

Ph 52

Ph 53

Ph

PdX

42%

Ph Pd

N

5-exo

reductive elimination

N

HX

54

55

Ph N

Ph 56

23%

Ph Ph

N

I

N

Pd(OAc)2, n-Bu4NCl

+ Ph

Et

AcONa, DMF, 81%

58

Et 59

50

The isoquinoline 61 was obtained by the reaction of t-butylimine 60 of oiodobenzaldehyde with internal alkyne [20]. The reaction was extended to synthesis of the γ -carboline 65 from the t-butylimine of N -methyl-2-iodoindole-3carboxaldehyde 62 [21]. The reaction is explained by 6-endo cyclization of the alkenylpalladium intermediate 63, followed by elimination of β-t-butyl group as isobutylene as shown by 64. This mechanism explains the importance of tbutylimine in this cyclization. t-Bu N

+

Ph

Ph

Pd(OAc)2, PPh3

N

Na2CO3, DMF, 96%

I 60

Ph 61

Ph

Reactions with Alkynes t-Bu

N

+ Pr

Pr

I

N

241 N

Pd(OAc)2, PPh3

PdI

Na2CO3, DMF, 78%

N Pr

Me

Me 62

Pr 63

H I-Pd

N N

6-endo cyclization

Pr

β-elimination N

Pr N

Pr

Me Pr

Me

t-Bu

+ Pd + HI

64

65

The indenone 70 is obtained by the reaction of o-iodobenzaldehyde (66) with alkyne [22,23]. Two mechanisms are suggested. One of them involves the formation of Pd(IV) species 68 from 67 by oxidative addition of aldehyde, and its reductive elimination affords the indenone 70. Another possibility is the insertion of carbonyl group (or nucleophilic attack) to form the indenyloxypalladium 69, and β-H elimination gives the indenone 70. Ph I

Pd(OAc)2, Na2CO3

+ Ph

t-Bu

CHO 66

t-Bu Pd-X H

Bu4NCl, DMF 100 °C, 81%

C

O 67

Ph

t-Bu Pd X

Ph

H 68

O

t-Bu

+ Pd(0) + HX

Ph

t-Bu H

O

70

O

Pd X

69

On the other hand, Yamamoto and co-workers observed that the Pd-catalyzed reaction of o-bromobenzaldehyde (71) with 4-octyne in DMF using Pd(OAc)2 gave rise to the indenol 74 in 71 % yield. Also it was confirmed that the indenol 74, once formed, was isomerized to the indanone 75 quantitatively in the presence of Pd(OAc)2 and AcOK [24]. Furthermore, reaction of o-bromoacetophenone (76) with 4-octyne afforded the substituted indenol 77 in 82 % yield, which has no

242 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides possibility of isomerization. Yamamoto proposed that the indenols 74 and 77 are formed by intramolecular nucleophilic attack of the vinylpalladium species 72 to the carbonyl group to form the Pd alkoxide 73; namely, a hitherto unknown catalytic Grignard-type reaction occurred. However, the formation of 73 may be explained by insertion of a carbonyl group, followed by protonolysis to afford 74 and Pd(II) [25]. Pr Br

Pr

Pd(OAc)2, KOAc

+ Pr

Pr

Pd-X H

EtOH, DMF 60 °C, 71%

CHO

C

71

O

72 Pr

Pr H

Pr H

+ Pr H

Pd X

O

73

+

Pd(II)

OH

74 Pr

Pr Pd(OAc)2, KOAc , DMF

Pr H

Pr

DMF,100 °C, 24 h, 100%

OH

O 75

74 O

OH Pd(OAc)2, KOAc

+ Pr

Pr

Pr

DMF,100 °C, 82 %

Br

Pr 77

76

Furthermore, as a related reaction, they obtained the cyclopentanol 79 by the Grignard-type reaction of 1-methyl-2-(o-bromophenyl)ethyl phenyl ketone (78) without alkynes in the presence of Pd(OAc)2 , PCy3 , Na2 CO3 and 1-hexanol. It was confirmed that the addition of 1-hexanol was crucial [26]. These reactions are mechanistically interesting. A similar catalytic reaction has been reported by Vicente. These reactions are considered again in Chapter 3.7.2 [27]. O Pd(OAc)2, PCy3, Na2CO3

Ph

O

C6H13-OH, 135 °C, 12 h, 69%

Pd

Br

Ph

Br

78 C6H13-OH Ph

O

PdBr

Ph 79

OH

Reactions with Alkynes

243

The substituted naphthalene 82 was produced from the o-(3-cyano-2-propenyl)iodobenzene (80) by carbopalladation of 4-octyne, followed by Heck reaction of 81 [28]. CN

+

n-Pr

n-Pr

Pd(OAc)2, PPh3, NEt3 DMF, 74%

I 80 CN CN Pd-I

n-Pr

n-Pr n-Pr

n-Pr 81

82

The cis-heteroannulation of alkyne extended to alkenyl halides 83 containing a proximate nucleophilic center to yield the heterocycles 86 by the reactions via 84 and 85 similar to those summarized in Scheme 3.9 (Scheme 3.10).

R1

X R2

Pd(0), R1 YH

R1

R2

R2

Pd-X

R2 = H or alkyl

Pd

YH

Y HX

83

84

85

R1

Y

Pd

R2

86

Scheme 3.10

The pyran 88 and α-pyrone 90 are prepared from the vinyl bromide 87 and the vinyl triflate 89 by intramolecular trapping of the alkenylpalladium intermediates with alcohol and ester [29,30]. The pyridine 92 was prepared by the iminoannulation of the iminoalkenyl iodide 91 [31]. The 2-iodo-3-tosylaminocyclohexene 93 underwent cis-carboamination of ethyl phenylpropiolate to give 94 [32].

OH Br 87

+ Ph

CO2Me

Pd(OAc)2, LiCl Na2CO3, DMF, 61%

O Ph CO2Me 88

244 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O CO2Me + Me

Si(i-Pr)3

O

Pd(OAc)2, LiCl Na2CO3, DMF, 64%

Si(i-Pr)3

OTf Me 90

89

Me

t-Bu

Me N Ph

N

Pd(OAc)2, PPh3, Na2CO3

+ Ph

CH2OH

I

DMF, 100 °C, 95%

Ph

Ph

CH2OH 92

91

CO2Et I + Ph

CO2Et

Pd(OAc)2, LiCl, Na2CO3 Ph

DMF, 100 °C, 64%

N

NHTs 94

93

Ts

3.4.3.5 Cyclization Type 2 Another heteroannulation is combination of aryl and alkenyl halides with orthofunctionalized phenylalkynes 95 to give heterocycles 97 such as benzofurans and indoles (Scheme 3.11). In this reaction, trans addition of Ar-Pd to a triple bond and endo cyclization, as shown by 96, occur. Ar-X Pd(0)

Ar-Pd-X

Pd-Ar

Ar-Pd-X R

R

endo-dig Y

YH

R = H or alkyl 2

95

YH 96

Ar

Y 97

+ Pd + HX

Scheme 3.11

The alkynes containing proximate nucleophiles (YH) undergo trans addition of the nucleophile and organopalladium species, as shown by 98 and 101, to generate 99 and 102, and reductive elimination produces the cyclized trans addition products 100 and 103. In this cyclization, either exo-dig or endo-dig cyclizations take place depending on the number of carbon atoms between the triple bond and the nucleophilic center to give 100 and 103 (Scheme 3.12).

Reactions with Alkynes Ar-X

Pd(0)

ArPd-X

Ar-Pd

exo-dig

Ar

99

A

YH = OH, NHR, HC

HY 98

A

R

Y

R

Ar-X

reductive elimination

A

R

Pd(0)

245

Y 100

E E

ArPd-X

Pd-Ar R

endo-dig R HY

R

A

Y

A

Ar reductive elimination

A

Y

102

103

101

Scheme 3.12

The indole synthesis was extended to an elegant synthesis of indolo[2.3-a]carbazole 106 by bis-annulation of the diacetylene 104 with the dibromomaleimide 105 [33]. Bn + NH

HN

COCF3

N

O

Pd(PPh3)4, K2CO3

O

MeCN, 50 °C, 52% Br

COCF3

Br 105

104 Bn O

N

Bn

O

N

O BrPd

Pd-Br

O

endo-dig Pd-Br N H

NH COCF3

H2N

HN Bn

COCF3

N

O

N H

O

N H 106

The isoquinoline 108 is prepared from the imine 107 as a variation of the iminoannulation [34]. When the iminoannulation of 107 is carried out under CO

246 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides atmosphere (1 atm), CO reacts with p-iodoanisole to generate the acylpalladium 110, which undergoes acylpalladation of the triple bond of 107 to afford the 4aroylisoquinoline 109 via 111 [35]. N

t-Bu

CO2Et

N

Pd(PPh3)4

+

Ph

K2CO3, DMF 100 °C, 67%

I Ph 107

108

CO2Et N

t-Bu

OMe

N + 107

Ph

Pd(PPh3)4

+ CO

Bu3N, DMF 1 atm, 100 °C, 74%

I Ph

O

MeO

+ CO

109

OMe

OMe Pd0) I-Pd

t-Bu N

I 110

O

Pd-I Ph

t-Bu

O

N MeO 107

Ph

111

Reaction of o-2-propynylphenol (112) with 2-iodothiophene (113) gave the 2alkylidenedihydrobenzofuran 114 and the benzofuran 115 [36]. The reaction of a nitrogen analog 116 afforded the pyrrolidine derivative 117 [37]. The propargyl tosylcarbamate 118 underwent trans carboamination with cyclohexenyl triflate to give the oxazolidinone 119 in the presence of TFP as a ligand and benzyltriethylammonium chloride [38,39]. The 1-(1-alkynyl)cyclobutanol 120 was expanded by Pd-catalyzed reaction with aryl- and alkenyl halides to produce the 2-(2-arylidene)cyclopentanones 123. The reaction can be understood formally by carbopalladation to give 121, and migration of an electron-rich carbon to Pd to form the palladacyclohexanone 122, and the cyclopentanone 123 is obtained by reductive elimination of 122 (see Chapter 3.8.2) [40]. A useful precursor 126 was prepared by coupling the triflate 124, derived from a γ -lactam, with the alkynyl amine 125. The cis addition product 128 was formed in this case via intramolecular amination as shown by 127 [41].

Reactions with Alkynes OH

247

1. BuLi +

2. Pd(OAc) 2, PPh3 THF, rt, 75%

I

S 113

112

+ O 114

S

O

3

:

S 115

1

Ph + PhI

1. BuLi 2. Pd(OAc) 2, PPh3, 85%

N

NHTs

Ts 117

116 OTf TsHN

O

Pd(OAc)2, TFP, BnEt3NCl

+

t-BuOK, MeCN, 60%

O 118

O

TsN O 119

OH Me + Ph-I

Pd(OAc)2, PPh3, n-Bu4NCl

H

i-Pr2NEt, DMF, 80 °C, 60%

Pd I

O Me

120

Ph 121

O

Me

Pd O

Ph Me

Ph 122

123

Me NC

Pd(PPh3)4, NEt3, THF

+ N

OTf

70%

H2N

N

HN

NC 125

124

126

H2N

NC

NC N

Pd-X

Pd-X N Me 127

NC

Pd

NH 126

N Me 128

248 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Reaction of the enyne 129 with p-bromoanisole gave the furan 130 smoothly in 53 % yield via Sonogashira coupling and carbopalladation of the triple bond, followed by intramolecular insertion of the double bond (Heck-type reaction) [42]. Br Bu4NHSO4, Et3N

+

O

Ph

Pd(OAc)2, PPh3

Ph

129

O

MeCN / H2O (10 : 1) 53%

OMe

OMe OMe Ph

MeO

Br Br-Pd-Ar

O

Pd(0)

Heck cyclization

Pd-X

OMe

Ph

Ar Ar

O

130

The stereo-defined benzylidenecyclopentane 132 was obtained by trans addition of a phenyl group and a carbanion to the terminal alkyne 131. The cyclization proceeds via trans carbopalladation [43]. As a related reaction, stereo-defined 3arylidenetetrahydrofuran 134 was prepared by the reaction of iodobenzene, propargyl alcohol, and Michael acceptor 133. The reaction is understood in terms of Michael addition of propargyl alcohol to 133, followed by carbopalladation of the triple bond as shown by 135 [44]. CO2Me

Pd2(dba)3, DPPE

+ Ph-I

t-BuOK, DMSO, 88%

CO2Me

131 I

Ph

Pd

Ph

Pd

Ph _

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me 132

EtO2C I

CO2Et

OH

1. n-BuLi 2. PdCl 2(PPh3)2 DMSO, rt, 89%

+

+

CO2Et

133 Ph

Pd

E

Pd E

O 135

Ph

O 134

Ph E

X

CO2Et

E O

Ph

Reactions with Alkynes

249

3.4.3.6 Cyclization Type 3 In type 3 cyclization, the aryl halides 136 having an alkyne side chain at ortho position undergo cis carbopalladation of 137 to generate 138, which is trapped by a nucleophile YH to give the cyclized product 139. In this cyclization, cis addition to triple bonds occurs (Scheme 3.13). R

Y-Pd

R

R X

Pd-X

Pd(0) oxidative addition

A 136

insertion or cis-carbopalladation A

A 137

Y-Pd

138

Y

R

R

reductive elimination

YH anion capture

A = (CH2)n, O, NR, S

A

A 139

Scheme 3.13

Reaction of 140 with vinyltin reagent yields the cyclized product 141. The conversion can be understood by cis carbopalladation, transmetallation with the Sn reagent, and reductive elimination [45,46]. This reaction is overall cis addition to the triple bond. The intramolecular version of furan synthesis was applied to the preparation of the key intermediate of halenaquinone and halenaquinol syntheses from 142 [47]. Me CH2=CH−Pd

I-Pd I

Me TM

Pd(OAc)2 PPh3, 60%

Me RE

Bu3SnCH=CH2

N

N

Ac

Ac

N Ac

140

O OMe I Si(i-Pr)3 N

Pd2(dba)3, K2CO3 DMf, rt, 72%

OH

Ac

OMe

141

O 142

O

O

OMe

OH Si(i-Pr)3 O

OMe

O

O OH

O halenaquinol

250 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The homopropargylic ether 143 undergoes 7-exo-dig cyclization in the presence of formic acid to generate the Pd formate 144, which is converted to the Pd hydride. Reductive elimination gives the cis hydroarylation product 145 [48]. Cyclobutane was formed by a rare unfavored 4-exo-dig cyclization of the γ -bromopropargylic diol 146 and trapped with an alkynyltin reagent to yield the cyclobutanediol 147 in 69 % yield. When a vinyltin reagent was used for the trapping, the unusual strained tricyclic system 148 was obtained in 35 % yield by 6π -electrocyclization of an intermediate [49]. Me

Me

HCO2-Pd I + HCO2H O

H-Pd

Me

7-exo-trig Pd(OAc)2, PPh3 Et4NCl, piperidine MeCN, 62%

143 Me

H-Pd

O

O

CO2

144

O 145 TMS HO

HO HO Br

+ Bu3Sn

Ph

Pd2(dba)3, K2CO3

TMS

HO

benzene 85 °C, 69%

Ph

146

147 TMS HO

HO

TMS

OH HO

HO

HO Br

+ Bu Sn 3

TMS

35%

H 148

The 3-substituted pentynoic acid 149 underwent 6-endo-dig cyclization to give rise to the γ -arylidenebutyrolactone 150 using TFP as a ligand [50]. On the other

I

O OH 149

6-endo-dig Pd(OAc)2, TFP

t-BuOK, DMSO O rt, 78%

O IPd OH

O 150

Reactions with Alkynes

251

hand, o-alkynylbenzoic acid 151 underwent 5-exo-dig cyclization to yield the γ arylidenebutyrolactone 152 using Cs2 CO3 as a base in DMSO. The product of 6-endo-dig cyclization 153 was obtained as a byproduct depending on reaction conditions [51]. O

CO2H I

O

O Pd(OAc)2, PPh3

O

Cs2CO3, DMSO, 64%

151

152

153

The reaction of the alkyne 154 in the presence of norbornene as a relay generates 155 by insertion of norbornene. The cyclopropane 156 is formed by 3-exo-trig cyclization, and the lactam 157 was obtained by β-H elimination [52].

H PdI I

H NMe

Pd(OAc)2, PPh3

+

3-exo-trig

K2CO3, Et4NCl 40%

NMe

O 154

155

O

H H PdI

b-H elimination H

NMe O

156

O

N Me 157

Allene can be used as a relay switch to generate a π -allylpalladium, which can be trapped by a nucleophile. The reaction of 158 with allene and an amine afforded 161. The 7-exo-dig cyclization of 158 gives 159, which is converted to the π -allylpalladium 160 by insertion of allene. The reaction is terminated by amination of 160 to yield 161 [53]. Curran reported an interesting synthetic method of skeletons of camptotecin analog [53a]. Reaction of 6-iodo-N -propargylpyridone 161a with an electron-rich aryl

252 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides X-Pd I

+

+ NHR2

Pd(OAc)2, PPh3

7-exo-dig

68%

O

O

158

159

X-Pd

N

X-Pd

H N

NHR2

NHR2

O

O

O

160

161

isonitrile in the presence of Pd(OAc)2 and Ag2 CO3 provided 11H -indolizino[1.2b]quinoline-9-one 161b in 83 % yield. The reaction is understood by insertion of the isonitrile to arylpalladium to generate 161c as the first step. It is known that isonitrile behaves similar to CO and undergoes insertion. Subsequent insertion of the triple bond and attack on the aromatic ring give rise to 161b. TBS

O MeO N TBS

Pd(OAc)2, Ag2CO3

+ NC

I

MeO

O N

25 °C, 1 d, 83%

N

161a

161b

TBS TBS

I-Pd MeO

MeO

O

Pd-I N

N N

O

N

161c

3.4.3.7 Cyclization Involving Attack on Aromatic Rings Termination by attack on an aromatic ring is discussed in Chapter 3.3.4. Similar termination occurs frequently in the reaction of alkynes with halides. The reaction of 2-iodobiphenyl (162) with alkynes offers a good synthetic method of 9,10-disubstituted phenanthrenes 164. The intermediate 163 undergoes attack on an aromatic ring as one possibility [54]. The reaction of functionalized diarylacetylene 165 with 162 was applied to the syntheses of an analog of antiviral agent hypericin 167 via 166 [55]. Also the indolocarbazole 169 was prepared from 3-iodobiindole 168 by attack on the indole ring [56].

Reactions with Alkynes

253 Ph

I Ph

Pd(OAc)2, n-Bu4NCl

+

Ph

162

Ph

Pd-X

AcONa, DMF, 89%

Ph

Ph

163

164

I

MeO

E

E

OMe Pd(0)

+ E = CO2Me

MeO 162

OMe

165 OMe

O

OMe

E

OMe

steps

OMe OMe

OMe

E O

OMe

OMe

166 167

I + N Me 168

Pd(PPh3)4

n-Bu

CO2Me

N Me

Ti2CO3, toluene 56% CO2Me

n-Bu

N Me

N Me 169

Regioselective carbopalladation of 1-alkynes substituted by bulky groups such as TMS with 9-bromoanthracene (170) generates 171, which attacks the aromatic ring to afford the 2-substituted aceanthrylene 172. The reaction offers a good synthetic method for this cyclic system [57].

254 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Br PdCl2(PPh3)2, PPh3, Al2O3

+ TMS

H

Et3N, PhH, ca. 70% sealed tube 110 °C

170 TMS

TMS

H Pd-Br

171

172

Reactions of diarylacetylenes with aryl iodides give different cyclic products under different conditions. 1,2,3,4-Tetraphenylnaphthalene 174 was obtained by the reaction of two molecules of diphenylacetylene with iodobenzene in nitromethane. In this reaction, the intermediate 173 attacks the benzene ring [22]. In the absence of PPh3 in DMF, 9,10-diphenylphenanthrene (175) was formed. I

Ph + 2 Ph

Ph

Ph Ph

Pd(OAc)2, PPh3 Et3N, MeNO2 3 days, 47%

i-Pd

Ph

173 I

Ph Ph 2 Ph

+ Ph

Ph

Pd(OAc)2, K2CO3 Bu4NBr, DMF 3 days, 77%

Ph 174

175

However, reaction of dianisylacetylene under similar conditions afforded a mixture of the regioisomers 176a and 176b. The result shows that cis–trans isomerization of the alkenylpalladium intermediate becomes possible due to the contribution of 177 which can rotate [58]. Furthermore, the reaction of diphenylacetylene with iodobenzene under Jeffery conditions gave rise to 9-alkylidene-9H-fluorene 178. The reaction is explained by a novel migration of the alkenylpalladium intermediate 179 to the arylpalladium species 180. Finally 178 is formed via the palladacycle 181 and reductive elimination [59].

Reactions with Alkynes

255

I Pd(OAc)2, K2CO3

OMe + 2

MeO

Bu4NBr, DMF 3 days, 89%

MeO

MeO

H

OMe

+

H 176a Ar1 X

OMe 176b

3:2

Ar1

Ar1

Pd

X

Ar2 Ar1

Ar2

Pd

Ar1

Ar1

X-Pd

Ar2 177

I +

Ph

Pd(OAc)2, PPh3

Ph

NaOAc, Bu 4NCl DMF, 100 °C, 62% 178

Pd

H Pd-I

Pd-I 179

180

181

Catellani reported that reaction of diphenylacetylene with the ortho-substituted phenyl iodide 182 in the presence of norbornene in a less than equivalent amount afforded the 1,5-disubstituted 9,10-diphenylphenanthrene 183 selectively [60]. The i-Pr

I

i-Pr Ph

Ph +

2 Pd(OAc)2, K2CO3 182

Bu4NBr, DMF 24 h, 93%

i-Pr Ph

Ph 183

256 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides role of norbornene as a ‘catalyst’ in this interesting conversion can be explained similarly as observed by Catellani in the reaction of alkenes with iodobenzene (see Chapter 3.8.1). 3.4.3.8 Formation of Tricycles from Halo Dienynes Domino cyclizations of various types of polyenynes offer powerful synthetic tools for efficient syntheses of polycyclic compounds. Among many possibilities, several representative patterns are cited here. A fully intramolecular version of a three-step domino reaction of 2-bromododeca-1,11-dien–6-yne 184 and 2-bromotrideca-1,12dien-7-yne 189 offers a useful synthetic method of the tricycles 188 and 191 with a central cyclohexa-1,3-diene moiety. In these compounds 184 and 189, an alkenyl bromide starter, an alkynyl relay, and an alkenyl terminator are all tethered as summarized by 184 in Scheme 3.14. The final step is facile 6-π -electrocyclization of 187 and 190 to give rise to 188 and 191 [61]. terminator starter Pd(0) X

OA

5-exo-dig

185

relay

184

Pd-X

5-exo-dig

Pd-X

Pd-X β-H elimination

6-p-electrocyclization up to 95%

186

187

X

188

60~82%

189

190

191

30~45%

X

192

X

193

194

9%

195

196

Scheme 3.14 Cyclization of 2-halo dienynes.

Reactions with Alkynes

257

The reaction of the dienyne 184 proceeds by oxidative addition of the alkenyl bromide, followed by 5-exo-dig cyclization to generate 185. Then 5-exo-trig cyclization of 185 gives the favored five-membered ring 186, and then generates the hexatriene system 187, which undergoes thermal 6-π -electrocyclization to give the 1,3-cyclohexadiene 188 [62]. Good yields are obtained when only fivemembered rings are formed by Pd-catalyzed cyclizations involving alkynes and alkenes. Formation of six-membered or larger rings 194 and 196 is less favorable. For example, reaction of the dienyne 197 proceeds at 80 ◦ C by oxidative addition of the alkenyl bromide, followed by 5-exo-dig cyclization to generate 198. Then 5-exo-trig cyclization of 198 gives the favored five-membered ring 199, and then generates the hexatriene system 200, which undergoes thermal 6π -electrocyclization at this temperature to give the 1,3-cyclohexadiene moiety 201 [62]. Lower yields are obtained when one of the Pd-catalyzed cyclizations leads to a six-membered ring. For example, the cyclization of 202 gave the hexatriene 203, and its 6-π -electrocyclization produced 204 in 37 % yield. Similarly, the tricycle 196 was obtained from the dienyne 195 in 9 % yield.

5-exo-dig Pd(OAc)2, PPh3, Ag2CO3 Br

PdX

exo-trig

MeCN, 88%

E

MeO

E

OMe

E

E

198

197 X-Pd b-H elimination E

MeO

E E

6p- electrocyclization MeO E

199

200

Pd(OAc)2, PPh3, Ag2CO3 MeO

Br

MeCN, 37%

OMe

E

E E

E 201

202 6p-electrocyclization

E

MeO

OMe

E E

E 203

204

In the cyclization of 2-bromotetradeca-1,13-diene-7-yne (205), which is expected to lead eventually to the three six-membered rings 211, an interesting

258 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides transformation was observed to give the tetracyclic system 209 containing a bridging cyclopropane ring. The intermediate 206 undergoes 5-exo-trig to give 207 and its 3-exo-trig cyclization yields the cyclopropane 208. Thus the tetracyclic system 209 was formed in 74 % yield. In this cyclization, 5-exo-trig cyclization of 206 to give 207 is faster than β-H elimination to generate the hexatriene system 210, and the expected tricyclic system 211 is not formed [63].

E

E E

E 210

β-H elimination

211

PdX 6-exo-dig Pd(OAc)2, PPh3, Br

PdX

E

E

E

E

E 205

5-exo-trig

6-exo-trig

Ag2CO3, MeCN, 74%

X-Pd

E 206

β-H elimination

3-exo-trig PdX

E

E E

E E

207

E 208

209

The cyclization discussed above offers attractive synthetic methods of steroid skeletons. Efficiency and selectivity of the cyclization of bromodienynes heavily depend on substituents. As an example, the attempted cyclization of the bromodienyne 210 with all functionalities essential for the synthesis of desired steroid skeletons is explained here. Formation of the intermediates 211 and 212 is straightforward. The expected β-H elimination of 212 and subsequent 6-π electrocyclization to afford the cyclohexadiene system 213 are minor paths. Rather unusual 6-endo-trig cyclization of 212 is faster than the β-H elimination. The generated intermediate 214 is converted to a mixture of the steroid skeletons 215, 216, and 217 which have double bonds in different places. On the other hand, the slightly different bromo keto dienyne 218 was converted to the unexpected pentacyclic non-steroidal system 222. In this case, 5-exo-trig cyclization of 219 gives 220 and its 3-exo-trig cyclization produces the cyclopropane 221 [63].

Reactions with Alkynes

OR

O

O O 6-exo-dig

Br

259

O

O

RO

O

RO

6-exo-trig

RO PdX

OR = OSiMe2-t-Bu

RO

RO

210

PdX

211

212 b-H elimination 6p-electrocyclization

6-endo-trig

O

RO

b-H elimination

O

RO

RO 216

hydrogenolysis

O

O

213

RO

O

minor product 9%

b-H elimination

O

RO

O

O

RO

RO

PdX 214

major product 22%

RO

O

RO

O

RO 217

215

O O O

Br

E

O

6-exo-dig, 6-exo-trig

O

Pd(OAc)2, PPh3, Ag2CO3

i-Pr2NH, MeCN, 120 °C, 40%

E

O E

H PdX

E

218

219 O

O O

5-exo-trig

O E

H

O

XPd 3-exo-trig E

O

E

H

E PdX 220

221 O O E E

O H 222

260 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The enyne system 223 with an o-iodophenyl starter and a vinylsilyl group terminator underwent 5-exo-dig and 5-exo-trig cyclizations to yield 225. No further cyclization of 225 took place. Instead the β-H elimination gave the vinylsilane 226 as the final product when PPh3 was used. No 6π -electrocyclization of 226 occurred. Also the reaction was terminated by elimination of the β-TMS group to give the olefin 227, when BINAP, which suppresses β-H elimination, was used [64].

5-exo-dig Pd(OAc)2, AgOAc

I TMS

DMF

5-exo-trig

X-Pd TMS

223

224 PPh3, 74%

X-Pd TMS

TMS

226 H BINAP, 81%

225

227

3.4.3.9 Formation of Tricycles from Halo Enediynes The bisannulated benzene derivative 232 is expected to be formed by the cyclization of the haloenediyne system 228 (Scheme 3.15). The formation of 232 is

6-exo-dig

Pd(0) X

Pd-X

Pd-X

228

Pd-X

Pd-X

6-exo-dig

6-p-electrocyclization

230 b-H elimination

229 6-endo-trig

b-H elimination

X-Pd

231

232

Scheme 3.15 Cyclization of 2-halo-trideca-1-en-6, 12-diyne.

Reactions with Alkynes

261

explained either by 6π -electrocyclization of 229 to form the cyclohexadiene 230, and subsequent β-H elimination, or 6-endo-trig cyclization of 229 to give the cyclohexadiene 231, followed by β-H elimination [65]. For example, the octahydrophenanthrene skeleton 237 was obtained from the 2-bromotetradeca-1-ene-7,13-diyne 233 when the triple bond was terminally substituted by a trialkylsilyl group. Formation of the benzene rings 237 at the last step can be understood either in terms of 6π -electrocyclization of the intermediate 234 to yield 235, followed by β-H elimination, or 6-endo-trig cyclization of 234 to produce 236 and β-H elimination. TBDMS

TBDMS

BrPd Pd(OAc)2, PPh3 K2CO3, MeCN, 79% exo-dig cyclization

Br E

E E 234

E 233

TBDMS

BrPd

6-p-electrocyclization b-H elimination

E E

TBDMS

235 TBDMS E

6-endo-trig

BrPd

b-H elimination

E

237

E E

236

On the other hand, the terminally unsubstituted bromoenediyne 238 undergoes 5-exo-trig cyclization, instead of 6-endo-trig, of 239 to generate the neopentylpalladium 240, and subsequent 3-exo-trig carbopalladation gives the cyclopropane 241, which is stabilized by the formation of π -allylpalladium 242. Then β-carbon elimination of 241 afforded the homoallylpalladium 243, and β-H elimination yields the fulvene 244 [66]. The 1,6-diyne system 245 with an iodophenyl starter was converted to the tetracycle 248. Carbopalladation of 245 generates 246 and subsequent 5-exo-dig cyclization affords 247. The last step is attack on the aromatic ring to give the tetracycle 248 [67]. 3.4.3.10 Formation of Polycycles The steroid skeleton 253 was constructed very efficiently by domino cyclization of the trienediyne 249. The vinyl iodide is a starter and two 6-exo-dig cyclizations

262 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Pd-Br

BrPd 6-exo-dig Pd(OAc)2, PPh3 Br

5-exo-trig

K2CO3, MeCN, 74% E

E

E E

E

E 239

240

238 BrPd rearrangement

3-exo-trig PdBr

E E

PdBr

E E

241

b-carbon elimination

E E

242

243

b-H elimination E 244

E

Et2N

SO2Ph Et2N

SO2Ph

N

N 6-exo-dig Pd(OAc)2, PPh3

I-Pd 5-exo-dig

Ag2CO3, MeCN, HCO2H, 60%

I

E

E E

245

E

246

SO2Ph

Et2N

SO2Ph

N

N Et2N

I-Pd

E

E

E 247

E 248

afford 250, and subsequent 6-exo-trig cyclization generates the neopentylpalladium 251, and its 5-exo-trig cyclization yields 252. The reaction is terminated by β-H elimination to give 253 [68]. In the Pd-catalyzed reaction of the enetetrayne alcohol 254 under CO atmosphere, 6-exo-dig cyclization occurs four times to generate 255, which then undergoes carbonylation to give the lactone 256 in 66 % yield [69]. The cyclization of the enetriyne 257 was carried out in the presence of allene and piperidine. Two 6-exo-dig cyclizations of 257 afford 258, and then 6-exo-dig cyclization gives the vinylpalladium 259. Insertion of allene to 259 occurs after these steps to generate the π -allylpalladium intermediate 260, and the reaction is terminated by amination of 260 to produce 261 [70].

Reactions with Alkynes Pd(PPh3)4, NEt3 E

6-exo-dig 6-exo-dig

Pdx E

MeCN, 76% I

E

263

E

249

250 PdX

6-exo-trig

E

5-exo-trig E

E

E

PdX

251 β-H elimination

252

E E 253 OH

n-Bu + CO E I

E

PdCl2(PPh3)2, NEt3

6-exo-dig (four times)

MeOH, 70 °C, 1 d, 66%

254 OH

O

O

Pd-I CO

n-Bu

n-Bu

E

E

E

E 255

E I

E

256

+

•

Pd(OAc)2, PPh3

HN

+

6-exo-dig 6-exo-dig

K2CO3, DMF, 40%

257 Pd-X Pd-X

E

6-exo-dig

E

E

•

E

insertion

258

259 HN Pd-X

E

E N

E

E 260

261

264 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

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3.5 Carbonylation and Reactions of Acyl Chlorides 3.5.1 Introduction Aryl and alkenyl halides and triflates undergo Pd-catalyzed carbonylation, offering useful synthetic methods for carboxylic acids, esters, amides, aldehydes and ketones. Facile CO insertion into aryl- or alkenylpalladium complexes generates acylpalladium intermediates 1. The intermediates are attacked by several

266 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides nucleophiles, affording different products. The nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aldehydes are produced by the reaction of hydrides. Transmetallation with main group organometallic compounds, followed by reductive elimination yields ketones. In general, iodides and triflates are most reactive substrates for the carbonylation. Bromides are moderately reactive. Although a number of smooth Pd-catalyzed reactions of aryl chlorides such as Heck and Suzuki couplings are known, aryl chlorides are regarded to be relatively inert for carbonylation except for a few chlorides which are highly activated with strong EWGs. Perhaps CO is a strong ligand and decreases the effectiveness of bulky and electron-rich ligands which are used satisfactorily for other reactions of chlorides. O H 2O R

OH O

ROH R O R-X + Pd(0)

R-Pd-X

R

X = I, Br, Cl, OTf, N 2X

O

NH2R

CO

OR

R

Pd-X

NHR

1

O

H−

R = aryl, alkenyl

R

H O

MR′ R

R′

3.5.2 Formation of Carboxylic Acids, Esters, and Amides Aromatic and α,β-unsaturated carboxylic acids and esters are prepared from aryl and alkenyl halides. O X + CO + NU-H

R

+ CO + NU-H X

Pd(0)

Nu

base

Pd(0)

R

base

Nu O

Carbonylation of reactive iodides proceeds using PdCl2 (PPh3 )2 as a standard catalyst under mild conditions in the presence of a base. Several modified catalyst systems have been reported. For example, ligandless Pd charcoal is an active catalyst at 140 ◦ C [1]. Uozumi reported that the amphiphilic phosphine-Pd complex (Pd-PEP) bound to PEG-PS resin is a very active and useful catalyst. Carbonylation

Carbonylation and Reactions of Acyl Chlorides

267

of iodobenzene proceeded in H2 O without an organic solvent at room temperature and under atmospheric pressure of CO in the presence of Pd-PEP and K2 CO3 to give benzoic acid in 97 % yield. No reaction occurred when Pd-PPh3 , instead of Pd-PEP, was used under similar conditions. The catalyst can be recycled [2]. Pdcomplex immobilized on PAMAM (polyamino amido) dendrimers supported on silica was found to be an active catalyst for efficient carbonylation of iodobenzene in MeOH at 100 ◦ C and 7 atm to produce methyl benzoate and the catalyst was recycled four to five times without loss of activity [2a]. Phenyl benzoate was obtained in high yield from iodobenzene in the presence of phenol in DMF under 1 atm of CO. Addition of CuI accelerated the reaction [3]. Chlorides are difficult to be carbonylated. However, Beller carried out the carbonylation of chlorobenzene using the ferrocenyldicyclohexylphosphine XI-9 in the presence of Na2 CO3 at 140 ◦ C in n-BuOH, and obtained butyl benzoate in high yield [4]. Chloropyridines are active chlorides and butyl picolinate (2) was prepared by carbonylation of 2-chloropyridine at 130 ◦ C. DPPF and DPPB were used as effective ligands [5]. I + CO + H2O

Pd-PEP, K 2CO3

CO2H

rt, 1 atm, 97%

I + CO + PhOH

DMF, 1 atm, 90 °C, 92%

Me

Cl

+ CO + n-BuOH

+ CO + n-BuOH N

CO2Ph

PdCl2(PPh3)2, CuI, n-Bu3N Me

PdCl2(PhCN)2, XI-9

CO2Bu

Na2CO3, MS 4a 1 atm, 145 °C, 97%

PdCl2(PhCN)2, DPPF Et3N, 25 atm, 130 °C, 95 %

Cl

N

CO2Bu

2

Alkenyl halides and triflates are easily carbonylated. Carbonylation of α-iodo enone 3 proceeded at 60 ◦ C using Pd(OAc)2 and DPPP, and the ester 4 was obtained in 62 % yield [6]. The lactam 5 was converted to the vinyl triflate 6, which was carbonylated to afford the α,β-unsaturated ester 7 [7]. Carbonylation of the alkenyl iodide 8, possessing a labile peroxy group proceeded smoothly to give the α,β-unsaturated ester 9 under 1 atm of CO at 60 ◦ C in DMF. The peroxy group remained intact [8]. Me

Me

H

+ CO + MeOH O

I Me O 3

H

H

H Pd(OAc)2, DPPP, 2,6-lutidine THF, 50 atm, 60 °C, 62%

O

MeO2C Me 4

O

268 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides H

H PdCl2(PPh3)2, Et3N,

R3SiO

N H H

O

MeOH, 75%

R3SiO

N

OTf

H

H CO2Me

5

6

TBDPSO N

CO2Me

H

CO2Me

7

O

O

OMe

Pd(OAc)2, PPh3, Et3N,

+ CO + MeOH

O

O

OMe

DMF, 60 °C, 1 atm, 60% CO2Me

I 9

8

Alkenyl iodides can be generated in situ by hydroalumination of alkynes, followed by iodination, and α,β-unsaturated esters are prepared by carbonylation without isolation of the iodide. As an example, the propargylic alcohol 10 was aluminated regio- and stereoselectively and converted to the alkenyl iodide 11. The intramolecular carbonylation of 11 afforded the dibutenolide 12 in 81 % yield. The reaction is a key step in the total synthesis of (+)-parviflorin [9]. OH OH

OTBDPS O

Me

3

TBDPSO

I

1. Red-Al ®

+ CO

2. AcOEt 3. I 2

I

TBDPSO

OH 11

O 3

OTBDPS 10

O

Me TBPPSO OH

O Me

O

3

PdCl2(PPh3)2, NH2NH2, K2CO3 81% O

Me

3

TBDPSO 12

O O

Carbonylation is widely utilized for preparation of complex molecules of natural products. As one example, Leighton constructed the fully elaborated tetracyclic

Carbonylation and Reactions of Acyl Chlorides

269

core of phomoiderides 16 efficiently by novel domino carbonylation–Cope rearrangement of the vinyl triflate 13 as a key step [10]. The acylpalladium species 14, generated by the carbonylation of the alkenyl triflate 13, was trapped intramolecularly by the hemiketal OH group, which was formed from the hydroxy ketone as shown by 14 to afford the unsaturated lactone 15 at 75 ◦ C. The strained molecule of 15 underwent Cope rearrangement as shown by 15 to give 16 in 78 % yield simply by raising the temperature to 110 ◦ C. Interestingly benzonitrile was used as the best solvent. TESO OTBDMS

R OTf

+ CO

O

Pd(PPh3)4, i-Pr2NEt, PhCN, 54 atm 70~115 °C, 78%

OH Me

OH

TESO

13

R

OTBDMS O O

Pd-X

OH OH 14

TESO OTBDMS

R O

Cope rearrangement

O O OH

Me

TESO 15

OTBDMS

R O O O OH

Me

16

OH O Me

OTES O

R

R= O OTBDMS

(E)-MeCH=CH(CH2)5-

270 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides In the total synthesis of ciguatoxins, the enol phosphate 18, derived from the nine-membered lactone 17, was carbonylated smoothly to give the unsaturated ester 19 [11].

O

OBn H

H

(PhO)2(O)PO

O

O O H

OBn H

H

O

O

Ph O

O

O

H

H

H

Ph

18

17 MeO2C Pd(PPh3)4, Et3N,

O

+ CO + MeOH

OBn H

H

O

DMF, 50 °C, 70% O H

Ph O

H

19

Benzylic alcohols are reactive in the presence of an acid as an activator. Asymmetric carbonylation of 1-(6-methoxy-2-naphthyl)ethanol (20) by using DDPPI as a chiral ligand in the presence of CuCl2 and p-TsOH as activators afforded the methyl ester of (S)-naproxen (21) with 81 % ee [12]. Benzyl alcohol was carbonylated to phenylacetic acid under somewhat harsh conditions in the presence of HI. Presumably the carbonylation of benzyl iodide, generated by the reaction of benzyl alcohol with HI, occurred. 1,2-Di(hydroxymethyl)benzene (22) was carbonylated to give 3-isochromanone 25 in 88 % yield. In this reaction, one of the benzylic alcohols is converted to benzylic iodide 23 and the lactone 25 was obtained via acylpalladium 24 [13]. Me OH + CO + MeOH MeO

PdCl2, CuCl2 DDPPI, p-TsOH 8 MPa, 100 °C 54%, 81% ee

20

PPh2

H Me

O H O

CO2Me Ph2P

MeO

H DDPPI

21

OH

+ CO

OH

Pd(PPh3)4, HI acetone-H2O

I

90 atm, 90 °C 88%

22

23 O

O PdI

+ Pd(0) + HI O

OH 24

CO

OH

25

Carbonylation and Reactions of Acyl Chlorides

271

Pd-catalyzed reaction of α-naphthol, isobutyraldehyde, and CO in the presence of CF3 CO2 H afforded naphthofuran-2(3H )-one 28 in 79 % yield. The reaction is explained by acid-catalyzed formation of 1-(2-naphthyl)butanol 27, followed by carbonylation of the benzylic alcohol. Although its reactivity is lower, the phenol derivative 29 reacted with acetaldehyde to generate the benzylic alcohol 30, which was carbonylated to provide the benzofuranone 31 in 54 % yield [14]. OH + CO + i -PrCHO

Pd(PPh3)4, CF3CO2H 120 °C, 5 atm, 79%

26

O OH

O

OH

i -Pr

CO

i -Pr

28

27 OH

+ CH3CHO + CO

Pd(PPh3)4, CF3CO2H 125 °C, 5 atm, 54%

O O

O OH

29

OH

O Me

Me

CO

O

O

O

O

30

31

Although it is not a benzylic type, the mesylate 32 was carbonylated under normal conditions to give the methyl ester 33 as a precursor of camptothecin in high yield [15]. O N + CO + MeOH

N

PdCl2(PPh3)2, Et3N 10 atm, 60 °C 84% from alcohol

OMs

32

O N

O N

steps

N

N

O Et CO2Me

33

camptothecin

HO

O

272 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Carbonylation in the presence of secondary amines provides either amides or αketo amides by single and double carbonylations. Also, the corresponding α-keto esters are prepared. It was reported that ratios of single and double carbonylations depend mainly on the nature of the phosphine ligands. It was claimed that PMePh2 or DPPB is a suitable ligand for double carbonylation [16]. O

O R2NH Ar

NR2

+

NR2

Ar O

Ar-I + 2CO + NuH

O

O ROH Ar

OR

+

OR

Ar O

Later several ligands, including PPh3 , were found to be effective depending on the substrate. Carbonylation of 2,5-dibromo-3-methylpyridine (34) in the presence of aniline produced the 2-picolinamide 35 regio- and chemoselectively when 2,2bipyridine was used as a ligand. Poor yield and selectivity were obtained by the use of ubiquitous phosphine ligands. The monoamide 35 was isolated in 82 % yield in a chemical plant in 600 kg scale production [17].

+ CO + PhNH2 N

Me

Br

Me

Br

Br

PdCl2(PPh3)2, bipyridine DBU, 65 °C, 5.5 atm, 90%

NHPh

N O

35

34

4-Pyridylglyoxamide 37 was prepared by double carbonylation of 4-iodopyridine (36). High selectivity and yield of 37 were obtained when PCy3 and i-PrOH were used as a ligand and nucleophile, respectively. When a primary amine, n-BuNH2 , was used, the Schiff base of keto amide 38 was obtained in high yield [18]. Domino double carbonylation and hydrogenation of the Schiff base occurred in the reaction of p-iodotoluene with cyclohexylamine under CO and H2 pressure using ligandless Pd on charcoal to afford the α-amino amide 39 in high yield [19]. O I + CO + i-Pr2NH

N

N-i-Pr2

Pd(OAc)2, PCy3 50 °C, 60 atm, 90%

N

36

O 37 N

I + CO + n-BUNH2

N

Pd(OAc)2, PCy3 50 °C, 60 atm, 91%

NHBu N

36

O 38

I

Me

Bu

+ CO + H2 + CyNH2 55 atm 7 atm

HN

Pd/C, Et3N

Cy NHBu

MS 4A 120 °C, 88% O

Me 39

Carbonylation and Reactions of Acyl Chlorides

273

Carbonylation of iodoferrocene 40 in the presence of morpholine gave rise to the amide 41 and the keto amide 42 by using PPh3 as a ligand [20]. A slight difference in temperature and pressure had a marked influence on the product ratios. The keto amide 42 was obtained as the main product with 80 % selectivity at 60 ◦ C and 50 atm. The amide 41 was obtained as a single product at 100 ◦ C. H N

I

Pd(OAc)2, PPh3

+ CO +

Fe

O 40

O

O

O N

N

+ O

Fe

O

Fe 41 temp.

42 press. (atm)

conv. %

ratio 41 : 42

60

50

92

20 : 80

100

40

100

>99 : 1

Carbonylation of a mixture of more reactive p-iodoacetophenone (44) and oiodoaniline (43) occurred stepwise chemoselectively to give the amide 45, and further carbonylation of 45 afforded 2-aryl-4H -3,1-benzoxazolin-4-one 46 [21]. I

I +

+ CO

Pd(PPh3)4, MeCN K2CO3, 1 atm, 60 °C, 85%

NH2 O

43

44

O I

O

O

CO N H

N COMe

45

46

COMe

Carbonylation of iodobenzene in the presence of N -benzylideneamine 47 using DPPF as a ligand proceeded via formation of amide 48 by insertion of 47 to the acylpalladium bond, and 3-phenyl-2,3-dihydro-1H -isoindol-1-one (49) was obtained [22]. Direct preparation of primary amides by carbonylation in the presence of NH3 is not easy. As one solution, Indolese carried out carbonylation of p-bromotoluene

274 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O PhN=CH

I

PdCl2(dppf), Et3N

+ CO +

N

benene, 120 °C 20 atm, 46%

47

Pd

Ph

Ph

X

O

48 N

Ph

Ph

49

using formamide as an ammonia equivalent in the presence of Lewis bases such as DMAP or imidazole, and obtained toluamide (50) in good yield [23]. Br + HCONH2 + CO Me

CONH2

PdCl2(PPh3)2, DMAP dioxane, 120 °C, 82%

Me 50

Several attempts to find CO-free preparative methods of esters and amides have been carried out using alkyl formate or formamide as CO sources. Methyl benzoate (51) was obtained in 98 % yield by the reaction of iodobenzene with methyl formate in the presence of MeONa [24]. DMF can be used as an amide source. Reaction of aryl iodides with DMF in the presence of 2 equivalents of POCl3 using ligandless Pd catalyst afforded the N ,N -dimethylbenzamide 52. Formation of a Vilsmeier reagent from DMF and POCl3 is expected and the amide may be formed by Pd-catalyzed reaction of aryl iodide with the Vilsmeier reagent [25]. Aminocarbonylation of aryl bromides with DMF was carried out using Pd-DPPF as a catalyst in the presence of stoichiometric amounts of imidazole and t-BuOK to afford N ,N -dimethylbenzamide 53 [26]. Also, N ,N -dimethylbenzamide (55) was prepared by the reaction of aryl bromide with carbamoylsilane 54, which is prepared from DMF [27]. CO2Me

I + HCO2Me + MeONa

PdCl2(PPh3)2, CH2Cl2 40 °C, 98% 51

I + HCONMe2 MeO

CONMe2

Pd2(dba)3, POCl3 120 °C, 87%

MeO 52

Carbonylation and Reactions of Acyl Chlorides

275 CONMe2

Br + HCONMe2 Me

Pd(OAc)2, DPPF, imidazole

t-BuOK, 180 °C, 15 min, 59% Me 53 Br

O DMF

TMS

NMe2

CONMe2 Pd(PPh3)4, toluene

+

+ Me3SiBr

100 °C, 88%

54

55

3.5.3 Formation of Aldehydes and Ketones Aldehydes are prepared by carbonylation in the presence of hydride sources. Formation of aldehydes can be understood by transmetallation of acylpalladium 56 with a hydride to give acylpalladium hydride 57, followed by reductive elimination. Metal hydrides and hydrogen are used for aldehyde synthesis. Hydrosilane is one of the hydrides. Reaction of β-naphthyl triflate (58) with Et3 SiH using DPPF as a ligand under mild conditions afforded the aldehyde 59 [28]. Carbonylation of the alkenyl triflate 60 in the presence of tin hydride and LiCl afforded the aldehyde 61 in 95 % yield [29]. O

O + M′H Ar

Ar

Pd-X 56

Ar

Pd-H

OTf

CHO

Pd(OAc)2, DPPF, Et 3N DME, 1 atm, 70 °C, 84% 59

58

+ CO + Bu3SnH TfO

H

H

57

M′X

+ CO + Et3SiH

O

reductive elimination

transmetallation

OTBS OTBS

Pd(PPh3)4, LiCl THF, 50 °C, 95% OHC

H 61

OTBS OTBS

60

Ketones are prepared by transmetallation of acylpalladium 62 with organometallic reagents. Phenyl triflate was converted to acetophenone (64) by carbonylation in the presence of Me4 Sn [30]. In the total synthesis of strychnine, Overman prepared the alkenyl aryl ketone 67 in 80 % yield by the carbonylation of the aryl iodide 65 with the alkenylstannane 66 using AsPh3 as a ligand [31]. Chloroanisole, activated by coordination of electron-attracting Cr carbonyl 68, reacted with CO and dimethylindium 69 to afford the methyl ketone 70 under mild conditions [32]. Also Bu3 In was used for the preparation of butyl phenyl ketone (71) [33].

276 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O

O + M′R Ar

Ar

Pd-X

O

reductive elimination

transmetallation

Ar

Pd-R

R

63

62 O OTf

Pd(OAc)2, DPPP, Et 3N

+ CO + Me4Sn

Me

DMF, 60 °C, 84%

64

Me N

O

OTIPS I N

MeN

+ CO +

Pd2(dba)3, AsPh3 Me3Sn

65

NMP, 70 °C, 80% 66

ButO

OTIPS Me N

O

O N

MeN

ButO

67

OMe

OMe

Me

Cl + CO + Cr(CO)3

PdCl2(PPh3)2,THF In

Me Me

68

50 °C, 5 atm, 84%

N

O Me

Cr(CO)3 Me

69

70 O

I + CO + n -Bu3In

Pd(PPh3)4, THF 1 atm, 66 °C, 87% 71

Ketones are also prepared by carbonylation in the presence of alkenes. Carbonylation of 4-iodoanisole in the presence of dihydrofuran (72) provided the ketone 73 via insertion of the double bond in dihyrofuran to acylpalladium, followed by β-H elimination [34]. MeO

I

PdCl2, PPh3, Et3N

+ CO + MeO

O 72

benzene, 5 atm 120 °C, 66%

O 73

O

Carbonylation and Reactions of Acyl Chlorides

277

Carbonylation of 2-iodostyrene (74) afforded indanone (75) and indenone (76) via intramolecular acylpalladation of the double bond. In the presence of Bu4 NCl and pyridine, protonation occurred to give indanone (75). When Et3 N was used, indenone (76) was obtained. Under high pressure CO (40 atm), the keto ester 77 was the main product [35]. O Pd(OAc)2, pyridine Bu4NCl, DMF, 100 °C 1 atm, 100% O

75

I

O

PdCl2(PPh3)2, Et3N

+ CO

MeCN, 80 °C, 1 atm, 50%

Pd-X

74

76

O

PdCl2(PPh3)2, Et3N MeOH, DMF, 100 °C, 40 atm, 74% 77

CO2Me

There are several possible reaction paths in the carbonylation of 1-iodo-1,4-, 1,5, and 1,6-dienes, and chemoselectivity depends on reaction conditions and ligands. For example, the 1-iodo-1,4-diene 78 reacted with two CO molecules to give the keto ester 79 in high yield by domino insertion of CO, alkene, and CO [36]. The diketo ester 81 was obtained from iodotriene 80. In this reaction, domino insertion of CO, alkene, and CO occurred to give rise to the diketo ester 81 in 54 % yield. The bicyclic monoketo ester 82 was formed in 14 % yield by premature trapping of acylpalladium intermediate with MeOH [37]. O

I + CO + MeOH

PdCl2(PPh3)2, Et3N MeCN, benzene 40 atm, 100 °C, 82%

CO2Me

78

79 I + CO + MeOH

PdCl2(PPh3)2, Et3N MeCN, benzene 40 atm, 95 °C, 54%

80 O

O O

CO2Me

+

CO2Me 54%

81

14%

82

278 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Carbonylation of 2-(3-pentenyl)iodobenzene (83) afforded a mixture of the ketone 84, γ -lactone 85, and δ-lactone 86. When DPPE instead of PPh3 was used, the γ -lactone 85 was obtained as the main product [38]. I

PdCl2(PPh3)2,Et3N

+ CO

THF, MeCN, 100 °C

83 Et3N, 100 °C Pd(OAc)2, DPPE, O O

O

+

O

85

Me

Me

Me

84 43%

52%

O

O

+

O

86

85 15%

26%

Efficient enantioselective carbonylative cyclization of the o-allylphenyl triflate 87 occurred using (S)-BINAP, Pd(OCOCF3 )2 , and PMP (pentamethylpiperidine) to provide the ketone 88 with 95 % ee [39]. O OTf + CO

Pd(OCOCF3)2, (S)-BINAP MS-4A, PMP, dioxane,1 atm 80 °C, 89%, 95% ee

87

88

In the carbonylation of the iodo amide 89, insertion of the sterically hindered double bond in 89 occurred at first, generating a quaternary carbon, and subsequent CO insertion gave the lactam ester 90 in 77 % yield [40]. I

Cl

O N

OTBS + CO + MeOH

Me

Cl

89

Br

Pd(OAc)2, P(o-Tol) 3 Et3N, Bu4NBr, DMA, 85 °C, 77%

TBSO CO2Me Cl O

Br

N Cl

Me 90

Carbonylation and Reactions of Acyl Chlorides

279

The three-component reaction of 2-iodophenol (91), norbornene (92), and CO provided the ketone 94 and the δ-lactone 93 depending on the order of insertions of CO and alkene, which was controlled by ligands [41]. The ketone 94 was produced via insertions of CO and then alkene when DPPP was used. Formation of the lactone 93 occurred via alkene and CO insertions when PPh3 was used [42]. I +

Pd(OAc)2, TlOAc

+ CO

DMF, 1 atm

OH 91

92 O + O

93

O 93 : 94

O

PPh3

100 : 0

DPPP

3 : 97

94 82% 70%

Carbonylation of 2-iodophenol (91) in the presence of 1,2-nonadiene (95) afforded 2-(n-hexyl)-3-methylene-2,3-dihydro-4H -1-benzopyran-4-one (97) in 74 % yield, showing that selective attack of phenoxy group at the substituted terminus of π -allylpalladium intermediate 96 occurred. Uses of DPPB and K2 CO3 were important [43]. O I + OH

C6H13 •

+ CO

95

91

Pd-X OH

C6H13

96

O

O 97

Pd(OAc)2, DPPB K2CO3, benzene 20 atm, 100 °C, 74%

C6H13

Acylpalladium was generated by the oxidative addition of acyl chloride 98 to Pd(0), and reacted with 1,1-dimethylallene (99) to give π allylpalladium intermediate 100. Then transmetallation of 100 with diborane and reductive elimination provided 2-acylallylboronate 101. Thus highly regio- and stereoselective acylboration of allenes occurred using ligandless Pd catalyst [44]. Cacchi found a new and simple CO-free methyl ketone synthesis using acetic anhydride. Acetophenone was obtained in 74 % yield by the reaction of iodobenzene with acetic anhydride using ligand-free Pd catalyst in the presence of

280 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O

O

t-Bu COCl

+

+

•

B

toluene, 80 °C, 80%

O

O

98

PdCl2(MeCN)2

B

99

t-Bu

t-Bu O

O O B

Pd-X

O

100

101

LiCl [45]. As one explanation, insertion of C=O bond to Ph-PdX generates 102, from which acetophenone is formed. O

I-Pd

I + (MeCO)2O

Pd2(dba)3, LiCl

Ph

i-Pr2NEt, DMF 100 °C, 74%

Me

O

O Ph

O

Me

Me

102

Miura found that the aldehyde group in salicylaldehyde (103) can be converted to aryl ketone 106 in high yield by the reaction with aryl iodide using ligandless PdCl2 and LiCl in the presence of Na2 CO3 in DMF. The reaction is explained by the following mechanism. The first step is formation of phenylpalladium phenoxide 104. Oxidative addition of the C-H bond of aldehyde to the phenyl(aryloxy)palladium 104 generates Pd(IV) species 105, which was converted to the ketone 106 by reductive elimination [46]. O CHO + Ph-l OH

103

PdCl2, LiCl Na2CO3 DMF, 91%

CHO

Ph

Pd

Ph

O

O

104

O

Pd H

105

Ph OH

106

A good synthetic method for substituted fluoren-9-ones is the carbonylation of ohalobiaryls [47]. Carbonylation of 2-bromobiphenyl (107) in DMF in the presence of cesium pivalate gave rise to fluoren-9-one (109) in quantitative yield via the palladacycle 108. Use of PCy3 as a ligand is important. Br + CO

107

O

O PdCl2(PCy)3

Pd

Cs pivalate, 1 atm 120 °C, 100% 108

109

Carbonylation and Reactions of Acyl Chlorides

281

A well-established preparative method of alkynyl ketones 110 is the Sonogashiratype carbonylation of aryl halides in the presence of terminal alkynes. (Trimethylsilyl)pyridylethyne (111), deprotected in situ, reacted with 3-iodotoluene and CO to give the alkynyl m-tolyl ketone 112 using DPPF as a ligand. Pd-catalyzed reductive cyclization of 112 using HCO2 H afforded the 1,8-naphthyridine 113 [48]. Ar-l

+

CO

+

R

O

Pd(0)

R Ar 110 TMS

Me

l

Me +

+ N

PdCl2(dppf), Et3N CO

Bu4NF, rt, 65%

NH2 111

O Pd(OAc)2(PPh3)2, Me HCO2H, Bu3N

Me

Me

DMF, 70 °C, 65% N

NH2

N

N

Me

112

113

The 12-membered cyclic alkynyl alkenyl ketone 115 was obtained by carbonylative cyclization of the alkenyl triflate with alkynylstannane in 114 [49]. O OTf

SnMe3

+

CO

PdCl2(dppf), LiCl DMF, 36%

114

115

Formation of flavone 116 and aurone 117 by carbonylation of 2-iodophenol (91) in the presence of terminal alkyne is known [50]. Also 1,4-dihydro-4-oxoquinoline 119 is obtained by the reaction of 2-iodoaniline with CO and terminal alkynes [51]. These reactions proceed via the formation of the aryl alkynyl ketones 118 as intermediates. O

O

l + CO +

Ph

Pd(0)

OH

+ O 116

91

Ph O

Ph

117

O

O

l + CO + NH2

Ph

Pd(0) NH2 118

Ph

N H 119

Ph

282 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Yang carried out extensive studies on selective formation of the flavones 116, and found that the acetate of iodophenol 120, as a latent hydroxy group, was superior to free iodophenol 91 and formation of the aurone 117 was suppressed. As a catalyst, PdCl2 (PPh3 )2 , combined with DPPP and thiourea, was found to be the best one. Under these conditions and 1 atm, the flavone 116 was obtained selectively in 92 % yield without isolating the alkynyl ketone 121 [52].

+ CO 120

O

PdCl2(PPh3)2, DPPP

I +

Ph

OAc

116

thiourea, Et2NH DBU, 40 °C, 1 atm 92%

Ph

OAc 121

Formation of indole derivative by the reaction of 2-ethynylaniline, aryl halide and CO is known [53]. Cacchi extended the reaction to the synthesis of indolo[3.2c]quinoline. Reaction of 2-(2
-aminophenylethynyl)trifluoroacetanilide 122, 4iodoanisole and CO occurred as shown by 123 to provide 124 and then the 3-aroylindole 125. Treatment of 125 with a base gave the indoloquinoline 126 in 70 % overall yield [54].

I + NH2

+ CO

Pd(PPh3)4, MeCN

ArCO-PdX

K2CO3, 70%

NH2

MeO

NHCOCF3 123

NHCOCF3 122 Ar ArCOPd

O NH2

NH2

N

N H 125

COCF3 124

MeO

N

K2CO3

N H 126

3.5.4 Reactions of Acyl Halides and Related Compounds Acylpalladiums are important intermediates of carbonylation reactions. Since similar acylpalladiums can be prepared directly by oxidative addition of acyl halides to

Carbonylation and Reactions of Acyl Chlorides

283

Pd(0), acyl halides and related compounds are useful substrates for the syntheses of various carbonyl compounds without using CO. Pd-catalyzed coupling of acyl halides with organometallic reagents is a useful synthetic method of ketones. The alkylzinc reagent 127, prepared from the corresponding alkyl iodide with Zn/Cu couple, was coupled with the acid chloride 128 to give the ketone 129 in 50 % yield and used for the total synthesis of amphidinolide T14 [55]. MOM TBDPSO

Cl

O Pd2(dba)3

+

TFP (I-3), 50%

ZnI O

O O 128

127 MOM TBDPSO O O O O 129

Coupling of chiral cyclopropylboronic acid 130 with benzoyl chloride catalyzed by PdCl2 (dppf) was achieved by the combination of Ag2 O and K2 CO3 as bases to provide the cyclopropyl phenyl ketone 131 with 92 % ee in 77 % yield [56]. O

n-Bu

B(OH)2

Ph 130

PdCl2(dppf), Ag2O, K 2CO3

+ Cl

Ph

n-Bu

toluene, 80 °C, 77%, 92% ee

90% ee

131

O

Coupling of the alkenylstannyl peroxyketal 132 with benzoyl chloride proceeded to give the phenyl ketone 133 without affecting the peroxy group using trifurylphoshine as a ligand [8]. Coupling of alkenylstannane 134 with benzoyl chloride afforded the ketone 135, which was cyclized to 6-phenylpyran-2one [57]. Phenyl seleno benzoate 136 was prepared in high yield by the reaction of phenyl tributylstannyl selenide with benzolyl chloride at room temperature [58]. O Ph

Cl

+ MeO

Pd2(dba)3, TFP (I-3) O

O

132

SnBu3

THF, 69%

MeO

O

O O

133

Ph

284 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O

O +

Ph

Pd(PPh3)4, dioxane

Bu3Sn

50 °C, 84%

OSnBu3

Cl 134 O

O

Ph

Ph

OSnBu3

O

O

135 O + Ph

PhSeSnBu3

Cl

O

Pd(PPh3)4, toluene 25 °C, 97%

Ph

SePh 136

The acylpalladiums such as 138 are generated by oxidative addition of thioesters and used for ketone synthesis as reported by Fukuyama. Coupling of ethyl thioester of phenylalanine 137 with alkylzinc reagent 139 using P(o-Tol)3 as a ligand gave 140 in high yield [59]. Phenyl thioesters are also used [60].

Ph

IZn

NHCbz

NHCbz

CO2Et

Pd(0)

139 Ph

COSEt

Pd

137 138

Pd2(dba)3, P(o-Tol) 3 toluene, rt, 88%

SEt

O

NHCbz Ph

CO2Et O 140

The acylpalladium 141 is formed by oxidative addition of acid anhydride to Pd(0), and can be used for synthetic purposes [61]. The mixed anhydride 143 was prepared in situ by the reaction of benzoic acid with dimethyl dicarbonate (142), and the benzoylpalladium methoxide 144 is generated by decarboxylative oxidative addition of 143, and is used for Suzuki coupling with arylboronic acid to yield the diaryl ketone 145 [62].

O

R

O

O

O

R

+ Pd(0)

R

O Pd

R

O

141

PhCO2H + (MeOCO)2O

88%

Ph

142

O OMe Pd

Ph 144

O

O

Pd(PPh3)4, dioxane

Pd(0) O

OMe

143

CO2 O

O

p-MeC6H4B(OH)2 Ph

Pd

C6H4Me

C6H4Me

Ph 145

Carbonylation and Reactions of Acyl Chlorides

285

Although less convenient, mixed acid anhydride 147 can be prepared in situ by the treatment of carboxylic acid with pivalic anhydride (146), and used for Suzuki coupling to afford the ketone 148 [63]. O C5H11CO2H +

O

O

t-Bu

H11C5

t-Bu

O

O O 147

146 O

O O

DME, rt, 98%

C5H11

+ t-BuCO2H

O

Pd(OAc)2, PPh3

+ o -Tol-B(OH) 2 H11C5

C5H11

o -Tol

H11C5

147

148

Phenyl trifluoroacetate (149) undergoes oxidative addition to generate the acylpalladium 150 [64]. Based on this reaction, trifluoromethyl ketones such as 151 can be prepared by Suzuki coupling with arylboronic acids. Similarly, anisyl heptafluoropropyl ketone (154) was prepared by the Suzuki coupling of phenyl heptafluorobutyrate (152) with anisylboronic acid 153 [65]. O F3C

OPh

+ PhB(OH)2

NMP, 80 °C, 81%

O

O

Pd(OAc)2, P(n-Bu)3 F3C

149

F3C

Pd-OPh 150

Ph 151

O O C3F7

OPh 152

B(OH)2

+

Pd(OAc)2, P(n-Bu)3

C3F7

NMP, 80 °C, 87%

MeO

OMe 153

154

Reduction of carboxylic acids to aldehydes can be carried out via in situ formation of acid anhydrides by the treatment of carboxylic acids 155 with an excess of pivalic anhydride (146). The acylpalladium intermediate, prepared in this way, is hydrogenolyzed to give aldehyde 156. Separation of the desired aldehyde 156 from other byproducts is tedious under these conditions [61,66]. C7H15CO2H + 3 (t-BuCO)2O + H2 155 C7H15CHO +

Pd(PPh3)4 THF

146

t-BuCO2H + (t-BuCO)2O

156 98%

Alkynic esters are prepared by the coupling of terminal alkynes with chloroformate 157. Butyl chloroformate (157) is an unstable compound, and the reaction

286 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides should be carried out carefully. Butyl phenylpropiolate (158) was prepared in high yield by the reaction of phenylacetylene with butyl chloroformate (157) using PMP as a hindered base and a small amount of DMAP in nonpolar solvents such as dichloromethane [67]. +

Ph

ClCO2Bu 157

Pd(PPh3)4 PMP, DMAP CH2Cl2, 98%

Ph

CO2Bu 158

3.5.5 Miscellaneous Reactions Some halides of sp3 carbons can be carbonylated. Carbonylation of α-halo ketones and esters is a known reaction [68,69]. β-Keto esters are prepared by the carbonylation of halomethyl ketones [70,71]. Methyl benzoylacetate (160) was obtained in 86 % yield by the carbonylation of 2-chloroacetophenone (159) in MeOH using PdCl2 (PPh3 )2 as a catalyst at 110 ◦ C and 10 atm in the presence of n-Bu3 N [71]. O

O Cl

CO2Me

PdCl2(PPh3)2, n-Bu3N

+ CO + MeOH

10 atm, 110 °C 2 h, 86%

159

160

Cyclization and dicarbonylation of 4-pentenyl iodide afforded the keto ester 161 in 82 % yield in benzene in the presence of Pd(PPh3 )4 , Et3 N, and DMAP at 100 ◦ C and 40 atm under irradiation with a xenon lamp [72]. O I

+ CO + BuOH

Pd(PPh3)4, DMAP CO2Bu

Et3N, xenon lamp 100 °C, 82% 161

Pd(0) CO O Pd-I

CO

BuOH

O Pd-I Pd-I

References 1. 2. 2a. 3.

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3.6 Cross-Coupling Reactions with Organometallic Compounds of the Main Group Metals via Transmetallation 3.6.1 Introduction A classical synthetic method of biaryls is Cu-promoted coupling of aryl halides, which is known as the Ullmann reaction. An interesting review on aryl–aryl bond formation one century after the discovery of the Ullmann reaction has been published [1]. However, the Ullmann reaction is far from satisfactory. Now Pdcatalyzed coupling reactions are emerging as excellent methods of biaryl formation. Pd-catalyzed cross-couplings of aryl and alkenyl (and some alkyl) halides with organometallic compounds (mainly Mg, Zn, B, Sn, and Si), which include a variety of groups such as aryl, alkenyl, alkynyl, and alkyl to form aryl–aryl, aryl–alkenyl, aryl–alkynyl, aryl–alkyl, alkenyl–alkenyl, alkenyl–alkynyl, alkenyl–alkyl, and alkyl–alkyl bonds, are powerful methods of C—C bond formation [2]. Coupling of aryl and alkenyl halides with alkynylmetal compounds is treated in section 3.4.2. An interesting historical survey on studies of cross-coupling reactions developed from the mid 1970s has been given by Negishi [3]. Recent remarkable progress in

Cross-Coupling Reactions with Organometallic Compounds

289

this field, which has been realized by the introduction of electron-rich and bulky ligands, is facile coupling of aryl chlorides. Typically commercially available and air stable Pd[P(t-Bu3 )]2 is used. An excellent review on Pd-catalyzed reactions of aryl chlorides has appeared [4]. Heterocyclic carbenes are also effective ligands for coupling reactions [5]. Aryl fluorides are considered to be inert. Electron-deficient aryl fluorides can be coupled when PMe3 [6] or biphenylylphosphines [7] are used. Organopalladium species formed by the oxidative addition of halides undergo transmetallation with alkyl, aryl, alkenyl, allyl, and benzyl compounds of main group metal elements, and then the carbon–carbon bond formation occurs by reductive elimination as a final step. Couplings of electropositive metals such as Mg and Zn show somewhat different features from those of electronegative elements such as B, Sn, and even Si. Sufficiently reactive Mg, Zn, and Sn reagents undergo transmetallation of R-Pd-X without an additive. On the other hand, transmetallation of B and Si reagents proceeds in the presence of additive or promoter. Facile preparation of stereo- and regiodefined alkyl- and alkenylmetals via hydrometallation or carbometallation of alkenes and alkynes enhances the usefulness of the coupling. Coupling of alkylmetals with alkyl halides has been regarded as a difficult reaction due to slow oxidative addition of alkyl halides and easy β-H elimination of alkylpalladium intermediates. Recently breakthrough has occurred in this area by using bulky bidentate ligands. Bidentate phosphines and bulky monophosphines, coordinated to Pd catalysts, are expected to help favor reductive elimination by enforcing cis geometry of alkyl and other organic groups. In addition, a large bite angle of ligands brings two organic groups closer, promoting the reductive elimination step. Ar-X + Pd(0)

OA

Ar-Pd-X RM

Ar-Pd-R + MX RE Ar-R + Pd(0)

P

R Pd

P

TM

R-R′ + Pd(0)

R′

3.6.2 Organoboron Compounds (Suzuki–Miyaura Coupling) 3.6.2.1 Introduction and New Preparative Methods of Organoboranes Coupling of organoboron compounds with aryl, alkenyl and alkynyl halides is one of the most useful coupling reactions and called Suzuki–Miyaura coupling (abbreviated to S-MC in this section) [8–10]. Due to low nucleophilicity of organic groups R on the B atom, their transmetallation is difficult. The coupling reaction proceeds via transmetallation in the presence of bases [11]. The role of the base is explained by activation of either Pd or boranes. The nucleophilicity of R is enhanced by quaternization of the boron with bases, generating the corresponding ‘ate’ complexes 1, which undergo facile transmetallation. Alternatively, the formation of (alkoxo)palladium species Ar-Pd-OR 2 from Ar-Pd-X facilitates the transmetallation with organoboranes. No reaction takes place under neutral

290 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides conditions. This is a characteristic feature of organoboron chemistry, which is different from that of other organometallic reagents. Various aryl, alkenyl, and even alkylborane reagents of different reactivity can be used for the coupling with aryl, alkenyl, alkynyl, and some alkyl halides, and the coupling offers very useful synthetic methods. −

Y

Y R1 B +

−OR

Ar-Pd-R1

R1 B-OR Y

Y

Y

1 RO

Ar-Pd-X −OR

Y B Y

B Y

Ar-Pd-X

R1

Ar-R1

Y

+ Ar-Pd-OR 2

1

Ar-Pd-R

+ RO

B Y

S-MC is the most popular among Pd-catalyzed cross-couplings on account of several advantages: 1. Commercial availability of a large number of organoboranes especially boronic acids and their esters. 2. Stability of boronic acids to heat, air, and moisture. 3. Tolerance to a broad range of functional groups. 4. Mild reaction conditions. 5. Low toxicity, but not non-toxicity. 6. Easy separation of inorganic boron from reaction mixture. Hydroboration of alkenes and alkynes is an established preparative method of alkyl- and alkenylboranes. Arylboranes, arylboronic acids and their esters (boronates) are prepared from aryllithium or Grignard reagents. Several new synthetic methods of arylboronates, such as pinacol ester, have been developed. A convenient preparative method of arylboronates 4 is Pd-catalyzed cross-coupling of aryl halides and triflates with bis(pinacolato)diboron (3), which can be handled easily in air. The best ligand for the coupling is DPPF [12]. In addition, one-pot biaryl synthesis can be carried out most conveniently without isolation of the boronate 4 to provide 5 [13]. Ligandless Pd(OAc)2 is active for O I

O

O B

+

PdCl2(dppf)

B 3

4

Br

Cl Cl PdCl2(dppf) aq. Na 2CO3

O

AcOK, DMF, 80 °C MeO

O

O

MeO

B

OMe 5

81%

Cross-Coupling Reactions with Organometallic Compounds

291

the coupling of aryl bromides having EWG in DMF [14]. The carbene (XVI-2) was found to be a good ligand for activated aryl chlorides to afford 6 [15]. Borylation of alkenyl triflate 7 with 3 affords alkenylboronate 8 when PdCl2 (PPh3 )2 -2PPh3 as a catalyst and PhOK as a base are used, and the method is applied to one-pot synthesis of asymmetrical 1,3-dienes and arylalkenes [16].

O Cl

O

O

+

B

B

O

O

MeO2C

B

Pd(OAc)2, XVI-2

O

AcOK, THF 6 h, 85% MeO2C

3

6 O

OTf

O

O B

+

B O

O 3

7

B

PdCl2(PPh3)4, 2PPh3 PhOK, toluene 50 °C, 88%

O 8

Borylation of benzyl chloride with 3 in toluene in the presence of AcOK, Pd(dba)2 , and tri(4-anisyl)phosphine gives pinacol benzylboronate 9 in high yield [17]. More conveniently benzylboronate 9 can be prepared by borylation of toluene with 3 by the use of Pd on carbon as a catalyst [18].

Cl

+

3

Pd(dba)2, P(4-MeOC6H4)3

B

AcOK, toluene, 85%

O

O

9 Me

Pd/C +

3

B

toluene 100 °C, 74%

O

O + H2

9

Masuda and co-workers have found a new and mechanistically interesting synthetic method of pinacol arylboronate by the coupling of pinacolborane 10 with aryl triflates and iodides in the presence of DPPF as a ligand and Et3 N as the most effective base in dioxane. In this case, the arylboronate 4 is produced as the main product, and hydrogenolysis of halides with boron hydride to give the reduced arene 11 is the minor path. The reaction mechanism is shown in the following. Transmetallation of 12 to form 13 is a key step. Direct transmetallation of boron hydride to form palladium-hydride is a minor path [19]. Reaction of 5bromo-2-pyrone (14) with 10 provided the pinacolboronate in 82 % yield by using PdCl2 (PPh3 )2 as a catalyst, but a very poor result was obtained when PdCl2 (dppf) was used [20]. Triflates are the most reactive.

292 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides H

O I

O + H

10

Ar-X

Pd(0)

O

+

Et3N, dioxane 77% MeO

O

MeO

B

PdCl2(dppf)

B

OMe 11 16%

4

Ar-Pd-X Ar-Pd-B(OR)2 +

H-B(OR)2

Et3NHB(OR)2

Et3N

Et3NHX

12 +

Ar-Pd-X

H-B(OR)2

Ar-B(OR)2

13

Ar-Pd-H

+ X-B(OR)2

Ar-H

O

O Br + H

O

B O

14

PdCl2(PPh3)2 Et3N, toluene 82%

O O

O B O

10

Although this is not a Pd-catalyzed reaction, direct borylation of arenes 15 with pinacolborane 10 to give arylboronate 16 can be achieved using several transition metal complexes as catalysts. Some Rh and Ir catalysts are known to be active [21,22].

O MeO

O +

H

B O

NMe2 15

10

Cp*Rh(η4-C6Me6)

MeO

B

O

cyclohexane, 75%

NMe2

16

Phenylboronic acid (17) and its derivatives are widely used. Boronic acids are sometimes difficult to purify because they undergo cyclotrimerization with loss of water to form boroxines. On the other hand, organotrifluoroborate salts 18 are easily prepared, purified, and handled [23]. Aryltrifluoroborate salts 18 are prepared by the reaction of arylboronic acid with HF and base [24]. Alkenyltrifluoroborates 19 are prepared by hydroboration of 1-alkynes, followed by treatment with KHF2 [25]. These potassium organotrifluoroborates are good partners of S-MC [26]. Coupling of PhBF3 K (20) with deactivated p-bromoanisole proceeds with ligandless Pd catalyst in refluxing MeOH in the presence of K2 CO3 [27]. Reaction of more

Cross-Coupling Reactions with Organometallic Compounds BF3−H3O+

B(OH)2

BF3−M+ base

+ HF + H2O

M = K, Cs, Bu4N

17 H2O

+ HBBr2-SMe2

C8H17

293

KHF2

C8H17

ether B(OH)2

18 C8H17

H2O, ether 71%

BF3K 19

reactive diazonium salt 21 with 20 proceeds at room temperature without addition of a base [28]. BF3K

OMe

Pd(OAc)2, K2CO3

+

MeOH reflux, 2 h, 95%

OMe

Br 20

OMe BF3K

N3BF4 +

Pd(OAc)2, dioxane rt, 69%

OMe

MeO 21 OMe

20

Vinylboronic acid is difficult to purify. On the other hand, coupling of vinyltrifluoroborate 22 with diazonium salt 23 occurs at room temperature in the presence of ligandless Pd without a base [28]. However, use of DPPB or DPPF is necessary for the coupling of K or Bu4 N salt 24 of alkenyltrifluoroborates with aryl bromides [24,25]. N2BF4 BF3K 22

Pd(OAc)2, dioxane

+

CO2Et

rt, 69% EtO2C 23 COMe + BF3M

Br COMe

24 M = Bu4N, Pd(OAc)2, DPPB, Cs2CO3, DME, 55% M = K, PdCl2(dppf), i-PrOH, BuNH2, 80%

3.6.2.2 Catalysts and Reaction Conditions A number of papers claiming ‘A highly active catalyst for Suzuki coupling’, ‘Convenient and efficient catalyst for S-MC’ or ‘Extremely high-activity catalysts’ have been published. In some cases, these catalysts seem to be active for only limited substrates, and not appropriate for every substrate.

294 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Several types of catalysts are used. From a practical standpoint, ligandless catalysts are most useful. Several reactions for the coupling have been reported. Coupling of phenylboronic acid (17) with iodophenol was carried out in the presence of Pd on carbon as a reusable catalyst and K2 CO3 in water [29]. Coupling of mainly electron-deficient aryl chlorides such as 4-chlorotrifluoromethylbenzene (25) catalyzed by Pd on carbon proceeded in DMA/H2 O (20 : 1) to give the coupling product 26 in high yield [30]. Also Pd on carbon and KF were used in MeOH [31]. Coupling of aryl iodides by a similar catalyst supported on alumina proceeds without solvent [32]. Hollow Pd spheres are active catalysts for aryl iodides and bromides in EtOH, and the catalyst was used six times without loss of activity [33]. Reactions catalyzed by Pd nanoparticles are carried out in water [34,35]. HO

B(OH)2 HO

I

+

Pd/C, K 2CO3 H2O, rt, 97%

17 B(OH)2 Cl Pd/C, K 2CO3 + F3C 17

CF3

DMA/H2O (20/1) 80 °C, 95%

26

25

Sulfur-containing palladacycle XVIII-13 is a precursor of an effective catalyst in the presence of Bu4 NBr [36]. Palladacycle XVIII-1 is an efficient catalyst, and high TON (74 000) was obtained in the coupling of electron-deficient aryl bromide 27 [37]. Preparation of sterically hindered biaryl 28 was carried out with bulky phenanthrene-based phosphine V-5 [38]. B(OH)2

Me Me

Br

Palladacycle (XVIII-13)

+

K2CO3, DMF, Bu 4NBr 130 °C, 100%

17 B(OH)2

Br Palladacycle (XVIII-1) 0.001 mol%

+ O

27

K2CO3, xylene, 130 °C 74%, TON = 74 000

O

17 Me (HO)2B Me

Me Me

Me + Me

Br Me

Pd2(dba)3, (V-5), K3PO4 toluene, 110 °C, 82%

Me Me Me 28

Cross-Coupling Reactions with Organometallic Compounds

295

Pd(dppe)2 with K2 CO3 in THF–MeOH [39], and combination of diazabutadiene (XVII-4) with Cs2 CO3 or CsF are effective catalysts. No coupling takes place with bases such as Na2 CO3 and MeONa [40]. B(OH)2 Br +

Pd(dppe)2, K2CO3 THF-MeOH reflux, 95%

17 B(OH)2

Br Pd(OAc)2, XVII-4

+

Cs2CO3, dioxane, 99%

Me

Me

17

In S-MC, ligands, solvents and bases have critical effects and careful selection is necessary. For example, the following comparative survey has been carried out in the coupling of formylated arylboronate 29. In this case, Na2 CO3 seems to be superior to K2 CO3 [41]. Br

CHO

CHO

O B O

+

O

O

29

solvent

base

catalyst

temp.

time

yield

xylene

K2CO3

XVIII-1

130 °C

16

0

THF

KOH

Pd(PPh3)4

60 °C

16

0

toluene-EtOH

Na2CO3

Pd(PPh3)4

80 °C

2

83%

Water is a good solvent for some S-MC. Reaction proceeds in a mixed solvent in the presence of water-soluble ligands which are listed in Table 1.2. Use of water-soluble sulfonate ligand II-1 in a mixed solvent of H2 O and MeCN at 80 ◦ C is typical [42]. Coupling of electron-rich bromide 30 with 17 proceeds at room temperature in high yield using di-t-butylphosphine, containing the water-soluble trimethylammonium group (II-12). The ligand II-12 gave higher yield than II-1 in this reaction at room temperature [43]. More conveniently, reaction can be carried out in water without a cosolvent under certain conditions. Coupling of substrates insoluble in water such as 30 proceeds with TON up to 20 000 in water when an insoluble and assembled Pd catalyst and a non-cross-linked amphiphilic (amphiphilic) polymer, containing diphenylphosphine group, are used. The catalyst system was used 10 times without any decrease in activity [44]. Also an amphiphilic resin-supported Pd catalyst can be used in water many times giving nearly quantitative yields of coupling products [45].

296 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Pd(OAc)2, II-1

i -Pr2NH, H2O, MeCN

Br

B(OH)2

80 °C, 98%

+ MeO 17

Pd(OAc)2, II-12

30

Na2CO3, H2O, MeCN rt, 98%

OMe

Furthermore, coupling of aryl bromides proceeds in water in the presence of ligandless Pd(OAc)2 as a precursor and 1 equivalent of Bu4 NBr. Use of 1 equivalent is important. Aryl iodides and triflates are not good substrates under the conditions [46]. 5-Phenylthiophene-2-carboxaldehyde (31) was prepared under similar conditions at room temperature [47]. Reaction of 17 with 30 proceeded rapidly in 5–10 min under microwave irradiation at 150 ◦ C [48]. Br

B(OH)2 +

OMe

Na2CO3, H2O MeO

17

100 °C, 87%

30

Br

B(OH)2 +

Pd(OAc)2, Bu4NBr K2CO3, H2O

AcHN

Me

Pd

70 °C, 98% Me

B(OH)2

NHAc

Pd(OAc)2, Bu4NBr

+ Br

CHO

S

rt, 2 h, 67%

17 Br

B(OH)2 + MeO 17

K2CO3, H2O

30

Pd(OAc)2, Bu4NBr Na2CO3, H2O 150 °C, 5 min. 86% microwave irradiation

S

CHO

31

OMe

S-MC of diazonium salt 32 proceeds with ligandless Pd at room temperature in dioxane in the absence of a base [49]. Pd(OAc)2 and carbene ligand XVI-2 are effective for the coupling of aryldiazonium tetrafluoroborates with aryl, alkenyl, and alkyl boronates at room temperature [50]. N2BF4

B(OH)2 +

rt, 4 h, 87% Me

17

Pd(OAc)2, dioxane

32

Me

Cross-Coupling Reactions with Organometallic Compounds

297

3.6.2.3 Coupling of Arylboranes Arylboranes with aryl bromides and iodides Coupling of arylboranes with aryl bromides and iodides offers an extremely useful synthetic method for biaryl compounds, and numerous examples are known. Asymmetric S-M aryl–aryl coupling of 33 with 34 in the presence of chiral 2-aminobinaphthyl-based phosphine (S)VI-8 afforded the highly enantiomerically enriched biaryl 35 (92 % ee), which was converted to the axially chiral 1-aryl-2-naphthylphosphine 36. BINAP is not an effective ligand for this asymmetric reaction [51]. Br

B(OH)2

P(O)(OEt)2

Et +

33

Pd2(dba)3, (S)-(+)-VI-8 K2CO3, toluene, 70 °C 96%, 92% ee

34

1. PhMgBr 2. PMHS, Ti(O-i-Pr) 4

Et

Et PPh2

P(O)(OEt)2

36

35

Total synthesis of proteasome inhibitor TMC-95A was achieved by smooth coupling of the functionalized boronate 37 with the iodide 38 without touching labile functional groups to give 39 in 75 % yield in the presence of PdCl2 (dppf) as a key reaction [52]. O O

N

O

Boc

B BnO

Cbz

PdCl2(dppf), K2CO3

+

DME, 80 °C, 2 h, 75%

HN CO2Me 37

N H I

O

38

O N Boc

N H

O

BnO

Cbz HN CO2Me 39

298 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Arylboranes with aryl chlorides and triflates Aryl chlorides are now regarded as good partners of the coupling by the discovery of a number of effective ligands. In this section, mainly coupling of aryl chlorides are surveyed. P(t-Bu)3 and PCy3 have been found to be very effective ligands [53]. In the case of S-MC, aryl triflates are known to be less reactive than the corresponding iodides and bromides. Curiously no coupling of aryl triflates took place with the catalyst [Pd/(P(t-Bu)3 ] even at 60 ◦ C. On the other hand, PCy3 , which is less bulky and less basic than P(t-Bu)3 , was found to be an effective ligand for triflates, and coupling of 43 with 4-methoxyphenyl triflate proceeded at room temperature using Pd(OAc)2 -PCy3 . The sterically hindered biaryl 42 was prepared at 90 ◦ C from 40 and 41 by the use of PCy3 . Since reaction of aryl triflates proceeds at room temperature when PCy3 is used, the different behavior of P(t-Bu)3 and PCy3 offers interesting chemoselective reactions. The most remarkable is the unprecedented chemoselectivity observed in the reaction of 4-chlorophenyl triflate (44) with 2-tolylboronic acid (43) at room temperature; chemoselective coupling of aryl chloride took place to give 45 when P(t-Bu)3 was used. On the other hand, chemoselective reaction of the triflate group occurred to afford 46 in 87 % yield at room temperature in the presence of PCy3 [54]. Me

Me Me +

(HO)2B Me

Me Pd2(dba)3, PCy3

Cl

40

Me Me

KF, THF, 90 °C, 93%

41

42

Me

Me

Me Pd2(dba)3, P(t-Bu)3

+ TfO

(HO)2B 43

Cl

KF, THF, rt, 95%

TfO

44

45

Me

Me Pd(OAc)2, PCy3

+ TfO

(HO)2B 43

Cl 44

KF, THF, rt, 87%

Cl 46

Furthermore higher reactivity of chloride over triflate was demonstrated by intermolecular competitive reaction of the aryl chloride 47 and the triflate 48 with 17. Reaction at room temperature in the presence of P(t-Bu)3 provided the biphenyl 49 with high selectivity. Recovery of the chloride 47 was only 8 %. The catalyst [Pd/(P(t-Bu)3 ] activates the C—Cl bond in preference to the C—OTf bond to afford 49 at room temperature in excellent selectivity and high yield. The chemoselectivity observed shows that the belief that the C—OTf bond is more reactive than the C—Cl bond is no longer valid when Pd/P(t-Bu)3 is used.

Cross-Coupling Reactions with Organometallic Compounds

299

O O

O

O

O

B(OH)2 +

Pd2(dba)3, P(t-Bu)3

+

17

Cl

+

Cl

47

OTf 48

1 equiv.

1 equiv.

1 equiv.

+

KF, THF, rt

OTf

47 49

48

8%

93%

99%

Generally speaking, alkenyl halides are more reactive than aryl halides. An opposite chemoselectivity was observed in the competitive reaction of chlorobenzene (50) and 1-cyclopentenyl chloride (51) with 43. A higher yield of 52 (62 %) than that of 53 (34 %) was obtained. The result shows that aryl chloride 50 is more reactive than the alkenyl chloride 51 in the presence of P(t-Bu)3 [54].

B(OH)2 Me

Pd2(dba)3, P(t-Bu)3 +

+

KF, THF, 60 °C

+

Me

Cl

Cl 43 1 equiv.

Me

50 1 equiv.

51 1 equiv.

52

53

62%

34%

P(t-Bu)3 is a remarkable ligand, but it is gradually oxidized. Fu reported that its phosphonium salt [P(t-Bu)3 H]BF4 , is air-stable and can be used more conveniently. The salt shows the same reactivity as that of free P(t-Bu)3 in the coupling of 43 with 54 to afford 55 [55]. Triarylphosphines are rather poor ligands for the reactions of aryl chlorides. However, ferrocenylphosphine VIII-6, which is a triarylphosphine, was found to be an unexpectedly effective ligand, and coupling of electron-rich and hindered aryl chloride 56 with 43 proceeded at room temperature to afford 57. The ferrocenyl ligand VIII-5, missing the TMS group, is ineffective [56]. B(OH)2

Me

I

Me

Pd2(dba)3, [P(t-Bu)3H]BF4

+

OMe

KF (3.3 equiv.), THF rt, 98%

MeO 54

55

43 Me

Me

Me

Pd2(dba)3, VIII-6

+ Cl

(HO)2B 43

Me

Me

K3PO4, toluene 70 °C, 88% Me

56 57

300 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Buchwald group reported biphenylyl(dicyclohexyl)phosphine derivatives such as IV-2 and IV-12 are effective for coupling of deactivated aryl chlorides. Reaction of the sterically hindered substrate 58 proceeds at 80 ◦ C, but coupling of 4chloroanisole (60) occurs at room temperature when IV-12 is used [57]. The polymer-supported ligand is equally active and can be recycled [58]. Carbene XVI1 is an excellent ligand, and the most effective base is Cs2 CO3 (96 % yield). Other bases such as CsF (65 %), K2 CO3 (53 %), and Na2 CO3 (6 %) are less effective [59]. B(OH)2

Me

Cl

Me

Pd(OAc)2, IV-2

Me +

43

K3PO4, toluene 80 °C, 96% Me Me

58

59

Me

B(OH)2 Cl Pd(OAc)2, IV-12

+

CsF, dioxane rt, 92%

MeO 17

OMe

60

B(OH)2 Cl Pd2(dba)3, XVI-1

+ Me 17

Cs2CO3, dioxane 80 °C, 96%

Me

High TON (11 600) was obtained in the reaction of m-chloroanisole with 17 in the presence of bulky diadamantyl-n-butylphosphine (I-20) [60]. Adamantyl(di-tbutyl)phosphine (I-21) is more effective and coupling of 4-chloroanisole (60) with 17 proceeded at room temperature in 5 min, giving 4-methoxybiphenyl in 96 % yield [61]. Aryldicyclohexylphosphine (I-17) is also an effective ligand for coupling of 3-chloroanisole [62]. ortho-Palladated triaryl phosphite complex (XVIII18) and additional PCy3 , is highly effective and TON as high as 33 000 was obtained. It should be pointed out that the triaryl phosphite alone is not an effective ligand [63]. High yield (97 %) was obtained by using di(t-butyl)phosphine oxide (XVIII-4) as a precursor of the phosphinous acid ligand [64]. It was claimed that very high TON (6 800 000) was obtained in the coupling of activated aryl chlorides, such as 2-chloro-5-(trifluoromethyl)nitrobenzene, with 17 using the tetraphosphine (X-1) [65]. Some heteroaryl halides are good coupling partners, and their reactions offer a versatile method of functionalization of heterocycles. Tosyl as a leaving group can be used for the coupling. 4-Tosyl-2-(5H )-furanone (61) has been found to undergo facile coupling in the presence of KF [66]. 2-Substituted oxazoles such as 62 were prepared by S-MC of ethyl 2-chloroxazole-4-carboxylate [67]. A practical kilogram scale synthesis of carbapenem L-742,728 was carried out by applying the coupling of the doubly quaternarized boronic acid 65 with the triflate 64 under carefully optimized conditions to afford the coupling product 66 after deprotection in a yield of 60 % over the four steps from 63. Li2 CO3 was the best base [68].

Cross-Coupling Reactions with Organometallic Compounds

301

Pd(OAc)2, I-20, K3PO4 B(OH)2

toluene, 100 °C, 58% TON 11 600

Cl +

Pd(dba)2, I-17, CsF toluene, 100 °C, 93%

MeO

17

OMe

B(OH)2 Pd(OAc)2, I-21, KOH THF, 5 min, 96% 17

XVIII-18 (0.0015) + PCy3 (0.003)

+ Cl

OMe

OMe

Cs2CO3, dioxane, 100 °C, 99% TON 33 000

60

Pd2(dba)3, [(t-Bu)2P(O)H] (XVIII-4) CsF, 100 °C, 97% B(OH)2 MeO

OTs PdCl2(PPh3)2, KF (H2O)

+ O

B(OH)2

THF, 60 °C, 63%

O 61

O

OMe

EtO2C

EtO2C

Pd(PPh3)4, K2CO3

N

+

N

toluene, 90 °C, 87% O

Cl

O 17

62

TESO

Me H

O

N2

H

CO2p-NB NH

O

O [Rh]

63 TESO H

H

O

Me

TfO − OTf

N O 64

+

N

(HO)2B

CO2p-NB

Br −

N

CONH2

65 O

1. Pd 2(dba)3, Li2CO3 DMF, CH 2Cl2, H2O

HO H

Me

H

2 TfO −

N N

2. deprotection N O

66 CO2p-NB

60% from 63

CONH2

302 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Heteroaromatic methyl thioethers (pyridyl, pyrimidyl, oxazolyl, thiazolyl, thiophenyl, 1,2,4-triazinyl) can be used for the coupling in the presence of 1.2 equivalents of copper thiophene-2-carboxylate (CuTC) and Zn(OAc)2 . Congested 2pyridyl methyl thioether 68 reacts with the boronic acid 67 using TFP [69,70]. 2
Deoxyguanosine O 6 -arylsulfonate 69 underwent facile coupling with 17. Aminobiphenylylphosphine IV-12 was the effective ligand [71]. Also 6-chloropurine can be used for the coupling [72]. Three chlorides in 2,4,6-trichloropyrimidine 70 have different reactivity, and couplings proceed step-wise in the order of positions 4 > 6 > 2 to give triphenylpyrimidine 71 in 93 % yield as the final product [73]. Me

Me Pd2(dba)3, TFP, CuTC Zn(OAc)2, Me SMe THF, 76%

OMe + MeO

CN

CN

B(OH)2

Me

67

N

OMe N

68

MeO

Ph

OSO2Ar B(OH)2

N +

RO

N

O

17

N

N

Pd(OAc)2, IV-12, dioxane K3PO4, 80 °C, 76%

RO

OR = OTBDMS OR

Ph Pd(OAc)2, PPh3, DME

N +

2

6 N 70

Cl 17

Cl

Na2CO3, 80 °C, 93%

Ph

N Cl

N

OR

69

Cl 4

B(OH)2

N

O

N N

Cl

Cl

N

Ph

Ph N Ph

N

Ph

71

The bipyridyl 74 was prepared by the coupling of 3-pyridylboronic acid 72 with 2-bromo-5-methoxypyridine 73 in good yield. Similarly heteroarylpyridines were prepared [74]. Coupling of the β-chloro-α,β-unsaturated aldehyde 75 occurred in water without a co-solvent in the presence of Bu4 NBr [75].

Cross-Coupling Reactions with Organometallic Compounds MeO

Br

Pd(PPh3)4, Na2CO3

+ N

DMF, 80 °C, 83%

N

B(OH)2

303

OMe

72

73 MeO

OMe N

N 74

Cl OMe

CHO Pd(OAc)2, K2CO3

+

MeO CHO

Bu4NBr, H 2O, 75%

B(OH)2 75

Arylboranes with alkyl halides Interestingly, Fu and co-workers discovered that alkyl halides can be used for the coupling. No β-H elimination occurs. Clearly, reductive elimination takes place before β-H elimination. Reaction of 17 with octyl bromide proceeded smoothly to give octylbenzene (76) in 85 % yield in the presence of P(t-Bu)2 Me as a ligand and t-BuOK as a base at room temperature [76]. Phenylacetate (77) was prepared by coupling 17 with bromoacetate. P(o-Tol)3 is the most effective ligand [77]. N ,N -Dimethyltolylacetamide (78) was obtained by the coupling of tolyldioxaborolane with 2-bromo-N ,N -dimethylacetamide using PCy3 as a ligand and hydroquinone as a free-radical scavenger [78]. Heteroarylboronic acids are used for coupling. Thiophene-3-boronic acid reacts with iodocyclopropane 79 to give 80 in the presence of CsF as a base. This reaction showed for the first time that cyclopropyl iodide can be used as a coupling partner [79].

Br

B(OH)2 + n-Hex

t-BuOK, tert-amyl alcohol rt, 85%

17

76

Pd(OAc)2, P(o -Tol)3

B(OH)2 +

Br

CO2Et

O + BrCH2CONMe2 O

CO2Et

K3PO4, THF, H 2O 89%

17

B

n -Hex

Pd(OAc)2, P(t-Bu)2Me

77

Pd(dba)2,PCy3 CH2CONMe2

K3PO4, hydroquinone THF, 72%

Me

Me

78

H H

B(OH)2 + S

Pd(OAc)2, PPh3 O

I

H 79

Ph

O H

CsF, DMF, 78% S

80

Ph

304 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.6.2.4 Coupling of Alkenylboranes 1-Alkenylboron derivatives are readily available by stereo-defined hydroboration of alkynes and used for the preparation of styrene derivatives by alkenyl–aryl coupling. Vinylboronic acid (81), the most simple alkenylboronic acid, is difficult to handle, because it undergoes uncontrollable polymerization. Its anhydride, 2,4,6-trivinylcyclotriboroxane (82)-pyridine complex, is stable, and can be used conveniently for the coupling. Vinylation of 2-bromoanisole with 82 proceeds in refluxing DME using K2 CO3 as a base to provide 2-vinylanisole (83) [80].

MgBr

B

B(OH)2

B(OMe)3

O

pyridine

aq. HCl, 79%

B O

+

B

B O 82

81

Br

O

B

O

Pd(PPh3)4, K2CO3

B

DME reflux, H2O,70% OMe

O

OMe

83

82

The coupling product 86 of alkenylboronic acid 84 with the bromothiazole 85 in the presence of CsOH as a base has been converted to cystothiazole E [81]. Br TBDMSO

OMe

N B(OH)2

+

CsOH, 95 °C, 94%

S

84 TBDMSO

Pd(PPh3)4

N

85

S

OMe steps

N

cystothiazole E

N 86

S S

1-Ethoxybutadienylboronate 88 was prepared from α,β-unsaturated acetal 87, and used for synthesis of phenyl 1-propenyl ketone (89) by S-MC and hydrolysis [82]. Similarly the 2-acyl-1,4,5,6-tetrahydropyridine 91 was prepared by the coupling of 90 with an alkenyl triflate, which was derived from the corresponding lactam [83]. Alkenyl–alkenyl coupling offers a versatile synthetic method of stereo-defined conjugated diene systems. Both (Z, E)-and (Z, Z)-conjugated alkadienyl carboxylates 95 and 96, which are present in a range of natural products, were obtained by coupling (Z)-and (E)-heptenylboronic acids 92 and 93 with (Z)-2-bromovinyl octanoate (94) [84].

Cross-Coupling Reactions with Organometallic Compounds

OEt

BuLi, t-BuOK

OH

OH

O

B(O-iPr)3

OEt

305

O B

87 OEt 88

1. Pd(PPh 3)4, K2CO3

Br

toluene, 60 °C, 83% 2. H 2O, H +

O 89

Cbz O Me

N

THF, 50 °C, 78% 2. H +, H2O

O TfO

B

Cbz

1. PdCl 2(PPh3)2, Na2CO3

N

+

O

OEt 90

Me 91

C5H11

C5H11

O +

Br

B(OH)2 94

Pd(PPh3)4, K2CO3

+

Br

95

86%

dioxane, 90 °C,

O B(OH)2

C7H15

C7H15

92

C5H11

O O

O

O

C5H11

O C7H15

O C7H15

93

94

96

80%

Coupling of alkenylboronic acid 97 with alkenyl iodide 98 to yield 99 in high yield was utilized in total synthesis of (−)-chlorothricolide [85]. MeO

HO

B(OH)2 97

1. Pd(PPh 3)4, TlOH, H 2O

+

2. DMSO, (COCl) 2 86%

I TMS

CHO

OMe

OMOM 98

MeO

TMS

OMe

OMOM 99

Synthesis of 19-nor-1α,25-dihydroxylvitamin D3 (102) was achieved by coupling the alkenylboronate 100 with the alkenyl bromide 101 in 72 % yield after deprotection [86].

306 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O OTMS

B O

TBSO

+

OTBS

Br 101

100

OH

1. PdCl 2(dppf), KOH, THF 2. aq. HF, THF, 72%

HO

OH

102

3.6.2.5 Coupling of Alkylboranes Alkylboranes with aryl and alkenyl halides Coupling of alkylboranes offers an important synthetic method for arylalkanes. It is somewhat surprising that the coupling of alkylboranes with aryl and alkenyl halides proceeds smoothly via reductive elimination without undergoing β-H elimination of alkylpalladium intermediates. Bidentate phosphine ligands play important roles by enforcing a cis geometry of alkyl and other organic groups and bringing two organic groups closer to favor the reductive elimination step. Alkylboranes 103 are easily prepared by hydroboration of 1-alkenes with 9BBN, and subsequent reactions with aryl, alkenyl, and alkyl halides offer versatile methods of alkylation to afford alkylated products 104, 105, and 106. The ‘hydroboration-coupling protocol’ has been utilized extensively in natural product syntheses [87]. R

Ar-X R1 R

R

104 R

Pd(0)

+ 9-BBN

X

BR2 103

Ar

R2-X

105 R

R1

2 106 R

In a concise formal total synthesis of strychnine, the cyclophane 108 was prepared in 65 % yield by applying the hydroboration–intramolecular coupling method to 107 under high dilution conditions, and converted to the pentacycle 109 by transannular inverse-electron-demand Diels-Alder reaction [88].

Cross-Coupling Reactions with Organometallic Compounds

307

NH NH

N

N N

1. 9-BBN, THF

N

2. Pd(PPh 3)4, Cs2CO3 THF, 2 days, 65%

N N

I

108

107

R N

steps

steps N

strychnine

H

109

Coupling of 1,3-dimethoxy-5-chlorobenzene (111) with 9-tetradecyl-9-BBN derivative 110 proceeded in THF with carbene ligand XVI-2 to give 1,3dimethoxy-5-dodecylbenzene (112) [89]. Cl

OMe Pd(OAc)2, XVI-2

OMe B (CH2)13CH3

K

+

THF reflux, OMe 82% MeO

MeO

110

111 112

Synthetic intermediate of the cytotoxic ketide callystatin A 115 was prepared by coupling the alkylboronate 113 with the alkenyl iodide 114. The coupling product 115 was obtained in 73 % yield when PdCl2 (dppf), AsPh3 , and Cs2 CO3 were used in aq. DMF [90]. OTBS Me +

OTBS

Me

Me Me

I 114

OH

Me Me

Me

BR2(OMe) 113

OTBS

OTBS OTBS

PdCl2(dppf), AsPh3 Cs2CO3, DMF, 73%

Me

Me

Me

Me

Me

Me

Me

115

OH

OTBS

308 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The bridged azadecalin core of xestocyclamine A 117 was constructed in 60 % yield by intramolecular coupling of the alkylborane derived from the terminal alkene 116. Both DPPF and AsPh3 as ligands and Tl2 CO3 as a base were used [91]. Similarly, the core structure of salicylihalamide A 119 was prepared under high dilution conditions from the iodoalkene 118. NaOH was used as a base [92]. HO

HO

TBDPSO

H

TBDPSO 1. 9-BBN, THF

Ts N

N

Ts N

2. PdCl 2(dppf), AsPh3 Tl2CO3, 60%

O

N O 117

116

I OPMB

OMe

OPMB

O

OMe OMOM

O

O

1. 9-BBN, THF

OMOM

O

2. PdCl 2(dppf) benzene/H2O NaOH, 48%

Me 119

I

118

In the total synthesis of epothilone B, intermolecular coupling of multifunctionalized alkylborane derived from 120 with the alkenyl iodide 121 to afford 122 was carried out without affecting the functional groups. Two ligands, DPPF and AsPh3 , were used [93,94]. TrocO

t-BuO2C

S

O N

Me +

OTBS

O OTroc

1. 9-BBN, THF 2. PdCl 2(dppf) AsPh3, Cs2CO3, THF DMF, H 2O, 65%

Me 120

121

I TrocO

S N OH CO2t-Bu O Me O OTroc 122

Me

Cross-Coupling Reactions with Organometallic Compounds

309

The first total synthesis of (−)-gambierol, a marine polycyclic ether toxin, has been achieved utilizing the coupling of alkylborane, derived by hydroboration of the terminal alkene in 123, with the enol phosphate 124 to provide 125 in high yield (86 %). Enol phosphates have been shown to be good coupling partners [95]. Ciguatoxin and gymnocin A, related marine polycyclic ether toxins, have been synthesized based on a similar methodology [96]. BnO Me BnO

Me O

OPMB +

O H

O H 123

H

H

O

H

O (PhO)2P

O

O Me

1. 9-BBN, THF

O Me

H

124

2. PdCl 2(dppf) DMF, 50 °C, 86%

O

O H

O

BnO Me BnO

Me

OPMB

O

H H

O O H

H

H

O

O Me

H

O Me

O

O H

125

H

O

Alkylboranes with alkyl halides Akylborane–alkyl halide coupling has been regarded as a difficult, but challenging reaction. In 1992, Suzuki and Miyaura showed for the first time that the coupling of n-octylborane 126 with n-hexyl iodide afforded tetradecane in 64 % yield. It should be noted that PPh3 was used as a ligand [97]. Recently, Fu and co-workers have revived the reaction. They carried out the coupling of dodecyl bromide (127) with octylborane 126 at room temperature smoothly to give eicosane (128) in 85 % yield. The best ligand is PCy3 .

n-Hex 9-BBN

+ n-Hex-I

126

n-Hex 9-BBN 126

+

Pd(PPh3)4, K3PO4 dioxane, 64%

Br

n-Dec 127

Pd(OAc)2, PCy3 K3PO4, THF rt, 85%

n-Hex

n-Dec 128

310 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Interestingly, P(t-Bu)3 and PPh3 are poor ligands, and the yields were < 2 % with these ligands [98]. Surprisingly even less-reactive alkyl chlorides undergo the coupling. Reaction of dodecyl chloride (129) with octylborane 126 at 90 ◦ C provided eicosane (128) in 83 % yield when PCy3 and CsOH were used [99]. Again P(t-Bu)3 , PPh3 and other easily available ligands gave poor results. It has been unexpected that alkyl chlorides undergo oxidative addition so easily. Furthermore, dodecyl tosylate (130) undergoes smooth coupling [100]. Interestingly, PCy3 is a poor ligand in this case. The best yield (80 %) was obtained when P(t-Bu)2 Me was used as a ligand. The discovery of facile reactions of alkyl chlorides has been a breakthrough in this field, and may yield further developments. n-Hex +

9-BBN 126

126

OTs

n-Dec 130

Pd(OAc)2, PCy3 CsOH, dioxane 90 °C, 83%

129

n-Hex +

9-BBN

Cl

n-Dec

n-Hex

n-Dec 128

Pd(OAc)2, P(t-Bu)2Me NaOH, dioxane 50 °C, 80%

n-Dec

n-Hex 128

References 1. Review: J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, and M. Lemaire, Chem. Rev., 102, 1359 (2002). 2. (a) N. Miyaura (Ed.), Cross-coupling Reactions, Springer Verlag, Berlin, 2002; (b) F. Diederich and P. J. Stang (Eds), Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, New York, 1998; (c) T. Tamao, T. Hiyama, and E. Negishi, (Eds), J. Organomet. Chem., 653 (2002); (d) S. -I. Murahashi and S. G. Davies (Eds), Transition Metal Catalyzed Reactions, Blackwell Science, Oxford, 1999. 3. E. Negishi, J. Organomet. Chem., 653, 34 (2002). 4. A. F. Littke and G. C. Fu, Angew. Chem. Int. Ed., 41, 4177 (2002). 5. A. C. Hilier, G. A. Grasa, M. S. Viciu, H. M. Lee, C. Yang, and S. P. Nolan, J. Organomet. Chem., 653, 69 (2002). 6. M. Jakt, L. Johannissen, H. S. Rzepa, D. A. Widdowson, and R. Wilhelm, J. Chem. Soc., Perkin Trans. 2, 576 (2002). 7. Y. M. Kim and S. Yu, J. Am. Chem. Soc., 125, 1696 (2003). 8. A. Suzuki, Organic Syntheses via Boranes, Vol.3, Suzuki Coupling, Aldrich, Milwaukee, WI (2003). 9. (a) Reviews: A. Suzuki, Acc. Chem. Res., 15, 178 (1982); Pure Appl. Chem., 66, 213 (1994); (b) A. Suzuki, in Metal-catalyzed Cross-coupling Reactions, Eds F. Diederich and P. J. Stang, Wiley-VCH, New York, 1998, p. 49; (c) A. Suzuki, J. Organomet. Chem., 653, 83, 147 (2002); (d) A. Suzuki, in Transition Metal Catalyzed Reactions, Eds S. -I. Murahashi and S. G. Davies, Blackwell Science, Oxford, 1999, p., 441; (e) N. Miyaura, in Cross-coupling Reactions (Ed. N. Miyaura), Springer Verlag, Berlin, 2002, p., 11; J. Organomet. Chem., 653, 54; (f) V. Snieckus, Chem. Rev., 90, 879 (1990); (g) D. S. Matteson, Tetrahedron, 45, 1859 (1989); A. Suzuki, J. Organomet. Chem., 576, 147 (1999). 10. Review: E. Tyrrell and P. Brookes, Synthesis, 469 (2003). 11. N. Miyaura, K. Yamada, and A. Suzuki, Tetrahedron Lett., 20, 3437 (1979); N. Miyaura and A. Suzuki, J. Chem. Soc., Chem. Commun., 866 (1979); N. Miyaura, T. Yanagi, and A. Suzuki, Syn. Commun., 11, 513 (1981).

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3.6.3 Organostannanes (Kosugi–Migita–Stille Coupling) 3.6.3.1 Introduction and Preparative Methods of Organostannanes Couplings of organostannanes with halides were discovered by the Kosugi–Migita [1] and Stille groups [2]; the reaction is called the Kosugi–Migita–Stille coupling [3–5]. It is a useful reaction due to air and moisture stability and excellent functional group compatibility of organostannanes, which can be prepared easily. The coupling can be run under neutral conditions. On the other hand, stoichiometric consumption of toxic organostannanes is a drawback, making it unsuitable for large-scale production. RSnBu3 + Ar-X

[Pd]

Ar-R + XSnBu3

Organostannanes are prepared by several methods. Hydrostannation of alkenes and alkynes is an established synthetic method of alkyl- and alkenylstannanes. Arylstannanes are prepared by the reaction of aryllithiums with R3 SnCl. The Pd-catalyzed reaction of aryl halides with hexa-n-butyldistannane (1), discovered by Eaborn [6] is a widely used synthetic method of arylstannanes. The method was applied to the preparation of 5, 5
-dibromo-2, 2
-bipyridine from 2,5dibromopyridine (2) [7]. Two bromines in 2 exhibit different reactivity, and 2bromo is selectively displaced by the tributylstannane group to give 3, which selectively reacts with 2 to afford 5, 5
-dibromo-2, 2
-bipyridine. Transmetallation of (Me3 Sn)2 is faster than (Bu3 Sn)2 . Sometimes, poor results are obtained with (Bu3 Sn)2 . In such a case, use of (Me3 Sn)2 is recommended [8]. The direct coupling can be carried out conveniently without isolation of organostannanes. The intramolecular version is a convenient method of cyclization via aryl–aryl coupling [9]. As an application, the synthesis of benzo[4.5]furo[3.2-c]pyridine (6) was achieved in high yield by the Pd-catalyzed reaction of the heterodiaryl ether 4 with hexamethyldistannane (5) [10].

314 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides X

Pd-X Pd(0)

Bu3SnSnBu3 1

XSnBu3 Pd-SnBu3

Br +

Br

SnBu3

Bu3SnSnBu3

Pd(PPh3)4

Br

xylene

N

SnBu3 N

2

3 Br

Br N 2

Br

Br

80%

I

N

N

I

N

+ O 4

PdCl2(PPh3)2

Me3SnSnMe3

xylene reflux 92%

5

N

SnMe3 I O

N

O 6

An interesting preparative method of arylstannanes based on the Pd-catalyzed reaction of aryl iodides with tributyltin hydride at room temperature has been reported by Murata et al. [11]. Interestingly, the reaction of p-iodoanisole with tin hydride generates the Pd—Sn bond 7, and not anisole by hydrogenolysis. Anisylstannane (7) is obtained in good yield, and the amount of anisole is small. The use of AcOK as a base and NMP as a solvent are most effective. Concerning the mechanism of the reaction, facile formation of hexabutyldistannane by Pd-catalyzed reaction of HSnBu3 is known [12]. This is the first step of the reaction, and transmetallation of anisylpalladium 8 with distannane generates 9 and its reductive elimination gives anisylstannane (7). From this mechanism, it is understandable that formation of anisole via the palladium hydride 10 is a minor path. Aryl, alkenyl, and alkynylstannanes, and some alkylstannanes are used for the coupling with aryl and alkenyl halides, pseudohalides and arenediazonium salts. The reaction of allylstannane with aryl iodides is the first example of the Pd-catalyzed cross-coupling of organostannanes [1]. Generally only one of four organic groups on the tin is utilized for the coupling reaction. Kosugi reported

Cross-Coupling Reactions with Organometallic Compounds

315

that four aryl groups of tetraarylstannanes can be utilized in the fluoride-assisted coupling in the presence of 4 equivalents of TBAF [13]. PhSnCl3 was used for the coupling with water-soluble p-iodophenol using water-soluble ligand II-2 [14,15]. I

SnBu3 + 2 H-SnBu3 + AcOK

PdCl2(PPh3)2

+ Bu3SnOAc + H2 + KI

NMP, rt, 90% OMe

OMe

7 Pd(0) cat

2 H-SnBu3 I

Pd-I

SnBu3

OMe

OMe

9

7

Pd-OAc

Pd(0)

OMe

Pd-SnBu3 H2 + Bu3SnSnBu3

Bu3SnOAc

AcOK

OMe

OMe 8

Pd-I

Pd-H

H

OMe 10

OMe

H-SnBu3

OMe

Sn + 4 Br

Me

OMe

4

+ PhSnCl3 HO

TBAF(4 equiv.) dioxane, reflux 74%

OMe

Me

I

Pd(dba)2, PPh3

PdCl2, (II-2) KOH, H 2O 87%

HO

Different groups are transferred from Sn with different selectivities. A simple alkyl group has the lowest transfer rate. Thus asymmetric organostannanes containing three simple alkyl groups (usually methyl or butyl) are chosen, and the fourth group, which undergoes transfer, is usually an alkynyl, alkenyl, aryl, benzyl, or allyl group. The cross-coupling of these groups with aryl, alkenyl, alkynyl, and benzyl halides affords a wide variety of cross-coupled products. Usually PPh3 is used as a ligand. However, a large acceleration rate is observed in some cases when tri2-furylphosphine (TFP) (I-3) and AsPh3 are used [16]. Also, addition of CuI [17], or CuCl and LiCl in DMSO is recommended [18]. In this case, transmetallation

316 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides of alkenylstannane 11 with CuCl takes place at first to generate alkenylcopper 12, which undergoes transmetallation with arylpalladium to give 13. Reductive elimination affords the coupled product 14. The rapid double transmetallation results in acceleration of the coupling reaction. 10 Bu3Sn

R

+ CuCl

R +ClSnBu3

Cu

11

12 Ar-Pd-X Ar-X CuX Pd(0)

Pd(0) + Ar

Ar-Pd

R 14

R 13

Mechanistic studies on the Kosugi–Migita–Stille coupling have been carried out [19]. The coupling consumes a stoichiometric amount of organostannanes. Attempting to improve the reaction, Maleczka’s group reported a coupling reaction, which is catalytic in Sn [20]. They found that the Pd-catalyzed reaction of terminal alkyne 15, alkenyl halide 16, PMHS (polymethylhydrosiloxane) and a catalytic amount of Me3 SnCl affords conjugated diene 17 when two kinds of Pd catalysts [PdCl2 (PPh3 )2 and Pd2 (dba)3 /TFP, 1 mol % each] are used. PMHS behaves as a reducing agent of Me3 SnX to Me3 SnH. The catalytic process is based on the following steps. At first Me3 SnH (18) is generated by reduction of Me3 SnX with PMHS, and alkenylstannane 19 is generated by Pd-catalyzed hydrostannation of alkyne with Me3 SnH. Then Pd-catalyzed cross-coupling of 19 with alkenyl halide affords conjugated diene 21 and Me3 SnX, which is reduced with PMHS. Transmetallation of 19 generates 20 as an intermediate. Two Pd-catalyzed reactions may Me OH + Me 15

Ph + PMHS

Br 16

SnMe3

R1

Me3SnCl (6 mol%) PdCl2(PPh3)2 (1 mol%) Pd2(dba)3 (1 mol%) TFP(I-3) (4 mol%) aq. Na 2CO3, Et2O, 91% R2

HO Me

Me Ph 17

R1

Pd-X

R2 21

19 R1

Pd H-SnMe3

X-SnMe3

18

R1

Pd 20

PMHS

R2

R2

X

Cross-Coupling Reactions with Organometallic Compounds

317

need two kinds of Pd catalyst. In this reaction, only trisubstituted alkynes, typically 15, are used, because hydrostannylation of alkynes should be regioselective. The coupling of organostannanes, partly due to functional group compatibility, has been used in efficient syntheses of medicinal compounds and natural products. 3.6.3.2 Coupling of Aryl- and Heteroarylstannanes Aryl- and heteroarylstannanes are used extensively for aryl–aryl or aryl–alkenyl coupling. First, examples of aryl–aryl coupling are cited. Several types of catalysts are used. A combination of Pd-P(t-Bu)3 is recommended as a mild and general catalyst for the coupling of aryl bromides, chlorides, and triflates with a range of organostannanes [21]. Couplings of congested aryl chloride 23 with the sterically hindered arylstannane 22 proceeded at 100 ◦ C in the presence of CsF as a base. The reaction of the corresponding aryl bromides occurs at room temperature. The most remarkable is the unprecedented chemoselectivity observed in the reaction of 4-chlorophenyl triflate (25) with phenytributylstannane (24) to give 26 selectively. Furthermore the higher reactivity of chloride over triflate was demonstrated by intermolecular competitive reaction of the aryl chloride 27 and the triflate 28 with 24 to produce the biphenyl 29 with high selectivity. Yield of the coupling product 30 of the triflate 28 was only 2 %. The catalyst Pd/P(t-Bu)3 activates the C—Cl bond in preference to the C—OTf bond to afford 26 and 29 at room temperature in excellent chemoselectivity and high yields. The observed chemoselectivity shows that the belief that the C—OTf bond is more reactive than the C—Cl bond is not valid any more when Pd/P(t-Bu)3 is used. Similar chemoselectivity was observed also in the Suzuki–Miyaura coupling of the corresponding compounds (see Chapter 3.6.2.3). Me

Me Me +

Bu3Sn

Me Cl

Me

Me 22

Pd2(dba)3, P(t-Bu)3 Me

CsF, dioxane 100 °C, 89% Me Me

23 Pd2(dba)3, P(t-Bu)3

+ TfO

Bu3Sn

Me

Cl

24

CsF, dioxane rt, 93%

TfO

25

26

n-Bu n-Bu

SnBu3

24 1 equiv.

Me Pd2(dba)3, P(t-Bu)3

+

+

Cl

Me

+

CsF, dioxane, 60 °C OTf

27

28

1 equiv.

1 equiv.

29

30

85%

2%

318 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Coupling of heteroarylstannanes with heteroaryl halides proceeds smoothly. The dimethylterpyridine (33), a useful pyridine-based ligand, was prepared by the coupling of 2,6-bis(trimethylstannyl)pyridine (31) with 6-bromo-3-picoline (32) in 68 % yield [22]. A first synthesis of thiophene dendrimers was carried out based on the coupling of the stannylthiophene 34 with both bromides of 2,3dibromothiophene (35) to give 36 in high yield in the presence of Pd(PPh3 )4 in DMF [23]. Me

Pd(PPh3)4, toluene

+ Me3Sn

N

100 °C, 68%

SnMe3

N

31

Br

32 C6H13 Br

S

N

+

Bu3Sn

N

S

S

C6H13

N

Me

Me

S

Br 35

33

34

C6H13 S C6H13

S

C6H13

S

Pd(PPh3)4, DMF 90%

S

S

S

S C6H13 36

Coupling of gem-dibromostyrene derivatives with organostannanes affords two kinds of products depending on the solvents. Reaction of the dibromide 38 with 2-stannylfuran 37 in toluene produced the (Z)-bromoalkene 39 stereospecifically. TFP was used as a ligand. Interestingly the internal alkyne 40 was obtained in DMF when an electron-rich triarylphosphine or TFP is used. The solvents (toluene or DMF) used make a difference in chemoselectivity [24]. Generally alkenyl halides are more reactive than aryl halides. An opposite chemoselectivity was observed in the competitive reaction of chlorobenzene and

Cross-Coupling Reactions with Organometallic Compounds

319

Br +

Br

SnBu3

O

MeO2C

37

38

Pd2(dba)3, TFP(I-3)

O

toluene, 100 °C, 80%

Br MeO2C 39 O

Pd2(dba)3, P(4-MeOPh)3

i-Pr2NEt, DMF, 80 °C 80%

MeO2C 40

1-cyclopentenyl chloride with the arylstannane 41 in the presence of P(t-Bu)3 . A larger amount of the aryl–aryl coupling product 42 was obtained than that of the aryl–alkenyl product 43 in the presence of P(t-Bu)3 , showing that aryl chloride was coupled in preference to alkenyl chloride [21]. SnBu3 Me

41 1 equiv

Pd2(dba)3, P(t -Bu)3

+

+

CsF, dioxane 100 °C, 82%

Cl

Cl

1 equiv

1 equiv

Me

+

Me

42

43

71%

34%

Methylation is possible by the reaction of arylstannane with MeI. In order to find a general protocol for the synthesis of short-lived 11 CH3 -labeled PET (positron emission tomography) tracers for incorporation of radionuclides into bioactive organic compounds, Suzuki and co-workers carried out the coupling of MeI with tributylphenylstannane (24) to afford toluene as a model reaction in 91 % yield within 5 min. P(o-Tol)3 was used as a ligand, together with CuCl [25]. SnBu3

Me +

24

MeI

Pd2(dba)3, P(o-Tol) 3 CuCl, K2CO3, DMF 60 °C, 5 min, 91%

320 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.6.3.3 Coupling of Alkenylstannanes Alkenyl–aryl and alkenyl–alkenyl couplings are also widely used. Pd/P(t-Bu)3 is an efficient catalyst for the coupling of aryl chlorides with aryl-, alkenyl-, and alkylstannanes [21]. Coupling of 4-chloroanisole with vinylstannane proceeded at 100 ◦ C with the use of CsF as a base. Addition of CuCl and LiCl in DMSO is recommended, which accelerates the transmetallation step in the coupling of sterically congested substrates. Coupling of the alkenylstannane 44 with naphthyl nonaflate proceeded smoothly to give 45 in 88 % yield [18]. Cl

Pd2(dba)3, P(t-Bu)3

+

Bu3Sn

CsF, dioxane 100 °C, 82%

MeO

ONf

C5H11

Bu3Sn

+

OH

MeO

Pd(PPh3)4 CuCl, LiCl

C5H11

DMSO, 60 °C 88%

44

OH 45

As an example of alkenyl–aryl coupling, solid-phase synthesis of the macrocyclic system of (S)-zearalenone (47) was achieved based on coupling and cyclorelease strategy. Cyclization of polymer-bound alkenylstannane with aryl iodide moiety proceeded in 54 % yield, and the product was deprotected to give 47 [26]. Aiming at the synthesis of penta(cyclopentadienyl)cyclopentane, Vollhardt prepared pentacyclopentadienylated cyclopentadiene complex 50 by coupling tributylcyclopentadienylstannane (48) with tricarbonyl(η5 -pentaiodocyclopentadienyl)manganese (49) in one step in 28 % yield [27]. MEMO

O 1. Pd(PPh 3)4, toluene 100 °C, 448 h, 54%

O MEMO

I Bu

2. THF, HCl aq, 23 °C 5 days, 80%

Bu Sn O 46

HO

O O

HO

O 47

I

I Mn(CO)3 I

+

Bu3Sn

I 48

PdCl2(MeCN)2, DMF

Mn(CO)3

90 °C, 15 min, 28%

I 49 50

Cross-Coupling Reactions with Organometallic Compounds

321

Alkenyl–alkenyl coupling is useful for the preparation of stereo-defined diene or polyenes, and applied extensively to efficient syntheses of natural products partly due to good functional group compatibility. In the total synthesis of (−)-gambierol, a marine polycyclic ether toxin, by two groups [28,29], the sensitive terminal (Z, Z)-triene side chain in 53 was constructed as a crucial step by stereoselective coupling of (Z)-alkenyl iodide 51 with (Z)-1,4-pentadienylstannane 52 in DMSO to afford 53 in 72 % yield without isomerization of the triene system. Pd2 (dba)3 and CuI as catalysts and TFP (I-3) as a ligand were used [29]. Similar coupling using the less reactive alkenyl bromide provided 53 in 43 % yield [28]. OH Me

Me

H

H

O

O

H O

H

HO O H

H

O H

H

O H Me

H

H

O

Me

51

SnBu3

O

H

OH

I

Me 52 Pd2(dba)3, CuI TFP, DMSO/THF 40 °C, 72%

H O

H H O

H

Me Me

O H

OH Me 53

In the total synthesis of amphidinolide A (57), a key step is the coupling of di(alkenylstannane) 54 with 55, which has the alkenyl iodide and allyl acetate moieties as reactive groups. The coupling proceeded in two steps when AsPh3 is used as a ligand. At first, reaction took place chemoselectively with the alkenyl iodide to give 56. Then cyclization of 56 occurred by the coupling of the allylic acetate moiety with the alkenylstannane in cyclohexane in the presence of LiCl to afford 57 [30]. The Sonogashira coupling of the terminal alkyne in 58 with the ditriflate 59 occurred selectively in the presence of Pd-CuI catalyst to give 60. Then domino coupling/Diels-Alder reaction of 60 occurred to afford 62 via 61 at room temperature. It is interesting that [4 + 2] cyclization of nonactivated diene and dienophile (a triple bond) occurred even at 20 ◦ C, and the result suggests a possible role of the Pd catalyst. The compound 62 was spontaneously transformed completely to the final product 63 through oxidative aromatization [31].

322 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides OTES AcO

TESO SnBu3 +

TESO

O I TESO

O

SnBu3

O

54

55 OAc OH HO SnBu3

1. Pd 2(dba)3, AsPh3 THF, 60 °C

HO

2. PPTS, MeOH, CH2Cl2, rt

HO

O O

51%

O 56 OH HO HO

Pd2(dba)3, AsPh3, LiCl

O

cyclohexane, 42%

O HO O 57

SnBu3

SnBu3 OTf OTf

+

O

O

TfO PdCl2(PPh3)4, CuI PhH, i-Pr2NH 79%

59

O

58

O 60 H

H PdCl2(MeCN)2 LiCl, DMF 20 °C, 48%

O O

O

O

61

62

O O

63

Cross-Coupling Reactions with Organometallic Compounds

323

Total synthesis of (−)-macrolactin A, a 24-membered macrolide, was achieved based on intramolecular coupling of alkenylstannane with iodide in 64 to afford the macrolide 65 as a key reaction. The cyclization occurred without a phosphine ligand in NMP in 42 % yield [32]. Bu3Sn

OTBS

OTBS

I Pd2(dba)3, NMP O

O

Hunig's base rt, 7 days, 42%

TBSO

O

O

TBSO TBSO

TBSO 64

65

Methyl ketones are prepared by the coupling of 1-ethoxyvinylstannane (67) and hydrolysis. The coupling of the bromonaphthoquinone 66 with 67 afforded 68, and was applied to synthesis of an azido analog of medermycin [33]. Me AcO O

OMe

O Br

N3

OEt

Pd(PPh3)4, CuBr

+ SnBu3 O

dioxane, 100 °C 71%

67 Me

66 AcO

O

OMe

O

O

N3

O 68

Stereoselective syntheses of the trienes 71 and 73 were carried out in very high yields by the coupling of the dienyl nonaflate 69 with the (E)- and (Z)alkenylstannanes 70 and 72 in the presence of AsPh3 as a ligand in DMF at room temperature. The nonaflate was found to be more reactive than the corresponding triflate [34]. The coupling of the enol triflate 74 with the stannyl enol ether 75 proceeded rapidly at room temperature to give 76 in good yield in the presence of CuCl as an additive, which plays a crucial role for the success of the coupling. The reaction has been utilized extensively for the construction of polyether systems of marine natural products such as maitotoxin [35].

324 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

Bu3Sn

OH 70

OH

Pd2(dba)3, AsPh3 DMF, rt, 100%

ONf

71

Bu3Sn

69

OH

72

Pd2(dba)3, AsPh3 DMF, rt, 92%

OH 73

Me Me

H

H

O

O

BnO

O BnO H

Me

OTf

H

O Me 74 + Me

Me

H

O

O

Me3Sn

OBn

O H

H

Pd(PPh3)4, CuCl K2CO3, THF 25 °C, 81%

OBn Me

75 Me Me

H

H

O

BnO

Me

O

O O

BnO

H

O H

Me

Me

H OBn

H H

76

Me

O O Me

OBn

Enol phosphate is a good coupling partner. Coupling of the lactone enol phosphate 77, derived from 11-undecanolide, with vinylstannane afforded the cyclic enol ether 78 in good yield [36]. The mimetic of brassinolide 81 was prepared in high yield by the coupling of trans-bis(tri-n-butylstannyl)ethylene (79) with the enol triflate 80 [37]. It is known that the reaction of 1,1-dibromo-1-alkenes with organostannanes affords internal alkynes [24]. The (chlorocyclopropyl)dienyne side chain 84 of callipeltoside A was prepared in 95 % yield by the coupling of the 1,3-dienylstannane 82 with the dibromide 83. The use of DMF is important [38].

Cross-Coupling Reactions with Organometallic Compounds

O

O

O

O

(PhO)2POCl

P

96%

O

(OPh)2

77

O Bu3Sn Pd(PPh3)4, LiCl THF, 84% 78 OTf H O

SnBu3

Bu3Sn

+ O HO

79

O

80

OH

O

O O H

Pd(PPh3)4 THF, LiCl, 89%

H O O HO

O

81 Br Bu3Sn

OH

+

Br Cl

82

H 83 OH

Cl

H

84

Pd2(dba)3, P(4-MeOPh)3

i-Pr2NEt, DMF, 80 °C 95%

325

326 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The N -alkoxyimidoyl bromide 85 is used as an efficient coupling partner with vinylstannane to afford the ketone oxime 86 in the presence of KF as a base [39]. Pd-catalyzed hydrostannation of the enamine 87 provided the N -tosyl-α-stannyl enamine 88. Functionalized α-substituted enamine 90 can be prepared by Pdcatalyzed coupling with alkenyl iodide 89. AsPh3 was used as a ligand [40]. OBn SnBu3

+

N

KF, toluene 110 °C, 30 min 90%

Br

Ph

OBn

Pd(PPh3)4

N

85

Ph 86

O I O

Ts Ts + HSnBu3

N Bn

Pd(PPh3)4

N

THF, 65% SnBu3

87

Ts

89

Bn

N

Pd2(dba)3, AsPh3

88

CuCl, THF 91%

Bn 90

Interestingly coupling of n-decyl bromide with alkenylstannane proceeded smoothly at room temperature to afford 1-dodecene in 96 % yield. Uses of P(t-Bu)2 Me as a ligand, Me4 NF (1.9 equiv.), and a molecular sieve are important. P(t-Bu)3 is not effective [41]. Similarly, tetradeca-1,6-diene was prepared [41].

n-Dec-Br +

(h3-allyl-PdCl)2, P(t-Bu)2Me

Bu3Sn

n-Dec

Me4NF, THF, rt, 96%

3.6.3.4 Coupling of Alkylstannanes Alkylstannanes are less reactive, and no reaction of the n-Bu group in RSnBu3 is usually observed. Pd-P(t-Bu)3 is a good catalyst for the coupling of 4-chloroanisole with tetra-n-butylstannane to give 4-n-butylanisole in good yield in the presence of CsF as a base [21]. The protected carbapenem 93 was prepared commercially in high yield by the coupling of the enol triflate 91 with the fully elaborated stannatrane 92 as a coupling partner by the use of TFP in NMP. Deprotection of 93 gave the desired carbapenem 94. Use of the stannatrane 92 as an organostannane reagent is crucial in this case [42]. Cl + MeO

Bu

Pd2(dba)3, P(t-Bu)3 Bu4Sn

CsF, dioxane 100 °C, 82%

MeO

Cross-Coupling Reactions with Organometallic Compounds

327

+ N N TESO H

H

+

Me

Me

CONH2

+

OTf

N

N O

N

SO2

2 OTf

−

Sn

CO2PNB 91

92 + N N

Pd2(dba)3, TFP(I-3)

i-Pr2NEt, NMP 98%

TESO H

H

+ CONH2

Me N

Me

SO2

2 OTf

−

N

+

N O CO2PNB 93 + N deprotection HO H

H

CONH2

Me N

Me

SO2

Cl

−

N O

− CO2 94

Morken and co-workers have accomplished enantioselective total synthesis of borrelidin, amply demonstrating the usefulness of several Pd-catalyzed reactions. Only a part of their efficient synthetic approach to this multifunctional macrolide is cited here [43]. The Sonogashira coupling of 95 with 96 afforded 97 in 94 % yield. Pd-catalyzed regioselective hydrostannation of the triple bond of 97, followed by iodination and deacetylation of the resulting alkenylstannane afforded the alkenyl iodide 98. Pd-catalyzed cyanation of 98 using Bu3 SnCN was carried out in the presence of CuI as a cocatalyst to provide the nitrile 99 in very high yield (97 %). 3.6.4 Organozinc Compounds (Negishi Coupling) 3.6.4.1 Introduction and Preparation of Organozinc Compounds Cross-coupling of organozinc reagents is called Negishi coupling [44]. Reaction of organozinc reagents (aryl, alkenyl, alkyl) with alkenyl and aryl halides proceeds generally with high yields and tolerates a wide range of functionality. Aryl-, alkenyl-, and alkylzinc reagents are prepared most conveniently in situ by the reactions of organolithium, magnesium, and aluminum reagents with ZnCl2 , and used without isolation. Gauthier and co-workers suggest that kilogram quantities

328 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Me

Me

Me

OTIPS I

OAc

CO2Me

OAc Me

Pd(PPh3)4, CuI

H

+

Et3N, 94%

CO2Me

95

96 Me

Me

Me OAc

CO2Me

1. HSnBu 3 PdCl2(PPh3)2

OTIPS

2. I 2, 97%

OAc Me

H

CO2Me

97

Me

Me

Me OH

OH

Me

CO2Me

Bu3SnCN

OTIPS

Pd(PPh3)4, CuI 97%

I H

H

CO2Me

98 Me

Me

Me

Me

Me

Me OH

OMOM steps

OMOM Me

CO2H OTIPS NC H

99

H

OH

O

Me NC H

CO2Me

O H

CO2H

borrelidin

of solid ZnCl2 can be oven dried at 120 ◦ C in vacuum with N2 purge for 3–5 days. Handling of a THF solution is preferred to the solid, but commercial ZnCl2 solution (THF, Aldrich) contains 0.5 % H2 O as determined by Karl Fisher titration [45]. Tetramethylpiperidine-zincate 1 is a good reagent for directed ortho zincation of various functionalized aromatic and heteroaromatic compounds. For example, benzoate was converted to biphenyl-2-carboxylate 2 by zincation with 1, followed by coupling with iodobenzene [46]. A facile and convenient preparative method of alkylzinc reagents is direct reaction of alkyl iodides with activated Zn/Cu couple [47] or Zn dust [48]. Huo reported an efficient, general preparative method of alkylzincs from unactivated

Cross-Coupling Reactions with Organometallic Compounds

329

alkyl bromides and chlorides, which relied on activation of Zn dust with 1–5 mol% of iodine [49]. Alkenylzinc reagents are prepared conveniently in situ by hydrozirconation of 1-alkyne, followed by transmetallation from Zr to Zn with ZnX2 . Then coupling is carried out without isolation of Zn reagents, and hence a catalytic amount of ZnX2 is enough. For example, hydrozirconation of 1-alkyne 3, followed by coupling with the alkenyl bromide 4 to provide the conjugated (all-E)-oligoene 5 with retention of stereochemistry, was carried out using both Pd complex and ZnCl2 as catalysts [50]. X

Li

CO2Et Me Me

t-Bu

Zn

X = Br, I

I

Me N

ZnX ZnX2

t-BuLi

+

Me

1. TMP-zincate THF, rt 2. Pd(PPh 3]4 rt, 58%

CO2Et

t-Bu 2

1 +

TBSO 3 1. HZrCp 2Cl 2. Pd(PPh 3)4 , ZnCl2

CO2Et

Br 4

CO2Et

TBSO

71%

5

3.6.4.2 Coupling of Aryl- and Alkenylzinc Reagents For aryl–aryl coupling, aryl iodides, bromides, and triflates are used. It has been shown that the Negishi coupling of arylzinc reagents with aryl chlorides proceeds smoothly by the use of commercially available, air-stable Pd[P(t-Bu3 )]2 . Coupling of arylzinc chloride 6 with electron-rich 4-chloroanisole (7) proceeds smoothly in THF–NMP using Pd[P(t-Bu3 )]2 as a catalyst to give 8 in high yield [51]. In synthetic studies toward diazonamide, aryl–aryl coupling was employed. Reaction of the arylzinc reagent 10, derived from the aryl iodide 9 via a Grignard reagent, with 4-iodoindole-3-carboxaldehyde (11) to afford 12 proceeded in high yield using Pd[P(t-Bu3 )]2 . The yield was poor when DPPF was used as a ligand [52]. Cl ZnCl

Me Me

Pd[P(t-Bu)3]2

+

THF, NMP 100 °C, 94% OMe

6

7

MeO 8

330 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides CO2TMSE

CO2TMSE 1. i-PrMgCl 2. ZnBr 2

OBn

OBn ZnBr

I 9

10

I

CHO BnO

CO2TMSE

N 11 Pd[P(t-Bu)3]2

CBz 87%

N

BzC

Pd(dba)2/DPPF 27%

CHO 12

A new ionic phosphine ligand (I-19) is effective for the coupling of arylzinc 13 with aryl iodide 14 at room temperature to give 15 in a biphasic system containing toluene, THF, and an ionic liquid [bdmim][BF4 ]. The Pd catalyst always stays in the ionic liquid and can be recycled [53]. ZnBr

I Pd(dba)2, I-19 +

OMe

OAc

13

14

MeO

rt, 0.3 h, 89% [bdmim][BF4] toluene, THF

OAc 15

Coupling of heteroarylzinc halides and heteroaryl halides proceeds smoothly. The bithiazole 18 was obtained in 85 % yield by regioselective coupling of the 2bromo group in 2,4-dibromothiazole (16) with the 4-thiazolylzinc chloride 17 [54]. The tri(furylzinc) reagent 19 undergoes smooth coupling with 2-chloropyridine to give the coupling product 20 in the presence of DPPF. All three furyl groups in 19 are utilized for the coupling [45]. Br N

t-BuLi ClZn ZnCl2

Br N S

Bu

S 16

N Bu

S

Br

Br N N

PdCl2(PPh3)2 85%

S 18

17

EtO O

ZnLi

EtO

N

+

N

1. PdCl 2(dppf) 2. 5 N HCl

Cl

OHC

O

89%

3

19

Bu

S

20

Cross-Coupling Reactions with Organometallic Compounds

331

Coupling of the sterically congested arylzinc chloride 21 with 1-cyclopentenyl chloride (22) gave 23 in high yield when Pd[P(t-Bu3 )]2 was used as a catalyst in THF–NMP [51]. ZnCl

Me

Me

Me

Pd[P(t-Bu)3]2

Cl +

Me

THF, NMP 100 °C, 96% Me

22

Me

23

21

Arylalkenes, conjugated dienes, and polyenes are produced by the coupling of alkenylzinc reagents. The first total synthesis of cystothiazole E was achieved by applying the Negishi coupling twice and Suzuki–Miyaura coupling once. Coupling of 2-propenylzinc chloride (24) occurred selectively with the 2-bromo group of 2,4-dibromothiazole (16), and 25 was obtained after hydrogenation of the coupling product. The 4-thiazolylzinc chloride 26 also reacted selectively with the 2-bromo group of 16 to afford the bromobithiazole 27. Finally Suzuki–Miyaura coupling of 27 with the alkenylboronic acid 28 provided the coupling product 29, which was converted to cystothiazole E [55]. Br

ClZn

N

+

Br

S 24

Pd(PPh3)4

H2

25 °C, THF

Pd/C 68%

16 ClZn

Br

N

N

16

t-BuLi ZnCl2 , 68%

S

Pd(PPh3)4 60 °C, THF 97%

S

25

26

Br TBDMSO

N N

OMe

+

S

B(OH)2

S 28

27 Pd(PPh3)4 , CsOH, 95 °C,

TBDMSO

OMe

PhH, EtOH, H2O, 94%

N N S S

29 O

OMe N N S cystothiazole E

S

332 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The Negishi coupling was applied as a key reaction to a short synthesis of calyculin. The key building block 33 of the tetraene fragment of calyculin was synthesized from trans-bis(tributylstannyl)ethene (30) via four consecutive transfer reactions (Sn-Li-Zn-Pd-C). Exchange of Bu3 Sn in 30 with ZnCl2 gave 31, which underwent chemoselective coupling with the vinyl bromide 32 to give 33 in 95 % yield [56]. CO2Me

Br

n-BuLi ZnCl2

SnBu3

Bu3Sn

32

ZnCl Bu3Sn

30

Pd(PPh3)4 95%

31 CO2Me

Bu3Sn 33

3.6.4.3 Coupling of Alkylzinc Reagents Alkylzinc reagents can be used for the coupling without undergoing β-H elimination. Coupling of n-butylzinc chloride with 2-chlorotoluene proceeds smoothly using Pd[P(t-Bu3 )]2 [51]. In the total synthesis of sphingofungin, the alkylzinc 34 was derived from the long-chain alkyl iodide. Coupling of 34 with the alkenyl iodide 35 afforded 36, and sphingofungin F has been synthesized from 36 [57]. Cl

n-BuZnCl

Pd[P(t-Bu)3]2

+

THF, NMP 100 °C, 83%

Me C6H13

I

O

Me

C6H13

t-BuLi ZnCl2

5

O

n-Bu

O

ZnI O

5

34 TBSO

H

O

Ph

I Me

35

TBSO

N

O

O Pd(PPh3)4, THF, rt, 68%

H

C6H13 O

O

5

O

Ph N

O

Me O 36 OH

OH

C6H13

CO2H O

sphingofungin F

OH

Me NH2

Cross-Coupling Reactions with Organometallic Compounds

333

Total synthesis of (+)-pumiliotoxin A (39) has been achieved based on the Negishi coupling of the alkylzinc chloride 37, derived from the alkyl iodide, with the alkenyl iodide 38 at room temperature, and subsequent deprotection [58]. The alkylzinc reagent 41 was prepared conveniently by the reaction of the alkyl iodide 40 with Zn/Cu couple, and treated with 2-iodoimidazole 42 to afford the adduct 43 [47]. Me

Me

I

ZnCl

N

N

t-BuLi ZnCl2

Me

OTBDMS

Me

OTBDMS 37

Me

Me

I

Me OBn

38

OH N

1. Pd(PPh 3)4 benzene rt, 60%

Me

2. Et 3N,-3HF MeCN, 88%

OH 39

O

O Zn/Cu couple

I BnO

ZnI BnO

NHTrt

NHTrt

40 Boc

41

NHBoc

N

Boc O

I

N

NHBoc

N

CO2-t-Bu 42

BnO

PdCl2(PPh3)2, DMA, 40 °C, 79%

CO2-t-Bu

N NHTrt 43

Coupling of the alkenyl triflate 44 with the Zn homoenolate 45 proceeded smoothly to give 46. The coupling of triflate is the key reaction to construct a cyclic polyether fragment in the total synthesis of gambierol [59]. The methyl group was introduced in high yield by the reaction of the alkenyl triflate 47 with Me2 Zn to afford 48 [60]. H Ph

H

O + IZn O O H 44

OTf

CO2Me 45

Pd(PPh3)4

Ph

benzene, rt 74%

O CO2Me O O H 46

334 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides CO2t-Bu

TfO

CO2t-Bu

+ Me2Zn

O

Pd(PPh3)4

Me

91%

DPSO

O

DPSO 47

48

A versatile and regio- and stereoselective synthetic method of terpenoids containing 1,5-diene units has been developed by Negishi. Chemoselective coupling of the alkylzinc bromide 49 with the alkenyl iodide in 50 provided 51. The alkyl iodide in 51 was converted to alkylzinc bromide, which was coupled again with the alkenyl iodide 50 to provide 52. Coenzyme Q10 (53) was synthesized in 26 % overall yield by repeating a similar sequence of the coupling reactions [61].

TMS

ZnBr

+

PdCl2(dppf)

I I

49

THF, 23 °C 96%

50

TMS

50

t-BuLi ZnBr2

I

PdCl2(dppf) THF, 23 °C, 90%

51 O MeO TMS

2

I

9

52

MeO O 53

Aryl cyanides can be synthesized by Pd-catalyzed cyanation of halides or pseudohalides with Zn(CN)2 . As an example, the triflate group in the pyrimidone 54 was displaced with CN group to afford 55 in high yield [62]. OTf

CN Et

Zn(CN)2 +

Et

Pd(PPh3)4

N

N

DMF, 94% Ph

O

N

54

Ph

TMS

N

O

55

TMS

A formal total synthesis of nostoclide has been carried out based on regioselective coupling of 3,4-dibromo-2(5H )-furanone (56). Coupling of the dibromide

Cross-Coupling Reactions with Organometallic Compounds

335

56 with 2-propenyltributylstannane (57) afforded 58 regioselectively using AsPh3 as a ligand. Coupling of the corresponding boron and magnesium reagents were unsatisfactory. After hydrogenation of 58, the key intermediate 61 was obtained by coupling 59 with benzylzinc bromide (60). Curiously, attempted coupling of 58 with 60 produced only 1,2-diphenylethane and no desired coupling product was obtained [63].

Br

Br

Br PdCl2(PhCN)2 +

O

SnBu3

O

56

H2

AsPh3, NMP rt, 78%

O

57

O

RhCl(PPh3)3

58 ZnBr

Br 60 O

nostoclide

PdCl2[P(o-Tol) 3]2 O DMF, 35%

O

O

59

61

The benzylzinc bromide 63 reacted preferentially with the polymer-bound aryl iodide 62, without attacking the triflate. Then the benzylzinc bromide 64 was added to the reaction mixture, and coupling with the triflate occurred to afford 65 after cleaving from the polymer [64].

1.

O P

OTf 63 Pd(dba)2, TFP, rt

I

O

2. 62

BrZn

BrZn

3. TFA CO2H

64

OMe

OMe 65

Pd(dba)2, DPPF, 70 °C

3.6.5 Organomagnesium Compounds As described in preceding sections, organoboron, tin, and zinc reagents are widely used for couplings. In many cases these reagents are prepared from organolithium or magnesium compounds. Therefore direct couplings of Mg and Li compounds, if they proceed smoothly, are more atom-economical and convenient. Numerous Grignard reagents are commercially available and readily prepared from the corresponding halides. They are reactive partners of coupling. However, a drawback of this method is the intolerance to many functional groups and moisture. Coupling of arylmagnesium halides takes place with aryl, alkenyl, and alkyl halides. Reaction of electron-rich chlorides can be carried out using carbene ligand XVI-2. For example, the coupling product of 4-chloroanisole (2) with phenylmagnesium bromide (1) was obtained in high yield at room temperature [65]. Also

336 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides the coupling of unactivated aryl chlorides such as 4-chloroanisole (2) using airstable phosphine oxide (t-Bu2 P)(O)H) (XVIII-4) as a ligand proceeded at room temperature in high yield [66]. MgBr

Cl

Pd2(dba)3, XVI-2

+ MeO 1

MeO

dioxane, 20 °C 97% 2

MgBr

Cl

Pd2(dba)3, XVIII-4

+

MeO

rt, 93%

Me

MeO

Me 2

An interesting chemoselectivity between aryl bromides and triflates depending on ligands was observed. In the reaction of 4-bromophenyl triflate, the bromide reacted chemoselectively without attacking the triflate when Pd-MeO-MOP (VI12) complex was used to give 3 in 97 % yield. On the other hand, 4-bromobiphenyl (4) was obtained chemoselectively by using Pd-DPPF as a catalyst [67]. For the coupling of congested o-substituted aryl triflate 5, aminophosphine alaphos (VII6) is an effective ligand [68]. Unactivated aryl tosylate 6 can be coupled at room temperature using P(t-Bu)2 attached to ferrocene XI-11 as an effective ligand [69]. PdCl2(VI-12) 20 °C, 68%

OTf

MgBr

TfO 3

+ Br

PdCl2(dppp)

1

LiBr, 0 °C, 97%

Br 4

OTf MgBr

PdCl2(alaphos) (VII-6)

+

95% 5

1 MgBr TsO

Pd2(dba)3, (XI-11)

+

toluene, rt, 86%

Me

MeO

Me

OMe 1

6

Highly asymmetric coupling of Grignard reagents is possible. The axially chiral (S)-biaryl 9 was prepared with 93 % ee in 87 % yield by the reaction of the bistriflate 7 with PhMgBr. (S)-phephos (VII-7) was the best chiral ligand [70]. The

Cross-Coupling Reactions with Organometallic Compounds

337

diphenylated product 8 was obtained in 13 % yield. Interestingly, kinetic resolution occurs in the second coupling to give 8. The (R) isomer of 9 undergoes the second phenylation about five times faster than its (S) isomer, indicating that the minor (R) isomer of 9 is consumed preferentially by the second asymmetric coupling, which causes an increase of the enantiomeric purity of (S)-9 as the amount of 8 increases. The chiral phosphine 11 was prepared by the Pd-catalyzed conversion of the remaining triflate in 9 to 10 using diphenylphosphine oxide, and reduction of 10 with HSiCl3 .

TfO

OTf

Ph + PhMgBr

Ph

PdCl2[(S)-VII-7]

Ph +

LiBr

7

(S) 9

8 13%

Ph2P(O)H

OTf

Ph

P(O)Ph2

Pd(OAc)2, DPPB, 99%

HSiCl3

87%

Ph

93% ee

PPh2

Et3N, 73%

10

11

Some heteroaryl halides are electron-deficient and reactive. 3-Pyridylmagnesium chloride (13) was prepared efficiently by the treatment of 3-bromopyridine (12) with isopropylmagnesium chloride, and 2-(3-pyridyl)pyridine (15) was prepared by coupling 13 with 2-bromopyridine (14) using DPPF as a ligand [71].

Br

MgBr

i-PrMgBr

Br

14

N

N

Pd(dba)2, DPPF, 64% N

N

12

13

N 15

The pure cis-stilbene derivative 18 was prepared cleanly in high yield by the reaction of sterically hindered 2,6-dimethylphenylmagnesium bromide (16) with trans-3,4-dibromo-3-hexene (17), which is easier to prepare than the corresponding cis-dibromide [72]. Interestingly, alkyl chlorides can be used for the coupling without undergoing β-H elimination. The best ligand for the efficient coupling of 1-chlorohexane is PCy3 , and the reaction in NMP or DMAC as a solvent gives n-hexylbenzene (19),

338 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Me

MgBr Me

Br PdCl2(PPh3)2

Me +

Me Me

THF, 96% Br 16

Me

17

18

which is difficult to synthesize by Friedel-Crafts alkylation [73]. It is remarkable that unusually facile oxidative addition of alkyl chloride to Pd(0) occurs at least in this case. Commercial production of alkylbenzene derivative can be carried out by the reaction of alkylmagnesium halides with aryl halides. For example, reaction of p-dichlorobenzene (20) (2 equiv.) with propylmagnesium chloride (1 equiv.) afforded p-chloropropylbenzene (21) cleanly by monosubstitution. Pd-DPPF is used as a catalyst [74]. MgBr +

Cl

1 Cl Pd(OAc)2, PCy3

MgCl

NMP, 96%

+ Cl

19

20

+

PdCl2(dppf), THF Cl 21

1%

84%

3.6.6 Organosilicon Compounds (Hiyama Coupling) 3.6.6.1 Introduction and Preparative Methods of Organosilicon Compounds In contrast to organometallic reagents of Mg, B, and Sn, organosilicon compounds are inert for transmetallation under normal Pd-catalyzed coupling conditions. Hiyama has discovered that the C—Si bond can be activated by nucleophiles such as F− and OH− by forming pentacoordianted silicates 1, and transmetallation of organosilicon compounds proceeds in the presence of a fluoride anion source as a promoter. Thus, smooth cross-coupling of organosilanes with halides is possible by the addition of a stoichiometric amount of promoters, typically TASF [(Et2 N)3 S+ (Me3 SiF2 − )] or TBAF [(n-Bu)4 NF], and the reaction is called Hiyama coupling [75,76]. KF and CsF are effective only in some cases. Recent improvement in the coupling reaction has been reviewed by Denmark and Sweis [77].

R1R2R3SiY + F

−

R1 R3 Si R2 Y F 1

−

Ar-PdX

Ar-Pd-R1 + R2R3SiYF Ar-R1 + Pd(0)

Carbonylation and Reactions of Acyl Chlorides

339

An established synthetic method for arylsilanes is lithiation of aryl halides, followed by the reaction with R3 SiCl. Alkenylsilanes are produced by hydrosilylation of 1-alkynes catalyzed by Rh or Pt complexes. Also aryl- and alkenylsilanes 2 are synthesized by Pd-catalyzed reaction of hexamethyldisilane with halides in the presence of TASF [78,79]. Br

BuLi

R

Li

R3SiCl

SiR3

R

+

R

MeO2C

I

8

R

Pt or Rh cat H-SiR3

R SiR3

+ Me3SiSiMe3

Pd(PPh3)4, TASF HMPA, rt, 92%

MeO2C

SiMe3

8 2

Masuda and co-workers have discovered a new synthetic method for aryltriethoxysilanes 3. They found that 3 can be prepared in high yields by Pd-catalyzed silylation of aryl iodides such as 4-iodoanisole and bromides with triethoxysilane using P(o-Tol)3 as a ligand in NMP [80]. Of course, the silylation is competitive with hydrogenolysis to form the reduced arene 4. DeShong and co-workers have studied the scope and limitation of the reaction [81]. They found that biphenylyl(dit-butyl)phosphine IV-1 is the most effective ligand. Although aryl iodides are the substrates of choice, an acceptable yield of arylsiloxanes may be obtained from the corresponding bromide. Interestingly, satisfactory results were obtained from electron-rich 4-iodoanisole and 4-bromoanisole (5). The steric effects on the reaction are serious and no reaction of 2-bromoanisole (6) occurs. I

Si(OEt)3

H

OMe

OMe

Pd2(dba)3, P(o-Tol) 3

i-Pr2NEt, NMP, 92% +

H-Si(OEt)3 Pd2(dba)3, IV-1

i-Pr2NEt, NMP, 86%

OMe

4

3 Br

Si(OEt)3 +

Pd2(dba)3, (IV-1) H-Si(OEt)3

i-Pr2NEt, NMP, 68%

OMe

OMe

5

Br + OMe 6

H-Si(OEt)3

Pd2(dba)3, (IV-1)

i-Pr2NEt, NMP, 68%

Si(OEt)3

OMe 0%

340 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides One of the advantages of Hiyama coupling is that silicon is a comparatively environmentally benign element, since organosilicon compounds are oxidized ultimately to inactive silica gel. Better tolerance to functional groups is another advantage. A drawback, however, is consumption of more than stoichiometric amounts of expensive additives. In addition, functional groups protected by silyl groups can not be tolerated, because they are deprotected by a fluoride anion. 3.6.6.2 Couplings of Arylsilanes Arylsilanes bearing heteroatoms such as F, Cl, OH, and OR can be used as coupling partners. Of these, OH appears to be most reactive. Easily prepared arylalkoxysilanes are good coupling partners [82,83]. The carbene ligand XVI-2 is a good ligand for the coupling of phenyltrimethoxysilane (7) with activated aryl chlorides. In the coupling of 4-bromotoluene, PCy3 is more effective than the carbene ligand [84]. Curiously, coupling of 7 with deactivated 4-bromoanisole (5) proceeded in DMF to afford 8 even when PPh3 was used. Furthermore, biphenylyldicyclohexylphosphine IV-2 is effective for the coupling of 4-chloroanisole with 7 to provide 8 [85]. Si(OMe)3

Me +

Pd(OAc)2, PCy3

Me

TBAF, dioxane, 100% Br

7 Si(OMe)3

OMe Pd(OAc) , PPh 2 3 + Br

7

OMe

TBAF, DMF 85 °C, 74% 5

Si(OMe)3

8 OMe

Pd(OAc)2, IV-2

+

OMe

TBAF, DMF 85 °C, 71%

Cl 7

8

Lee and Fu reported that coupling of phenyltrimethoxysilane (7) with alkyl bromides is possible under selected conditions. 1-Phenyldodecane was obtained in 81 % yield by the reaction of 7 with n-dodecyl bromide at room temperature. P(t-Bu)2 Me as an effective ligand and Bu4 NF (2.4 equiv.) as an activator were used [86]. Si(OMe)3 + C12H25Br

PdBr2, P(t-Bu)2Me Bu4NF, rt, 81%

C12H25Ph

7

Some halides on silicon are activating groups. Generally two fluorine atoms are required for aryl–aryl coupling. For example, coupling of ethyl(2-thienyl)difluorosilane (9) with 3-iodothiophene 10 afforded the bisthiophene 11 using a ligandless Pd catalyst in the presence of KF [87].

Carbonylation and Reactions of Acyl Chlorides

341

I (h3-allyl-PdCl)2

+ Si(Et)F2

S

MeO2C

DMF, KF, 100 °C 82%

S

9

10

S MeO2C

S

11

Electron-deficient aryl chlorides can be coupled with organo di- or trichlorosilanes such as aryldichloroethylsilane and aryltrichlorosilane in the presence of KF. In this case, the in situ fluorination of chlorosilanes with KF occurs. Electron-rich alkylphosphines such as tri(isopropyl)phosphine or bis(dicyclohexylphosphino)ethane are effective ligands. For example, coupling of the dichlorosilane 12 with 4-chloroacetophenone at 120 ◦ C in DMF gave 13 in 62 % yield [88].

SiEtCl2 MeO

PdCl2[P(i-Pr)3]2

O

+

KF, DMF 120 °C, 62%

Cl 12

OMe O 13

In addition to dichloro groups, some other activating groups are known. Denmark and Wu found that arylchlorosiletanes [aryl(chloro or fluoro)silacyclobutanes] are reactive coupling partners and ascribed the high reactivity at first to ‘strain release Lewis acidity’ of the siletane, but later to the formation of ring-opened silanol derivatives. The anisylchlorosiletane 14 reacted smoothly with iodobenzene using P(t-Bu)3 as a ligand in the presence of TBAF [89]. I

(h3-allyl-PdCl)2

OMe +

Si

P(t-Bu)3, TBAF THF reflux, 91%

Cl 14

OMe 8

3.6.6.3 Couplings of Alkenylsilanes Trimethylsilanes are easily available. Coupling of commercially available trimethylvinylsilane (15) with the iodide 16 proceeds most satisfactorily using TASF and ligandless Pd in HMPA [90]. I SiMe3

+

(h3-allyl-PdCl)2, TASF, HMPA 50 °C, 98%

15 16

Silanes couple under promoter-free conditions with good electrophiles like aryldiazonium salts. Matsuda and co-workers have discovered that benzenediazonium tetrafluoroborate reacts with β-trimethylsilylstyrene derivative 17 using ligandless

342 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Pd(dba)2 in MeCN at room temperature. Two products, namely the expected ipso product 18 and the cine product 19, were obtained [91]. On the other hand, reaction of α-trimethylsilylstyrene 20 with 21 afforded the cine product 22 regioand stereoselectively [92]. An application of the coupling of aryldiazonium salt to α,α
-bis(trimethylsilyl)-1,4-divinylbenzene derivative 23 afforded the (E, E)bis(styryl)benzene derivative 24 cleanly [93]. Me

N2BF4 +

Pd(dba)2 MeCN, 25 °C 100%

SiMe3 17

Me Me +

18

N2BF4

74 : 26

Pd(dba)2

+

MeCN, 25 °C 97%

Me

Me

21

SiMe3

19

22

20

C8H17O

Pd(dba)2 MeCN, 80%

N2BF4 + Me3Si

SiMe3 OC8H17

Br 23

C8H17O Br

Br OC8H17 24

The reaction of 17 (or 25) to give 19 (or 31) can not be explained by the ‘oxidative addition–transmetallation–reductive elimination’ mechanism. In the reaction of 25, carbopalladation to form 26 and 27 is the first step. Desilylpalladation of 26 affords the expected ipso product 28. On the other hand, the intermediate 27 undergoes syn dehydropalladation to give 29, to which syn addition of H-PdX occurs to generate 30. Then anti desilylpalladation provides the cine product 31. This reaction is not completely fluoride-free, because the BF4 − anion is present.

Carbonylation and Reactions of Acyl Chlorides +

ArN2BF4

Pd(0)

Ar-Pd-X F

Ph

H

H

H H

Ph Ar-Pd-X syn addition

SiMe3

343

−

anti elimination Ph

SiMe3

H

Pd Ar

25

H Ar 28

26

syn addition H

Ph

syn elimination

SiMe3

Ar Pd F Ar

SiMe3

Ar

H

H-PdX

27

Ph

Ph

29

−

SiMe3

H-PdX syn addition

anti elimination

Ph Ar

Pd H 30

31

Reactivity of alkenylsilanes changes by replacing one to three methyl groups in 32 with other groups. Introduction of F enhances reactivity as shown by the reaction of 1-silyl-1-octene 32 with 1-naphthyl iodide (33) to afford 34. Introduction of one F gives the highest reactivity possible owing to easy formation of the pentacoordinate silicate from the alkenylsilane without any electron-donating group. No reaction occurs with octenyltrimethylsilane under this condition [94]. C6H13 I

C6H13

+

(h3-allyl-PdCl)2, TASF, THF, 50 °C

SiMe3-nFn 32

n=0 n=1 n=2 n=3

33

24 h 10 h 48 h 24 h

0% 81% 74% 0%

34

Coupling of the trans-styrylsilane 35 with iodobenzene gave rise mainly to transstilbene (36) as the ipso product and only a small amount of the cine product 37. Under the same conditions, cine product 41 was obtained to some extent from the α-silylstyrene 38 in addition to ipso product 40. The ipso : cine ratios change depending on substituents (R) of the aryl iodides 39 [95]. Ph

+ Ph-I SiFMe2

(h3-allyl-PdCl)2 Ph TBAF, THF 60 °C, 93%

35

Ph

+ Ph

Ph

36

37 96 : 4

I

Ph + Me2FSi 38

R 39

(h3-allyl-PdCl)2, TBAF, THF 60 °C, 93%

Ph

Ph +

Ar

Ar 40

41

R = CF3 72% 93 : 7 69% 75 : 25 =H = OEt 63% 60 : 40

344 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The 2-thienyl (Th) group in the alkenylsilane 42 also promotes the coupling, which occurs at room temperature in the presence of TBAF to provide 43 [96]. The 2-thienyl group is considered to facilitate the formation of pentacoordinate silicate or to be replaced readily by OH. I C6H13 42

C6H13

Pd(OAc)2, TBAF

SiMe2Th +

THF, rt, 97% MeO

Th = 2-thienyl

OMe 2

43

The alkenylsiletane 44 is very reactive and reacts with 4-iodoanisole (2) at room temperature with ligandless Pd catalyst in 10 min to give 46 in 94 % yield [97]. Here again 44 is considered to be transformed to a silanol before coupling. n-C5H11

Me

I +

Si

C5H11

Pd2(dba)3, TBAF rt, 10 min, 94%

MeO

MeO

44

2

46

3.6.6.4 Couplings of Aryl- and Alkenylsilanols, and Alkoxysilanes Silanols are apparently the most effective coupling reagents, which react under mild conditions in the presence of promoters [98]. The coupling of alkenylsilanols with deactivated aryl iodides occurs with ligandless Pd(dba)2 [99]. Reaction of the silanol 47 with the triflate 48 proceeded smoothly in the presence of bulky biphenylylphosphine (IV-1). Curiously, PdBr2 was a more active catalyst than PdCl2 and use of TBAF · 6H2 O gave better results [100,101]. Coupling of the silanol 47 with electron-deficient 4-iodoacetophenone proceeded at room temperature in 10 min to afford 49 in 79 % yield using ligandless Pd catalyst. Also coupling with the less reactive aryl iodide 2 occurred efficiently with ligandless Pd catalyst [99]. OMe

Me Me +

Si C5H11

TBAF-6H2O dioxane, 93%

TfO

OH 47

C5H11

PdBr2, IV-1 MeO

48

46 I

Me

Me Si

n-C5H11

OH

+

47

rt, 10 min, 79% O

O I

Me

Me Si

n-C5H11

OH 47

C5H11 Pd2(dba)3, TBAF

+

49 C5H11

Pd2(dba)3, TBAF rt, 10 min, 95%

MeO

MeO 2

46

Carbonylation and Reactions of Acyl Chlorides

345

Vinylation of aryl iodides can be carried out using the commercially available cyclooligodisiloxane 50 at room temperature [102]. Me

Me Si

O

Si

Me

I

Si +

O

O O

Si

Pd2(dba)3, TBAF rt, 6 h, 63%

MeO

OMe 2

Me

51

50

The coupling products are obtained by one-pot hydrosilylation/cross-coupling of alkynes. Pt-catalyzed hydrosilylation of alkyne with tetramethyldisiloxane (52) generates the alkenylsilane 53, which is coupled with 4-iodoanisole (2) using ligandless Pd catalyst and TBAF at room temperature to afford 46 in 84 % yield [103]. H Me

Si

H O

Me

Si

Me Me + n-C5H11

t-Bu3P-Pt(DVDS) n-C5H11

Me 52

Si Me 53

DVDS = 1,3-divinyl-1,1,3,3-tetramethyldisiloxane

O 2

I

MeO

n-C5H11

2

Pd2(dba)3, TBAF rt, 10 min., 84%

MeO 46

Coupling of reactive alkoxyalkenylsilanes has been applied to the synthesis of medium-sized rings. The cyclic silyl ether 54 was converted to cyclodeca3,5-dienol (55) at room temperature [104]. In many silane coupling reactions, it has been claimed that ligandless π -allylpalladium chloride is an effective catalyst precursor. Possibly, chloride ion is essential for transmetallation as compared with unreactive Pd(OAc)2 . Me

Me Si

I

O

(h3-allyl-PdCl)2, TBAF, THF, rt, 63%

54

OH 55

3.6.6.5 Fluoride-Free Procedures The couplings of organosilanes discussed so far are carried out in the presence of more than equimolar amounts of promoters, typically TBAF, which is expensive.

346 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The promoters preclude wide use of the reaction. Mori and Hiyama discovered that Ag2 O can be used as a promoter for the reaction of silanols [105]. Reaction of the arylsilanol 56 with iodobenzene to give 8 proceeded smoothly in THF in the presence of an equimolar amount of Ag2 O. Interestingly no reaction occurred when Pd(OAc)2 , PPh3 , and TBAF were used. Silanediols and silanetriols are more reactive than silanols. Coupling of the arylsilanediol 57, alkenylsilanediol 58, and the triol 60 with less reactive 4-iodoanisole (2) occurred smoothly to provide 8, 59 and 61. These silanols are prepared easily by hydrolysis of the corresponding chlorosilanes and used without isolation. I

SiMe2OH

Pd(PPh3)4, Ag2O

+

OMe

THF, 60 °C, 80%

MeO 8

56 SiEt(OH)2

I

Pd(PPh3)4, Ag2O

+

OMe

THF, 60 °C, 80% MeO

57

8

2

Ph I

Ph

+

Ph SiMe(OH)2

Pd(PPh3)4, Ag2O

Ph

THF, 60 °C, 71% OMe

MeO

58

59

2 I

Ph Si(OH)3

+

Ph

THF, 60 °C, 76%

MeO

60

Pd(PPh3)4, Ag2O

OMe 61

2

Arylsilanols, although less reactive than alkenylsilanols, can be coupled in the presence of Cs2 CO3 (2 equiv.) and AsPh3 in toluene. Under these fluoride-free conditions, coupling of p-methoxyphenylsilanol 56 with phenyl iodide afforded the coupling product 8 in high yield. Homocoupling occurred to a small extent. Coupling of less reactive phenyl bromide proceeded selectively using DPPB as a ligand. Control of water content in Cs2 CO3 is important for maximum activity [106]. Me

Me

(h3-allyl-PdCl)2, AsPh3 Cs2CO3 + 3H2O

Si OH +

90 °C, toluene, 91%

I

MeO 56

8 + MeO 93.7 : 6.3

OMe

Carbonylation and Reactions of Acyl Chlorides Me

Me

(h3-allyl-PdCl)2, DPPB Cs2CO3 + 3H2O

Si OH +

90 °C, toluene, 85%

Br

MeO

347

56 8 + MeO

OMe

100 : 0

A straightforward route to diarylmethanes is double cross-coupling of (2-pyridyl)silylmethylstannane 62 with aryl halides. First, chemoselective coupling of alkylstannane in 62 with 3-iodoanisole produced 63 using P(C6 F5 )3 as a ligand. Then reaction of 4-iodoanisole (2) with the pyridylsilane 63 took place in the presence of Ag2 O to give the diarylmethane 64. The pyridyl group in 63 seems to activate the silane group for the coupling by coordination to Pd to assist transmetallation [107].

I Bu3Sn

Si Me2

OMe

MeO Si Me2

PdCl2(MeCN)2, P(C6F5)3

N

N

THF, 65% 63

62

OMe MeO 2

I

Pd(PPh3)4, Ag2O THF, 44%

OMe 64

As a more useful fluoride-free process, the Hiyama group reported that coupling of ArSiRCl2 occurs smoothly by the addition of powdered NaOH (6 equiv.) as an activator, instead of fluorides. Coupling of activated aryl bromide 66 with 65 proceeded in refluxing benzene using Pd(OAc)2 and PPh3 [108]. LiOH, K2 CO3 , and Na2 CO3 are less effective. Similarly, coupling of alkenyldichlorosilane 68 with 3-chlorotoluene (69) took place at 80 ◦ C to give 70. P(i-Pr)3 is an effective ligand. Br

SiEtCl2 + 65

NaOH, benzene 80 °C, 89% 67

O

66 Cl

n-Bu

O

Pd(OAc)2, PPh3

n-Bu

Me

Me

PdCl2[P(i-Pr)3]2

SiMeCl2 + 68 69

NaOH, benzene 80 °C, 91%

70

348 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Another good solution for the desirable fluoride- and silver-free procedure has been demonstrated by the Denmark group. They found that the reaction of the alkenylsilanol 47 with 4-iodoanisole (2) to afford 46 proceeded smoothly in the presence of 2 equivalents of KOSiMe3 as a base without other promoters using ligandless Pd(dba)2 as a catalyst in DME at room temperature [109]. Coupling of TBS-protected 2-iodophenol (71) with 47 by this method proceeded to afford 72 without cleaving the silyl protection. Further development of the fluorine-free procedure will certainly promote silane coupling chemistry. Me

I

Me Si

C5H11

OH +

DME, rt, 1 h, 88% MeO

47

C5H11 2

Me

Me Si

C5H11

46

TBSO

OTBS

OMe

Pd(dba)2, KOSiMe 3

OH +

DME, rt, 9 h, 80% C5H11

I 47

OMe

Pd(dba)2, KOSiMe 3

72

71

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3.7 Arylation and Alkenylation of C, N, O, S, and P Nucleophiles Arylation and alkenylation of various nucleophiles with aryl and alkenyl halides have been underdeveloped for a long time except for the coupling of halides with organometallic compounds of main group metals via transmetallation. However, recently remarkable progress has occurred by the discovery that Pd catalysts are effective for arylation of C, N, O, S, and P nucleophiles. For example, it is now possible to arylate ketones with aryl chlorides to prepare α-aryl ketones. The progress has led to new innovations in organic synthesis. The new reaction became possible by the selection of the proper ligands and bases. Bulky ligands have been found to accelerate reductive elimination, and a number of effective bulky ligands for arylation have been synthesized. 3.7.1 α-Arylation and α-Alkenylation of Carbon Nucleophiles In contrast to facile α-alkylation of carbonyl compounds, α-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth α-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now α-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for α-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct α-arylation of acetate or propionate.

CO2H

Pd(0)

Br +

CO2R

1

The breakthrough became possible by the emergence of new ligands, particularly bulky and electron-rich ligands. The selection of bases is also important, and stable

352 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides bases such as MN(TMS)2 (M = Li, Na, K), NaH, and t-BuONa are used. MeONa and EtONa are usually not effective because they are easily oxidized to aldehydes with aryl halides as shown below. Cs2 CO3 is a unique and very effective base in some reactions. CH3CH2ONa CH3CH2O

Ar-X + Pd(0)

CH3CHO + Pd(0) + Ar-H

Pd-Ar

3.7.1.1 Arylation of Active Methylene Compounds Arylation of active methylene compounds has been carried out using Cu salts as promoters under severe conditions [2]. Recently it was discovered that the reaction can be carried out much more smoothly using Pd catalysts. The first Pd-catalyzed intermolecular arylation of cyanoacetate and malononitrile with aryl iodides was carried out by Takahashi using PPh3 as a ligand, and was applied to a simple synthesis of tetracyanoquinodimethane (2) by the reaction of p-diiodobenzene with malononitrile [3]. The intramolecular arylation of malonates and β-diketones with aryl iodides proceeds smoothly. Presence of a cyano group seemed to be important [4,5]. The arylation has been successfully extended to halides of heterocycles, such as pyridine, quinoline and isoquinoline. The reaction of bromoxazole 3 with sulfone 4 is an example [6]. CO2Et

+

I

t-BuOK, DME, 73%

CN CN I

+

I

CO2Et

PdCl2(PPh3)2

CN

CN

PdCl2(PPh3)2 NaH, THF, 72%

NC

CN

NC

NC

CN

NC

CN CN 2 Ph

Ph N Br

O 3

Ph

+

SO2Ph CN 4

N

Pd(PPh3)4 NaH, DME, 85%

PhSO2

O

Ph

CN

Facile stepwise mono- and diarylations of cyanoacetate took place with aryl bromides and electron-rich p-chloroanisole (5) [7]. Recently Kawatsura and Hartwig [8] and Fox et al. [9] have shown that the presence of the cyano group is not crucial, and β-diketones are monoarylated with aryl bromides when bulky and electron-rich ligands such as P(t-Bu)3 are used. For example,1,3cyclopentanedione (6) was arylated intermolecularly to give 7 using biphenyl-type phosphine IV-4 as a ligand [9]. Arylation of bis(phenylsulfonyl)methane (8) with 1-bromonaphthalene proceeded using even PPh3 as a ligand [10].

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles Cl

CO2Et

+

Na3PO4, toluene, 90%

CN

MeO

Pd(dba)2, P(t-Bu)3

353 CO2Et

MeO CN

5 MeO Cl

CO2Et

+

2

Na3PO4, toluene, 93%

CN

MeO

CO2Et

Pd(dba)2, P(t-Bu)3

5

CN MeO O

O Br Pd(OAc)2, IV-4

+

K3PO4, THF

t-Bu

t-Bu O

O 7

6 PhO2S

Br +

SO2Ph

Pd2(dba)3, PPh3

SO2Ph

NaH, dioxane, 77%

SO2Ph

8

Di-t-butyl malonate can be arylated with electron-rich aryl chlorides using NaH and P(t-Bu)3 [11]. The arylation suffers steric effects, and no arylation takes place with diethyl methylmalonate (9). Thus, diethyl methylphenylmalonate (10) can be prepared via arylation of malonate to give 11, followed by methylation as a onepot reaction. When the arylation of diethyl malonate is carried out at 120 ◦ C, phenylacetate (12) is obtained as a one-pot reaction product [12]. Cl

CO2t-Bu

+

CO2t-Bu

MeO

Me

Pd(dba)2, P(t-Bu)3 NaH, THF, 84%

CO2t-Bu MeO

Br

CO2Et

+

CO2t-Bu

Me

CO2Et

Ph

CO2Et 9

CO2Et 10

MeI CO2Et CO2Et

MeI Br +

Pd2(dba)3, P(t-Bu)3

Ph

CO2Et

K3PO4, toluene, 91% 11

CO2Et

354 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Br

CO2Et

+

CO2Et

Pd2(dba)3, P(t-Bu)3

CH2CO2Et

Cs2CO3, DME, 87%

12

Hartwig and Wolkowski have synthesized arylpalladium complexes of malonates, and have shown that the greater steric hindrance of bulky ligand FcP(t-Bu)2 (VIII-2), relative to that of phenylphosphines, induces reductive elimination from the complexes [13]. 3.7.1.2 Arylation of Ketones Direct arylation of ketones was a difficult reaction. Arylation of ketones has been carried out by the Pd-catalyzed reaction of tin enolates of ketones, generated in situ, with aryl halides [14,15]. Facile direct arylation of ketones has been reported by the groups of Miura, Buchwald, and Hartwig almost simultaneously [16–18], and α-aryl ketones are now easily available by Pd-catalyzed arylation. Miura reported the arylation of dibenzyl ketone (14) with iodobenzene using PdCl2 as a catalyst and Cs2 CO3 as a base without any ligand to give tetraphenylacetone (15) [16]. Buchwald and Hartwig reported monoarylation of ketones such as propiophenone (16), acetophenone, and cyclohexanone with aryl bromides gave 17 and 18 using BINAP (XV-1), Tol-BINAP (XV-2), DPPF (XI-1), DtBPF (XI-4) and Xantphos (IX-10) as ligands, and strong bases such as KN(TMS)2 or t-BuONa [8,17,18]. O I

PdCl2, LiCl

O

+

Cs2CO3, DMF 48%

14

15 OMe

OMe

O Me

Pd2(dba)3, BINAP (XV-1)

+

O

t-BuONa, THF, 91%

Br 16

Me 17 O

Br +

Br

O

Pd2(dba)3, XI- 2 Ph

KN(SiMe3)2, THF

Ph Ph O

O Pd(dba)2, Tol-BINAP ( XV-2) +

t-BuONa

83%

t-Bu t-Bu

18

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

355

Selective and smooth monoarylation of benzyl phenyl ketone (19) gave 20 using K2 CO3 as a base. It should be noted that PPh3 is an effective ligand [19]. On the other hand, the polyarylated ketone 21 was obtained when Cs2 CO3 was used. This is an interesting example which shows different actions of two carbonates (K2 CO3 and Cs2 CO3 ) as bases. Formation of 21 and related arylation of phenyl rings are treated in Chapter 3.3.4. Preparation of 20 by selective monoarylation of 19 was applied to the synthesis of the tamoxifen structure 23 from 22 [20].

O O

Br

Pd(OAc)2, PPh3

+

K2CO3, o-xylene 96% 20

19

O Pd(PPh3)4 Cs2CO3, o-xylene 61%

21

OMe

OMe OMe

OMe

Br O

Pd(OAc)2, PPh3

+

O

Cs2CO3, DMF 85% OMe

OMe

OMe 22

OMe 23

The arylation of the ketone 24 with 3,5-dimethylbromobenzene was carried out even without any phosphine [9]. The arylation with p-chloroanisole can be carried out by using P(t-Bu)3 , PCy3 , and IV-6 as effective ligands [8,9]. The airstable carbene complex (XVI-1) Pd(allyl)Cl is a good catalyst for the arylation of ketones with unactivated aryl chlorides and triflates [21]. It is still not known which phosphine is most effective for the arylation of individual ketones.

356 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O Me

Br O

+ Me

Pd(OAc)2

Me

Me

Me

Me

t-BuONa, toluene 85%

24

Me

Me

Me

Me

Cl Ph

Pd(OAc)2, P(t-Bu)3

O

+

t-BuONa, THF 91%

Me Ph

O OMe Me

OMe

Buchwald and co-workers observed the persistent formation of 2-nitrophenols in an attempted arylation with reactive o-chloronitroarenes. They found an unusual effect of phenolic additives, and developed an annulative approach to highly substituted indoles. The arylation of acetophenone with 3-nitro-4-chlorobenzoate proceeded smoothly in the presence of 20 mol% 4-methoxyphenol and K3 PO4 to give 25, which was methylated without isolation. Reduction of the methylated ketone 26 with TiCl3 afforded 2,3-disubstituted indole 27 in 61 % overall yield [22]. O Ph

Cl NO2

O Me

CO2Et

NO2

Pd2(dba)3, (IV-12)

+ Ph

K3PO4, toluene p-methoxyphenol (20 mol%)

CO2Et 25

O Me

Ph NO2

Me

MeI, NaH

TiCl3, EtOH

THF

NH4OAc, rt, CO2Et

Ph N H

EtO2C 61%

27

26

The arylation is explained by the following mechanism. Arylpalladium halides 28 are formed by oxidative addition of aryl halides. Then the arylpalladium enolates 30 are generated by transmetallation of 28 with alkali enolates of ketones 29. Finally reductive elimination of the arylpalladium enolates 30 affords α-aryl ketones. Hartwig isolated the arylpalladium enolate complexes 31 of ketones, esters and amides, and confirmed formation of α-arylated products on heating [23].

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles O Ar-Br + Pd(0)

Ar-Pd-Br

357 O-Pd-Ar

Pd-Ar

28 O

30

O

O-Cs

Cs+

Cs2CO3

Pd(0) O

29

Ar Ph2 P

O

Ar Pd

R'

O

P Ph2

R

R' Ar

R 31

Facile intramolecular arylation using PPh3 as a ligand was reported in 1988 by Ciufolni et al. [24]. Reaction of the bromo ketone 32 afforded the cyclic compound 33 [25]. Intramolecular arylation of the triflate 34 gave the heterocycle 35 [26]. Similarly, a Pd-catalyzed reaction of the ketone with the vinyl iodide in 36 yielded the cyclized product 37 in 84 % yield at room temperature using Pd(PPh3 )4 as a catalyst by slow addition of t-BuOK to avoid competing alkyne formation [27]. Br

O PdCl2(PPh3)2 Cs2CO3, THF 83%

32

33

O

N

N

1. PdCl 2(PPh3)2 OTf

O

Cs2CO3, benzene 90%

NaH THF, DMF

O

O

O

Me Me 36

O

O OCO2Me 35

34

I

N

2. ClCO 2Me

Pd(PPh3)4

t-BuOK, rt 84%

Me

Me O 37

Sole and co-workers constructed the 2-azabicyclo[3.3.1]nonane framework 39 from the keto iodide 38 [28]. The group has observed two reaction paths in the

358 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides cyclization of amino-tethered aryl halides and ketones, namely attack to the ketone to give alcohols and the enolate arylation [29]. Cyclization of 39a using PPh3 and Cs2 CO3 afforded the arylated ketone 39b in 75 % yield in toluene. On the other hand, reaction of 39c under similar conditions afforded the arylated ketone 39d in 31 % yield and the alcohol 39e in 45 % yield. The latter was formed by addition to the ketone. The intramolecular carbonyl attack by aryl halides has been discovered by Yamamoto recently, and the topic is treated separately in Chapter 3.7.2.

Bn

Bn N

N I

Pd(PPh3)4, t-BuOK THF reflux 75% O

O 38

39 O

O

I

PdCl2(PPh3)2, Cs2CO3 Et3N, toluene, 75%

N

N 39a

Bn 39b

Bn

I

O

O

PdCl2(PPh3)2, Cs2CO3 Et3N, toluene

N

HO

+ MeO2C

N

MeO2C

N

39c

39d 31%

CO2Me 39e

45%

In the total synthesis of complex indole alkaloids, intramolecular alkenylation of the ketone 39f was carried out successfully by Cook to give 39g in 82 % yield [30]. H

H O MeO

N

N Me H

I

O

Pd(OAc)2, PPh3 Bu4NBr, K 2CO3 DMF/H2O, 82%

MeO

N Me

N H

39g

39f

Arylation of the cyclopentanone derivative 40, in which one of the α-carbons is protected as an enamine, with 4-bromo-t-butylbenzene using BINAP as a

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

359

chiral ligand gave 41. Deprotection of 41 afforded the the chiral α,α-disubstituted cyclopentanone 42 with 89 % ee [31]. The chiral ligand VI-15 is highly effective and the arylation proceeded at room temperature to give 41 with 93 % ee [32]. Asymmetric α-alkenylation of ketones proceeds similarly. New phosphine ligands possessing both axial chirality and a chirogenic phosphorus center such as VI11 were prepared. Asymmetric vinylation of 40 gave 43 with 92 % ee by using VI-11 as the chiral ligand, and 43 was converted to optically active 2-vinyl-2methylcyclopentanone (44) [33]. O

Br

O +

Ph

Ph Me

N Me

Pd(OAc)2, VI-15

N

t-BuONa, toluene 84%, 93 % ee

Me

t-Bu

40

t-Bu

41

O 1. HCl 2. NaOH 42

t-Bu

O

O Ph

Me

N

Br Pd(dba)2, VI-11

+

t-BuONa, toluene 94%, 92% ee

Me

Ph

O Me

Me

N Me

40

43

44

3.7.1.3 Arylation of Aldehydes and α,β-Unsaturated Carbonyl Compounds Usually aldol condensation occurs first when arylation of aldehydes is carried out using PPh3 as a ligand, and then γ -arylation of the aldol products takes place. Smooth α-arylation of the aliphatic aldehyde 45 with 4-bromotoluene afforded 46 when P(t-Bu)3 as a ligand and Cs2 CO3 as a base were used in dioxane without undergoing aldol condensation [34]. Intramolecular reaction of the secondary aldehyde 46a afforded the arylation product 46b as the main product in polar solvents such as THF, and mainly the ketone 46c was obtained in toluene as a nonpolar solvent. In this reaction, use of Cs2 CO3 gives satisfactory results, while Et3 N, NaH, t-BuONa, and KN(TMS) are ineffective [35]. Br H

n-hex

Pd(OAc)2, P(t-Bu)3

+

Cs2CO3, dioxane 72%

O 45

H

Me

O Me

n-hex 46

360 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides MeO

OMe

CHO

OHC PdCl2(PPh3)2, Cs2CO3 H

Br O

O

O

O

46a

46b

trans/cis = 2.2

toluene

cis / trans = 7.5 : 1, 14%

+

THF

4.2 : 1, 65%

H

O

H OMe O

O 46c

trans 34%, cis 10% trans 11%, cis 6%

On the other hand, regioselective γ -arylation of the α,β-unsaturated aldehyde 47 and ketone 48 with bromobenzene takes place using PPh3 . For example, one of the methyl groups of isophorone (48) was regioselectively γ -arylated to give 49 without attacking the γ -carbon of the ring [36]. γ -Alkenylation of α,β-unsaturated aldehydes was successfully applied to the total synthesis of (+)-vellosimine. The α,β-unsaturated aldehyde 50 was γ -alkenylated intramolecularly and stereospecifically to afford 50a in 71 % yield [37]. CHO Br CHO

+ 47 Br

Pd(OAc)2, PPh3 Cs2CO3, DMF 96%

O

O Pd(OAc)2, PPh3

+

Cs2CO3, DMF 71% 49

48

H

H CHO N

N H H I 50

Pd(OAc)2, PPh3 Bu4NBr, K 2CO3 DMF/H2O, 71%

N H

N H H 50a

CHO

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

361

Various cyclic compounds can be prepared by the reaction of ketones with bifunctional aryl halides. The β-naphthol derivative 52 was obtained by α-arylation of dibenzyl ketone (14) with o-bromobenzaldehyde derivative 51, followed by aldol condensation [38]. Also the indole derivative 54 was synthesized by the reaction of cyclohexanone with 2-iodoaniline (53). Formation of 54 may be explained by enamine formation at first, followed by intramolecular Mizoroki–Heck reaction, rather than via α-arylation [39]. OMe MeO

CHO

O +

Br

Ph

Pd(OAc)2, PPh3 Ph

14

K2CO3, o-xylene 75%

51 Ph

Ph O Ph

MeO

CHO

OH

MeO

OMe

Ph OMe 52

I Pd(OAc)2

+ O

NH2

DABCO, DMF 77%

53

N H 54

1,2-Dibromobenzene (55) is a good building block for cyclic compounds. The indanone 56 was obtained as expected by diarylation of dibenzyl ketone (14). On the other hand, α-arylation of benzyl tolyl ketone (57) with 55 afforded 58, and subsequent O-arylation of the enolate 59 gave the furan 60 [40]. By the reaction of α,β-unsaturated carbonyl compounds with the dibromide 55, cyclization occurs by α-arylation, followed by intramolecular Mizoroki–Heck reaction. For example, reaction of verbenone (61) with 55 using PPh3 generates 62 by γ -arylation of 61, and subsequent intramolecular Mizoroki–Heck reaction affords the indane 63. The benzocyclobutane 67 was obtained unexpectedly

Br + Br 55

Pd(OAc)2, PPh3 O 14

K2CO3, o-xylene 64% O 56

362 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Br O

Me Br

Pd(OAc)2, PPh3

+

O

Br 55

57

Cs2CO3, o-xylene 74%

Me 58

PdBr OCs

Pd O

Me

Me

59

Me O 60

from the α,β-unsaturated aldehyde 64 via γ -arylation, followed by an interesting Mizoroki–Heck reaction to give the strained cyclobutane 67 via 66, rather than a cyclopentane derivative. For this creation, P(t-Bu)3 is a good ligand [40]. 3.7.1.4 Arylation of Esters, Amides, and Nitriles Direct α-arylation of esters had been regarded as impossible. New methods of facile α-arylation of esters and amides have been developed as useful synthetic methods by selection of appropriate ligands and bases [41]. Bulky and electron-rich ligands such as P(t-Bu)3 and carbene ligand XVI-6 are suitable, and NaN(TMS)2 , LiN(TMS)2 and LiNCy2 are used as bases. Use of t-butyl esters is recommended to minimize a O

O

Br

Br Pd(OAc)2, PPh3

+

Cs2CO3, DMF 62%

Br 55

61 O

62 O

PdBr

Pd(0) HBr

63

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles Et

Br +

Br

Pd(OAc)2, P(t-Bu)3 Et

CHO

Cs2CO3, DMF 77%

Br

Et

64

55

CHO

Et 65 PdBr

363

Et Pd-Br CHO

insertion Et Et

Et

CHO

66 Et CHO Et 67

competing Claisen condensation. Arylation of t-butyl acetate gives t-butyl phenylacetate 68 in 92 % yield using carbene ligand XVI-6. Arylation of methyl isobutyrate (69) proceeded smoothly using P(t-Bu)3 as a ligand and LiNCy2 as a base at room temperature, and the quaternary carbon was constructed in 70 [42]. α-Arylated carboxylic acids (particularly α-arylacetic acid and propionic acid), such as naproxen and ibuprofen, are important medicinal compounds. These acids can be prepared easily by α-arylation of esters, followed by hydrolysis. For example, the naproxen derivative 72 was prepared by the reaction of t-butyl propionate with 2-bromo-6methoxynaphthalene (71) using IV-12 [43] or XVI-6 as ligands [41]. Similarly, the ibuprofen derivative 73 was obtained by the arylation of t-butyl propionate with p-chloroanisole using IV-13 [43]. t-Bu + CH3CO2t-Bu

Br

CO2Me

t-Bu +

Br

CO2t-Bu

Pd(dba)2, XVI-6 LiN(TMS)2, toluene 92%

t-Bu 68

Pd(dba)2, P(t-Bu)3 LiNCy2, toluene rt, 91%

CO2Me

t-Bu

69

70

Br +

Pd(OAc)2, IV-12 CO2t-Bu

MeO

CO2t-Bu

LiN(TMS)2, toluene MeO rt, 79%

72

71

Cl

OMe +

CO2t-Bu

CO2t-Bu

Pd(OAc)2, IV-13 LiN(TMS)2, toluene 80 °C, 56%

MeO 73

364 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides A new synthetic method for physiologically important unnatural α-aryl amino acids has been developed based on α-arylation of N-protected glycine ester. αArylation of ethyl glycinate 74, in which the amino group is protected by benzylidenation, with aryl bromides and aryl chlorides using P(t-Bu)3 as a ligand affords 75. The subsequent hydrolysis gives α-phenylglycinate. No coupling was observed with α-substituted amino acid esters [41]. α-Arylated quaternary amino acids can be prepared by α-arylation of azlactones and hydrolysis. The azlactone 76, derived from alanine, was arylated with p-bromoanisole in 85 % yield using bulky phosphines such as (t-butyl)diadamantylphosphine [Ad2 P(t-Bu)] [44]. Cl

p-MeOC6H5 H2N

CO2Et

N

CO2Et

+

H 74

p-MeOC6H5 N

CO2Et

H2N

CO2Et

H

Pd2(dba)3, P(t-Bu)3 K3PO4, toluene, 67%

75 OMe O Ph

Me N H

N

Ph CO2H

Me

+ Br

O O 76

Pd(OAc)2, Ad2P(t-Bu) K3PO4, toluene 85%

N

Ph

Me

O O

OMe

Intramolecular arylation of the amino acid ester 77 afforded the tetrahydroisoindole carboxylate 78, and the tetrahydroisoquinoline carboxylate 80 was obtained from the amino acid ester 79. In the cyclizations, ligand IV-12 was used [45]. CO2t-Bu MeO

H

N Ph Br

MeO

MeO Pd2(dba)3, IV-12

t-BuOLi, dioxane 89%

77

N-Ph MeO 78

CO2t-Bu

N Pd2(dba)3, IV-12 CO2t-Bu Br 79

t-BuOLi, dioxane 66%

N

t-BuO2C 80

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

365

N ,N -dialkylamides can be arylated. Arylation of dimethylacetamide (81) using BINAP as a ligand and KN(TMS)2 as a base yields the phenylacetamide derivative 82 [46]. Intramolecular arylation proceeds more smoothly, and the oxindole 84 was prepared by intramolecular arylation of N -methyl-2-chloroacetanilide (83). For this reaction, PCy3 as a ligand is superior to BINAP and P(t-Bu)3 . When the reaction was carried out in the presence of 2-chloroanisole, the 3-aryloxindole 85 was obtained by domino intramolecular and intermolecular arylations. Asymmetric cyclization of the amide 86 using chiral carbene XVI-11, derived from (+)-isobornylamine as a chiral ligand, gave the oxindole 87 in 75 % yield with 76 % ee [47]. Br

+ MeCONMe2

Pd2(dba)3, XV-I KN(TMS)2

81

NMe2 O Me

72%

Me

82 Pd(OAc)2, PCy3 O

t-BuONa, dioxane 66%

N Me 84

Cl O Cl N Me

MeO

MeO

83 Pd(OAc)2, PCy3 O

t-BuONa, dioxane 60%

N Me 85 Me

Cl

Naph

O

Pd(dba)2, carbene (XVI-11) Naph

N Bn

O

t-BuONa, 10 °C 75%, 76% ee

N Bn

Me 86

87

In general, in contrast to high reactivity of malononitrile for arylation, mononitriles are less acidic than ketones and hence less reactive. Hartwig reported, however, that α-arylation of nitriles is possible by using BINAP or P(t-Bu)3 as a ligand. Diarylation of butyronitrile and acetonitrile occurred to give 87a and 87b Me + CH3CN Br

NaN(TMS)2, toluene 60%

MeO + Br

Ar

Pd(OAc)2, BINAP

CN

CN

Ar 87a

Pd2(dba)2, P(t-Bu)3 LiN(TMS)2, toluene 69%

CN Ar

Ar 87b

366 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides in preference to monoarylation, because monoarylated nitriles are more reactive than simple nitriles [48]. 3.7.1.5 Arylation of Other Compounds Bearing Acidic Hydrogens In addition to carbonyl compounds, nitro alkanes which have acidic hydrogens can be arylated with aryl bromides and chlorides using Cs2 CO3 as a base [49]. Stronger bases are not suitable. It is important to use IV-4 as a ligand. Interestingly this ligand is less active for the arylation of ketones. Only monoarylation takes place and no diarylation occurs. Reaction of 3-chloroanisole (88) and 4-bromoacetophenone (91) with nitropropane (89) afforded 90 and 92. Arylation of the nitro alkene 93 with the electron-deficient bromide 91 gave 94 selectively and no Mizoroki–Heck reaction of the olefin occurred under the conditions used. Intramolecular arylation of the nitro alkane 94a, followed by treatment of the primary product 94b with sulfuric acid yielded the α-tetralone 94c [35]. Cl

MeO +

n-Pr-NO2

MeO 88

Pd2(dba)3, IV-4

Et

Cs2CO3, DME, 68%

NO2

89

90

Br

+

NO2

Me

Pd2(dba)3, IV-4

n-Pr-NO2

Cs2CO3, DME, 80%

O

Et

89

COMe

92

91 Br

+

NO2

Pd2(dba)3, IV-4 Cs2CO3, DME, 64%

93

COMe 91

NO2

MeOC 94 NO2

O

NO2 PdCl2(PPh3)2, Cs2CO3

H2SO4

toluene, 59% Br 94a

94b

94c

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

367

Furthermore, arylation of the methyl group of p-nitrotoluene (95) with bromobenzene occurs at 140 ◦ C using Cs2 CO3 . As a ligand PPh3 is effective [50]. Both the monophenylated product 96 and the diarylated one 97 were obtained selectively depending on the reaction conditions. NO2

Br

Pd(OAc)2, PPh3

+

O2N

Cs2CO3, DMF 140 °C, 70% Me 95

C H2 96

NO2

97

As expected, less activated 3-nitrotoluene was not arylated, and the monoarylated product 100 was obtained selectively from 3,4-dimethylnitrobenzene (99) and sterically hindered 2-bromo-1,4-dimethylbenzene (98). On the other hand, diarylation of 4-methylpyrimidine (101) with 2-bromo-1,4-dimethylbenzene (98) gave 102 smoothly. No arylation of 4-methylbenzonitrile occurs. NO2 Br

NO2 Me

Me

Me

Pd(OAc)2, PPh3

+

Cs2CO3, DMF 140 °C, 96%

Me Me 98

Me

Me

99

100 N

Br Me

N +

N Me

Cs2CO3, DMF 89%

N Me Me 98

Me

Pd(OAc)2, PPh3

101

Me

Me 102

368 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides An interesting and efficient perarylation of metallocenes with aryl bromides has been reported by Miura et al. [51]. Typically, pentaphenylcyclopentadiene (104) was obtained in 70 % yield by reaction of zirconocene dichloride (103) with bromobenzene. Cs2 CO3 is the best base in this reaction. The first phenylation to give phenylcyclopentadiene seems to proceed via transmetallation. Then, sequential perphenylation of the intermediary cyclopentadienyl anions leads to the product 104. The pentaarylcyclopentadiene 106 was obtained in 87 % yield by the direct reaction of cyclopentadiene (105) with 4-chlorotoluene using t-Bu3 P as a ligand at a somewhat higher temperature of 160 ◦ C. Also the 1,3-diarylated cyclopentadiene 107 was triarylated further with 5-bromo-1,3-dimethylbenzene to give the pentaarylated products 108 as a mixture of double bond isomers [52]. The reaction is useful as a simple synthetic method of pentaarylcyclopentadienes, which are used as bulky Cp ligands. The bulky Cp complexes have considerable importance because their catalytic activity is different from non-substituted Cp complexes [53]. Ph +

ZrCl2

5 PhBr

Ph

Pd(OAc)2, PPh3 Cs2CO3, DMF 130 °C, 70%

Ph

Ph Ph

103

104 Me

Me

Cl

+ 105

Pd(OAc)2, P(t-Bu)3

5

Cs2CO3, DMF 160 °C, 87% Me Me

Me

Me 106 Br

+ Cl

Cl

Me

Me

107 Me

Me

Me

Me

60% Cl

Cl Me

Me

108 + double bond isomers

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

369

Interestingly, di-t-butylpentaphenylferrocenylphosphine 110(VIII-7) was prepared via direct pentaphenylation of a ferrocenyl phosphine without decomposition of the complex. First, di-t-butylphosphinoferrocene (109) was prepared, and its reaction in neat chlorobenzene afforded 110 in 40–65 % yield. The reaction may be explained by arylation via C—H bond activation by Pd coordinated to P(t-Bu)3 [54]. P(t-Bu)2 Fe

t-BuLi

Fe

ClP(t-Bu)2

P(t-Bu)2 PhCl Pd(OAc)2, t-BuONa 110 °C, 40~65%

Ph

Fe

Ph

Ph

109

Ph Ph 110 (VIII-7)

Facile ortho-arylation of phenols is known; this is covered in Chapter 3.3. 3.7.2 Intramolecular Attack of Aryl Halides on Carbonyl Groups It has been well-established that organopalladium intermediates are electrophilic, and clearly different from other organometallic compounds such as Grignard reagents which are nucleophilic. It is highly desirable to achieve a catalytic version of Grignard reactions. Yamamoto and co-workers reported a ‘formal’ Pd-catalyzed Grignard-type reaction [55]. They obtained the cyclopentanol 114 in 69 % yield by the reaction of the phenyl ketone 111 in the presence of Pd(OAc)2 , PCy3 , and Na2 CO3 in DMF. PPh3 is not effective. Furthermore, addition of 1-hexanol (5 equiv.) was crucial. The reaction is explained by nucleophilic attack of the Pd intermediate 112 to form 113, from which the cyclopentanol 114 is provided. At the same time Pd(II) is generated and reduced to Pd(0) probably with 1-hexanol. Similarly the cyclopentanol 116 and the cyclohexanol 118 were obtained from the bromo ketones 115 and 117. The reaction proceeds at high temperature (ca. 150 ◦ C). Interestingly no αarylation of ketones occurred under these conditions. Also, bromides gave better results than iodides. O Ph

Ph

Pd(OAc)2, PCy3 Na2CO3, DMF, 1-hexanol 135 °C, 12 h, 69%

Br

Pd

O

Br 112

111 base

+ Pd(II)

H+ Ph 113

O-PdBr

Ph 114

OH Pd(0)

370 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides O Bu Pd(OAc)2, PCy3 AcOK, DMF, 1-hexanol 150 °C, 24 h, 85%

Bu

Br

OH 116

115

Ph O Br

Pd(OAc)2, PCy3 AcONa,DMF, 1-hexanol 150 °C, 16 h, 62%

Ph

OH

118

117

Sole and co-workers found the smooth carbonyl addition reaction of aminotethered aryl iodides and ketones [29]. Treatment of the 2-iodoanilino ketone 119 with PPh3 , Et3 N and Cs2 CO3 in toluene afforded the alcohol 120. The cyclized product 122 was obtained from 2-iodobenzylamino ketone 121. The cyclized product 124 of the iodo ketone 123 was converted to the indole derivative 125 in high yield by acid-catalyzed dehydration. In these reactions, no α-arylation was observed. HO

O

I

PdCl2(PPh3)2, Cs2CO3 Et3N, toluene, 100 °C, 65% N

N Ac

Ac

119

120 I

Me O

Me

N

PdCl2(PPh3)2, Cs2CO3 Et3N, toluene, 100 °C, 73%

N

OH 121 HO

I

PdCl2(PPh3)2, Cs2CO3 Et3N, toluene, 100 °C, 87%

N Bn 123

cis/trans = 3.5 /1

122

O

TFA N

N

Bn 124

Bn 125

The tethered amino groups seem to play an important role. In the mechanistic studies, the rare four-membered palladacycle 127 was isolated in high yield as a stable compound by treatment of the iodoaniline-derived ketone 126 with Pd(PPh3 )4 , and converted to the alcohol 130 in high yield on heating with Cs2 CO3 . The cyclization is explained by the formation of the complex 127, which makes insertion of the C=O bond (or carbopalladation) to form the Pd alkoxide 128 easier. The alcohol 130 and Pd(II) are generated by the reaction of 128 with Cs2 CO3 via 129.

References

371 L

I Pd

I

O L

O

I O Pd

Pd(0)

insertion

N

N

N Bn

Bn

Bn

126

128

127 HO

Cs-O H+

Cs2CO3

N

N Pd(II)

Bn

Bn 129

130

Cs2CO3 127

110 °C

130

So far, these Pd-catalyzed Grignard-type reactions are limited to intramolecular versions to form five- and six-membered alcohols. Further extension and mechanistic studies are highly desirable. Also, it should be added that β-carbon elimination is the reverse process of these reactions (see Chapter 3.8.2).

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Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

373

3.7.3 Arylation of Nitrogen Nucleophiles 3.7.3.1 Introduction Preparation of aromatic amines by the reaction of aryl halides with aliphatic and aromatic amines has been regarded as a difficult reaction. Recently a facile synthetic method for aromatic amines by amination of aryl halides has been discovered, and rapid progress has occurred in the Pd-catalyzed reaction of amines with aryl halides [1]. One simple example which shows the usefulness of the new method is cited here. The commercially important arylpiperazines 1 have been synthesized by intramoleular N-alkylation of aniline derivatives with N ,N di-(2-chloroethyl)amine (2), which is highly carcinogenic. Now the amines 3 can be prepared efficiently by coupling aryl iodides, bromides or chlorides with Nsubstituted piperidines. This example provides a big contribution to synthetic chemistry by the new Pd-catalyzed efficient preparative method for arylamines, which are useful in medicinal and material chemistry. Cl R′

R′ NH2 +

NR

N

NR

N

NR

Cl 2

1

R′

[Pd] X

+ HN

R′

NR 3

X = I, Br, Cl

The first report on the Pd-catalyzed preparation of arylamines by the reaction of aryl bromides with N ,N -diethylaminotributyltin (4) was given by Kosugi et al. in 1983. A poor result was obtained with aryl iodides. In this reaction, bulky P(o-Tol)3 was used as the most suitable ligand [2]. Br

Bu3SnNEt2

+

4

NEt2 PdCl2[P(o -Tol) 3]2

+

toluene, 100 °C 81%

Bu3SnBr

Reinvestigation of the Kosugi and Migita reaction was carried out by the Buchwald and Hartwig groups leading to the discovery of a tin-free synthetic method for arylamines based on the Pd-catalyzed reaction of aryl bromides with amines using P(o-Tol)3 as a ligand [3,4]. MeO

Ph

Br + HN

Br + MeHN

PdCl2 [P(o -Tol) 3]2 LiN(SiMe3)2, toluene 100 °C, 89%

MeO

N

Pd2(dba)3, P(o-Tol) 3

t-BuONa, toluene 80 °C, 88%

Ph

N Me

374 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides The success of the new method is due to selection of bases which are stable under the reaction conditions and also the use of bulky phosphine ligands. Later, reductive elimination was found to be crucial in the C—N bond formation, which is accelerated by bulky ligands. As bases, MN(TMS)2 (M = Li, Na, K) and t-BuONa give good results. Alkoxides such as MeONa, EtONa, and n-BuONa seem to be unsuitable, because oxidation of alcohols and reduction of aryl halides occur via facile β-H elimination of the palladium alkoxide 5. t-BuONa is a good base. Formation of aryl t-butyl ether to some extent is competitive with arylamine formation. Reductive elimination of Ar-Pd-O-t-Bu to form aryl t-butyl ethers is slower, and the amine formation takes place preferentially. But, interestingly Prashad et al. reported that β-hydrogen-containing alkoxides such as MeONa and sodium isopropoxide can be used satisfactorily in the amination as a base even at 110 ◦ C [5]. Amination of the bromide 5a with N -methylaniline proceeded smoothly to give the diarylamine 5b in good yields using MeONa and BINAP as a ligand. Surprisingly even sodium isopropoxide can be used so that easier oxidation to acetone is expected. H Ar-X + Pd(0)

Ar-Pd-X + R2CHONa

Ar-H

+

Ar

R

Pd O

R

R O

+

Pd(0)

5

R

Me

Pd2(dba)3 , BINAP, toluene,110, °C

MeHN +

Me

Me

MeONa, 23 h, 82% Me2CH-ONa, 22 h, 85% Me

Br

N Me

5a

5b

Aryl iodides, bromides, chlorides, triflates and some tosylates are used for the arylamine synthesis. Secondary (dialkyl, alicyclic, alkyl–aryl, and diarylamines) and primary amines (alkyl and arylamines) participate in the reaction with different reactivity. In general, more basic and less bulky amines react faster. Generally aryl bromides are better substrates than aryl iodides. A disappointing result was obtained in the reaction of aryl iodides when IV-1 was used as a ligand. Satisfactory results were obtained by using IV-2, IV-12 and xantphos (IX10). Reaction of o-iodoanisole 5c with morpholine using IX-10 provided 5d in 94 % yield [6]. H N

I + OMe 5c

O

O Pd2(dba)3 , IX-10

t-BuONa, dioxane 60 °C, 94%

N

OMe 5d

Also it is important to consider that reactivity of halides is dependent on whether aryl groups are electron-deficient, neutral or electron-rich. Electron-deficient aryl

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

375

halides have higher reactivity. Less reactive electron-rich aryl halides have considerable practical importance and optimum conditions must be found for the reaction of these aryl substrates. Therefore, proper ligands and bases should be selected carefully for each amine and aryl substrate. Mechanism of the arylamine formation is the following. Oxidative addition of aryl halide generates the arylpalladium 6, to which an amine coordinates. Abstraction of proton from the coordinated amine with a base (BM) affords the arylpalladium amide 7, and its reductive elimination yields the arylamine 8. Reductive elimination of 7 is a rate-determining step. A path, competitive to the path from 7 to 8, is β-H elimination to give the imine 9 and the Pd hydride 10, and the reduced arene 11 is formed by reductive elimination of 10. This is a serious side reaction. The elimination of β-H may be minimized by the use of chelating ligands. R Ar

Ar

H

N

Ar-X

LnPd(0)

CH2R′

11 8 LnPd(0)

R H

H N

LnPd

LnPd

Ar

Ar

10

LnPd

R′

X Ar

7 6

R N R′

H

BH + MX

9

B-M base

R N

CH2R′

H

3.7.3.2 Importance of Bulky and Electron-Rich Phosphines Bidentate phosphine ligands such as BINAP and DPPF were found to give much better results than P(o-Tol)3 in the reaction of N -methylaniline with electron-rich aryl bromides as shown by the following examples [7,8]. OMe Br

OMe Me + HN

Pd2(dba)3, L

t-BuONa, 80 °C

N Me

L = BINAP 75% L = P(o-Tol) 3 0%

Me COPh

HN

+

Br

(dppf)PdCl2

t-BuONa, 80 °C 87%

PhOC

N Me

376 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides However, the bidentate ligands are not always effective. An important discovery by Koie and co-workers in 1998 that bulky and electron-rich P(t-Bu)3 is an excellent ligand for amination of aryl bromides has had a big impact on this research area. More importantly, even aryl chlorides react with amines using this ligand [9]. Preparation of triarylamines 12 and 13 by coupling aryl halides with diarylamines can be carried out smoothly using P(t-Bu)3, . Known ligands P(o-Tol)3 and BINAP gave poor results in the same reactions. N -(3-methylphenyl)diphenylamine (13) was prepared in 99 % yield, but the yield was 5 % when P(o-Tol)3 was used and 0 % with BINAP. Amination of electron-rich aryl bromides and chlorides was carried out at room temperature with this ligand [10]. Recently, air stable, sterically hindered pentaphenylferrocenyl di-t-butylphosphine (VIII-7) has been synthesized, which creates a remarkably active catalyst. Triphenylamine was prepared in 86 % yield by coupling chlorobenzene with diphenylamine using this ligand [11]. Br +

Br

i

N H

80% Me

N

N

Me

Me 12

Cl

+

HN

NH

i

N

83%

NH

Cl i

+

N H

N

99% Me Me

i = Pd(OAc)2, P(t-Bu)3, t-BuONa, xylene, 120 °C

t-BuONa, xylene, 120 °C = 5% yield

Pd(OAc)2, P(o-Tol) 3,

H N

Cl

13

Pd(dba)2, (VIII-7), Ph5FcP(t-Bu)2

+

t-BuONa, toluene, 80 °C, 99%

MeO

N

MeO

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

377

The use of P(t-Bu)3 was an important discovery, because this phosphine has scarcely been used as a ligand of active transition metal catalysts. It was believed that P(t-Bu)3 is too bulky for stable coordination. It is known that only two molecules of P(t-Bu)3 can coordinate to Pd to form the highly coordinatively unsaturated, but stable bis(tri-t-butyl)phoshinepalladium complex [12]. This complex is commercially available as a good precursor of active Pd catalysts. Inspired by the discovery that P(t-Bu)3 is an important ligand, several researchers have synthesized a number of electron-rich and bulky phosphine ligands. For example, the asymmetric triarylamine 15 was prepared from 3-methoxyaniline (14) using the biphenylylphosphine IV-1 in a one-pot reaction. Similarly, the arylamine 17 was prepared by one-pot, step-wise arylation of m-diaminobenzene (16) [13]. t-Bu

S

Br MeO

NH2

t-Bu Br

Pd2(dba)3, IV-1 t-BuONa, 92%

N

MeO

14 S 15 Me

t-Bu

Cl

Br H2N

NH2 16

Pd2(dba)3, IV-1, t-BuONa, 95% t-Bu

t-Bu

N

N

Me

Me 17

In 1997, Reddy and Tanaka discovered that aryl bromides and even aryl chlorides are aminated using PCy3 as a ligand [14]. Beller et al. found that the palladacyle XVIII-1 (the Herrmann complex) is active for the amination of electron-deficient aryl chlorides [15]. Reaction of p-chlorotrifluorobenzene 17a with piperidine using palladacycle XVIII-1 was carried out to give the coupled product with high regioselectivity, mainly a para isomer as expected. On the other hand, the reaction proceeded without the Pd catalyst, but para and meta products were obtained in equal amounts presumably via benzyne intermediate. Also aryldicyclohexylphosphine I-17 with a rigid cyclic acetal catalyzed amination of the aryl chloride 18 [16]. Zim and Buchwald reported that the air and

378 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Cl

+

HN

Pd(PCy3)2Cl2, t-BuONa

NMe

Me

120 °C, Toluene 12 h, 76%

N

NMe

Me Cl

NHMe Pd(PCy3)2Cl2, t-BuONa

+

Me N

Me

120 °C, Toluene 6h

54%

Me

thermally stable palladacycle XVIII-20, prepared by the treatment of biphenylylphosphine IV-1 with Pd(OAc)2 , is an active one-component catalyst for the amination of aryl chlorides. The complex is commercially available. More importantly, they found that, in addition to commonly used t-BuONa, bases such as MeONa and even KOH are effective bases in the amination of chlorides when this catalyst is used [5,17]. Cl

+

Palladacycle (XVIII-1) t-BuONa, 135 °C

HN

74%

F3C

N para/meta = 7 : 1

CF3

No cat. = 79%, p / m = 1: 1

17a

Me

Cl + Me

HN

O

Pd2(dba)3, I-17

N

t-BuONa, 105 °C

Me

Me

O

92%

18 NH2

Cl

XVIII-20 +

t-Bu

P(t-Bu)2

t-Bu

N H

t-BuONa, toluene 80 °C, 97%

+ Pd(OAc)2

toluene

P(t-Bu)2

rt

Pd OAc

IV-1

XVIII-20

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

379

It is interesting to compare cone angles of monophosphines as a measure of their bulkiness [18]: ◦

PPh3 = 145 ;

◦

P(o-Tol)3 = 194 .

P(n-Bu)3 = 132 ; P(t-Bu)3 = 182 ;

◦

◦

PCy3 = 170 ; ◦

It is commonly recognized that electron-rich phosphines facilitate oxidative addition of aryl chlorides and bromides, and bulky phosphines accelerate reductive elimination. From these considerations, P(t-Bu)3 is one of the best ligands. ‘Bulky’ and ‘electron-rich’ are key words in discovering good ligands for active catalysts. Amination of iodides and bromides proceeds in DME at room temperature using IV-12 [19,20]. Reaction of p-bromo-t-butylbenzene (19) with dibutylamine, which is relatively less reactive, was carried out to afford 20 using several ligands, and it was found that BINAP, DPPF, and BPPFA are poor ligands. On the other hand, P(o-Tol)3 , PPFA (VIII-9), and PPF-OMe (VIII-11) gave good results [21]. Br +

NBu2

Pd2(dba)3, Ligand (L)

n-Bu2NH

t-Bu

t-BuONa, toluene 105 °C

t-Bu

19

20 L = P(o-Tol) 3 : 48 h, 83% L = (rac)-PPFA (VIII-9) : 24 h, 92% L = (rac) PPF-OMe (VIII-11) : 5 h, 97%

Tosylates are not reactive partners of amination. Even P(t-Bu)3 is not effective. Buchwald reported that amination of tosylates and benzene sulfonates with various amines proceeded smoothly by using biphenyl-based phosphine IV-17 in the presence of Cs2 CO3 [21a]. Bidentate ferrocenyl ligands, Dt-BPF (XI-4), XI-9, and XI-10 are effective not only for aryl chlorides, but also for aryl tosylates 21 to give 22 [22]. OTs

H N +

t-Bu

Pd(OAc)2, IV-17 Cs2CO3, toluene t-BuOH, 110 °C, 84%

t-Bu

N

NH-n-Hex

OTs + (n-Hex)NH2 Me 21

Pd(OAc)2, XI-9

t-BuONa, toluene 110 °C, 2 h, 83%

Me 22

Another good ligand is carbene XVI-6, and its derivatives. Synthesis of these carbene ligands is rather simple. Pd–carbene complexes prepared in situ are active catalysts. For example, reaction of chlorotoluene with N -methylaniline was carried out at 100 ◦ C using the imidazol-2-ylidene complex XVI-2 to give 23 in

380 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides high yield [23]. The Pd complex of XVI-2 is an air and moisture-stable complex and shows a remarkable insensitivity to oxygen and water. Amination of aryl bromides and chlorides with a variety of amines proceeds under mild conditions by utilizing the complex as a catalyst [24]. The dihydroimidazole carbene complex XVI-6 is more active and the reaction of chlorotoluene with aniline proceeded even at room temperature to afford 4-methyldiphenylamine (24) in 82 % yield [25]. Usually, but not always, reactions of aryl halides with amines proceed at an elevated temperature when phosphine ligands are used. It is claimed that Pd-catalyzed reaction of 3-chloropyridine with amines is very slow when monodentate phosphines are used due to stronger coordination of pyridine to Pd. The reaction with morpholine proceeded smoothly at room temperature by using XVI6 to afford 25 in 93 % yield. This means that the carbene ligand coordinates to Pd more strongly than phosphines and pyridine. However, amination of 3-bromo-, 2-chloro-, 4-chloropyridines, and 2-chloropyrimidine with heterocyclic amines has been reported to proceed smoothly using xantphos (IX-10) as a ligand and either Na2 CO3 or Cs2 CO3 as a base [26]. Me HN Pd2(dba)3, carbene ligand (XVI-2)

Cl +

t-BuOK, dioxane 100 °C, 98%

Me

Me

N Me 23

NH2 Pd2(dba)3, carbene ligand (XVI-6)

Cl +

t-BuONa, DME rt, 82%

Me

Me

N H 24

Pd2(dba)3, carbene ligand (XVI-6)

Cl +

HN

O

N

t-BuONa, DME 20 h, rt, 93%

N

O

N 25

Commercially available and stable monoligated complex XVIII-19 is a very active catalyst, and coupling of p-chloroanisole with dibutylamine proceeded at room temperature in 15 min to give the aminated product 26 in 87 % yield [27]. The catalyst is also active for amination of aryl bromides with hindered N-alkylsubstituted anilines [28]. [PdBr2P(t-Bu)3)2 , (XVIII-19)

Cl + NHBu2 MeO

NBu2

t-BuONa, THF rt, 15 min, 87% MeO 26

Amination of aryl halides containing OH, amide, or enolizable keto groups can be carried out without protection of these functional groups by the use of bulky

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

381

ligand IV-12 and 2.2 equivalents of LiN(TMS)2 as a base as shown by the reaction of p-bromo(2-hydroxyethyl)benzene (26a) [29]. HO

Pd(dba)2, IV-12

+ MeHN

HO

LiN(TMS)2, 80%

Br

N

26a

Ph

Me

3.7.3.3 Arylation of Various Amines Aryl chlorides have been regarded as inert substrates in catalytic reactions. Recent developments in facile Pd- and Ni-catalyzed reactions of aryl chlorides, which are cheaper than iodides and bromides, have made a big impact on the chemical industry. Aryl triflates react with amines using BINAP and DPPF (XI-1) as ligands and Cs2 CO3 as a base. t-BuONa can not be used for some reactive triflates 27 and 28, because they tend to be decomposed with this base [30]. NHMe Pd(OAc)2, BINAP

OMe +

TfO 27

H N OTf

88%

N

t-BuONa, toluene 100 °C

OTf

O

90% MeO2C

H N

Pd(OAc)2, BINAP

+

N

Cs2CO3 dioxane, 80 °C

O

28

N Me

Pd(dba)2, DPPF

+ O

MeO2C

MeO

Cs2CO3 toluene, 80 °C

O

91%

On account of the facile amination of triflates, arylamines 31 can now be prepared from phenols 29 via their triflates 30. It should be added that electrondeficient aryl triflates 32 can be aminated without a catalyst [31,32]. R HN OH R

OTf R

29

[Pd]

30

OTf + H2N

t-BuO2C 32

R

R

N R

R 31

no cat,110 °C 3 h, 81%

t-BuO2C

N

382 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Selective monoamination of ortho-, para-, and meta-dibromobenzenes 33 with the polyamine 34 took place using DPPF (XI-1) as a ligand to give 35 in a reasonable yield even in the presence of an excess of the polyamine without giving the diamination product. In addition, selective monoarylation of the primary amine moiety in the polyamine 34 was observed [33]. Br NH2

NH

t-BuO Na, dioxane 100 °C

NH2

Br 33 1 mmol

34

NH

Pd(dba)2, DPPF

+

HN Br

NH2

3 mmol

35

Pd-catalyzed reactions of chiral amines with aryl halides can be carried out without racemization by selection of proper ligands. Intramolecular reaction of the 2bromophenyalanine derivative 36 using P(o-Tol)3 proceeded without racemization to give 37, which is a key intermediate in the synthesis of ACR inhibitor 38. On the other hand, racemization was observed to a considerable extent using the same ligand in intermolecular reaction. Reaction of (R)-α-methylbenzylamine (39) with a bromide afforded the arylated amine 40 with 70 % ee. Racemization is explained by reversible elimination of benzylic hydrogen to form imine. Intermolecular arylation of 39 to give 40 proceeded without racemization when racemic BINAP was used as a ligand [34]. The reaction of aniline with 2, 2
-dibromobiphenyl yielded the carbazole 40a in good yield. The reaction offers a facile synthetic method for multisubstituted carbazoles [35]. CO2Me

Pd2(dba)3, P(o-Tol) 3

Br 36

CO2Me

Cs2CO3, 100 °C

NHAc

N Ac

93%

99% ee

37

99% ee

Me Ph NH2 CO2Me N 98% ee

CO2Et 38

O

Me

H

H

39

Me

Ph

Me Pd2(dba)3, P(o-Tol) 3

t-BuONa, 100 °C, 60%

N H 40

70% ee

+ Br

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

383 Ph

Me

Me Ph NH2

Pd2(dba)3, (rac) BINAP

+ Br

39

NH2

N H

t-BuONa, 100 °C, 86%

+

99% ee

40

Br

Pd2(dba)3, P(t-Bu)3

Br

t-BuONa, toluene 80 °C, 86%

N

40a

Enantiopure tetrahydrobenzo-1,4-diazepin-3-(3H )-one 42 was obtained by intramolecular amination of the aryl iodide 41 using BINAP as a ligand without racemization [36]. The chiral imidazole 47 was prepared by successive Pdcatalyzed amination of the chiral amine 43 with 1,2-dibromobenzene to give 44, which was iminated with benzophenone imine (45). Then deprotection gave 46, and acid-catalyzed ring closure yielded 47 [37]. The reactions have been applied to the synthesis of various chiral imidazolium salts as precursors of chiral carbene ligands [38]. Amination of aryl bromides proceeds very rapidly by temperaturecontrolled microwave heating [39].

I

Me

H N Bu

Pd2(dba)3, (R)-BINAP

NH2

O

t-BuOK, 66%

N

N

Me (S)

41

Bu

O

42

Me

+ Br Me

H2N

NH

Pd(dba)2 , BINAP

t-BuONa

Ph

44 Me

Ph NH2OH

Me

Ph NH

Ph N

CH(OMe)3 91%

N

N

NH2 46

Ph

Ph

45

Ph

Pd(dba)2 , BINAP t-BuONa

Br

43

NH

Ph

Ph HN

Me

Br

99% ee

47

99% ee

384 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.7.3.4 Arylation of Amides, Carbamates, and Azoles In addition to amines, some derivatives of amines can be arylated. Weakly basic amides are arylated, and intermolecular reactions between aryl bromides and triflates 48 with benzamide can be carried out. Combined uses of xantphos (IX-10) and Cs2 CO3 in THF or dioxane gave the most successful results. The cyclic urea 49 was diarylated [40]. Sulfonamides are also arylated [41]. Intramolecular reaction of the secondary amides such as 50 or carbamates offers convenient synthetic methods for five-, six-, and seven-membered lactams like 51. As ligands, MOP (VI-12), DPEphos (IX-9), xantphos (IX-10), and BINAP are used depending on the size of the rings. As an example, ligand IX-9 is the most suitable for the preparation of the five-membered N -carbobenzyloxy derivative 52a from 52, but BINAP was not effective. O

t-Bu

Pd2(dba)3, IX-10

+

OTf

H2N

Ph

48

Cs2CO3, dioxane reflux 94%

t Bu

NH O Ph

Br +

NH

HN

MeO

49

OMe

N

N

Cs2CO3, dioxane reflux 92%

O

MeO

Pd2(dba)3, IX-10

O

Pd(OAc)2, MOP (VI-12) Br

O HN

50

Cs2CO3, toluene 100 °C

Bn

51

NHCO2CH2Ph

52

O

88%

Pd(OAc)2, IX-9 Cs2CO3, toluene 100 °C, 92%

Br

N Bn

N CO2CH2Ph 52a

Yang and Buchwald reported that the following preparative method of the catalyst is important. First, a toluene solution of Pd(OAc)2 , a ligand and an amine is heated at 100 ◦ C for 2 min in the absence of a base, and the base is added at 0 ◦ C. Good results are obtained for the catalyst prepared in this way [42]. Preparation of DPEphos (IX-9) and xantphos (IX-10) is easier and cheaper than that of racemic BINAP, and they are used as good bulky bidentate ligands [43]. Also, xantphos (IX-10) gave excellent results in arylation of 2-oxazolidinones 53 with aryl bromides [44]. The 1β-methylcarbapenem 53b was prepared from 53a by Mori by using IX-9 as the ligand and K2 CO3 as the best base. The lactam 53b

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

385

was obtained in 90 % yield when the catalyst was prepared by the Buchwald recipe in the absence of the base [45]. Pd-catalyzed cyclization of the iodide 53d, prepared from 53c, was applied to the synthesis of (−)-asperlicin. The iodide 53d has two amino groups, but the cyclization afforded 53e chemoselectively. In addition, two epimerizable stereocenters in 53e were preserved [46]. Br O

HN +

t-BuONa, 73%

O

MeO

O

N

Pd(OAc)2, IX-10

O

53

OMe TBSO

TBSO H

H

H

H

Pd(OAc)2, IX-9 K2CO3, toluene 100 °C, 90%

NH O

N O

CO2Et

I

CO2Et 53b

53a CO2Ph

CO2Ph

TrocHN

TrocHN

CO2Ph

TrocHN Pd(dba)2 P(o-Tol) 3 I

N

N

NHCbz

O

t-Bu

NCbz N

t-Bu

O

53c

K2CO3 NHCbz

O

t-Bu 53d

53e (−) Asperlicin

Heterocycles were synthesized by arylation of vinylogous amides, followed by Heck reaction. Monoarylation of the vinylogous amide 54 with 1, 2-dibromobenzene afforded 55. The indole derivative 56 was obtained by intramolecular Heck reaction of 55 [47]. O Br

Pd(dba)2 , IV-12

+ Br

O

Cs2CO3, 61%

H2N 54

O

N H 56

Br

N H 55

386 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Azoles such as pyrrole (57), carbazole (58), and indole can be N-arylated in the presence of DPPF [48]. Various N-arylated indoles were prepared conveniently by N-arylation of indole with aryl iodides, bromides, chlorides, and triflates. Suitable ligands are selected from bulky biphenyl- or binaphthyl-based phosphines IV-12, IV-14, and VI-3 depending on the kinds of aryl halides used [49]. Br Pd(OAc)2, DPPF

+

N H

OMe

N

t-BuONa, 74%

57

OMe

Br Pd(OAc)2, DPPF

+

N

Cs2CO3, 97% N H

CN

58 CN

Vinylation of azoles is also possible. The vinylation of indole with cis-βbromostyrene proceeded with retention of configuration to afford 59 in high yield using P(t-Bu)3 as a ligand [50]. Cl Pd(dba)2 , IV-12

N

+

t-BuONa, 87%

N H Me

Me Br +

N H

Ph

Pd(dba)2, P(t-Bu)3 toluene, DME 85 °C, 2 h, 99%

N Ph 59

3.7.3.5 Arylation of Ammonia Surrogates So far no arylation of ammonia has been reported, and it is difficult to prepare aniline derivatives directly by the Pd-catalyzed reaction of aryl halides with ammonia. Aniline derivatives are prepared indirectly by the reaction of ammonia surrogates (ammonia equivalents). The reaction of the ammonia surrogates with aryl halides, followed by deprotection affords aniline derivatives. As one of them, LiN(TMS)2 (61) reacts with aryl bromides and chlorides. P(t-Bu)3 is the best ligand, and the coupled products are converted easily to anilines by treatment with aq. HCl.

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

387

Synthesis of 62 from 60 is an example [51]. Use of LiN(TMS)2 as the ammonia surrogate is problematic for aryl bromides containing an amide group, but the reaction of p-bromoacetanilide (63) proceeds smoothly using 2.2 equivalents of 61 [29]. Cl

NH2 +

LiN(TMS)2

1. Pd(dba) 2 , P(t-Bu)3 2. HCl, 90%

61 OMe

OMe

60

62 NHCOMe + LiN(TMS)2

Br

1. Pd(dba) 2, IV-12 dioxane

NHCOMe

2. H +, 71%

H2N

63

No smooth reaction of LiN(TMS)2 was observed with sterically congested orthosubstituted aryl halides. In such a case, Ph3 SiNH2 can be used as an ammonia surrogate and the coupled product 64 was converted to 65 [52]. Benzophenone imine (66) is another ammonia surrogate. Arylation of the imine 66 is carried out using BINAP and Cs2 CO3 . Hydrolysis of the arylated imine 67 affords the aniline derivative 68 [53]. Cl

NH2

NHSiPh3 OMe + Ph3SiNH2

OMe

Pd(dba)2, IV-2

OMe

H2O

LiN(TMS)2 98% 64

65

OTf

Ph +

Ph HN Ph

Pd(OAc)2, BINAP Cs2CO3, 83%

Ph MeOC

N

66 67

COMe H2O, HCl MeOC

NH2 68

3.7.3.6 Arylation of Other Nitrogen-Containing Compounds The arylation of imines can be applied to indole synthesis. The Fischer indole synthesis was carried out by Pd-catalyzed arylation of benzophenone hydrazone (69) to give N -arylbenzophenone hydrazone 70. The subsequent exchange reaction

388 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides of 70 with cyclohexanone afforded the N -arylcyclohexanone hydrazone 71 as a requisite intermediate of the Fischer indole synthesis. The hydrazone 71 was converted to the indole 72 [54]. Br

+

H2NN

Ph

Cl

Pd(OAc)2, BINAP

Ph

t-BuONa, 80%

Ph

Ph N

N H

69 Cl

70 Cl Cl

O TsOH, 95%

N

N H

N H

72

71

Intramolecular amination of N ,N -dimethylhydrazone of o-chlorophenylacetaldehyde (73) offers a facile synthetic method of indoles. 1-Aminoindole 75 was prepared by intramolecular arylation of 73. For this reaction, (ferrocenyl)aminophosphine VIII-3 was a better ligand than P(t-Bu)3 . N ,N -dimethylhydrazones have no hydrogen to be displaced, and the arylation is explained by isomerization to the enamine form 74. Another possibility may be insertion of C=N bond to Ar-Pd bond, followed by dehydropalladation. Similarly, the quinoline 77 was obtained by intramolecular amination of 2,6-dichlorophenylpropionaldehyde N ,N dimethylhydrazone (76) [55]. H

H Pd(dba)2,VIII-3

N Cl

NMe2

Cs2CO3, 75%

N Pd

N

NMe2

NMe2

Cl 73

74 Cl

75 Cl

H N

NMe2

Pd(dba)2,VIII-3 Cs2CO3, 32% N

Cl 76

NMe2 77

Sulfoximines 78 are N-arylated with aryl iodides and bromides to give 79 using BINAP or Tol-BINAP as a ligand and Cs2 CO3 as a base [56]. The reaction of 78 with 2, 2
-dibromobiphenyl (80) using rac-BINAP and t-BuONa afforded the seven-membered ring compound 82 by sequential N-arylation and C-arylation as shown by 81. The reaction shows that a methyl group activated by a sulfoximino group can be arylated as in the reaction of carbonyl compounds [57].

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

Br

S

O

Pd(OAc)2, Tol-BINAP ( XV-2)

H

N

+

O

Cs2CO3, toluene 110 °C, 96%

Me

Ph

N

Br

+

O

S

Ph

79

O

Pd(OAc)2, Tol-BINAP ( XV-2)

H

N

S

Me

78

Br

389

Me

N Br

t-BuONa, toluene 98%

Ph

S

Ph CH2

78 80

81 N

O

S

Ph

82

3.7.3.7 Arylation with Nitrogen-Containing Heterocyclic Halides Arylation with various heterocyclic compounds can be carried out when their reactive halides are available at proper positions. For example, the antihistamine norastemizole derivative 85 was synthesized by the reaction of the chlorobenzimidazole 83 with the diamine 84. Selective arylation of the primary amine in the diamine 84 proceeded with high selectivity [58]. BINAP is a good ligand for the amination of 3-bromopyridine (86) [59]. Similarly benzylamine was introduced to the bromopyridine moiety of the 3-carboxy-β-carbolines 87 to give 88 [60]. Another example is the C-8 aminated adenosine derivative 90 was obtained in a high yield by the amination of 89 [61]. NH

NH2 N N

N

Pd(dba)2 , BINAP

+

Cl

NH

t-BuONa, 84%

N

N H F

84

F

83

85

Br + H2N N 86

H N

Pd(dba)2 , BINAP

t-BuONa, 82% N

390 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides CONHPh

CONHPh

N

N Br +

Me2NO2S

NHBn

Pd(dba)2 , BINAP BnNH2

N

t-BuONa, 52% Me2NO2S

87

88 N N +

O

N

NH2

Br RO

NHPh N

Pd(dba)2 , BINAP

t-BuONa, 84%

OR

RO

N

O

RO

OR

RO

89

90

References 1. Reviews: J. F. Hartwig, Angew. Chem. Int. Ed., 37, 2046 (1998); J. F. Hartwig, Synlett, 329 (1997); J. P. Wolfe, S. Wagaw, J. F. Marcoux, and S. L. Buchwald, Acc. Chem. Res., 31, 805 (1998); B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 576, 125 (1999). 2. M. Kosugi, M. Kameyama, and T. Migita, Chem. Lett., 927 (1983). 3. A. S. Guram and S. L. Buchwald, J. Am. Chem. Soc., 116, 7901 (1994); A. S. Guram, R. A. Rennels, and S. L. Buchwald, Angew. Chem. Int. Ed. Engl., 34, 1348 (1995). 4. F. Paul, J. Patt, and J. F. Hartwig, J. Am. Chem. Soc., 116, 5969 (1994); J. Louie and J. F. Hartwig, Tetrahedron Lett., 36, 3609 (1995). 5. M. Prashad, B. Hu, Y. Lu, R. Draper, D. Har, O. Repic, and T. J. Blacklock, J. Org. Chem., 65, 2612 (2000). 6. M. H. Ali and S. L. Buchwald, J. Org. Chem., 66, 2560 (2001). 7. J. P. Wolfe, S. Wagaw, and S. L. Buchwald, J. Am. Chem. Soc., 118, 7215 (1996). 8. M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 118, 7217 (1996). 9. M. Nishiyama,, T. Yamamoto, and Y. Koie, Tetrahedron Lett., 39, 617 (1998); T. Yamamoto, M. Nishiyama, and Y. Koie, Tetrahedron Lett., 39, 2367 (1998). 10. J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy, and L. M. AlacazarRoman, J. Org. Chem., 64, 5575 (1999). 11. N. Kataoka, Q. Shelby, J. P. Stambuli, and J. F. Hartwig, J. Org. Chem., 67, 5553 (2002). 12. S. Otsuka, T. Yoshida, M. Matsumoto, and K. Nakatsu, J. Am. Chem. Soc., 98, 5850 (1976). 13. M. C. Harris and S. L. Buchwald, J. Org. Chem., 65, 5327 (2000). 14. N. P. Reddy, and M. Tanaka, Tetrahedron Lett., 38, 4807 (1997). 15. M. Beller, T. Riermeier, C. P. Reisinger, and W. A. Herrmann, Tetrahedron Lett., 38, 2073 (1997). 16. X. Bei, A. S. Guram, H. W. Turner, and W. H. Weinberg, Tetrahedron Lett., 40, 1237 (1999). 17. D. Zim and S. L. Buchwald, Org. Lett., 5, 2413 (2003). 18. C. A. Tolman, Chem. Rev., 77, 313 (1977). 19. D. W. Old, J. P. Wolfe, and S. L. Buchwald, J. Am. Chem. Soc., 120, 9722 (1998). 20. M. H. Ali and S. L. Buchwald, J. Org. Chem., 66, 2560 (2001). 21. J. F. Marcoux, S. Wagaw, and S. L. Buchwald, J. Org.Chem., 62, 1568 (1997). 21a. X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, and S. L. Buchwald, J. Am. Chem. Soc., 125, 6653 (2003).

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

391

22. B. C. Hamann and J. F. Hartwig, J. Am. Chem. Soc., 120, 7369 (1998). 23. G. A. Grasa, M. S. Viciu, J. Huang, and S. P. Nolan, Org. Lett., 1, 1307 (1999); J. Huang, G. A. Grasa, and S. P. Nolan, J. Org. Chem., 66, 7729 (2001). 24. M. S. Viciu, R. M. Kissling, E. D. Stevens, and S. P. Nolan, Org. Lett., 1, 1307 (1999). 25. S. R. Stauffer, S. Lee, J. P. Stambuli, S. I. Hauck, and J. F. Hartwig, Org. Lett., 4, 2229 (2002). 26. J. Yin, M. M. Zhao, M. A. Huffman, and J. M. McNamara, Org. Lett., 4, 3481 (2002). 27. J. P. Stambuli, R. Kuwano, and J. F. Hartwig, Angew. Chem. Int. Ed., 41, 4746 (2002). 28. M. Prashad, X. Y. Mak, Y. Lu, and O. Repic, J. Org. Chem., 68, 1163 (2003). 29. M. C. Harris, X. Huang, and S. L. Buchwald, Org. Lett., 4, 2885 (2002). 30. J. P. Wolfe and S. L. Buchwald, J. Org. Chem., 62, 1264 (1997). 31. H. Kotsuki, S. Kobayashi, H. Suenaga, and H. Nishizawa, Synthesis, 1145 (1998). 32. L. Schio, G. Lemoine, and M. Klich, Synlett, 1559 (1999). 33. I. P. Beletskaya, A. G. Bessmeertnykh, and R. Guilard, Synlett, 1459 (1999). 34. S. Wagaw, R. A. Rennels, and S. L. Buchwald, J. Am. Chem. Soc., 119, 8451 (1997). 35. K. Nozaki, K. Takahashi, K. Nakano, T. Hiyama, H. Z. Tang, M. Fujiki, S. Yamaguchi, and K. Tamao, Angew. Chem. Int. Ed, 42, 2051 (2003). 36. M. Catellani, C. Catucci, G. Celentano, and R. Ferraccioli, Synlett, 803 (2001). 37. F. M. Rivas, A. J. Giessert, and S. T. Diver, J. Org. Chem., 67, 1708 (2002). 38. F. M. Rivas, U. Riaz, A. J. Giessert, J. A. Smulik, and S. T. Diver, Org. Lett., 3, 2673 (2001). 39. Y. Wan, M. Alterman, and A. Hallberg, Synthesis, 1597 (2002). 40. J. Y. Yin and S. L. Buchwald, Org. Lett., 2, 1101 (2000), J. Am. Chem. Soc., 124, 6043 (2002). 41. A. J. Pet and S. L. Buchwald, J. Am. Chem. Soc., 118, 1028 (1996). 42. B. H. Yang and S. L. Buchwald, Org. Lett., 1, 35 (1999). 43. J. P. Sadighi, M. C. Harris, and S. L. Buchwald, Tetrahedron Lett., 39, 5327 (1998). 44. S. Cacchi, G. Fabrizi, A. Goggiamani, and G. Zappia, Org. Lett., 3, 2539 (2001). 45. Y. Kozawa and M. Mori, Tetrahedron Lett., 43, 111 (2002); J. Org. Chem., 68, 3064 (2003). 46. F. He, B. N. Foxman, and B. B. Snider, J. Am. Chem. Soc., 120, 6417 (1998). 47. S. D. Edmondson, A. Mastracchio, and E. R. Parmee, Org. Lett., 2, 1109 (2000). 48. G. Man, J. F. Hartwig, M. S. Driver, and C. Fernandez-Rivas, J. Am. Chem. Soc., 120, 827 (1998). 49. D. W. Old, M. C. Harris, and S. L. Buchwald, Org. Lett., 2, 1403 (2000). 50. A. Y. Lebedev, V. V. Izmer, D. N. Kazuyul’kin, I. P. Beletskaya, and A. Z. Voskoboynikov, Org. Lett., 4, 623 (2002). 51. S. Lee, M. Jorgensen, and J. F. Hartwig, Org. Lett., 3, 2729 (2001). 52. X. Huang and S. L. Buckwald, Org. Lett., 3, 3417 (2001). 53. J. P. Wolfe, J. Ahmann, J. P. Sadighi, R. A. Singer, and S. L. Buchwald, Tetrahedron Lett., 38, 6367 (1997). 54. S. Wagaw, B. H. Yang, and S. L. Buchwald, J. Am. Chem. Soc., 120, 6621 (1998). 55. M. Watanabe, T. Yamamoto, and M. Nishiyama, Angew. Chem. Int. Ed., 39, 2501 (2000). 56. C. Bolm and J. P. Hildebrand, J. Org. Chem., 65, 169 (2000). 57. C. Bolm, M. Martin, and L. Gibson, Synlett, 832 (2002). 58. Y. Hong, C. H. Senanayana,ke, T. Xiang, C. P. Vandenbossche, G. J. Tanoury, R. P. Bakale, and S. A. Wald, Tetrahedron Lett., 39, 3121 (1998). 59. S. Wagaw and S. L. Buchwald, J. Org. Chem., 61, 7240 (1996). 60. A. Batch and R. H. Dodd, J. Org. Chem., 63, 872 (1998). 61. E. Schoffers, P. D. Olsen, and J. C. Means, Org. Lett., 3, 4221 (2001); M. K. Lakshman, J. C. Keeler, J. H. Hilmer, and J. Q. Martin, J. Am. Chem. Soc., 121, 6090 (1999).

392 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.7.4 Arylation of Phenols, Alcohols, and Thiols 3.7.4.1 O-Arylation of Phenols Synthesis of diaryl ethers and alkyl aryl ethers by the reactions of aryl halides with phenols and alcohols has been regarded as a difficult reaction. The Pd-catalyzed reaction of aryl halides with phenols and alcohols has been discovered recently and is now attracting attention as a new synthetic method for aryl ethers. Reductive elimination to form the C—O bond as the last step of the ether formation is a rate-determining step. As supporting evidence, Hartwig isolated the DPPF (XI-1) complex of arylpalladium t-butoxide 1 from electronically neutral p-t-butylphenyl bromide, and has shown that complex 1 resists reductive elimination to afford the t-butyl ether 2, and gives biaryls and t-butylbenzene on heating. On the other hand, the thermally unstable DPPF complex 3 of electron-deficient aryl bromide gives the ether 4 in 85 % yield [1]. Thus a number of bulky and electron-rich ligands which accelerate the reductive elimination are used for successful synthesis of aryl ethers. Ring arylation of phenols with aryl halides to produce arylphenols is competitive with aryl ether formation. As discussed in Chapter 3.3.2, it is known that the ring arylation proceeds with Pd(0)-PPh3 catalyst.

+

t-Bu

t-Bu

PPh3 25~80 °C

(dppf)Pd

t-Bu

O-t-Bu

t-Bu +

Pd(0)

1 O-t-Bu

t-Bu

2 CHO PPh3 (dppf)Pd O-t-Bu

25~80 °C 85%

O-t-Bu

OHC

+ Pd(0)

4

3

Hartwig and co-workers found that DPPF is a suitable ligand for formation of the ether 4 from p-bromobenzaldehyde (5) and t-BuONa, but this ligand is effective only for electron-deficient aryl bromides [1]. Later they found that reaction of electronically neutral o-chlorotoluene with sodium phenoxide 5a gave 6 in toluene by using monodentate ferrocenylphosphine FcP(t-Bu)2 (VIII-2) as a ligand. Other ligands such as BINAP and DPPF are ineffective [2]. Pentaphenylated ferrocenyl ligand VIII-7 is a very effective ligand, and the t-butyl ether 7 and the diaryl ether 6 were obtained by the reactions of o-bromotoluene with t-BuONa and the sodium phenoxide 5a at room temperature [3].

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles +

Br

OHC 5

393

Pd(dba)2, DPPF (XI-1)

t-BuONa

O-t-Bu

OHC

toluene, 100 °C 66%

4

ONa

Cl

O

Pd(dba)2, FcP(t-Bu)2 (VIII-2)

+

toluene, 82% Me

Me OMe

OMe

6

5a Br

O-t-Bu

Pd(dba)2, Ph5FcP(t-Bu)2 (VIII-7)

+

t-BuONa toluene, rt, 14 h, 79%

Me

Me 7

ONa Br

O

Pd(dba)2, Ph5FcP(t-Bu)2 (VIII-7)

+

toluene, rt, 70 h, 99%

Me

Me

OMe

6

OMe 5a

Buchwald expanded the versatility of the ether formation by finding that biphenylor binaphthyl-type phosphines (IV-1, IV-3, IV-4, IV-13, and VI-9) are effective ligands [4]. Reactions of electron-deficient aryl chlorides, bromides, and triflates, and also some electron-neutral halides, and triflates proceed smoothly using these bulky ligands. The triflate 8 reacts smoothly using biphenylylphosphine IV-1 as a ligand. Good results were obtained in the reactions of electronically neutral or electron-rich aryl bromide 9 by using binaphthyl-based aminophosphine VI-9. K3 PO4 or NaH is a suitable base. Toluene is the only solvent in which efficient reaction proceeds. Other solvents such as THF, DME, and dioxane give poor results. For the reaction of highly electron-rich 4-chloroanisole (10), these ligands gave poor results and only diadamantylphosphine I-20 gave the aryl ether in 73 % yield. i-Pr

i-Pr OTf

OH +

Pd(OAc)2, IV-1 K3PO4, toluene 100 °C

t-Bu

O

t-Bu 84%

8 Me Me

Me OH

Br +

Pd(OAc)2, VI-9

Me

K3PO4, toluene 100 °C, 95%

Me

O

Me

9 Me

+ MeO 10

Me OH

Cl

O

Pd(OAc)2, I-20 K3PO4, toluene 110 °C, 73%

MeO

394 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 3.7.4.2 Arylation of Alcohols Efficient formation of aryl t-butyl ethers from electron-rich chlorides or bromides can be carried out using biphenyl-type monophosphines (IV-1, IV-4, IV-12) [5]. The aryl t-butyl ether 12 was prepared from electron-rich m-chloroanisole (11) using IV-4 as a ligand. The t-butyldimethylsilyl ether 13 was obtained from the electron-deficient bromides 5 using DPPF (XI-1) [1]. Also t-butyl ether formation is carried out by using P(t-Bu)3 . + MeO

Pd(OAc)2, IV-4

t-BuONa

84% MeO

Cl

O-t-Bu 12

11 + MeO

t-BuONa

Pd(OAc)2, P(t-Bu)3

Br

xylene, 120 °C 82%

MeO

O-t-Bu

11

12

Br Pd(dba)2, DPPF (XI-1)

+ t-BuMe2SiONa

OHC

76%

OTBDMS 13

CHO 5

The aryl t-butyl ether 15 and silyl ether 18, prepared by the Pd-catalyzed reaction, can be converted easily to phenols 16, and these reactions offer convenient synthetic methods for phenols 16 from aryl halides 14 and 17. Based on this reaction, the first synthesis of 4-chlorobenzofuran (18c), which is difficult to synthesize by conventional methods, was carried out. Selective mono-tbutoxylation of 2,6-dichloroacetaldehyde dimethylacetal (18a) using P(t-Bu)3 as a ligand gave the t-butyl ether 18b, and subsequent treatment with aq. HCl afforded 4-chlorobenzofuran (18c) in 51 % overall yield. Further conversion of 18c to various 4-substituted benzofurans is possible by Pd-catalyzed substitutions of the 4-chloro group in 18c [6]. O-t-Bu

Cl

OH R

R

14

15 16

R

R 17

18

Cl

Cl

Cl OMe OMe Cl

18a

R

OTBDMS

Br

OMe

Pd(OAc)2, P(t-Bu)3

t-BuONa, xylene, 120 °C 82%

HCl OMe O-t-Bu 18b

O 18c

51%

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

395

Formation of the alkyl ethers 21 from alcohols, except t-BuOH which lacks βH, is not easy. In this case, the following competing oxidation–reduction reaction of halides with alcohols to afford the arenes 20 as shown by the intermediate 19, should be suppressed. Ethers from electron-rich aryl halides and primary alcohols such as 1-butanol can be prepared using binaphthyl ligands. Aryl alkyl ethers are prepared by Pd-catalyzed reaction of aryl bromides with secondary alcohols in toluene using Tol-BINAP (XV-2) [7]. The alkyl ether 23 and the arene 24 were obtained smoothly from the chloride 22 in a ratio of 8 : 1 from primary alcohols such as 1-butanol by using several biphenyl and binaphthyl-type ligands such as VI-1 and VI-9. Cs2 CO3 was used as a base [8]. R

O + R

R H R Br

H 20

O

Na

H

R

R

Pd

O R

Pd-Br

R

Pd 19

R

R

HCR2

R

O 21

Cl

O-n-Bu Me + n-BuOH

Me

H

Me

Pd(OAc)2, VI-9 Cs2CO3, toluene 89%

Me +

Me

22

Me 23

8:1

24

Strongly electron-deficient aryl halides react with alcohols without any catalyst. Catalyzed reaction is sometimes better than uncatalyzed reaction as shown by the reaction of 4-bromo-2-chlorobenzonitrile (25) with cyclohexanol. The ether 26 was obtained in 80 % yield using Pd(0)-VI-9 as a catalyst. On the other hand, the uncatalyzed reaction gave equal amounts of 26 and 27 [7]. CN

CN

HO

Pd(OAc)2, VI-9

+ Br

Cs2CO3, toluene 80%

Cl 25

Cl 26

uncatalyzed DMF 54% CN

O 26

CN

Br

Cl 1:1

O 27

396 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Preparation of cyclic ethers by intramolecular reactions of the primary (29 and 33) and the secondary alcohols (31 and 35) proceeds more easily using Cs2 CO3 or K3 PO4 , and binaphthyl-based monophosphine ligands VI-1, VI-9 [9]. The five-, six-, and seven-membered cyclic ethers 30, 32, and 34 were prepared from the aryl chloride 31 and bromides 29 and 33. The benzoxazapine 36 was obtained without racemization of chiral alcohol by the cyclization of the optically active bromo alcohol 35. OH

Pd(OAc)2, VI-9 Cs2CO3, toluene 85%

Br

O 30

29 Me OH

Pd(OAc)2, V-6 Cs2CO3, toluene 78%

Cl

Me

O

31

32 OH Pd(OAc)2, VI-9 Cs2CO3, toluene 73%

Br

O 34

33

Me

Me

OH

N

N

Pd(OAc)2, VI-1

t-BuONa, toluene 94%

Br

O 36 98% ee

35 99% ee

An antidepressant MKC-242 39 was synthesized by applying the cyclization of the optically active alcohol 37 as a key step to form the benzodioxane 38 using aminobiphenylylphosphine (IV-13) as a ligand. OH

Ac N

O

Br

O

O

Pd(OAc)2, IV-13 K3PO4, toluene 94%

O

37

O Ac O

O

N

O

38

HCl

O O H N

O 39

HCl O

MKC-242

O O

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

397

3.7.4.3 Arylation of Thiols Aryl sulfides (thioethers) are prepared by the reaction of aryl halides with mercaptans or thiophenols in DMSO. Synthesis of the phenyl thioether 41 using the thiol 40 is an example. DPPF is a good ligand [10,11]. Phenyl n-butyl thioether (43) was prepared by the reaction of triflate 42 with n-butylmercaptan. BINAP is an effective ligand, but Tol-BINAP is more effective. t-BuONa is used as a base, but interestingly no t-butyl phenyl ether is formed in this reaction [12]. Total synthesis of chuangxinmycin (45) was carried out by intramolecular reaction of the aryl iodide 44 [13]. The asymmetric bispyrimidine thioether 48 was prepared in high yield by coupling pyrimidine-2-thiol 46 with 2-bromopyrimidine (47) [14]. SH

I +

S Pd2(dba)3, DPPF (XI-1) DMSO, 76%

AcNH

CO2Me

AcNH

CO2Me

40

41 OTf + n-BuSH

Pd(OAc)2, Tol -BINAP (XV-2)

t-BuONa, toluene, 94%

42

43

I

CO2Me

Me

S CO2Me

Me

Pd(PPh3)4 Et3N, 74%

SH N H 44 Me

S-Bu

N

N

Br

SH +

N

Me

N H

45 Pd(PPh3)4

t-BuOK, THF 72 °C, 88%

N

Me

S N

Me

47

OH 46

N

N N

OH 48

Commercially available, air-stable Pd phosphinous acid complex is an active catalyst for the thioether formation by the reaction of 1-cyclopentenyl chloride (49) with thiophenol (50) and hexylmercaptan (52) to give the thioethers 51 and 53 [15]. 1-Cyclopentenyl phenyl thioether (55) was obtained by the reaction of 1-cyclopentenyl triflate (54) with lithium phenyl sulfide [16]. HS

Cl

S

[(t-Bu)2P(OH)PdCl]2

+

t-BuONa, toluene, 88%

49 50 Cl HS + 49

51 S

[(t-Bu)2P(OH)PdCl]2

t-BuONa, toluene, 94% 52

53 OTf

SPh + LiSPh

54

55

398 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides As a related reaction, thiophenols are prepared from phenols. For example, the Pd-catalyzed reaction of 2-naphthyl triflate with sodium triisopropylsilane thiolate (56) gives the silyl ether of 2-thionaphthol 57. Deprotection of 57 affords 2thionaphthol (58) [17]. OH

OTf +

(i-Pr)3SiSNa 56

SSi(i-Pr)3

Pd(PPh3)4 THF/benzene 86% SH

TBAF 60%

57

58

References 1. G. Mann and J. F. Hartwig, J. Am. Chem. Soc., 118, 13 109 (1996); J. Org. Chem., 62, 5413 (1997). 2. G. Mann, C. Incarvito, A. L. Rheingold, and J. F. Hartwig, J. Am. Chem. Soc., 121, 3224 (1999). 3. N. Kataoka, Q. Shelby, J. P. Stambuli, and J. F. Hartwig, J. Org. Chem., 67, 5553 (2002). 4. A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P. Sadighi, and S. L. Buchwald, J. Am. Chem. Soc., 121, 4369 (1999). 5. C. A. Parrish and S. L. Buchwald, J. Org. Chem., 66, 2498 (2001). 6. M. Watanabe, M. Nishiyama, and Y. Koie, Tetrahedron Lett., 40, 8837 (1999). 7. M. Palucki, J. P. Wolfe, and S. L. Buchwald, J. Am. Chem. Soc., 119, 3395 (1997). 8. K. E. Torraca, X. Huang, C. A. Parrish, and S. L. Buchwald, J. Am. Chem. Soc., 123, 10 770 (2001). 9. S. Kuwabe, K. E. Torraca, and S. L. Buchwald, J. Am. Chem. Soc., 123, 12 202 (2001). 10. M. Kosugi, T. Shimizu, and T. Migita, Chem. Lett., 13 (1978); Bull. Chem. Soc. Jpn., 53, 1385 (1980). 11. P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 36, 4133 (1995). 12. N. Zheng, J. C. McWilliams, F. J. Fleitz, J. D. Armstrong III, and R. P. Volante, J. Org. Chem., 63, 9606 (1998). 13. K. Kato, M. Ono, and H. Akita, Tetrahedron Lett., 38, 1805 (1997). 14. M. S. Harr, A. L. Presley, and A. Thorarensen, Synlett, 1579 (1999). 15. G. Y. Li, J. Org. Chem., 67, 3643 (2002). 16. A. G. Martinez, J. O. Barcina, A. F. Cerezo, and L. R. Subramanian, Synlett, 561 (1994). 17. J. C. Arnould, M. Didelot, C. Cadihac, and M. J. Pasquet, Tetrahedron Lett., 37, 4523 (1996).

3.7.5 Arylation of Phosphines, Phosphonates, and Phosphinates Pd-catalyzed arylation of various phosphorus compounds containing P—H bonds with aryl and alkenyl halides, or triflates offers useful methods of C—P bond formation. After pioneering work on Pd-catalyzed arylation and alkenylation of dialkyl phosphonates by Hirao et al. [1], extensive studies have been carried out on arylation of various phosphorus compounds. The methods are particularly useful for the synthesis of various chiral phosphines used in Pd-catalyzed asymmetric reactions.

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

399

3.7.5.1 Arylation of Phosphines and Phosphine Oxides Arylations of phosphines and phosphine oxides are carried out as shown by the following general equations. The reactions are explained by oxidative addition of aryl halides, followed by ligand exchange with Ph2 P-H, which is similar to transmetallation. Finally, reductive elimination affords arylated products. Arylation of phosphines and phosphine oxides PhPH2 +

ArX

Ph2PH +

ArX

Pd(0) Pd(0)

P

O H +

ArX

Pd(0)

Ph

base

Ph Ar-X +

PhPArAr′

Ph2PAr

base

O Ph

Ar′X

PhP(H)Ar

base

P

Ar

Ph Ar-Pd-X

Pd(0)

Ph2PH ligand exchange

Ar-Pd-PPh2

RE

Ph2PAr +

Pd(0)

Recently, extensive synthetic studies on multiply functionalized chiral arylphosphines by Pd-catalyzed arylation of primary and secondary phosphines with aryl halides have been carried out by Stelzer [2]. The synthetic methods can be summarized by the following general schemes. Diphenyarylphosphines 3 are prepared by coupling Ph2 PH (1) with aryl iodides 2. Coupling of Ph2 PH (1) with 2-bromoiodobenzene derivatives 4 affords chemoselectively the bromophenylphosphines 5, and Suzuki coupling with 6 gives the biphenyl-type phosphines 7. Consecutive displacements of the hydrogen atoms of the primary phosphine 8 with different aryl iodides 2 and 10 yield the multiply Y I Y

2 Ph2P Y 3

I

Ph2PH

Z (HO)2B

1 Br

Y

4

6

Ph2P Br

Z

5

7

Y

Y

I PhPH2 8

Y Ph2P

I 2

Z

H

Y P

10 Y

Ph

P 9

Ph 11

400 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides functionalized phosphines 11. Similarly alkylarylphosphines 13 and 15 are prepared by the coupling of primary and secondary alkylphosphines 12 and 14 with aryl iodides 2 and 10. Some examples of the syntheses of interesting polyfunctionalized phosphines are cited here. Y I Y

2

R2PH

R2P

12

13 Y

Z

I

I 2

RPH2 14

Z 10

Y P R 15

The chiral phosphine ligand 17 was prepared by coupling the congested iodide 16 with Ph2 PH (1). 5-Diphenylphosphinobenzene-1,2,3-tricarboxylic acid 19 as a water-soluble ligand (II-4) was prepared by smooth coupling of bromobenzenetricarboxylic acid 18. Similarly the water-soluble phosphine 21 was obtained from 1 and 20. The bidentate ligand 24 was prepared by smooth reaction of 1,3bis(phenylphosphino)propane (22) with 2-iodoaniline (23) using DPPP as a ligand. The ligand 24 was a 1 : 1 mixture of two diastereomers, and enrichment of one of the diastereomers in a ratio of 8 : 3 was achieved by recrystallization from MeOH. It is somewhat surprising that the couplings of aryl iodides, 16, 18, and 20, substituted by highly polar substituents, proceed smoothly. A racemic phosphine 28 was obtained by consecutive displacement of hydrogen atoms of phenylphosphine (8) with two different aryl iodides 25 and 27. For the coupling of diphenylphosphine with aryl iodides, Pd on carbon is a good catalyst in DMF under microwave dielectric heating in DMF [3]. A P-chirogenic phosphine can be synthesized by Pd-catalyzed asymmetric phosphination. Coupling of the racemic phosphine 28a with iodobenzene afforded the Ph O Ph2PH

+

1

Pd(OAc)2

Ph Me

HN

DMA 89%

N H

O

Me

I

Ph2P

16 17 CO2H Ph2PH

+

Br

CO2H

1 18

CO2H

Pd(OAc)2 n-Bu3N, DMA 130 °C, 48 h 79%

CO2H Ph2P

CO2H

19

CO2H

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles HO Ph2PH

+

CO2H

Pd(OAc)2 n-Bu3N, DMA

I

135 °C, 16 h 54%

1 SO3H

HO

Ph P

P

+

H

Pd(OAc)2, DPPP

I

Ph

+

P

NH2

23

H2N 24

Me PhPH2

Ph P

AcOK, DMA 65%

22

SO3H

21

Ph

H

CO2H

Ph2P

20 H2N

401

Me

I

Pd2(dba)3, DPPP

Ph

Et3N, MeCN 90 °C, 77%

H

P

8 CO2H

CO2H

25

26

CO2H Me Ph

I 27

HO2C

P

Pd(OAc)2, Et3N 81%

CO2H 28

enantio-enriched phosphine 28b in 88 % yield with 73 % ee. (R,R)-Me-Duphos (XII-10) was used as a chiral ligand [4]. i-Pr

i-Pr P

i-Pr

H Me + PhI

i-Pr 28a

Me3SiONa, toluene, 21 °C, 88% 73% ee

Ph

P

Pd(OAc)2, (R,R )-Me-Duphos (XII-10)

Me

i-Pr

i-Pr 28b

The biphenyl-based phosphine 34 was prepared from 2-bromoiodobenzene (29). Chemoselective coupling of the iodide in 2-bromoiodobenzene (29) with diphenylphosphine (1) gave 2-bromophenyldiphenylphosphine (30), and its Suzuki–Miyaura coupling with 31 afforded the biphenylylphosphine 32. Reaction of 29 with the primary phosphine 8 afforded the di(2bromophenyl)phenylphosphine (33), and bis-biphenylylphosphine derivative 34 was obtained by Suzuki–Miyaura coupling of 33 with 31, although the yield was not high [2]. Phosphine oxides are conveniently used for the coupling, because diphenylphosphine oxide (36) is more easily handled than Ph2 PH (1). Reaction of (Z)alkenyl bromide 34a with diphenylphosphine oxide (36) gave (Z)-diphenylvinylphosphine oxide 34c with complete retention [5].

402 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Br I

29 Pd(PPh3)4, Et3N PhPH2 toluene, 85% 8 Br

Ph

Br

Pd(PPh3)4, Et3N Ph2PH toluene, 94% 1 Br PPh2

P

30

33 B(OH)2

B(OH)2

Me

Pd(OAc)2, K2CO3 toluene, 22%

Me

Pd(OAc)2, K2CO3 toluene, 63% 31

Me

31

Me

Me

Ph

PPh2

P

34

32

O Br

Ph

+

H

P

Ph

Pd(PPh3)4 Et3N, 90 °C, 91%

Ph

O P

Ph

Ph

Ph 34a

36

34c

Triarylphosphine oxides are prepared by coupling aryl halides or triflates with diphenylphosphine oxide (36), and they are reduced to triarylphosphine with HSiCl3 . Selective monophosphination of 2, 2
-bis-triflate of binaphthol (35) with diphenylphosphine oxide occurred to give the optically active phosphine oxide (37) using DPPB or DPPP. No bis-substitution was observed [6,7]. The phosphine oxide 37 can be converted to the phosphine by treatment with HSiCl3 and an amine. Various optically active monodentate phosphines such as MeO-MOP (VI12) are prepared from 37 via 38. On the other hand, bis-substitution of 35 takes place to afford the bis-phosphine when NiCl2 (dppe) is utilized as a catalyst, and the reaction is used for the preparation of BINAP (XV-1) [8].

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

NiCl2(dppe), DABCO

PPh2

DMF, 100 °C, 75%

PPh2

403

Ph2PH 1 (S)-XV-1

O

OTf

Ph

+

P

OTf

H

Ph 36

Pd(OAc)2, DPPB, EtN(i-Pr)2

OTf

DMSO, 90 °C, 16 h 95%

(S)-35

P(O)Ph2

(S)-37

1. NaOH

OMe

2. MeI

P(O)Ph2

OMe

HSiCl3

PPh2

(S)-VI-12

38

Reaction of 2-bromobenzaldehyde (39) with diarylphosphine oxide using Pd(OAc)2 and DPPP afforded the mixed triarylphosphine oxide 40, which was converted to the chiral phosphine ligand 40a [9]. CHO

CHO O Br

O +

P

H

Ar 39

P

Pd(OAc)2, DPPP, EtN( i-Pr)2

Ar Ar = 3,5-Me2-C6H4

Ar Ar

DMSO, 100 °C, 20 h 40% 40

OH SH O S 40a

PAr 2

Imamoto reported that Pd-catalyzed coupling of phosphine-borane with aryl halides is useful for preparation of asymmetric phosphines. Phosphines can be easily isolated from phosphine-boranes by exchange reaction with amines such as pyrrolidine and DABCO [10]. Lipshutz found that aryl nonaflates (∗ Nf = nonafluorobutanesulfonate) and triflates are good substrates for coupling with BH3 -stabilized diarylphosphines. Selective coupling with nonaflate without

404 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides attacking bromide in 41 gave the asymmetric phosphine-borane 42 in MeCN using Pd(PPh3 )4 and K2 CO3 [11]. In the synthetic studies directed toward P-chiral phosphines, Imamoto disclosed that the reaction of optically active (S)-(menthyloxy)phenylphosphine-borane (43) with 2-iodoanisole (44) gave the phosphine-borane 45 with complete retention of configuration in MeCN using K2 CO3 as a base. Solvents are crucial and nearly complete inversion was observed to give 46 in THF [12–14]. Ph2PH

BH3

NR3

Pd(0)

+ Ar-X

base

Ph2PAr

Br + Ph2PH

BH3

BH3

Pd(PPh3)4, K2CO3

NR3

BH3

Br

BH3

MeCN, 93%

ONf

PPh2

41

42 BH3

BH3 I

P

MenO

BH3

OMe

H

Pd(PPh3)4, K2CO3 MenO

+

Ph 43

MeCN, 93%

OMe

MenO

Ph

P

OMe

+

Ph

44

P

100 : 0

45

46

Phosphorylation of Ar2 PH-BH3 with aryl halides proceeds under mild conditions using Pd-Cu catalyst and P-chiral phosphine-boranes of high enantiopurity are prepared by this method. As an effective ligand, MePPh2 is used with Pd(OAc)2 . The phosphine-borane 50 was prepared in 68 % yield by phosphorylation of optically active (Sp)-methylphenylphosphine-borane (47) via 48 with the iodide 49 in the presence of the Pd(OAc)2 -MePPh2 catalyst and CuI as a cocatalyst at 0 ◦ C for 3 days. The reaction proceeded with retention of stereochemistry and the asymmetrically substituted phosphine 51 with 99 % ee was obtained [15].

N

Ph

P Me 47

CuI H

H3B

BH3

BH3

EtN(i-Pr)2

Ph

P

N

O I

Cu

Ph

49

Me

Pd(OAc)2, PMePh2

48

THF, 0 °C, 3 days 68%, >99% ee

Me 50

N

amine Ph

P

P Me 51

O

O

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

405

An interesting direct synthetic method of phosphines 53 is an exchange reactions between Ar-Pd-X and PPh3 via the phosphonium salt 52. The exchange is frequently observed as a side-reaction in coupling reactions catalyzed by Pd(0)PPh3 [16]. The functionalized phosphine 56 was prepared by the Pd-catalyzed exchange reaction between the triflate 54 and the phosphine 55. Pd(OAc)2 or Pd/C is used as a catalyst. Treatment of either the triflate 54 or bromide 57 wih 2.5 equivalents of PPh3 for 20–30 h afforded the phosphine 58 in 40–50 % yield. Triflates are more reactive than bromides in the exchange reaction [17]. Ph3P X

Ar

Ph3P

Pd

X

PPh3

Ph

X = Br, I, Cl, OTf

Pd PArPh 2

Ar-X Pd(0) PPh3

Ar-Pd-X

Ar-PPh2 + Ph-X 53

Ar-PPh3,X 52

Me O Me O

Me

Pd(OAc)2

OTf + P Me

54

P

DMF, 160 °C 8 h, 28%

Me

3

55 Me 56

O Br + PPh3 (2.5 equiv.)

Pd/C, 160 °C

O PPh2

32 h, 46%

57

58

3.7.5.2 Arylation of Phosphonates and Phosphinates Phosphonates and phosphinates are arylated as shown by the following general schemes. Hirao et al. synthesized diethyl p-anisylphosphonate 61 by arylation of diethyl phosphonate (60) with p-bromoanisole (59) [1]. The reaction was applied to the synthesis of the phosphonate 63a by coupling of the alkenyl bromide 62 with the phosphonate 63 [18]. The optically active isopropyl methylvinylphosphinate 65 (97 % ee) was prepared from isopropyl methylphosphinate 64 (97 % ee) with complete retention of stereochemistry [19]. Formation of monoaryl, and symmetric or asymmetric diarylphosphinates is expected by stepwise arylation of methyl phosphinate (66). However, methyl phosphinate is a very unstable compound. Lei et al. found that its reaction can

406 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Arylation of dimethyl phosphonate (dimethoxyoxophosphorane) O MeO

O

Pd(0)

H + ArX

P

base

MeO

P

OMe

Ar

OMe

Arylation of methyl phosphinate (methoxyoxophosphorane) O H

P

O

Pd(0)

+

H

ArX

base

H

P

OMe

Ar

OMe

Arylation of methyl arylphosphinate (arylmethoxyoxophosphorane) O H

P

+

Ar

O

Pd(0) Ar′X

base

Ar′

P

OMe

Ar

OMe

EtO O

Br H

+

P

OEt

OEt

MeO 59

O P

Pd(PPh3)4

OEt

Et3N, 90 °C, 90% MeO

60

61 Me

O

O

Me

NH Br

NH + TBSO

O O

O

Pd(OAc)2, PPh3 Et3N, DMF, 42%

O Me O TBDPSO MeO

P

O NH H

62

O

TBSO

O

63

O Me

O

O

O P

NH

MeO

O O TBDPSO 63a

Me

O P

i-PrO

H

97%ee 64

+

Pd(PPh3)4 Br

Et3N, 98%

Me

O P

i-PrO 97%ee 65

Arylation and Alkenylation of C, N, O, S, and P Nucleophiles

407

be carried out smoothly in the presence of trimethyl orthoformate [20]. Methyl phenylphosphinate 67 was obtained from 66 in 63 % yield by this method. Asymmetric methyl diarylphosphinate 68 was prepared by stepwise reaction of 66 with two different aryl iodides. Schwabacher and Stefanescu reported that t-butyl phosphinate (69) is much more stable than the corresponding methyl ester 66 and preparative method of phosphinates can be improved by using t-butyl phosphinate (69). Actually the functionalized arylphosphinate 70 was prepared in good yield as the t-butyl ester [21]. Reaction of anilinium hypophosphite 71a with alkenyl bromide or triflate 71 afforded the monosubstituted alkenylphosphinic acid 72 without forming the symmetric phosphinic acid by disubstitution. The best ligand is DPPP [22]. O H

P

OMe

+

O

Pd(OAc)2, PPh3, HC(OMe)3

Ph-I

Ph

N-methylmorpholine, 63%

H 66

P

OMe

H 67 O

O H

1. Ph

P

I

OMe

P

OMe

Pd(PPh3)4 N-methylmorpholine, 51%

Pd(OAc)2, Ph3P HC(OMe)3, Et3N

H 66

Ph

I

2.

68 O I

P

O + BocHN

P

H

H

NHBoc

PdCl2(PPh3)2 O-t-Bu

Et3N, MeCN 90 °C, 75%

69

O-t-Bu

H

BocHN

NHBoc 70

O OTf

H

O + PhNH3O N CO2-t-Bu 71

P H 71a

H

P

OH

Pd(OAc)2, DPPP Et3N, benzene reflux, 64%

N CO2-t-Bu 72

Reaction of dimethyl phosphonate (74) with the steroidal dienyl triflate 73 gave the dimethyl alkenylphosphonate 75 [23]. Dimethyl alkynylphosphonate (77) was produced in one step by the reaction of 1,1-dibromo-1-alkenes 76 with dimethyl phosphonate (74) in DMF using Pd(OAc)2 -DPPF as a catalyst and propylene oxide as a scavenger of HBr. The expected monocoupling product, bromovinylphosphonate, was not obtained [24]. Phosphonates 78 can be converted to arylphosphines 79 by reaction with aryl Grignard reagents, followed by reduction with HSiCl3 [25].

408 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides C8H17

C8H17 O + H

P(OMe)2

Pd(PPh3)4 90%

O

74

(MeO)2P

TfO 73

75 O

Br Br

O +

H

P(OMe)2 74

76

O

DMF,

OMe OMe

76% 77

O Ph

P

Pd(OAc)2, DPPF

O

P(OMe)2 +

2 ArMgX

Ph

PAr 2

HSiCl3

78

PPhAr2 79

As a related reaction, functionalized arylarsines 81 can be prepared by the Pdcatalyzed exchange reaction of activated aryl triflates 80 with AsPh3 under solventfree conditions at 115 ◦ C [26]. OTf + AsPh3

O

AsPh2

Pd(OAc)2 110 °C, 51%

O

81

80

References 1. T. Hirao, T. Masunaga, Y. Oshiro, and T. Agawa, Tetrahedron Lett., 21, 3595 (1980); Synthesis, 56 (1981); T. Hirao, T. Masunaga, N. Yamada, Y. Ohshiro, and T. Agawa, Bull. Chem. Soc. Jpn., 55, 909 (1982). 2. D. J. Brauer, M. Hingst, K. W. Kottsieper, C. Like, T. Nickel, M. Tepper, O. Stelzer, and W. S. Sheldrick, J. Organomet. Chem., 645, 14 (2002). 3. A. Stadler and C. O. Kappe, Org. Lett., 4, 3541 (2002). 4. J. R. Moncarz, N. F. Laritcheva, and D. S. Glueck, J. Am. Chem. Soc., 124, 13 356 (2002). 5. Y. Xu, J. Xia, and H. Guo, Synthesis, 691 (1986). 6. L. Kurz, G. Lee, D. Morgans, Jr, M. J. Waldyke, and T. Ward, Tetrahedron Lett., 31, 6321 (1990). 7. Y. Uozumi, A. Takahashi, S. Y. Lee, and T. Hayashi, J. Org. Chem., 58, 1945 (1993). 8. D. Cai, J. F. Payack, D. R. Bender, D. L. Hughes, T. R. Verhoeven, and P. J. Reider, J. Org. Chem., 59, 7180 (1994). 9. H. Nakano, Y. Suzuki, C. Kabuto, R. Fujita, and H. Hongo, J. Org. Chem., 67, 5011 (2002). 10. T. Imamoto, T. Oshiki, T. Onozawa, T. Kusumoto, and K. Sato, J. Am. Chem. Soc., 112, 5244 (1990). 11. B. H. Lipshutz, D. J. Buzard, and C. S. Yun, Tetrahedron Lett., 40, 201 (1999). 12. T. Oshiki and T. Imamoto, J. Am. Chem. Soc., 114, 3975 (1992).

Miscellaneous Reactions of Aryl Halides

409

13 Account, T. Imamoto, T. Oshiki, T. Onozawa, M. Matsuo, T. Hikosaka, and M. Yanagawa, Heteroatom Chem., 3, 563 (1992). 14. J. R. Moncarz, T. J. Brunker, D. S. Glueck, R. D. Sommer, and A. L. Rheingold, J. Am. Chem. Soc., 125, 1180 (2003). 15. M. Al-Masum, G. Kumaraswamy, and T. Livinghouse, J. Org. Chem., 65, 4776 (2000). 16. T. Yamane, K. Kikukawa, M. Takagi, and T. Matsuda, Tetrahedron, 29, 955 (1973). 17. F. Y. Kwong and K. S. Chan, Organometallics, 20, 2570 (2000); F. Y. Kwong, C. W. Lai, Y. Tian, and K. S. Chan, Tetrahedron Lett., 41, 10 285 (2000); C. W. Lai, F. Y. Kwong, Y. Wang, and K. S. Chan, Tetrahedron Lett., 42, 4883 (2001). 18. S. Abbas and C. J. Hayes, Synlett, 1124 (1999). 19. Y. Xu, H. Wei, J. Zhang, and G. Huang, Tetrahedron Lett., 30, 949 (1989). 20. H. Lei, M. S. Stoakes, and A. W. Schwabacher, Synthesis, 1255 (1992). 21. A. W. Schwabacher and A. D. Stefanescu, Tetrahedron Lett., 37, 425 (1996). 22. Y. R. Dumond and J. L. Montchamp, J. Organomet. Chem., 653, 252 (2002). 23. D. A. Holt and J. M. Erb, Tetrahedron Lett., 30, 5393 (1989). 24. M. Lera and C. J. Hayes, Org. Lett., 2, 3873 (2000). 25. J. Yun and S. L. Buchwald, J. Am. Chem. Soc., 122, 12 051 (2000). 26. F. Y. Kwong, C. W. Lai, and K. S. Chan, J. Am. Chem. Soc., 123, 8864 (2001).

3.8 Miscellaneous Reactions of Aryl Halides 3.8.1 The Catellani Reactions using Norbornene as a Template for ortho-Substitution In continuing studies on Pd-catalyzed reactions of norbornene (1), Catellani has discovered very interesting reactions, in which norbornene shows unique behavior [1]. Catellani and co-workers carried out a three-component reaction of iodobenzene, methyl acrylate, and n-butyl iodide in the presence of 1 equivalent of norbornene (1), and obtained methyl 2,6-di-n-butylphenylacrylate (2) in 93 % yield using cis-exo-2-phenylnorbornylpalladium chloride as a catalyst. Norbornene (1) was recovered after the reaction [2]. No direct Heck reaction of iodobenzene with acrylate occurred showing that the strained double bond in norbornene undergoes insertion much faster than that of acrylate. The behavior of norbornene (1) is truly remarkable. I + n-Bu-I +

+ 1

n-Bu

CO2Me

[Pd], K2CO3, DMA 20 °C, 30 h, 93%

[Pd] = cis-exo-2-phenylnorbornylpalladium chloride

CO2Me +

n-Bu 2

1

This reaction revealed several very interesting and unexpected (or curious) steps. The mechanistic explanation given by Castellani can be summarized in the following scheme. First, syn insertion of 1 to Ph-Pd-I affords the cis, exo complex 3. In this case, syn β-H elimination to give phenylnorbornene is impossible due to the rigid trans configuration of the Pd atom and β-hydrogen. The

410 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides next step is facile formation of the palladacycle 4 under mild conditions mainly by virtue of the coordination of the aromatic ring to Pd. The complex 4 was isolated. The reaction corresponds to activation of an inert aromatic C—H bond. In general, reductive elimination in a five-membered palladacycle 4 to form a cyclobutane is disfavored, and hence unusual oxidative addition of n-BuI occurs to give 5, which is an uncommon Pd(IV) species. The reductive elimination gives the ortho-n-butylphenylnorbornylpalladium iodide 6 without undergoing βH elimination of the butyl group. Then similar steps, namely the palladation of 6 to form the palladacycle 7, the oxidative addition of n-BuI to give 8, and the reductive elimination to afford the 2,6-dibutylphenylnorbornyl complex 9, are repeated. The 2,6-di-n-butylation is explained in this way. Then interestingly, βcarbon elimination of 9 (deinsertion of 1 or decarbopalladation) occurs to yield 2,6-di-n-butylphenylpalladium iodide (10) and 1 is regenerated. Several further transformations of 10, such as Heck, Suzuki, and Sonogashira reactions, are possible as expected. Formation of 2,6-di-n-butylphenylacrylate (2) via insertion of acrylate to 10 and β-H elimination is understandable. The total yields of 2 after multi-step reaction were remarkably high (93 %). The Suzuki and Sonogashira reactions of 10 are shown later. Examples of this type of palladacycle formation by electrophilic attack on benzene rings are increasing (Chapter 3.3.4).

Pd(0) I

palladation

1 I

3

n-Bu-I OA

Pd

Pd

insertion

Pd

4

HI

RE

palladation Pd n-Bu

Pd n-Bu I 5

I 6

n-Bu-I

RE

OA 7 b-carbon elimination

n-Bu

CO2Me Pd I

n-Bu 1

n-Bu

Pd n-Bu I 8

Pd

10

HI

n-Bu

n-Bu

n-Bu

I

Pd

I

9

n-Bu

CO2Me + Pd(0)

insertion b-H elimination

n-Bu 2

The reaction of o-iodotoluene (11) with acrylate and a large excess of n-PrI in the presence of 1 proceeded more efficiently using ligandless Pd(OAc)2 , and 2-methyl-6-n-propylphenylacrylate (12) was obtained [3].

Miscellaneous Reactions of Aryl Halides

411

Me

Me I CO2Me

+ n-Pr-I +

CO2Me

Pd(OAc)2, 1, K2CO3 AcOK, DMF, 55 °C, 74%

n-Pr

11

12

There are several interesting features in this reaction, although they may be understood by high reactivity of the strained double bond in norbornene: 1. Facile selective oxidative addition of alkyl halide to 4, which is regarded as uncommon. 2. No β-H elimination of n-butyl group in 5. 3. Easy formation of the palladacycles 4 and 7, which undergo further reactions. 4. Facile β-carbon elimination (deinsertion of 1) in 9. 5. No direct Heck reaction and Suzuki coupling of aryl halides occur at all in the three-component reactions of aryl halide, alkyl halide, and alkene (or phenylboronic acid). 6. Smooth reactions with ligandless Pd catalysts. The process shows a new and unique type of ‘catalysis’ by 1. The Catellani’s alkylation–alkenylation sequence using norbornene offers a useful synthetic method for 2,6-dialkylated 1-substituted benzenes. Lautens applied the reaction to the synthesis of fused aromatic compounds using ortho-substituted iodobenzenes and bromoalkenes. Reaction of o-iodotoluene (11) with ethyl 6bromo-2-hexenoate (13) afforded the benzocarbocycle 14 via monoalkylation and intramolecular Heck reaction. It is important to use tri-2-furylphosphine (I-3) as a ligand [4]. Similarly the 2,5-disubstituted 4-benzoxepine 17 was obtained in 72 % yield by the reaction of 1-iodonaphthalene (15) with the unsaturated bromo ester 16 [5]. EtO2C

Me I

+

CO2Et

Br

Me

Pd(OAc)2, TFP(I-3), I Cs2CO3, MeCN, 90%

13 11

14 CO2Et I + Br

O

CO2Et Pd(OAc)2, TFP(I-3) I, Cs2CO3, MeCN 72%

O

16 15

17

Similar to the formation of the ortho-alkylated phenylnorbornyl complex 6, ortho arylation is possible. Reaction of the palladacycle 18, which has an ortho methyl group, with methyl p-iodobenzoate afforded the substituted biphenyl 22 [6]. The formation of 22 can be understood by oxidative addition of iodobenzoate to 18 to generate 19, reductive elimination to form 20 by sp2 –sp2 C—C bond formation,

412 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides and deinsertion of norbornene from 20 to provide 21. Treatment of 21 with H2 produced the meta-substituted biphenyl 22. Although the reaction is stoichiometric, it shows the possibility of ortho arylation. Me Me

I K2CO3, DMF

+

Pd

rt, 61%

MeO2C

I

Pd 18

19 CO2Me Me

Me

Me

b-carbon elimination

H2 I-Pd

1

Pd-I

CO2Me

20

CO2Me

21

CO2Me

22

The ortho arylation was combined with the Heck reaction. Reaction of oiodotoluene (11) with methyl acrylate in the presence of 1 gave rise to the substituted biphenylylacrylate 23 [7]. This Pd-catalyzed reaction is understood by the sequential formation of 24, 25 and 26. It is very interesting that no direct Heck reaction of 11 with acrylate occurs at all under the conditions due to higher reactivity of norbornene compared with acrylate. The reaction of allyl alcohol provided 3-biphenylylpropanal [7a]. The norbornene-catalyzed reaction has also been extended to synthesis of 2,6dialkyl-1, 1
-biphenyl 28 by 2,6-dialkylation of aromatic ring via palladacycles and Suzuki–Miyaura coupling. The reaction of phenylboronic acid (27), iodobenzene, and n-propyl bromide (excess) in the presence of norbornene (1) afforded 2,6-din-propyl-1-biphenyl (28) in 95 % yield via 29 and 30. B(OH)2

n-Pr I +

+

27

2 n-PrBr

Pd(OAc)2,

1

K2CO3, DMF, rt, 95%

n-Pr 28

27

steps b-carbon elimination

n-Pr

n-Pr PdBr

n-Pr Pd-Br 29

1

n-Pr 30

Miscellaneous Reactions of Aryl Halides

413

Me Me I, Pd(OAc)2, K2CO3

I +

CO2Me

CO2Me DMF, 105 °C, 79% Me

11

23

1 Me

Me b-carbon Me elimination

Me

I-Pd

Pd

Me

Pd-I

I

1 Me 24

25

26

Me

CO2Me

MeO2C

Me 23

The reaction proceeds via the formation of the palladacycles 4 and 7a. After the formation of 29 by 6-propylation of 31, elimination of β-carbon regenerates norbornene (1) and 2,6-dipropylphenylpalladium bromide 30. At the final step, Suzuki coupling of 30 with 27 gives 2,6-di-n-propyl-1-biphenyl (28) in a surprisingly high yield (95 %) after so many steps [8]. n-Pr

n-Pr n-Pr-Br

steps Pd

Pd

Pd

n-Pr 4

n-Pr

b-carbon elimination

RE

n-Pr Pd-Br

n-Pr 27

n-Pr

Pd 29

Br

31

7a

Br

1

n-Pr 30

n-Pr 28

Combination of the ortho arylation with Suzuki coupling as a good synthetic method of terphenyls was carried out [9]. Reaction of o-iodotoluene (11) with phenylboronic acid (27) afforded dimethylterphenyl 32 in 88 % yield. The reaction is easily understandable by formation of the biphenylylpalladium 26 via 24 and 25. The Suzuki coupling of 26 with 27 yields the terphenyl 32 as expected.

414 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Me Me

B(OH)2 1, Pd(OAc)2, K2CO3

I +

11

DMF, 105 °C, 88% Me

27

1

27 32

24

25

26

When sodium formate is used as a terminating agent, hydrogenolysis of arylpalladium occurs [10]. Reaction of iodobenzene, n-propyl bromide, and sodium formate afforded 1,3-di-n-propylbenzene (35) in 78 % yield. In this case, the 2,6di-n-propylphenylpalladium 30 was hydrogenolyzed with sodium formate, and 35 was obtained via Pd formate 33 and hydridopalladium 34. This is not only very interesting, but also useful, because meta dialkylation of benzene can be achieved in this way, which is difficult to carry out by conventional methods. n-Pr I + 2 n-PrBr + HCO2Na

Pd(OAc)2, 1, K2CO3

H

DMF, rt, 78%

n-Pr 35

n-Pr

n-Pr

n-Pr

HCO2Na Pd-Br

Pd-O2CH

n-Pr

Pd-H

n-Pr

30

33

n-Pr 34

The reaction can be combined with Sonogashira coupling to give o, o
-dialkylated diphenylacetylenes [11]. Pd-catalyzed reaction of iodobenzene, ethyl bromide, and phenylacetylene (36) afforded 2,6-diethyldiphenylacetylene 37 in 78 % yield with remarkable chemoselectivity. In this reaction, CuI as a cocatalyst was not used. The direct Sonogashira coupling of iodobenzene with phenylacetylene (36) was suppressed by slow addition of excess ethyl bromide and phenylacetylene at room temperature. Et I

Pd(OAc)2, 1, AcOK

+ 2 Et-Br +

Ph

Ph

DMF, rt, 77%

36 Et 37

References

415

Substituted phenanthrene 38 was prepared by the reaction of o-iodotoluene (11) with diphenylacetylene in the presence of n-Bu4 NCl in 82 % yield [12]. The reaction is explained by insertion of diphenylacetylene to the biphenylylpalladium 26 to form 39, which undergoes well-known cyclization to provide the dimethyldiphenylphenanthrene 38. Me Me I

Pd(OAc)2, 1, K2CO3,

+ Ph

Ph

n-Bu4NBr, DMF 105 °C, 82%

Me Ph

Ph 38

11

1 Me

Me 11

Me RE Me

Pd

Pd I

18

PdI

Me 24

25

Me b-carbon elimination

Ph

1

Me

Ph

Pd-I 26

Me

Me

Me

Me

Pd-I

Ph

Ph

Ph

Ph 39

38

Although norbornene is recovered at the end of the reactions, it is used in a large amount, and it is not a true catalyst in the exact sense. However, the remarkably high chemoselectivity of the norbornene ‘catalyzed’ reactions is impressive.

References 1. Account: M. Catellani, Synlett, 298 (2003). 2. M. Catellani, F. Frignani, and A. Rangoni, Angew. Chem. Int. Ed. Engl., 36, 119 (1997). 3. M. Catellani and F. Cugini, Tetrahedron, 55, 6595 (1999).

416 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides 4. 5. 6. 7. 7a. 8. 9. 10. 11. 12.

M. Lautens and S. Piguel, Angew. Chem. Int. Ed., 39, 1045 (2000). M. Lautens, J. F. Paquin, S. Piguel, and M. Dahlmann, J. Org. Chem., 66, 8127 (2001). M. Catellani and E. Motti, New J. Chem., 759 (1998). E. Motti, G. Ippomei, S. Deledda, and M. Catellani, Synthesis, 2671 (2003) in press M. Catellani, S. Deledda, B. Ganchegui, F. Henin, E. Motti, and J. Muzart, J. Organomet. Chem., 687, 473 (2003). M. Catellani, E. Motti, and M. Minari, Chem. Commun., 157 (2000). E. Motti, A. Mignozzi, and M. Catellani, J. Mol. Catal. A : Chem., 204/205, 115 (2003). M. Catellani and F. Cugini, unpublished results. See ref. 1. M. Catellani, M. Rissetti, and E. Motti, unpublished results. See ref. 1. M. Catellani, E. Motti, and S. Barratta, Org. Lett., 3, 3611 (2001).

3.8.2 Reactions of Alcohols with Aryl Halides Involving β-Carbon Elimination A unique method of oxidation of primary and secondary alcohols was found by Tamaru, who reported that the Pd-catalyzed oxidation of alcohols with aryl halides proceeds under basic conditions involving β-H elimination of the alkoxypalladium 1 [1]. Guram et al. reported that cheaply available chlorobenzene can be used for the oxidation of benzyl alcohols and some secondary aliphatic alcohols in toluene at 105 ◦ C using biphenylyl(dicyclohexyl)phosphine (IV-2) as a ligand. Sterically hindered aliphatic alcohol was oxidized using t-BuONa as a base [1a].

Ph-Br +

OH

Pd(PPh3)4, K2CO3

H

DMF, 110 °C, 88%

O

Pd-Ph

1 O

+

H-Pd-Ph

H-Ph Pd(0)

O

Cl

OH

Pd2(dba)3, IV-2, K3PO4

+

toluene, 105 °C, 92%

O

Cl +

Pd2(dba)3, IV-2, t-BuONa toluene, 105 °C 100%

O

CHO + PhH

O

O

+ PhH

OH

Miura and co-workers made an interesting observation when they treated α,αdisubstituted arylmethanols 2 with aryl halides. In this case, there is no possibility of β-H elimination, and they observed two transformations of the palladium alkoxide 3: ortho-arylation to give biarylyl alcohol 4; and β-carbon elimination to afford biaryl 5 and ketone [2]. A general aspect of ortho-arylation of aromatics is surveyed in Chapter 3.3, and reactions involving β-carbon elimination are treated in this section. Examples of β-carbon elimination are still rare, but numbers are increasing.

Miscellaneous Reactions of Aryl Halides

417

Ar-Br R

R

H

Pd(0)

OH

R

O-Pd-Ar

a

+ Ar-Pd-Br b

2

R

3 Ar

R

a. ortho-arylation

OH R

4 b. b-carbon elimination

Ar +

R O R

5

The frequently observed β-carbon elimination is expressed by the following two types. As discussed in Chapter 1.3.5, the directions of arrows as indicated by 6a and 6b have no exact mechanistic meaning. The arrows are used in this book in order to help synthetic organic chemists understand the chemical transformations. CHR3R4

X-Pd

X-Pd R1

R2

CHR3R4 + R1

R2

6a R2

CHR3R4

X-Pd

R2

O

R1

+ X-Pd

O

CHR3R4

R1

6b

Miura et al. carried out extensive studies on the reaction of 2-(biphenyl-2-yl)2-propanol (7) with aryl bromide and related reactions using Cs2 CO3 as a suitable base [3]. A mechanistic explanation of the whole process is summarized in the following. In the reaction with bromobenzene, first the phenylpalladium alkoxide 8 is formed. They found that ortho-arylation to produce 12 (21 %) and 15 (45 %) is the main path when PPh3 is used as a ligand as indicated by the paths from 8 to 15 via 11,12,13 and 14. On the other hand, arylative coupling via β-elimination of aryl group as indicated by 8a occurs to yield o-terphenyl (10) in 21 % yield. When bulky bromides such as 2-substituted 1-bromonaphthalenes are used, the ether 17 is produced as the major product via the formation of the palladacycle 16. The β-carbon elimination becomes the main path when PCy3 is used. Reaction of triphenylmethanol (18) with bromobenzene gave rise to biphenyl (19) in 93 % yield, along with o-terphenyl (10) in 6 % yield. For the arylation, aryl chlorides can be used as coupling partners. The coupling of 2,6-dimethylphenyl(diphenyl)methanol (20) with chlorobenzene afforded, 2,6-dimethylbiphenyl (21) in 98 %

418 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

Ph-Br

Pd(OAc)2, PPh3

OH

+

Me

O

Pd-Ph Me

Cs2CO3, o-xylene

Me

Me

7

8

O

Pd-Ph Me

Pd-Ph

Me

Me 10

O Me

8a

9

8

Pd-Ph OH Me

21%

OH Me Me

Me 12 21%

11

Ph-Pd-Br

O

Pd-P Me Me

13

Pd-Ph OH

OH Me

Me

Me

Me 15

14

45%

Pd Ar-Br + 7

O

O Me Ar-H

Me 16

Me Me

Pd(0) 17

Miscellaneous Reactions of Aryl Halides

419

yield without giving biphenyl at all. The result clearly shows that the bond to the bulky aryl group is cleaved preferentially. In other words, the aryl group having one or two ortho substituent(s) is selectively eliminated. Br Ph OH

+

Ph 18

Ph

Pd(OAc)2, PCy3

+

Cs2CO3, o-xylene

+

O Ph 88%

19

93%

10

6%

Cl

Me

Me

Ph

Pd(OAc)2, PCy3

OH +

Cs2CO3, o-xylene, 98%

Ph Me

Me

20

21

The coupling reaction offers a very useful synthetic method of various biaryls. Coupling of 2-(2,6-dimethylphenyl)-2-propanol (22) with 2-chloroanisole (23) was carried out and the asymmetric biphenyl 24 was obtained. The smooth coupling of 22 demonstrates a synthetically more useful method than that of 20, because readily removable acetone is the byproduct. OMe

Me Me OH +

Cl

Me

Pd(OAc)2, PCy3 Cs2CO3, o-xylene, 90%

Me 22

Me

23

Me OMe 24

The coupling of the naphthalene derivatives 25 with 26 using (R)-BINAP as a chiral ligand provided the (R)-enantiomer-enriched binaphthyl 27 with 63 % ee, suggesting a possibility of asymmetric syntheses of substituted chiral binaphthyls. The coupling can be extended further to heteroaryl derivatives. Reaction of (2thienyl)diphenylmethanol (28) with chlorobenzene gave 2-phenylthiophene (29) in 89 % yield.

420 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides OH Br

Me

Me

OMe

Pd(OAc)2, (R)-BINAP

+

Cs2CO3, o-xylene 83%, 63% ee

25

OMe

26 27 Cl Ph

S

OH

Ph

Pd(OAc)2, PCy3

+

S

Cs2CO3, o-xylene, 89%

28

29

β-Carbon elimination is observed in other systems. Ring-opening of tertcyclobutanols 30 by the reaction with aryl halides has been reported and the reaction is explained to proceed via β-carbon elimination as shown by 31 to generate alkylpalladium 32, which is converted to 33 [4]. Asymmetric arylation of the cyclobutanol 34 with N ,N -dimethylaminobromobenzene (35) using the bulky N -adamantyl derivative of (R), (S)-PPFA VIII-10 as a chiral ligand afforded the γ phenylated ketone 36 in 89 % yield with 95 % ee. In this reaction, enantioselective C-C bond cleavage (a or b) as explained by 38 occurs to provide one of the enantiomers 39 and 40. It was concluded that the b-bond cleavage occurred when the ligand VIII-10 was used [5].

3

R

R1

OH

2

R

+ Ph-Br

R3

R2

O-Pd-Ph

30 H

OH

Ph 34

Br + Me2N

R1

1

R

O Pd-Ph

R2

31 Ph

33 Ph

Pd(OAc)2, (R,S)-VIII-10 89%, 95% ee

Ph

Me2N

O

(S)-36

35

H a

Ph

O Ph

R2

32

Ar-Pd-X H

R3

R3

R1

H

Ph O Pd-Ar

Ph

37 Me

Me N

Fe PPh2

(R,S)-VIII-10

a

COAr 39

Ph O Pd-Ar

b

Ph Ph

38

H b

COAr Ph Ph 40

Miscellaneous Reactions of Aryl Halides

421

Kinetic resolution of the racemic cyclobutanol 41 occurred by the reaction with bromobenzene using (R), (S)-PPFA (VIII-9) to give the chiral ketone 42 and the recovered cyclobutanol 43 with moderate enantioselectivity [6]. It is noted that in this type reaction, less-substituted carbon is eliminated selectively. H

H

Ph OH + Ph-Br

O

H

Pd(OAc)2, [(R)-(S)-PPFA]

Ph

Cs2CO3, toluene, 96%

Ph

Me

+

OH

Me

41

Ph

Me

42

43

45%, 56% ee

46%, 59% ee

Ring expansion occurs by the reaction of allenylclobutanols with halides to cyclopentanones [7]. Intermolecular reaction of the allenylcyclobutanol 44 with iodobenzene afforded the cyclopentanone 45. Larock and Reddy explained the reaction by the following mechanism. The carbopalladation of the allene with PhPd-I generates the π -allylpalladium 46, and the concerted rearrangement and ring expansion as shown by 47 provide 48, which isomerizes to 45 [8]. O OH

• +

Me

Pd(OAc)2, PPh3 Ph-I

44

Ph

Bu4NCl, i-Pr2NEt DMF, 70%

45

Ph-Pd-I

H

Ph

H

O

Ph O

O

Ph

PdX

Pd-I 46

47

48

As another possibility, the reaction of 44 might be explained by the formation of palladium alkoxide 49, followed by β-carbon elimination to afford 50. Carbopalladation (5-exo cyclization) of 50 gives 51, and reductive elimination produces 45 via 48. However, this route seems to be less likely, since more substituted carbon migrates in this type of reactions as demonstrated by the following examples [9]. Ihara et al. carried out interesting applications of the cyclopentanone formation. Stereoselective synthesis of α-substituted cyclopentanone 54 with a quaternary carbon stereocenter was carried out by the reaction of the allenylcyclobutanol 52 with 4-iodoanisole (53) [9]. Intramolecular reactions of the stereoisomers 55 and 57 in the presence of silver salt in toluene afforded different products depending on their stereochemistry. The macrocyclic dimeric product 56 was obtained from

422 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides b-carbon elimination mechanism Ph-I + Pd(0)

Ph-Pd-I

Pd-Ph O

OH

•

•

44

49 O

O

•

b-carbon elimination

Pd-Ph

5-exo cyclization Pd-Ph 50

51

O

O

Ph

reductive elimination

Me Ph

48

45

55 in 80 % yield, a surprisingly high yield, and the monomeric product 58 was obtained from 57 [7].

I

HO +

O Pd(PPh3)4 Ag2CO3, toluene 72%

MeO

OMe

Ph

Ph 52

53

54 O

HO I

H

Pd(PPh3)4, Ag2CO3 toluene, 80% H

55

56

O

O HO I

57

Pd(PPh3)4, Ag2CO3 toluene, 67%

58

Similar carbopalladation–ring expansion was observed in the Pd-catalyzed reaction of the (hydroxy)- methoxyallenylisoindoline bearing an iodophenyl moiety 59. In this case, carbopalladation of the allene to form the π -allylpalladium is followed by rearrangement–ring expansion, as shown by 60, to give the isoquinolinedione

Miscellaneous Reactions of Aryl Halides

423

61 [10]. The allenyl alcohol without the iodophenyl moiety 62 alone undergoes the Pd-catalyzed rearrangement–ring expansion to give the isoquinolinedione 63 [11].

Pd-X

MeO HO

MeO O

H I

N

Pd(PPh3)4, K2CO3 N

THF reflux, 74%

O

O

59

60 OMe O

N O 61 MeO HO

O OMe

• Pd(PPh3)4, K2CO3

N

Me

N

THF, 79%

O

O

62

63

Me

Interestingly, formation of the cyclopentanone 66 from the cyclobutanol having propargyl carbonate moiety 64 occurred by treatment with p-cresol (65) using DPPE as a ligand. OH

H

OH Pd2(dba)3, DPPE

+ H

n-C7H15 64

Me

O

OCO2Me

O

dioxane, 80 °C, 80%

Me

H 65

n-C7H15 66

Ihara et al. explained the reaction by the formation of the allenylpalladium 68, which is attacked by phenoxide to form π -allylpalladium intermediate 69. Finally, ring expansion of 69 gives the cyclopentanone 70 [12]. Larock and Reddy obtained the 2-alkylidenecyclopentanone 72 by the reaction of 1-(1-alkynyl)cyclobutanol 71 with iodobenzene. The bicyclononanone 74 was obtained from 73. Selective formation of 74 demonstrates that the more substituted bond a in the cyclobutanol 73 undergoes exclusive cleavage (or migration) [8,13]. Larock proposed the mechanism of the reaction of 75 involving ring expansion of 76 to form palladacycle 77 and reductive elimination to give 78.

424 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides

OH

OCO2Me

OH

Pd(0)

−

− OPh

+Pd O OPh

Pd-OMe R

R 67

R 68

69

O OPh R 70

O

OH

Ph

Pd(OAc)2, PPh3, n-Bu4NCl Ph

+

Ph-I

i -Pr2NEt, DMF, 70%

Ph

71

72 Ph Ph

a OH Ph + Ph-I b

Pd(OAc)2, PPh3, n-Bu4NCl

i -Pr2NEt, DMF, 60%

O

73

74

Pd

Pd-X

OH R

Ph-Pd-I H O

R Ph

R 75

O

O Ph 76

R

Ph 77

78

A somewhat different example of β-carbon elimination was observed by Catellani and Chiusoli in 1983 [14]. Reaction of two molecules of norbornene (79) with bromobenzene gave rise to 83. Stepwise carbopalladations of norbornene generate 80 and 81. Then β-carbon elimination yields the alkylpalladium 82 and β-H elimination affords 83. As described in Chapter 3.8.1, the deinsertion of norbornene from 84 to generate norbornene (79) and arylpalladium 85 is an example of βcarbon elimination. Although no aryl halide is involved, Pd-catalyzed ring cleavage of cyclobutanone oximes 86, leading to unsaturated nitriles 89 via β-carbon elimination as shown by 87 to give the alkylpalladium 88, was reported by Nishimura and Uemura [15]. The tricyclic O-benzoyloxime 93 was converted to the nitrile 94 by selective bond cleavage. Interestingly the cyclopropanecarbonitrile 99 was obtained from the spiro compound 95. In this reaction, β-carbon elimination generates the alkylpalladium 97, which has no possibility of β-H elimination. Under basic conditions, intramolecular nucleophilic attack of the carbanion to the alkylpalladium provides the palladacyclobutane 98, and the cyclopropanecarbonitrile 99 is formed by reductive elimination.

Miscellaneous Reactions of Aryl Halides

+ PhBr

425

Pd(PPh3)4, HC(OEt)3 anisole, 1−5 °C, 41% Pd-Br

79

80

b-carbon elimination

Br-Pd Br-Pd 81

82 b-carbon elimination

R

83

R + X-Pd

R

79

R

Pd-X 84

85

C Pd(0) Ph

N

Ph

N Pd

OCOR 86

OCOR

Pd-X

87 C

N

Ph

88

N

Ph 89

Pd2(dba)3, BINAP

N

t-Bu

OBz

K2CO3, THF reflux, 71%

CN

t-Bu

90 OBz

CN

t-Bu

64 : 36

91 N

+

92

CN

Pd2(dba)3, BINAP K2CO3, THF reflux, 79%

93

94

OBz N

Pd-OBz

Pd2(dba)3, BINAP

N

K2CO3, THF reflux, 67%

95

96 CN

CN

b-carbon elimination

Pd

CN

Pd-OBz 97

HOBz

Pd(0) 98

99

426 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides As a related reaction, ring opening of cyclopropyl alcohols was reported by the Uemura and Cha groups using Pd(II). Two products 101 and 102 were obtained in a ratio of 1 : 1.2 by the ring opening of bicyclo[1.0.3]hexane 100 as shown by 103 [16]. Pd(OAc)2 in DMSO under oxygen was used and they claim that the reaction is promoted by Pd(II). On the other hand, Okumoto and co-workers carried out the ring cleavage of 104 using ligandless Pd2 (dba)3 alone to afford the unsaturated ketone 105 and a negligible amount of the saturated ketone 106 [17]. Formation of hydridopalladium alkoxide 107 by oxidative addition of Pd(0) to alcohol and β-H elimination in 108 are assumed in their case. O

O

HO Pd(OAc)2 Me

DMSO, O 2 rt, 73% OTIPS

+ Me

Me

100

OTIPS

OH

102

O +

Ph

Ph 106

105

104 H2

Pd(0)

O-Pd-H

b-carbon elimination

OTIPS 103

O Pd2(dba)3, MeCN 50 °C, 98%

Ph

Me

OTIPS 1 : 1.2

101

Ph

AcO-Pd-O

b-H elimination O Pd-H

Ph 107

108

As described in Chapter 5.3, a number of addition reactions to methylenecyclopropanes are explained by β-carbon elimination.

References 1. Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z. Yoshida, J. Org. Chem., 48, 1286 (1983). 1a. A. S. Guram, X. Bei, and H. W. Turner, Org. Lett., 5, 2485 (2003). 2. Y. Terao, H. Wakui, T. Satoh, M. Miura, and M. Nomura, J. Am. Chem. Soc., 123, 10 407 (2001). 3. Y. Terao, H. Wakui, M. Nomoto, T. Satoh, M. Miura, and M. Nomura, J. Org. Chem., 68, 5236 (2003). 4. T. Nishimura and S. Uemura, J. Am. Chem. Soc., 121, 11 010 (1999). 5. S. Matsumura, Y. Maeda, T. Nishimura, and S. Uemura, Chem. Commun., 50 (2002); J. Am. Chem. Soc., 125, 8862 (2003). 6. T. Nishimura, S. Matsumura, Y. Maeda, and S. Uemura, Tetrahedron Lett., 43, 3037 (2002). 7. H. Nemoto, M. Yoshida, and K. Fukumoto, J. Org. Chem., 62, 6450 (1997). 8. R. C. Larock and C. K. Reddy, J. Org. Chem., 67, 2027 (2002). 9. M. Yoshida, K. Sugimoto, and M. Ihara, Tetrahedron Lett., 41, 5089 (2000).

References

427

10. Y. Nagao, S. Tanaka, A. Ueki, I. Y. Jeong, S. Sano, and M. Shiro, Synlett, 480 (2002). 11. Y. Nagao, A. Ueki, K. Asano, S. Tanaka, S. Sano, and M. Shiro, Org. Lett., 4, 455 (2002). 12. M. Yoshida, H. Nemoto, and M. Ihara, Tetrahedron Lett., 40, 8583 (1999). 13. R. C. Larock and C. K. Reddy, Org. Lett., 2, 3325 (2000). 14. M. Catellani and G. P. Chiusoli, J. Organomet. Chem., 247, C59 (1983). 15. T. Nishimura and S. Uemura, J. Am. Chem. Soc., 122, 12 049 (2000). 16. S. B. Park and J. K. Cha, Org. Lett., 2, 147 (2000), T. Nishimura, K. Ohe, and S. Uemura, J. Am. Chem. Soc., 121, 2645 (1999). 17. H. Okumoto, T. Jinnai, H. Shimizu, Y. Harada, H. Mishima, and A. Suzuki, Synlett, 629 (2000).

3.8.3 Hydrogenolysis with Various Hydrides Pd-catalyzed hydrogenolysis of aryl and alkenyl halides and pseudohalides such as triflates using various hydride sources is an established process. The reaction can be explained by the transmetallation with hydride to form palladium hydride, which undergoes reductive elimination. Among several hydride sources, HCO2 H/Et3 N, HSnBu3 , and R3 SiH are most extensively used. Typical recent examples of hydrogenolysis using these hydrides are briefly cited in this section. _

H

Pd(0) Ar-X

Ar-Pd-X

Ar-Pd-H

Ar-H Pd(0)

Ammonium formate, typically a mixture of HCO2 H and Et3 N, is soluble in organic solvents and hydrogenolysis proceeds under mild conditions [1]. In the synthesis of (−)-enterolactone from natural lignan hydroxymatairesinol 1, OH groups were removed by hydrogenolysis of their 4, 4
-bistriflates 2 using HCO2 H and Et3 N to yield 3, 3
-dimethylenterolactone (3) in 85 % yield [2]. H

MeO

O

H

MeO O

O O

HO

TfO HO

H

+

H

OMe

HCO2H

OMe

OH

OTf

hydroxymatairesinol (1)

2 H

MeO

O HO

H

O

O PdCl2(PPh3)2 H

Et3N, DMF, 85%

79%

OMe 3

O BBr3

H

OH (−)-enterolactone

428 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides Stereoselective hydrogenolysis of 1,1-dibromo-1-alkenes with HSnBu3 proceeds at room temperature to afford (Z)-1-bromo-1-alkenes [3]. The dibromide 4 was converted to (Z)-bromide 5 cleanly. The (Z)-bromide 7 was obtained from1,1dibromo-1,3-diene derivative 6. PPh3 as a ligand gave the best results. An unsatisfactory result was obtained when HCO2 H/Et3 N was used. (Z)-1-Bromo-1-alkenes are useful to prepare conjugated (Z)-alkenyl compounds by Pd-catalyzed reactions. Br +

Br

Me2N

HSnBu3

Pd(PPh3)4, benzene rt, 90%

H Br

Me2N

4

5

Me THPO

+

HSnBu3

Br

Me

Pd(PPh3)4, benzene

Me THPO

rt, 88%

Br

6

Br

Me 7

H

Aryl and alkenyl triflates 8 and 9 were hydrogenolyzed with Et3 SiH in DMF [4]. OTf +

Et3SiH

Pd(OAc)2, DPPP DMF, 100 °C, 100%

CO2Me

CO2Me

8

O

OTf

+ Et3SiH

Pd(OAc)2, DPPP DMF, 100 °C, 88%

9

3.8.4 Homocoupling of Organic Halides (Reductive Coupling) Homocoupling of aryl halides promoted by Cu metal is an old reaction, called the Ullmann reaction. An interesting review on the historical background of Ullmann coupling was published recently [5]. Pd(0) can be used for the coupling. The Ullmann coupling of aryl and alkenyl halides catalyzed by Pd(0) to give symmetrical biphenyl and conjugated dienes proceeds smoothly with proper reductants. Pd(0) species mediate the coupling with concomitant oxidation of Pd(0) to Pd(II)X2 , and a reducing agent is required to regenerate Pd(0) from Pd(II) in order to make the reaction catalytic. The reaction is reductive coupling of the halides, which is

Miscellaneous Reactions of Aryl Halides

429

X + PdX2

+ Pd(0)

reductant

mechanistically different from all the reactions of aryl halides so far discussed. The efficiency of the catalytic reaction depends on the activity of the reductants. A number of reductants are used. Zn or Cu powder are frequently used. Recent reports on the reductive coupling using other reductants are cited in this section. As a convenient process, Rawal used Pd(OAc)2 combined with As(o-Tol)3 or P(o-Tol)3 as a catalyst, and hydroquinone as a reductant in DMA in the presence of Cs2 CO3 for the coupling of mainly aryl iodides. The coupling product 10 was obtained in 95 % yield. Intramolecular coupling of the diiodide 11 afforded 12 in 70 % yield [6]. OH

O Pd(OAc)2, As(o-Tol) 3

I + MeO OH

Cs2CO3, DMA, 95 °C 1 d, 95%

OMe +

MeO 10

O

I

I

Pd(OAc)2, As(o-Tol) 3

O

O

Cs2CO3, DMA, 100 °C 70%

11

12

The coupling catalyzed by Pd/C in the presence of Zn powder proceeds smoothly at room temperature in a mixed solvent of acetone and water as the best solvent. Venkatraman and Li carried out the reductive reaction even under an air atmosphere, and claimed that the Pd catalyst is not sensitive to oxygen [7]. Br Pd/C, Zn, rt, air H2O, acetone, 92%

Tanaka et al. reported that tetrakis(dimethylamino)ethylene (TDAE) (13) is an efficient reductant for the coupling of aryl bromides. Ligandless Pd compounds such as PdCl2 (PhCN)2 and Pd(OAc)2 are active catalysts. Phosphine-ligated complexes such as Pd(PPh3 )4 are not effective. The coupling proceeds in DMF at 50 ◦ C to give the coupling product in 98 % yield [8].

430 Pd(0)-Catalyzed Reactions of sp2 Organic Halides and Pseudohalides I

PdCl2(PhCN)2, TDAE MeO

DMF, 50 °C, 98%

MeO

OMe 10

Me2N

NMe2

Me2N

NMe2

TDAE 13

Ullmann coupling is homocoupling. Banwell et al. reported an interesting cross coupling of o-halonitroarenes with α-halo enones [9]. As an example, reaction of o-bromonitrobenzene (14) with 2-bromocyclohexenone 15 proceeded in the presence of ligandless Pd catalysts such as Pd2 (dba)3 or Pd/C and Cu powder in DMSO to yield the cross coupling product 16 in 89 % yield based on 15. The homocoupling of bromonitrobenzene (14) is a competitive reaction. This unwanted process could be suppressed by slow addition of the aryl bromide 14 in an excess. The indole derivative 17 was produced by Pd/C catalyzed hydrogenation of 16 and condensation.

Br

Br

NO2 14

H2, Pd/C

Pd2(dba)3, Cu

+

DMSO, 70 °C 2 h, 89%

O

O NO2

N H

16

17

15

References 1. N. H. Cortese and R. F. Heck, J. Org. Chem., 42, 3491 (1977). 2. P. Eklund, A. Lindholm, J. P. Mikkola, A. Smeds, R. Lehtil¨a, and R. Sj¨oholm, Org. Lett., 5, 491 (2003). 3. J. Uenishi, R. Kawahama, O. Yonemitsu, and J. Tsuji, J. Org. Chem., 63, 8965 (1998); J. Uenishi, R. Kawahama, O. Yonemitsu, and J. Tsuji, J. Org. Chem., 61, 5716 (1996). 4. H. Kotsuki, P. K. Datta, H. Hayakawa, and H. Suenaga, Synthesis, 1348 (1995). 5. Review, J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, and M. Lemaire, Chem. Rev., 102, 1359 (2002). 6. D. D. Hennings, T. Iwama, and V. H. Rawal, Org. Lett., 1, 1205 (1999). 7. S. Venkatraman and C. J. Li, Org. Lett., 1, 1133 (1999). 8. M. Kuroboshi, Y. Waki, and H. Tanaka, Synlett, 637 (2002); J. Org. Chem., 68, 3938 (2003). 9. M. G. Banwell, B. D. Keely, O. J. Kokas, and D. W. Lupton, Org. Lett., 5, 2497 (2003).

Chapter 4 Pd(0)-Catalyzed Reactions of Allylic Compounds via π-Allylpalladium Complexes

4.1 Introduction and Range of Leaving Groups Pd-catalyzed reactions of various allylic compounds via the formation of π allylpalladium complexes offer many synthetically useful methods. The following allylic compounds are known to form π -allylpalladium complexes by oxidative addition. Allylic compounds used for Pd-catalyzed reactions OAc

OCO2R

OPh

OH

NR2

NR3X

Cl

O

OP(O)(OR)2

OCONHR

NO2

SO2Ph

SR2X EWG EWG

N R

In addition, π -allylpalladium complexes 1 and 2 are formed as intermediates in the reactions of organic halides with 1,3- and 1,2-dienes. Usually these π allylpalladium complexes, without isolation, undergo a variety of transformations as summarized in Scheme 4.1, offering many useful synthetic methods. Reaction of π -allylpalladium chloride with malonate and acetoacetate was reported in 1965, showing that π -allylpalladium complexes are electrophilic [1]. Most importantly, electrophilic π -allylpalladium complexes react with various kinds of pronucleophiles of carbon, oxygen, and nitrogen. Then Pd(0) is regenerated after the reactions. The generation of Pd(0) offers the possibility of a catalytic process. This is the characteristic feature of π -allylpalladium chemistry. π -Allyl complexes of other transition metals, typically π -allylnickel complexes are either nucleophilic or electrophilic depending on the nature of the reactants, Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

432

Pd(0)-Catalyzed Reactions of Allylic Compounds + Ar-X

Pd(0)

Ar

Ar

Pd

Pd-X Ar + Ar-X

•

X 1

Ar

Pd(0) X-Pd

Pd-X 2

Nu X

R

R

C, O, N nucleophile (NuH)

R M′R′

X

R′

transmetallation

R

M′Ar transmetallation

Pd(0)

R′

Ar R

M'

transmetallation

R′

R

R Pd-X

CO, ROH

1

carbonylation

CO2R

R

R′M′M′R′

M′R′

metallation

R

R H hydrogenolysis R b-elimination

R

Scheme 4.1 Pd-catalyzed reactions of allylic compounds.

R

X

Pd(0)

NuH

R Pd X

R

Nu + Pd(0) + HX−

Introduction and Range of Leaving Groups

433

and generate either Ni(II) or Ni(0) after the reaction. When Ni(II) is regenerated, the reaction is stoichiometric.

R

X

M(0)

E+

R

R

E + M(II)XY

M X

Although it is not a common reaction, some nucleophiles, particularly ester enolates, are known to attack the central sp2 carbon of π -allyl group in the presence of σ -donor ligands to generate palladacyclobutane 3, which is converted to the substituted cyclopropanes 4 by reductive elimination [2,3]. Satake et al. reported that π -allylpalladium-pyridinylimidazole complex 7 is a very effective catalyst for the cyclopropanation [4]. Ethyl α-cyclopropylisobutyrate (6) was obtained in high yield with high chemoselectivity by the reaction of the ketene silyl acetal 5 with cinnamyl acetate using 7 as a catalyst.

R

R

R Pd

Pd X

Nu X

Nu

R Pd

+ Pd(0)

Nu

3

Ph

OEt

OAc + 5

4

Pd cat

Me N

AcONa, DMSO OSiMe3 87%

N

N

Ph

Pd CO2Et + Ph

CO2Et 7

6

22 : 1

As shown above many allylic compounds can be used for catalytic reactions with different reactivity. Allylic esters such as carbonates, acetates, and phosphates are widely used. Allylic acetates and phosphates react in the presence of bases such as Et3 N and AcONa. However, Giambastiani and Poli reported that allylation of β-keto esters, but not malonates, with allylic acetates can be carried out under neutral conditions, although the reaction is slower [5]. O Ph

OAc

+

O CO2Me Pd(PPh3)4 , PPh3

CO2Et

CH2Cl2, 69% Ph

434

Pd(0)-Catalyzed Reactions of Allylic Compounds

Allylic carbonates are more reactive than acetates. In addition, reaction of carbonates proceeds in the absence of bases [6]. Formation of π -allylpalladium 9 from allyl methyl carbonates 8 proceeds by oxidative addition, followed by decarboxylation, and π -allylpalladium methoxide 9 is generated at the same time, which abstracts a proton from a pronucleophile to form 10. In situ formation of methoxide is a key in the allylation under neutral conditions. Allylation under neutral conditions is useful for the reaction of base-sensitive compounds. For example, exclusive chemoselective reaction of the carbonate group in 4-acetoxy-2-butenyl methyl carbonate (11) occurred in the absence of a base to yield 12. Similar chemoselective reaction of the allyl carbonate group in the chiral cyclopentenyl methyl carbonate 13 with the β-keto ester 14 without attacking the allylic acetate group to give 15 was observed even in the presence of NaH. As expected, retention of stereochemistry (see Chapter 4.2.1) was observed in this substitution [7]. R

R R

O

OMe

NuH

Pd

Pd+

Pd+ _

O CO2

8

OMe

9

MeOH

_

Nu 10

R

Nu

O OCO2Me

AcO

+

CO2Me

11

Pd2(dba)3 , PPh3 THF, 77%

CO2Me AcO 12

O

OCO2Me

AcO

O

+ t-Bu-O 13

Pd2(dba)3 , PPh3 CO2Et

NaH, 91%

14 H

CO2Et

AcO

O-t-Bu O 15

Alkenyloxirans 16 are reactive allylating agents used under neutral conditions. The epoxy ring is opened by Pd(0) to form π -allylpalladium with generation of an alkoxide anion, which abstracts a proton from a pronucleophile to produce the α-hydroxy-π -allylpalladium 17. Reductive elimination of 17 affords either 1,4-adducts 18 or 1,2-adducts 19 [8,9]. The 1,4-adducts are mainly obtained under usual conditions due to the electronic effect of the epoxide oxygen. The 1,4-adducts 18 are allylic alcohols, and can be used again for the allylation after esterification to yield 19a.

Introduction and Range of Leaving Groups

435 OH

R R′

O− O

Pd(0)

R

NuH

R

Nu

18

OH

1,4-addition

R R′

R′

R′ 16

1,2-addition

Pd

Pd Ln

Ln

Nu−

17 OH R R′ 19 OH

OCO2Me

R

Nu NuH

R R′

R

R′

Nu

Nu

R′

Nu

Nu

18

19a

Reaction of isoprene monoepoxide (20) with acetoacetate afforded the allylic alcohol 21. The pheromone 24 was synthesized after second allylation of acetoacetate with 22 to provide 23 [8]. The regioselectivity is controlled by ligands. The 1,4-adducts such as 21 are formed when achiral ligands are used. Interestingly, the same reaction of 20 afforded the 1,2-adduct 25 (64 % yield) and the 1,4-adduct 26 in a ratio of 79 : 16 when Trost L-1 as a bulky chiral ligand (even racemic) was used [10].

O

+

COMe

Pd(PPh3)4

HO

COMe

CO2Me THF, rt, 62%

20

CO2Me

21 AcO

COMe 22

COMe COMe

CO2Me Pd(PPh3)4 NaH, 91%

steps COMe

MeO2C 23

CO2Me

MeO2C 24

436

Pd(0)-Catalyzed Reactions of Allylic Compounds Me O

+

COMe Pd2(dba)3, Trost L-1 CO2Me

O

MeO

CH2Cl2, rt

O

20

+

Me O H

25

64%

79 : 16

HO

COMe 26

CO2Me

Trost designed chiral diamides of 2-diphenylphosphinobenzoic acid (DPPBA) and 2-diphenylphosphinoaniline (DPPA), and their derivatives (abbreviated as Trost L-1, L-2, L-3, L-4, and L-5), which are remarkably effective ligands in asymmetric allylations as described later.

O

O NH PPh2

O

O

HN

NH

Ph2P

PPh2

Trost L-1 (XIII-1)

HN Ph2P

Trost L-2 (XIII-2)

O

O NH

HN

PPh2

Ph2P

Trost L-3 (XIII-3) PPh2

NH O

Ph2P

HN

O NH

HN

PPh2 Trost L-4 (XIII-4)

O

O

Ph2P Trost L-5 (XIII-5)

Less reactive allylic alcohols can be used in the presence of some activators. Lewis acids are used for this purpose. Allylation of amines and malonates with allyl alcohols was carried out by Ozawa using a sp2 -hybridized bidentate phosphine-Pd

Introduction and Range of Leaving Groups

437

in the presence of pyridine [10a]. Et3 B is one of them, and allyl alcohols behave as good electrophiles in the presence of the borane. Amination of cis-5-methoxycarbonylcyclohexen-3-ol (27) with N -methylaniline proceeded at 50 ◦ C in the presence of 2 equivalents of Et3 B to yield a mixture of cis- and trans-cyclohexenylamines 28. The hydroxy group is activated by coordination of Et3 B as shown by 29 [11]. Also Ti(O-i-Pr)4 is used for allylation with allylic alcohols in benzene [12]. CO2 activates allylic alcohols presumably by forming monoallyl carbonate, and amination proceeds under 1 atm of CO2 . Allylation of α-methylacetoacetate with allyl alcohol occurred at room temperature under 30 atm of CO2 [13]. OH

H

MeNPh + PhNHMe

BEt3

Pd(PPh3)4, Et 3B 50 °C, 73%

MeO2C

MeO2C 27

MeO2C 29

28

O OH

O

O CO2Me Pd(PPh3)4, CO2 (30 atm)

+

CO2Me

rt, 77%

Allylamines are less reactive allylating agents. Bricout et al. reported that C and N-allylations with allyldiethylamine occurred using Pd(OAc)2 and DPPB, but Ni catalysts were found to be better [14]. The nitro group is a good leaving group, and allyl nitro compounds are used conveniently for allylation because they can be prepared easily by the reaction of nitromethane with aldehydes and ketones, and used for Pd-catalyzed reactions [15]. As an interesting application, the alkenyl triflate 30 was converted to the allyl nitro derivative 31, which was, without isolation, subjected to the Pd-catalyzed amination with 32 in the presence of tetramethylguanidine (TMG) as a strong amine base to afford the anti-MRS carbapenem intermediate 33 in 34 % overall yield [16]. OH TBSO

TBSO H

H

H OTf

H

HN NO2

CH3NO2 O

CO2PNB

CO2PNB 31

30

OH

TBSO H N O 33

CO2PNB

32

Pd(OAc)2, P(OEt)3

O

H

S O2

S O2

TMG, MeOH, 34%

438

Pd(0)-Catalyzed Reactions of Allylic Compounds

Intramolecular amination of the allyl sulfone 34 proceeded regioselectively in MeCN in the presence of TMG to give cephalotaxine intermediate 35 in 98 % yield. The use of TMG is important. When Et3 N was used, the yield was 64 % [17]. NHPMB PhSO2

N PMB

Pd(PPh3)4, MeCN O

TMG, 98% OMOM

O

S

O OMOM

O

S

S

34

S 35

4.2 Allylation 4.2.1 Stereo- and Regiochemistry of Allylation Stereochemistry of Pd-catalyzed allylation of nucleophiles has been studied extensively. In the first step, formation of π -allylpalladium complexes 37 by the attack of Pd(0) on allylic compounds 36 proceeds with inversion of configuration (anti attack). Subsequent reaction of 37 with nucleophiles occurs in different stereochemistry depending on the nature of the nucleophiles. The ‘soft’ (stabilized) nucleophiles which are derived from conjugate acids with pKa < 25, such as active methylene compounds, attack 37 from the backside of the Pd atom to give 38 with inversion of stereochemistry. Thus overall retention is observed. On the other hand, ‘hard’ nucleophiles (pKa > 25), typically organometallic compounds of main group metals (Mg, Zn, B, Sn and others) generate 39 by transmetallation, and subsequent reductive elimination affords 40. Both the transmetallation and R

R

R

Pd(0)

Nu−

inversion

inversion

OAc

Nu

36

37 R'M

Pd OAc

retention R

R

retention

R' 40

Pd 39

R'

(inversion)

38 (retention)

Allylation

439

reductive elimination proceed with retention, and hence overall inversion is observed with hard nucleophiles. However, Kurosawa and co-workers observed both inversion and retention of stereochemistry in the oxidative addition of 5(methoxycarbonyl)-2-cyclohexenyl chloride to Pd(0) depending on the ligands and solvents used [18]. Pd-catalyzed allylation of nucleophiles with substituted π -allyl systems usually occurs at the less substituted allylic terminus with high regioselectivity. Exceptional regioselectivity has been reported depending on the substrates and ligands. Hayashi found that regiochemistry of allylation of NaCMe(CO2 Me)2 with allyl acetates is partially retained in the final products when (η3 -allyl-PdCl)2 and bulky ligands are used [19]. For example, attack at the less-substituted terminus of 41 occurred to give the product 42 when bulky (R)-MeO-MOP (VI-12) was used as a ligand. Substitution took place with preference at the position originally occupied by the leaving acetate group in 41. On the other hand, substitution of the allyl acetate 44 occurred at the more crowded carbon of 44 to give 43 as the major product. This is known as a memory effect. Similar memory effect of π -allylic ligands was observed by the reaction of the deuterated cyclic allyl acetates 45 and 46. The substituted cyclohexene 47 was obtained mainly from the acetate 45, while the acetate 46 afforded 48 as a major product. The results show that the geometrical isomerization of π -allylpalladium intermediates is slow when bulky ligands are used. The original regiochemistry was lost when PPh3 was used.

Ph

OAc

+

41

NaCMe(CO2Me)2 (R)-MeO-MOP THF, rt, 99%

Ph +

NaCMe(CO2Me)2

OAc

Ph

(h3-allyl-PdCl)2 Ph

(h3-allyl-PdCl)2 (R)-MeO-MOP THF, rt, 96%

Nu

+ Nu

42

43

79 : 21

42 + 43 23 : 77

44

D

OAc

(h3-allyl-PdCl)2 D

+ NaCMe(CO2Me)2 (R)-MeO-MOP THF, rt, 95% 45 AcO

Nu

Nu

D

+ 47

83 : 17

48

D + NaCMe(CO2Me)2

(h3-allyl-PdCl)2

47 + 48

(R)-MeO-MOP THF, rt, 85%

17 : 83

46

Aremoglu and Williams found a strong memory effect in the reaction of the allylic acetate 50 to give 52 by using bulky aliphatic phosphines, typically PCy3 [20]. No memory effect was observed in the reaction of the acetate 49. In these

440

Pd(0)-Catalyzed Reactions of Allylic Compounds Me

Me

OAc + NaCH(CO t-Bu) 2 2

(h3-allyl-PdCl)2 Me

Nu

P(t-Bu)3, THF, 99%

Nu 51

49 Me + NaCH(CO2t-Bu)2 OAc

+

(h3-allyl-PdCl)2 P(t-Bu)3, THF, 96%

52

1.6 : 1

51 + 52 1 : 58

50

reactions, P(t-Bu)3 is a more effective ligand than PCy3 . Also ferrocenyl phosphines showed large memory effect [21,22]. Retention of geometry, perfect chirality transfer, and high reactivity have been observed by the reaction of the chelated Zn enolate of amino acid ester 53 even when PPh3 was used [23]. In addition, the non-stabilized enolate 53 was found to be very reactive. Reaction of the allylic carbonates 54 and 56 with the enolate 53 gave 55 and 57 with perfect chirality transfer and high diastereoselectivity. The carbonates and the enolates are highly reactive and the reaction starts even at −78 ◦ C. Lower selectivity was observed by the reaction of the corresponding allylic acetate. Ot-Bu CO2t-Bu

TfaN

LHMDS ZnCl2

TfaN Zn

O

53

Ot-Bu

Ph

+

TfaN Zn

OCO2Et (S)-54

OCO2Et

(S)-56

−78 °C

Ot-Bu

Ph CO2t-Bu

PPh3

O

53

96% ee

+ Ph

NHTfa (h3-allyl-PdCl)2 rt, 73% 55 NHTfa

(h3-allyl-PdCl)2 PPh3

TfaN Zn 53

O

−78 °C

96% ee

CO2t-Bu rt, 69%

Ph 57

97% ee

97% ee

Remarkable control of regioselectivity has been observed by the use of some chiral ligands. For example, the diallylation of 2-iodoresorcinol (58) with the allyl carbonate 59 occurred regioselectively at the substituted terminus to give 60 in very high yield (97 %) with a good diastereomeric ratio (dr) (dr = 92/8) using one of the Trost ligands (R,R)-Trost L-2 [24]. No attack at the unsubstituted terminus took place. In addition, efficient deracemization of the racemic carbonate 59 occurred. Reductive Heck reaction of 60 using HCO2 H afforded 61 with 87 % ee. Use of the sterically hindered base pentamethylpiperidine (PMP) gave good

Allylation

441 (R) CN

OH

OCO2Me

I

CN

+

Pd2(dba)3, (R, R)-Trost L-2

O

CH2Cl2, rt, 97%, dr 92/8

I

OH

CN

58

O

59

(R)

60

O

O HCO2H, PdCl2(MeCN)2

Ac2O, Et 3N

PMP, DMF

81%, 87% ee

O

R

CN

OAc

MeO

OH O

61

furaquinocin

results. Concise total synthesis of furaquinocin has been achieved employing these two Pd-catalyzed reactions in key steps. Allylation of the phenol 62 with geranyl methyl carbonate (63) provided the more congested allyl aryl ether 64 with excellent regioselectivity (92 : 8) and 76 % ee when Trost L-1 was used. The reaction offers a good synthetic method of chroman [25]. On the other hand, curiously Shishido and co-workers found that the congensted isomer 67 was obtained as a single product in 82 % yield by the allylation of the phenol 65 with the allyl carbonate 66 even when PPh3 was used. It is puzzling why this unusual regioselective reaction occurred under normal reaction conditions [26]. Me MeO + Me

OCO2Me

OH Me 62 MeO

63

85%, 76% ee

Me steps

Me

MeO O

O Me

MOMO Me

Pd2(dba)3, (R, R)-Trost L-1

H chroman

64

+

i-BuO

O O

OH 65

Me Me

66

Pd(PPh3)4 MOMO THF, 82% Me

O Me 67

Me

Some tethered alkene affects regioselectivity remarkably. The reaction of the diene 68 with malonate occurred at the more substituted allylic terminus proximal to the tethered alkene to give 69, having a quaternary stereocenter with

442

Pd(0)-Catalyzed Reactions of Allylic Compounds

complete regiocontrol. Thus the double bond at this position showed complete regiocontrol [27]. The seven-membered ring was obtained regioselectively as a single product by the cyclization of the asymmetric allylic acetate 69a. Substitution occurred at the allylic terminus proximal to the amino group [28]. Me

Me (h3-allyl-PdCl)2,

+ LiCH(CO2Me)2

OBz

PPh3, THF

65% (>95 : 5)

CH(CO2Me)2 69

68 OAc

NMe2 (h3-allyl-PdCl)2,

CO2Me

PPh3

NaH, THF, 38% CO2Me

Me2N

MeO2C MeO2C

69a

Substituents in allylic systems also control regiochemistry. The TMS group is one of these substituents. The vinylsilane 71 was obtained exclusively by the reaction of TMS-substituted allyl carbonate 70. Desilylation of 71 afforded 72. In this way, nucleophilic substitution at the more substituted carbon of 73 can be achieved indirectly by using 70 [29]. Unusual 1,2-addition of a nucleophile to TMS-substituted vinyloxirane 74 was observed to afford vinylsilane 75. TMS

C5H11

TMS

COMe +

CO2Me

OCO2Me

C5H11

Pd2(dba)3, P(n-Bu)3 THF, rt, 81%

COMe

MeO2C

70

71

TMS

C5H11

C5H11 88%

COMe

MeO2C

O

74

OCO2Me

COMe

MeO2C

73

72

71

TMS

C5H11

p-TsOH

COMe +

CO2Me

TMS Pd2(dba)3, P(n-Bu)3

OH

THF, rt, 76% COMe

MeO2C 75

EWGs show a decisive effect on regioselectivity, and nucleophiles selectively attack the electron deficient side of π -allyl systems as expected. Reaction of αacetoxy-β,γ -unsaturated nitrile 76 with a nucleophile afforded the γ -substituted α,β-unsaturated nitrile 77 and the ester 81 exclusively by 1,3-transposition. Also the reaction of γ -acetoxy-α,β-unsaturated ester 80 gave 81 regioselectively [30]. Clean 1,5-transposition occurred by the reaction of the dienyl carbonate 78 with NaN3 to afford 79 [31].

Allylation

C5H11

Ac2O

COMe

CN

HCN

CHO

443

CO2Me

OAc

C5H11

Pd(PPh3)4

76 MeO2C CH

THF, rt, 97%

COMe

CN

C5H11 77

N3

OCO2Et CN

+ NaN3

Pd(PPh3)4

CN

86%

78

79

OAc

+ C5H11CH(CO2Me)2 CO2Me

Pd(PPh3)4

MeO2C

E/Z = 1/1 C5H11 CO2Me

THF, rt, 54% CO2Me

80

81

Regioselective reaction of sulfone-substituted allyl carbonate 82 with acetoacetate generated 83, which underwent Michael-type addition to afford 4-substituted dihydrofuran 84 in one step [32].

SO2Ph

Me OCO2Me

+

COCH3

Pd2(dba)3

CO2Et

DPPE, THF 100 °C, 76%

Me

EtO2C

SO2Ph O Me

82 EtO2C Me

83 Me

O 84

SO2Ph

cis/trans = 78/22

4.2.2 Asymmetric Allylation Asymmetric versions of several Pd-catalyzed reactions have been under active study. Among them, Pd-catalyzed asymmetric allylations have been carried out most extensively with much success. Several types of Pd-catalyzed asymmetric allylation, by which racemic, meso, and achiral substrates are converted into enantiomerically enriched compounds, have been extensively studied using a number of chiral ligands [33]. Attention should be paid in the studies on asymmetric allylation to the fact that allylation of malonates is reversible and under thermodynamic control at higher temperature and longer reaction time [34]. For example, the congested malonate

444

Pd(0)-Catalyzed Reactions of Allylic Compounds CO2Me

CO2Me

Pd(dppb)2, THF

CO2Me NaCH(CO2Me)2 17 h. 89% 85 MeO2C

Ph

86 CO2Me

Ph

87

CO2Me

Pd(dppb)2, THF

MeO2C

CO2Me

NaCH(CO2Me)2 100 °C, 165 h Ph

Ph

87% ee

5% ee

85 rearranged to 86 under catalysis of Pd. Also the chiral malonate 87 (87 % ee) was racemized to 5 % ee after treatment with Pd(dppb)2 for 165 h [35]. A general view of asymmetric allylation is summarized briefly here, and numerous examples of asymmetric syntheses are cited in individual sections. The asymmetric synthesis is classified into the following types based on how the differentiation or enantio-discriminating events occur: 1. differentiation of the enantiotopic leaving groups of meso compounds; 2. differentiation of the enantiotopic allylic termini of symmetric intermediates; 3. differentiation of two interconverting intermediates (the enantiotopic faces exchange); 4. differentiation of the enantiotopic face of alkenes; 5. differentiation of the enantiotopic faces of nucleophiles; 6. desymmetrization by differentiation of enantiotopic geminal leaving groups. These aspects of asymmetric allylation are explained by citing a few typical examples. 1. Differentiation of the enantiotopic leaving groups of meso compounds. Desymmetrization of meso compounds occurs by Pd-catalyzed monosubstitution using a chiral Pd catalyst by differentiating enantiotopic leaving groups. Reaction of mesocyclohexene-3,6-diol (88) with p-tosyl isocyanate (89) afforded the oxazolidin-2one 90 via ureathane 89a with 99 % ee using Trost L-1 as a chiral ligand [36]. OH + TsN=C=O

HO 88

Pd2(dba)3, (S,S)-Trost L-1 THF, rt, 85%, 99% ee

89 H

HO

O

O O TsN 89a

H

N Ts 90

O

Sulfonylnitromethane (92) is an interesting nucleophile, which undergoes double substitution. Double C-, and O-allylation of 92 with meso-3,6-dibenzoyloxycyclohexene (91) provided the enantiomerically pure heterocycle 93 in 87 % yield, and asymmetric synthesis of valienamine was achieved [37].

Allylation

445 O

OCOPh + PhSO2

NO2 92

PhCO2

O

(h3-allyl-PdCl)2 (S,S)-Trost L-1

N SO2Ph

NaHCO3, THF rt, 87%, >99% ee

91

93 OH

HO steps

OH HO NH2 valienamine

2. Differentiation of the enantiotopic allylic termini of symmetric intermediates. 1,3-Diphenyl-2-propenyl acetate (94) as a chiral racemic precursor is a standard compound used for testing effectiveness of chiral ligands, and very extensive studies on asymmetric allylation using 94 to provide the chiral compound 96 have been carried out. π -Allylpalladium intermediate 95, formed from 94, is symmetric and differentiation of enantiotopic termini of the π -allyl system occurs. Numerous examples of achieving >95 % ee have been reported. As one example of early studies, high ee of 96 was obtained by using 2-(2-phosphinophenyl)dihydrooxazoles (PHOX)(VII-2) as an effective ligand. Desymmetrization of 1,3-diisopropylallyl acetate 97 was carried out to provide 98 successfully using VII-3 [38]. Interestingly, while a poor result was obtained by the reaction of 94 with malonate when Trost ligands were used, 92 % ee was obtained in 98 % yield by the reaction of 1,3-dimethylallyl acetate with malonate [39].

Ph

Ph Pd(0)

Ph

Ph

OAc

Pd

94

i-Pr

OAc

CH2(CO2Me)2

+ NaCH(CO2Me)2

OAc 97

O

N R

VII-1 : R = i-Pr VII-2 : R = Ph VII-3 : R = t-Bu

CH(CO2Me)2 96

(h3-allyl-PdCl)2, i-Pr

99%, 99% ee

i-Pr

VII-3, BSA, DMF

CH(CO2Me)2 98

PPh2

Ph

(h3-allyl-PdCl)2, VII-2, BSA, CH2Cl2

95

i-Pr

Ph

88%, 96% ee

446

Pd(0)-Catalyzed Reactions of Allylic Compounds

The desymmetrization of 1,3-diphenylallyl esters 94 using malonates has been widely studied with numerous chiral ligands to evaluate their effectiveness. However, it should be noted that the reaction of 1,3-diphenylallyl system is a special case, and thus, effective ligands in the desymmetrization of 1,3-diphenylallyl esters are not necessarily good ligands for other allylic compounds. The epoxide 100 generated a symmetrical π -allylpalladium intermediate and reacted with phthalimide (99) using Trost L-1 to provide 101 in 87 % yield with 82 % ee, and polyoxamic acid was synthesized from 101 [39].

+ O

N H

O

Pd2(dba)3, Trost L-1 Cs2CO3, THF, rt 87%, 82% ee

100

O

O

O

N

OH

HO

99 steps

OH

NH2

101

OH OH

HO2C OH polyoxamic acid

Similar desymmetrization occurs via symmetric intermediate in cyclic allylic compounds. Synthesis of enantiomerically pure jasmonoids has been reported by Helmchen based on this method. The symmetric intermediate complex 102 is generated from 3-chlorocyclopentene. The allylated malonate 103 was obtained with high % ee using the phosphinyloxazoline ligand 105 and converted to the important intermediate 104 with 99 % ee [40]. Cl Pd NaCH(CO2Me)2

Cl Pd(0)

102

(h3-allyl-PdCl)2, 105 THF, 93%, 95% ee

CH(CO2Me)2

103

Mn(CO)3

O

O O H

H

L= Ph

N

P

t-Bu

2-Biph 104 99.9% ee

105

The Uozumi group developed unique recyclable amphiphilic resin-supported triarylphosphines (PEP) attached to polyethylene glycol-polystyrene graft copolymer (PEG-PS), and found that Pd(PEP) is an active catalyst for allylation in water [40a]. They immobilized a chiral amine on PS-PEG-NH2 resin to give PS-PEG resinsupported chiral P,N-ligand (R,S) 106. Asymmetric allylation of diethyl malonate

Allylation

447

with 2-cycloheptenyl carbonate was carried out in water in the presence of Li2 CO3 at 40 ◦ C using the chiral ligand 106, and diethyl 2-cycloheptenylmalonate with 98 % ee was obtained in 94 % yield [40b]. OCO2Me + CH2(CO2Et)2

CH(CO2Et)2

Pd-cat, Li2CO3 H2O, 40 °C, 94%

(S) 98% ee O

H

O PS

O

O

n

(H2C)3

HN

N

N Pd PPh2 106

In the asymmetric total synthesis of (−)-mesembrane, Mori carried out asymmetric N-allylation of N-tosylallylamine with the 2-substituted cyclohexenyl-3carbonate 107 using (S)-BINAPO (XV-4). The allylamine attacked one of the allylic termini of the symmetric intermediate 108 to provide 109 with 86 % ee. Recrystallization from MeOH gave 109 with 99 % ee [41]. A similar method was applied to the total synthesis of (−)-tubifoline [42]. OMe Nu

OMe

OMe OMe TsHN THF, rt 80%, 86% ee

Pd2(dba)3, (S)-XV-4

Pd

OCO2Me

*

OMe OMe 108

109

N Ts

107 OMe OMe

O

N Me (−)-mesembrane

3. Differentiation of two interconverting intermediates. Reaction of allylic acetates 110 and 111 proceeds via the formation of interconverting π -allyl intermediates 112 and 113 (by enantiotopic faces exchange), and affords 114 and 115 using chiral catalysts. In this case, control of regioselectivity to minimize the

448

Pd(0)-Catalyzed Reactions of Allylic Compounds Nu PdXLn R 114

R OAc

R

112

110 achiral

R

OAc

PdXLn

R 111 racemic

Nu 116 Nu

R

R 113

115

formation of the achiral product 116 is a crucial problem, and selection of ligands is important. Pfaltz succeeded to achieve high regioselectivity in the allylation of malonate with cinnamyl acetate (41) using the ligand III-10 and obtained 117 with 90 % ee along with achiral 118 [43]. Ph

OAc +

(h3-allyl-PdCl)2,

CH2(CO2Me)2

III-10, BSA, AcOK CH2Cl2, 23 °C 86%

41 CH(CO2Me)2 + Ph 117

Ph

CH(CO2Me)2

90% ee

118

achiral

76 : 24

Deracemization of 3-nonyl-3,4-epoxybut-1-ene (119) occurred by the Et3 Bassisted reaction with p-methoxybenzyl alcohol (PMB) to afford the chiral product 120 with 99 % ee by using (R,R)-Trost L-1. In addition to high enantioselectivity, unusual exclusive 1,2-addition of the alcohol at the more substituted terminus occurred to generate a chiral center. The reaction is a key step in total synthesis of (−)-malyngolide [44]. OH

+

Et3B, CH2Cl2, rt 74%, 99% ee

C9H19 119

O Pd2(dba)3, (R,R)-Trost L-1

O

OMe

OPMB

Me

steps

HO C9H19 120

O HO

H

C9H19 (−)-malyngolide

4. Differentiation of the enantiotopic face of alkenes. Asymmetric induction occurs in the allylation of the prochiral allylic acetate 121 via enantiotopic face discrimination of the double bond to afford 122 with high ee using Trost L-1 as a ligand. Tethering of the nucleophile as in 121 made the reaction regioselective and gave the high ee. On the other hand, the same product 122 was obtained from the chiral racemic allyl acetate 123 with only 4–6 % ee, showing that

Allylation

449 (s)

(h3-allyl-PdCl)2, (R,R)-Trost L-1

NH OAc

N

MeO

122

MeO 121 prochiral

H

Et3N, THF, −45 °C 97%, 91% ee

S : R = 95.5 : 4.5

4~6% ee

NH

MeO

OAc

123

enantiodiscrimination is the ionization event, namely at a π -coordination step of the alkene moiety of the substrate 121 or 123 [45]. 5. Differentiation of the enantiotopic faces of nucleophiles. A stereogenic center is generated in a nucleophile by enantioface differentiation of a prochiral nucleophile. Asymmetric allylation of the β-keto ester 124 with cinnamyl acetate (41) gave 125 with 95 % ee using (R)-BINAP (XV-1) as a chiral ligand via differentiation of enantiotopic faces of enolate of 124, generating the stereogenic center at α-carbon [46]. Allylation of the racemic alanine-derived azlactone 127 with racemic 3-acetoxycyclohexene (126) using Trost L-1 as a ligand produced the allylated product 128 in 96 % yield with a 2.5 : 1 diastereomeric ratio. The enantiomeric excesses were 94 % and 92 % for the major and minor diastereomers. The reaction offers a good method of asymmetric synthesis of α-alkylated amino acid 129 [47]. O OAc +

Ph

CO2Me

Ph

NHAc 41

t-BuOK, toluene, −30 °C, 71%, 95% ee

(h3

+ OAc

Me

O N 127

Ph

-allyl-PdCl)2, Trost L-1

Cs2CO3, CH2Cl2 rt, 96%, 94% ee

Ph

H

CO2Me NHAc

Ph

124 O

126

O

Pd2(dba)3, (R)-XV-1

125 O CO2−

Me 128

N

O Ph

NH3+

Me 129

6. Desymmetrization by differentiation of enantiotopic geminal leaving groups. Differentiation of the two enantiotopic leaving groups located on the same carbon atom of an achiral substrate offers a possibility of asymmetric synthesis. Asymmetric monoallylation of malonate with the achiral allylic geminal diacetate 130 afforded 131 with 93 % ee as the major product and the enol acetate 132 as the minor product. Based on this chemoselective monoallylation, these geminal diesters can be regarded as ‘prochiral carbonyl surrogates’ in Pd-catalyzed asymmetric allylation [48].

450

Pd(0)-Catalyzed Reactions of Allylic Compounds (h3-allyl-PdCl)2 (S,S)-Trost L-1

OAc + MeCH(CO2Me)2

Pr

CMe(CO2Me)2

0 °C, 73%

OAc

Pr

OAc

130

131 93% ee + 12 : 1 CMe(CO2Me)2 Pr

OAc 132

Asymmetric allylation of the azlactone 134 with the prochiral gem-diester 133 involves differentiations of both enantiotopic geminal leaving groups and enantiotopic faces of the azlactone, and was applied to the elegant total synthesis of sphingofungin E. The reaction of 133 with 134 by using (R,R)-Trost L-1 afforded 2.4 : 1 mixture of the diastereomers 135 and 136. The major isomer 135 (96 % ee) was converted to 137 and the long chain was introduced by Suzuki coupling of 137 with 138. Asymmetric synthesis of sphingofungin E has been achieved using the product [49]. O OAc + PhMe2Si

TBDPSO

OAc

THF, 0 °C

N

133

134

Ph

O

H

AcO

(h3-allyl-PdCl)2, (R,R)-Trost L-1

O

TBDPSO

O

+ TBDPSO

O

N

N

PhMe2Si 135

PhMe2Si

Ph 136

68%, 96% ee

O

135

4 N

I

OPMB O 137

O

138 BBN

O

PMBO

Ph

23%, 96% ee

Ph steps

O

H

AcO

4

PdCl2(dppf), AsPh3, Cs2CO3 DMF-THF-H2O, rt, 2 h, 92%

O OH

OH CO2H

O sphingofungin E

NH2

HO OH

steps

Allylation

451

4.2.3 Allylation of Stabilized Carbon Nucleophiles Extensive studies have been devoted to allylation of carbon pronucleophiles as important methods of C—C bond formation. As described before briefly, reactions with allylic carbonates and alkenyloxiranes proceed under neutral conditions due to in situ generation of alkoxides which abstract protons from nucleophiles. Also allylation with allyl aryl ethers can be carried out without addition of bases. Reactions of allylic acetates and other allylic compounds are carried out in the presence of bases [5]. Usually presence of two electron-withdrawing groups (EWGs) in carbon pronucleophiles are required for facile allylation. Ketones, CHO, CO2 R, CN, NO2 , SO2 are effective EWGs. Derivatives of malonates and β-keto esters are most extensively used. Aryl groups are weakly effective. One NO2 and SO2 are active enough for the allylation. A number of ligands have been utilized for allylation, showing different activities. Santelli and co-workers reported that tetraphosphine, Tedicyp (X-1), combined with (η3 -allyl-PdCl)2 generates a very efficient catalyst. They claimed that TON 10 000 was attained in a typical allylation of β-keto ester 140 with allyl acetate using this catalyst [50]. Uozumi and co-workers prepared amphiphilic resin-supported triarylphosphine (PEP) attached to polyethylene glycol-polystyrene graft polymer, and they found that Pd complexes of PEP [Pd(PEP) and Pd(PEP)2 ] are recyclable active catalysts for allylation in water. Ethyl acetoacetate was allylated with the allyl acetate 94 in water in the presence of K2 CO3 at room temperature using Pd(PEP)2 (1 mol%) as a catalyst to give rise to the allylated product in 98 % yield [40a]. Intramolecular reaction of the cyclic β-keto ester 141 proceeded with high enantio- and diastereoselectivities. When (R,R)-Trost L-1 was used, a mixture of the [2.2.2]bicycles 142 (99 % ee) and 143 was obtained in 84 % yield in a ratio of 4.6 : 1. On the other hand, Eu(fod)3 as an additive showed a remarkable effect. The diastereoselectivity was reversed when (S,S)-Trost L-1 and Eu(fod)3 were used to give a mixture of 142 and 143 (68 % ee) in a ratio of 1 : 8 in 85 % yield [51]. O OAc

+

OAc

COMe

Ph

+

94

CO2Et H2O, K 2CO3 rt, 98%

CH2Cl2, rt, 82% OCO2Me

141

Ph

COMe

EtO2C H

Pd2(dba)3,Trost L-1 N

TOF = 341 TON = 10,000

Ph

Pd-PEP

CO2Et O

CO2Me

48 h, 99% conv. 140 : (h3-allyl-PdCl)2 10,000 : 1

140

Ph

O

(h3-allyl-PdCl)2, X-1 CO2Me NaH, THF, rt

CO2Et

O N 142

H CO2Et O

+ N 143

(R,R)-Trost L-1: 84%, 4.6 : 1, 142 = 99% ee (S,S)-Trost L-1: 85%, 1 : 8, 143 = 68% ee

452

Pd(0)-Catalyzed Reactions of Allylic Compounds

Intramolecular allylation with alkenyloxiranes offers a good method of macrocyclization. In the total synthesis of roseophilin by F¨urstner, the alkenyloxirane 144 was cyclized smoothly to yield the 13-membered carbocycle 145 in high yield (85 %) in the presence of two ligands DPPE and PPh3 . Then Pd-catalyzed reaction of the allylic lactone 146 with benzylamine afforded the pyrrole carboxylic acid 147 cleanly in 70 % yield via regioselective allylation of benzylamine at the electron-deficient terminus of the allylic lactone 146 [52]. O Pd(PPh3)4, DPPE

TBSO

THF, 85%

PhO2S

steps PhO2S MeO2C

MeO2C 144

145

+ BnNH2

PhO2S O

Pd(PPh3)4 THF, 70%

PhO2S

O

O

OH OTBS

N

OH

O

146

Bn

147

Usually no reaction of alkenyloxiranes bearing a methyl group at the terminus as in 149 takes place; instead isomerization to enone occurs. The reaction of the epoxide 149 with the Meldrum’s acid derivative 148 proceeded at room temperature in THF using a precatalyst generated by mixing Pd2 (dba)3 (1.5 mol%) and cyclic phosphite TMPP (III-2) (20 mol%) to afford 150 in 75 % yield, and macrolactam aglycon of fluviricin B1 was synthesized [53].

O

O

O

O

O

O

+

Pd2(dba)3, III-2 THF, rt, 75%

O

O OH

O CO2Bn

CO2Bn N3

N3 148

149

150

OH O HN fluviricin B1 aglycon

Allylation

453

In the reaction of the activated alkene 151 with allyl carbonate, Michael attack of an alkoxide to the alkene occurs at first. Then the generated anion 152 is allylated to afford 153. The THF derivative 155 was obtained in high yield by the coupling of the alkene 151 with monocarbonate of 2-buten-1,4-diol 154 in the absence of a base [54]. CN

Ph

O +

O

NC

Ph

Pd(0) OR

CN

RO

CN

+

Pd

CO2

151

152 NC

Ph

CN

RO 153 CN CN

Ph CN

Ph

+

OCO2-i-Pr

HO

Pd2(dba)3, DPPE THF, rt, 92%

O

CN 151

154

155

One pot synthesis of tricyclic enone 158 is possible via domino Pd-catalyzed allylation and Co-catalyzed Pauson-Khand reaction. Allylation of the propargylic malonate 156 with 3-acetoxycyclopentene under CO pressure afforded the fused tricyclic compound 158 via 157 in 73 % yield. Bimetallic catalyst PCNS (Pd and Co nanoparticles immobilized on silica) was used as a catalyst [55]. OAc Me

MeO2C

+

156

MeO2C

PCNS, NaH, THF, 130 °C CO (10 atm), 18 h, 73%

Me Me

MeO2C

MeO2C O

MeO2C

MeO2C 158

157

A phosphonate is an activating group. Asymmetric allylation of the chiral racemic α-acetamido-β-keto phosphonate 159 with cinnamyl acetate (41) was carried out at −30 ◦ C to afford α-alkyl-α-aminophosphonic acid derivative 160 with 88 % ee in 78 % yield when (R)-BINAP was used as a chiral ligand [56]. O

O P(OMe)2

Ph

NHAc 159

O [Pd], (R)-BINAP

+ Ph

OAc 41

t-BuOK, toluene −30 °C, 78%, 88% ee

O P(OMe)2

Ph

NHAc Ph 160

454

Pd(0)-Catalyzed Reactions of Allylic Compounds

Allylation of simple ketone is not possible under usual conditions, but the reaction can be carried out under selected conditions. Asymmetric allylation of the chiral racemic α-methylcyclohexanone 161 with allyl carbonate proceeded in the presence of LDA as a base with or without Me3 SnCl as a Lewis acid at room temperature to provide the allylated ketone 162 in very high yield with 82 % ee when (S,S)-Trost L-1 was used. The choice of base is crucial, and it was claimed that no reaction took place when Na or K bases were used in this reaction [57]. Asymmetric allylation of α-aryl and heteroaryl ketones has been carried out. Asymmetric allylation of 2-indolylcyclohexanone 163 took place at 0 ◦ C to give the the allyl ketone in 82 % yield with 84 % ee. In this reaction, NaHMDS was used as a base and Trost L-2 as chiral ligand [58]. Asymmetric allylation of the tetralone 164 with allyl acetate was carried out using Trost L-6 in the presence of Cs2 CO3 to provide the allylated ketone with 91 % ee in 90 % yield [59]. O OCO2Me

+

Ph

(h3-allyl-PdCl)2,(S,S)-Trost L-1 LDA, DME, Me 3SnCl rt, 98%, 82% ee O

161

Ph

162 O

O N Me

OAc (h3-allyl-PdCl)2,(S,S)-Trost L-2

+

N Me

NaHMDS, DME 0 °C, 82%, 84% ee

163 OMe

OMe OAc (h3-allyl-PdCl)2,(R,R)-Trost L-5

+

Cs2CO3, 90%, 91% ee

Me O

O 164

Non-stabilized ketone enolates are also allylated. The reaction of Mg enolate of cyclohexanone 165 with 94 afforded the chiral ketone 166 with high diastereoand enantioselectivities by using (R)-BINAP [60]. O

O

OMgCl MeMgCl

+

(i-Pr)2NH

Ph Pd2(dba)3, (R)-BINAP

Ph

OAc 165

Ph

94

Ph

0 °C, 67%, 99% ee 166

Allylation

455

Direct allylation of esters is difficult, but their enolates are allylated. Expected 1,4-addition of Li enolate of ethyl isobutyrate to the isoprene monoxide 20 took place to give 167 at room temperature by using DPPE as a ligand [61]. OLi

O

+

Pd(OAc)2, DPPE

CO2Et

THF, rt, 90%

OEt

E:Z=8:2

OH 167

20

Tamaru reported that Pd-catalyzed α-allylation of aldehydes to afford 168 can be carried out even with allyl alcohols in the presence of a stoichiometric amount of Et3 B, NEt3 , and LiCl. Although the mechanism is not clear, activation of allyl alcohol by Et3 B occurs by coordination to generate π -allylpalladium. In addition, boron enolates are formed by the reaction of aldehydes with Et3 B and Et3 N, and attacked by π -allylpalladium [62]. Similarly allylation of malonates and ketones with allylic alcohols 169 and 169a were carried out [63]. Ph CHO

HO

OHC + Ph

Ph

Et3B, Pd(OAc) 2, PPh3

OH

+

THF, NEt 3, LiCl, rt

168

92%

4%

R H Et3B R

R

OH

R Pd(0)

O

LiCl

Pd OH

BEt3

Cl

Et3B

R H R

NEt3

H

H

Et3B O

Cl

O R BEt2

Pd

H O R R

OH CH2(CO2Et)2 +

CH(CO2Et)2

Et3B, Pd(OAc) 2, PPh3 THF, NaH, rt, 74%

169 OH

OH

O OH

+

Et3B, Pd(OAc) 2, PPh3 THF, NaH, rt, 81%

169a

O

Pd

456

Pd(0)-Catalyzed Reactions of Allylic Compounds

Nitroalkanes are smoothly allylated. Asymmetric allylation of nitromethane with the carbonate 169b at room temperature afforded 170 in 90 % yield with 98.5 % ee. PHOX derivative VII-3 was used as a chiral ligand [64]. Ph CH3NO2

NO2

Ph

+

OCO2Me

Pd2(dba)3, VII-3

Ph

THF, rt, 90%, 98.5% ee

169b

Ph

170

N -(Diphenylmethylene)glycine t-butyl ester (t-butyl glycinate-benzophenone Schiff base) (171) is a reactive prochiral nucleophile and α-allyl-α-amino acids can be prepared by allylation and hydrolysis of the allylated product. Asymmetric allylation of 171 with cinnamyl acetate (41) afforded 172 regioselectively with high % ee when the reaction was carried out in presence of achiral phosphite P(OPh)3 , and a chiral phase-transfer catalyst of alkaloid [O-allyl-(9anthracenylmethyl)cinchonidinium iodide] [65,66].

Ph + Ph Ph

N

CO2-t-Bu

171

OAc

(h3-allyl-PdCl)2, P(OPh)3

Ph Ph

chiral PTC, KOH toluene, 89%, 96% ee PTC = O-methyl cinchonidinium iodide 41

Ph

CO2-t-Bu

N 172

As a different type C-allylation, Trost reported asymmetric ring expansion involving Wagner–Meerwein shift of the allyl carbonate 173 bearing a cyclopropanol group to give the 2-vinylcyclobutanone 175 as shown by 174 in quantitative yield with 92 % ee, when Trost L-2 as a chiral ligand and TMG as a base were used. Efficient differentiation of the prochiral face of the alkene occurred [67].

OH

Me

MeO2CO

O

Pd2(dba)3, Trost L-2 TMG, toluene 100%, 92% ee

H

Me

O

Me X-Pd

173

174

175

4.2.4 Allylation of Oxygen and Nitrogen Nucleophiles 4.2.4.1 Allylation of Oxygen Nucleophiles Pd-catalyzed O-allylation of aliphatic alcohols is sluggish particularly in the intermolecular version due to poor nucleophilicity of alcohols. As one solution, metal alkoxides are used to make nucleophilicity of alcohols stronger. Lee reported that Zn alkoxides are good coupling partners. Reaction of the cyclic allyl acetate 176 with benzyl alcohol proceeded smoothly at room temperature in the presence of Et2 Zn (0.5 equiv.) using Pd(OAc)2 with bulky biphenyl-based phosphine IV-1 and gave two ethers with retention of stereochemistry in high yield (70 %) in a ratio

Allylation

457

of 40 : 1. On the other hand, inversion occurred to give a ratio of 1 : 2 in low yield (20 %) when PPh3 was used [68]. Interestingly allylation of OH group in a β-Lribose 177 with the cyclic allylic acetate 178 proceeded smoothly using Pd2 (dba)3 and PPh3 in dichloromethane to afford the disaccharide precursor with 96 % de in 55 % yield without activation of OH group [69]. CO2Me

CO2Me + BnOH

CO2Me

Et2Zn (0.5 eq), THF

+ OBn

OBn

OAc 176

Pd(OAc)2, IV-1 Pd(PPh3)4

70%

> 40 : 1

20%

1:2 O

O

O OH + AcO

O

RO

O

O

55%, 96% de

(−)-178

O

O

O Pd2(dba)3, PPh3 O

RO

O

177

Stereoselective formation of 3-methylenetetrahydrofuran such as 180 by intramolecular allylation of alcohol with allyl benzoate in 179 was utilized in synthetic studies of the core of amphidinolide [70]. Thus treatment of 179 with Pd(OAc)2 and PPh3 in the presence of Me3 SnCl (1 equiv.) and NaH in THF afforded the cis-tetrahydrofuran 180 stereoselectively in 77 % yield. In this reaction, the less reactive hydroxy group was converted to the more reactive tin alkoxide by the reaction of Me3 SnCl (1 equiv.) and NaH. H

Bu3Sn

OTBS

OH O

Pd(OAc)2, PPh3

OTIPS H

NaH, Me3SnCl, THF, 60 C, 77%

OBz 179

Me H

H O

H O

Bu3Sn

OTIPS H TBSO H 180

Me

Tetrahydrofuran formation proceeds with high stereocontrol. Cyclization of (E)allylic ester 181 proceeded at room temperature with overall retention of configuration to give the 2,5-cis-tetrahydrofuran 182 using Pd(PPh3 )4 in the presence of neocuprone (2,9-dimethyl-1,10-phenanthroline). On the other hand, overall inversion occurred in the reaction of (Z)-allylic ester 183 to afford the 2,5-transtetrahydrofuran 184 with (E)-alkene [71].

458

Pd(0)-Catalyzed Reactions of Allylic Compounds Pd(PPh3)4 CO2R*

PivO OH

neocuprone, THF PivO

25 °C, 76%

OPiv

CO2R*

O

181

182 Pd(PPh3)4 neocuprone, THF

OPiv R*O2C

OPiv

65 °C, 79%

OH

OPiv

R*O2C

O 184

183 Me

Me neocuprone = N

N

Formal total synthesis of uvaricin was achieved by applying double cyclization of vicinal diol bis(allylic acetate) to afford bis-THF core selectively using chiral ligand Trost L-1 as a key reaction [72]. Thus the cyclization of 185 afforded the diene 186 with two new stereocenters in 97 % yield as a single diastereomer.

OAc Pd2(dba)3

HO

HO

H O

H

H

(R,R)-Trost L-1 THF, 97%

H O

H

H

OAc 185 186

The F-ring of the polyether macrolide halichondrin was constructed by Pdcatalyzed selective monocyclization of 187 and 189. No dicyclization took place due to steric reasons. Desymmetrization of the meso-diol 187 gave the tetrahydrofuran 188 in high yield using Trost L-1 as a chiral ligand, and cyclization of the C2 symmetric diacetate 189 afforded the desired diastereoisomeric tetrahydrofuran 190 [73]. HO

OAc

OAc

H Pd2(dba)3

OAc HO

(R,R)-Trost L-1 THF, 81%

O

HO

H

188

187 HO OAc

OAc HO 189

OAc H

Pd2(dba)3

O

H

(R,R)-Trost L-1 THF, 0 °C, 87% HO 190

Allylation

459

In contrast to less efficient allylation of alcohols, allylation of phenols proceeds much more smoothly. In the enantioselective synthesis of (−)-galanthamine by Trost, two Pd-catalyzed reactions were utilized. Asymmetric allylation of the bromovanillin 191 with the cyclic allylic carbonate 192 gave the ether 193 by using (η3 -allyl-PdCl)2 and chiral Trost L-2. Subsequent Heck reaction of 194 afforded 195 in 91 % yield when DPPP was used as a ligand. DPPF and DPPE gave lower yield [74].

(h3-allyl-PdCl)2, Trost L-1

OH Br + TrocO

MeO

O

72%, 87~88% ee

Br CO2Me

MeO

steps

CO2Me 192

CHO 191

CHO 193

Troc = 2,2,2-trichloroethoxycarbonyl

OH

H Pd(OAc)2, DPPP

O Br

MeO

CN CHO

H

O

O

MeO

Ag2CO3, toluene 107 °C, 91%

MeO CN CHO

194

195

NMe (-)-galanthamine

In the total synthesis of callipeltoside, Pd-catalyzed asymmetric allylation of pmethoxyphenol with the allylic carbonate 196 was carried out. When chiral ligand (R,R)-Trost L-2 was used, a mixture of regioisomers 197 and 198 was obtained in high yield. The regioselectivity to form the branched and linear isomers was 3 : 1, and the diastereomeric ratio was 19 : 1. The branched isomer 197 was the major product [75]. OTBS

OMe Pd2(dba)3, (R,R)-Trost L-2

+

MeO

n-Bu4NCl, CH2Cl2 rt, 100% conv.

HO OTroc 196 OTBS

OTBS MeO

dr =19/1

OPMP

+

MeO OPMP

197

3:1

198

The enantioselective total synthesis of (+)-aflatoxin B1 has been achieved by Oallylation with γ -acyloxybutenolide and reductive Heck reaction [76]. The coumarin derivative 199 was O-allylated with γ -O-Boc-butenolide 200, which is an

460

Pd(0)-Catalyzed Reactions of Allylic Compounds

allyl carbonate, to give 201 in 89 % yield in the presence of Bu4 NCl and Trost L-1. Reductive Heck reaction of 201 by using ligandless Pd catalyst afforded the coumarin 202 in 93 % yield with higher than 95 % ee, and aflatoxin B1 was prepared from 202. Efficient deracemization of the butenolide by differentiation of the enantioface occurred. O EtO2C

O +

I

Pd2(dba)3, (R,R)- Trost L-1 BocO

Bu4NCl, CH2Cl2, rt, 89%

O

O 200

MeO

OH 199 O

EtO2C

O HCO2H, EtO2C PdCl2(MeCN)2,

O I

MeO

O 201

O

O

Et3N, DMF, 50 °C 93%, > 95% ee

O

O

H O O

MeO

H

202 O

O

O

H O O

MeO

H

aflatoxin B1

Efficient intramolecular O-allylation of L-N -benzoylphenylalaninol derivative 203 to form trans-oxazoline 204 with high diastereoselectivity (14 : 1) was utilized for the enantioselective total synthesis of (+)-preussin [77]. OAc

OH

Pd(PPh3)4, K2CO3 HN

O Ph

203

MeCN, 83%

N 204

O Ph

C9H19

N Me (+)-preussin

4.2.4.2 Allylation of Nitrogen Nucleophiles Amines are reactive nucleophiles and allylation of amines proceeds smoothly using various ligands. Santelli reported that amination of allylic acetates proceeds

Allylation

461

smoothly in water by using tetradentate Tedicyp (X-1) as a ligand. Allylmorpholine was obtained in 96 % yield by allylation of morpholine in water alone when the substrate/catalyst ratio of 100 000/1 was used. But 1000/1 was necessary for diallylamine formation from allylamine in 85 % yield. Pd-Tedicyp is soluble in water [78]. H N OAc

(h3-allyl-PdCl)2,, X-1

+

N

H2O, K 2CO3 55 °C, 20 h, 96%

O

O amine : Pd cat = 100000 : 1

Reaction of meso-bis-carbonate 204 with the sulfonamide 205 afforded 206 with 99 % ee. The second regio- and diastereoselective allylation of the amine 207 with 206 gave the diamine 208 using DPPB as a ligand. Ru-catalyzed metathesis of the diene 208 afforded 209 and tetraponaine was synthesized [79]. MeO2CO

MeO2CO +

Pd2(dba)3, (S,S)-Trost L-1 NsNH

MeO2CO

99% ee 205

Ns

204

N 206

OC2H5

Ns

NsNH

OC2H5 N

OC2H5

OC2H5 metathesis

207 DPPB Ns

79% overall one pot

N 208

Ns

OC2H5

H

H

N

N

N OC2H5

steps

Ns = O2N

Ns

SO2

tetraponaines

N 209

Asymmetric synthesis of nucleoside has been carried out based on desymmetrization of the meso form of cis-2,5-dibenzoyloxy-2,5-dihydrofuran diester (210), which possesses two allylic leaving groups at 2,5-positions with correct stereochemistry. N-allylation of 6-chloropurine (211) with 210 using Pd(0)-(R,R)Trost L-1 afforded 212. Reaction of 212 with a malonate derivative using PPh3 afforded 214, which was converted to adenosine 216. The enantiomeric adenosine 217 was prepared via 213 and 215 simply by using (S,S)-Trost L-1 in the first allylation [80].

462

Pd(0)-Catalyzed Reactions of Allylic Compounds PhOCO Cl Pd2(dba)3 (R,R)-Trost L-1

N

N

85% N

N

Cl Pd2(dba)3 (S,S)-Trost L-1

210 +

N

PhOCO

N H

Cs2CO3, Pd2(dba)3 PPh3, 97%, 93% ee

O

N

212 CbzOCH(CO2Bn)2

N

N

74%

Cl

OCOPh

O

OCOPh

O

N

N

213

N

CbzOCH(CO2Bn)2 Cs2CO3, Pd2(dba)3 PPh3, 96%, 93% ee

211

Cl

Cl N

N

N

N

N

CbzO

CO2Bn

BnO2C

OCbz

O

CO2Bn

BnO2C

O

214

N

N

N 215

steps

steps NH2

NH2 N

N

N

N

N

O

OH

HO

O

216

N

N

N 217

Allylation of ammonia gives a mixture of products, and it is difficult to prepare primary amines from ammonia, and several ammonia surrogates are used. Allylation of sodium diformylamide (219) with the allyl acetate 218 proceeded smoothly by using DPPF as a ligand to afford 220, which was hydrolyzed to provide the primary allylamine 221. The reaction was sluggish when PPh3 was used. The primary allylamine 224 with high ee (95.5 %) was obtained from 94 via 223 by the use of (S)-BINAP [81]. OAc Me

Me 218

+ NaN(CHO)2 219

OAc Ph

Ph 94

+ NaN(CHO)2 219

N(CHO)2

(h3-allyl-PdCl)2 DPPF, MeCN 60 °C, 79%

Me

Me

Me

220

(h3-allyl-PdCl)2, (S)-BINAP ClCH2CH2Cl, 0 °C 85%, 95.5% ee

NH2 Me 221

N(CHO)2 Ph

Ph 223

NH2 Ph

Ph 224

Allylation

463

Tosyl isocyanate (226) was allylated smoothly with the alkenyloxirane 225 using isopropyl phosphite as a ligand to give the oxazolidinone 227 in 75 % yield, which was converted to the syn amino alcohol 228 in high yield. Oxazolidinone formation proceeds with overall retention of configuration, and is used for the synthesis of regioisomers of sphingosine [82].

BnO

C13H27 + TsN=C=O

O

226

225

Pd2(dba)3, P(O-i-Pr)3 THF, rt, 75%

Pd-X C13H27

BnO H

O O=C=NTs

C13H27 BnO

NH2 O

NTs BnO O

C13H27 OH

227

228

Azide is a reactive nucleophile and is used as an ammonia surrogate. Desymmetrization of the dicarbonate 229 occurred by the reaction with TMS azide to afford azide 230 in 82 % yield with higher than 95 % ee. The reaction is a key step in the asymmetric total synthesis of (+)-pancratistatin [83]. OCO2Me

OCO2Me

O +

Me3SiN3

(h3-allyl-PdCl)2, (R,R)-Trost L-1

O OCO2Me

CH2Cl2, rt, 82%, >95% ee

O

steps

pancratistatin

O N3

230

229

2-Allyltetrazoles are selectively prepared by three-component coupling of allyl carbonate, TMS azide and nitrile. Reaction of dimethylcyanamide (231) afforded 2-allyl-4-(dimethylamino)tetrazole 232 using TFP (1–3) as a ligand. π -Allylpalladium tetrazole is the proposed intermediate [84].

OCO2Me

+

Me3SiN3

+ Me2N-CN 231

Pd2(dba)3, TFP(I-3) octane, 100 °C, 52%

Me2N

N N

N N 232

A lactam analog of epothilone has been synthesized by replacing allylic (and lactonic) OH with amino group in epothilone B 233 via Pd-catalyzed reaction of allylic lactone 233 with NaN3 to provide the azide 234 [85].

464

Pd(0)-Catalyzed Reactions of Allylic Compounds O

S N

OH Pd(PPh3)4 + NaN3

O

N

OH N3 HO2C

70%

O

O

S

OH

O

OH

233

O

234

Allyl cyanamide 236 was prepared in good yield by the reaction of aryl isocyanide 235, allyl carbonate, and TMS azide by using DPPE as a ligand [86]. A proposed mechanism is the following. Insertion of isocyanide to Pd-azide generates π -allylpalladium intermediate 237. Elimination of N2 generates the Pdcarbodiimide complex 238, and 1,3-migration of π -allylpalladium group from the nitrogen to α-nitrogen atom affords the cyanamide complex 239. It should be noted that the conversion from 237 to 238 is a π -allylpalladium mimic of the Curtius rearrangement. The complex 238 is in equilibrium with the Pd-cyanamide complex 239. Then reductive elimination provides the allyl cyanamide 240. MeO +

OCO2Me

+ Me3SiN3

NC

Pd2(dba)3, MeO DPPE toluene, 60 °C 99%

235 R

R N

N

N 236

Pd

N

N2

N 237

N

R

Pd

C

N

N

C Pd

R

CN

N C N

N

238

239

240

Asymmetric cyclization of the cyclic allyl carbonate 241 is a good synthetic method for 9-azabicyclo[4.2.1]non-2-ene system 242, which can be converted to Ts TsNH

CO2Me

CH2Cl2, 0 °C 90%, 88% ee

OCO2Me 241

O HN

PPh2 L-6 (XIII-6)

H N O

MeO2C 242

O NH

N

Pd2(dba)3, L-6

N

anatoxin-a

Allylation

465

anatoxin-a [87]. Cyclization of cis-amino carbonate 241 was a delicate reaction. No cyclization occurred in DMF using Trost L-1 as a ligand. Good results (90 % yield, 88 % ee) were obtained using monophosphine ligand Trost L-6 (XIII-6) in dichloromethane. Net retention took place in the cyclization, and no cyclization of the corresponding trans-amino carbonate occurred. Allylation of the bis-indole lactam 243 with fucose-derived glycal (cyclic allyl carbonate) 244 proceeded at room temperature using PPh3 , affording the single regio- and stereoisomer 245 in 87 % yield [88]. Bn N

O

O

BocO + O

O N H

N H

O

243

244 Bn N

Pd2(dba)3, PPh3

N

O

N H

THF, rt, 87% O

BocO

OH 245

Due to ring strain, π -allylpalladium is generated by ring-opening of 2-vinylazetidine 246. It undergoes different reactions depending on the substituent on nitrogen. When triflyl group was used as N-protection, N-allylation between two molecules occurred to afford N ,N -1,7-bis(trifluoromethanesulfonyl)-1,7-diazacyclododeca-3,9-diene 247a as a cyclic dimer in very high yield as shown by 247. No dimerization occurred when the N -tosyl group was used [89]. Alper carried out reaction of N -cyclohexyl-2-vinylazetidine with phenyl isocyanate at room temperature and obtained the 4-vinyltetrahydropyrimidin-2-one in high yield. Formal insertion of C=N bond of isocyanate occurred as explained by 247b [90]. Even strain-free 2-vinylpyrrolidine can be cleaved by Pd to generate the π allylpalladium intermediate, and the 1,3-diazepin-2-one 248a was obtained by the reaction with phenyl isocyanate as shown by 248. The use of Pd2 (dba)3 and DPPP is important. When Pd(OAc)2 and PPh3 were used, conjugated diene was obtained by elimination [91].

466

Pd(0)-Catalyzed Reactions of Allylic Compounds Tf Pd2(dba)3, PPh3 NTf

THF, 0 °C, 95%

NTf

N

Pd TfN Pd

N

246

Tf 247a 247

O + Ph-N=C=O

NCy

C

N

Ph

Pd(OAc)2, PPh3 THF, rt, 89%

N Cy

N

Pd 247b

O

Cy

Ph

Bu N Bu

+ Ph-N=C=O

Ph

N

N

N

Pd2(dba)3, DPPP THF, 60 °C, 62%

O

Pd

N

Ph-N=C=O

248a Bu

248

4.2.5 Allylation with Bis-Allylic Compounds and Cycloadditions Reactions of the three bis-allylic compounds 249, 250, and 251 with various nucleophiles are useful for the preparation of a number of cyclic compounds. X X X

X

X

249

Y

X

250

X 251

250a

Total synthesis of racemic huperzine was achieved by Kozikowski utilizing bisallylation of the β-keto ester 253 with 2-methylenepropanediol diacetate (252) to give 254 [92], and the enantioselective synthesis of (−)-huperzine has been carried out by Terashima [93] and Bai [94] using BPPFA-type ligands. The derivative 255 of (R)-(S)-BPPFA (XI-12) was found to be the most effective chiral ligand among several known chiral ones (82 % yield, 90 % ee).

N OAc +

AcO

OMe

N

(h3-allyl-PdCl)2, L TMG, toluene 82%, 90% ee

O CO2Me

252

O

253

CO2Me 254

Me H N

Me

L=

Fe

N PPh2 PPh2

NH2 huperzine A

R1

O

255

R2

R1 = cyclopentyl R2 = (CH2)5OH

OMe

Allylation

467

Bis-allylation of 3-methylcatechol (257) with the allylic bis-carbonate 256 using Pd(OAc)2 and DPPB offers a facile synthetic method of the substituted 3-methylene-3,4-dihydro-2H -1,5-benzodioxepine (258). The reaction proceeds at room temperature to give 258 in high yield [95]. OCO2Me

O

HO

O

THF, rt, 99%

OCO2Me HO

O

Me 257

256

O

Pd2(dba)3, DPPB

+

O Me

Me

258

Tamaru discovered that 2-methylenepropane-1,3-diol (260) showed a different type of bifunctionality under slightly different conditions in the reaction with the aldehyde 259. In the presence of Et3 B, Et3 N, and LiCl, electrophilic α-allylation of the aldehyde took place to afford 261 in 93 % yield. Then nucleophilic allylation of the aldehyde 261 in the absence of Et3 N and LiCl occurred to give the homoallylic alcohol 262. Et3 B plays interesting dual roles; first, it promotes α-allylation of the aldehyde enolate in the presence of amine, and second, umpolung of an allyl alcohol exhibits nucleophilic attack to aldehyde (Chapter 4.3.3) [96]. OH Ph

Pd(OAc)2, PPh3 Ph

+

Et3B, Et3N, LiCl

CHO

Pd(OAc)2, PPh3

260

Ph

Et3B, 93%

CHO

H

OH

93%

OH 259

Me

Me

Me

HO

261

262

2-(Trimethylsilylmethyl)allyl acetate (263) is a useful compound, which generates Pd-trimethylenemethane complex (TTM) 264 and undergoes [3 + 2] cycloadditions with 265 to afford 266. Also [3 + 3] cycloaddition is possible [97]. The carbonate 267 can be used for similar cycloadditions under neutral conditions [98]. OAc

TMS

OAc

Pd

Pd(0)

Pd+ _

TMS 263

264

E 265

Pd+

_ E

E 266

Pd+

Pd(0) EWG

E

OCO2Me 267

EWG

EWG

E

468

Pd(0)-Catalyzed Reactions of Allylic Compounds

Enantioselective synthesis of brefeldin A was achieved by utilizing [3 + 2] cycloaddition of 263 with the chiral butenolide 268 to provide 269 as a key reaction [99]. Less basic triisopropyl phosphite was used as a suitable ligand. Functionalized piperidine 271 was prepared in an enantiomerically pure form by [3 + 3] cycloaddition of enantiomerically pure aziridine 270 with 263 and the total synthesis of (−)-pseudoconhydrine has been achieved [100].

Pd(OAc)2, P(O-i-Pr)3

+ AcO O

O

H

THF, 93% dr = 98/2

263

O

268

SiMe3

H

H O

O

97% ee

H

O

269 Me

Me N Ts

Pd(OAc)2, P(O-i-Pr)3

+ AcO

NTs

SiMe3

Me

n-BuLi, THF, 82%

270

263

N Ts

271

2-(Acylmethylene)propanediol diacetate 274 was prepared by Wadsworth–Emmons olefination reaction of 1,3-diacetoxyacetone (272) with β-keto phosphonate 273, and Pd-catalyzed reaction of 274 with methyl glycinate afforded the trisubstituted pyrrole 275 [101]. O O

O

O AcO 272

Et

base

OAc + (MeO)2P

Et 273

OAc

AcO 274

AcO H2N

CO2Me

Pd(dba)2, PPh3 THF, rt, 82%

N

Et CO2Me

275

Diacetate of 2-butene-1,4-diol (276) reacts with nucleophiles in two ways, cyclization and polymerization. Intermolecular reaction of 276 to afford 277, followed by intramolecular reaction with active methylene compounds using BSA and DPPB afforded the furan derivative 278 [102]. Under different conditions, the polymer 280 was obtained. 1,2,3,4-Tetrahydro-2-vinylbenzo[g]quinoxaline 283 was prepared in 95 % yield by diamination of 2-butene-1,4-diol (282) with 2,3diaminonaphthalene (281) [103].

Reactions with Main Group Organometallic Compounds

469 COMe

OAc

AcO

+

276

COMe

Pd2(dba)3, DPPB

COMe

BSA, CH2Cl2 RT, 82%

AcO

COMe 277

O

COMe 278

OAc

AcO

CO2Et

+

EtO2C

Pd2(dba)3, DPPB

CO2Et

279

n

280

NH2 OH

+ HO

CO2Et

H N

Pd(acac)2, PPh3 Ti(Oi-Pr)4, MS 4A benzene reflux, 95%

NH2 281

N H

282

283

Allylic geminal dicarboxylates 285 are prepared by Pd-catalyzed reaction of propargyl acetate 284 with AcOH [104]. Two products 287 and 288 are obtained from gem-allylic compounds 286, and 288 is an allylic ester and undergoes the second allylation. Several applications to asymmetric syntheses have been reported [48]. Reaction of 289 with dimethyl methylmalonate afforded 290 with 95 % ee. OAc

TBDPSO

OAc

+ AcOH

Pd(PPh3)4 toluene, 110 °C 81%

OAc TBDPSO 285

284 X + R

NuH

Nu

Pd(0), L

Nu +

R

X 286

X

R

X 287

288 OAc

OAc + NaCMe(CO2Me)2 Ph

OAc 289

(h3-allyl-PdCl)2 Trost L-1 92%, > 95% ee

Me

Ph MeO2C

CO2Me

290

4.3 Reactions with Main Group Organometallic Compounds via Transmetallation 4.3.1 Cross-Coupling with Main Group Organometallic Compounds Allylic compounds undergo smooth Pd-catalyzed cross-coupling with main group organometallic compounds as expected. Substitution occurs mainly at less-substituted allylic termini. A few examples are cited here.

470

Pd(0)-Catalyzed Reactions of Allylic Compounds R

Pd(0) R

R R'-M'X

X

transmetallation

Pd

Pd

X

R'

R' R' +

R

R

Reaction of geranyl bromide with benzyl Grignard reagent proceeded regioselectively to give 291 in high yield [105]. Desymmetrization of gem-dizincioethane (292) occurred by cross-coupling with cinnamyl acetate (41) by using MeO-MOP (VI-12) as a chiral ligand to generate the homoallylzinc reagent 293 and Cucatalyzed cross-coupling of 293 with propargyl bromide afforded the allene 294 in good yield, although % ee was not high (22 %) [106]. 2-Bromophenylzinc iodide (295) was prepared from 2-bromoiodobenzene and coupled with allyl chloride using phosphine-free Pd(dba)2 catalyst at room temperature to give 2-bromoallylbenzene [107].

Br + PhCH2MgCl

Pd(PPh3)4

Ph

THF, rt, 94%

291

Me OAc +

Ph

Pd2(dba)3, VI-12 lZn

41

Znl

THF, 78%

Znl Ph Me

292

Br

293

•

Ph

CuCN

Me 294

I

Znl Zn Me3SiCl, 95%

Br

Br

Cl Pd(dba)2, 0 °C 10 min., 91%

Br

295

Suzuki coupling of the allyl acetate 296 with phenylboronic acid took place to give 297 as a single diastereomer using polymer-supported Pd, showing that inversion occurred cleanly as expected [108].

OAc

(HO)2B +

Pd(PEP) K2CO3, H2O 45%

CO2Me 296

CO2Me PEP = poly(ethylene glycol)-polystyrene graft copolymer

297

Reactions with Main Group Organometallic Compounds

471

Cross-coupling of the alkenylstannane 299 with the congested allyl acetate 298 has been carried out using ligandless Pd catalyst to give 300 in 87 % yield in convergent synthesis of guanacastepene [109]. The cyclic carbonate 301 reacted with vinylstannane 302 to give the allylic alcohol 303 in good yield using ligandless Pd catalyst [110]. Cross-coupling of the alkenylsilane 304 with cinnamyl ethyl carbonate took place to give 1,4-diene 305 without addition of fluoride as a promoter, because an ethoxide which activates the C—Si bond is generated from the carbonate [111]. O

PMP Pd2(dba)3, LiCl

O

AcO

O

O

O SnMe3

+

O

NMP, 50 °C, 87%

H 298

H

299

300

O

O

OH PdCl2(MeCN)2

+ Bu Sn 3 O

CO2Me 302

DMF, H 2O 0 °C, 71%

CO2Me

301

303 Ph

Pd(OAc)2, PPh3

OCO2Et +

Ph

PMP

304

SiFMe2

DMF, 91%

Ph

Ph 305

Allyl ketones are prepared by cross-coupling of allyl esters with acyl metals. For the coupling, allyl trifluoroacetate (306) and the acylstannane 307 were used to provide the ketone 308 [112]. Similarly, acylsilanes such as 310 are used for the coupling with allyl trifluoroacetate 309 to give 311 [113]. For these couplings, use of allyl trifluoroacetate is important. No reaction occurred with allyl acetate. While ligandless palladium trifluoroacetate is most effective, Pd(OAc)2 shows low activity. O

O Pd(OCOCF3)2

OCOCF3 + Ph 306

SnMe3

THF, rt, 76%

307

308 O

309

O Pd cat

OCOCF3 +

Ph

Ph

SiMe3 310

THF reflux 65%

Ph 311

Pd cat = [Pd(h3-PhCH=CHCH2)(CF3CO2)]2

4.3.2 Formation of Allylic Metal Compounds Allylpalladium compounds are electrophilic. Conversion of allylpalladium to nucleophilic allyl compounds of main group metals 312 is called ‘umpolung’, and offers

472

Pd(0)-Catalyzed Reactions of Allylic Compounds

a useful synthetic method. Allyl metal compounds can be prepared and isolated, but in many cases umpolung reactions are carried out via in situ formation of nucleophilic allyl compounds. One well-established synthetic method of allylic compounds of main group metals is the Pd-catalyzed reaction of allyl compounds with homodimetal compounds such as R2 B-BR2 , R3 Si-SiR3 , and R3 Sn-SnR3 as shown by the following general scheme. Also heterodimetals of B, Al, Sn, and Si compounds are used. An excellent review covering Pd-catalyzed syntheses and reactions of allyl metal compounds has been written by Marshall [114]. M′R′ R′-M′-M′R′

Pd(0)

R

X

transmetallation

Pd

O X +

R

312 M′R′

X

M' = Zn, B, Si, Sn

M′R′ + R

R Pd

O

O

B

R

B B

O

O

O

R

X

+

Me3Si-SiMe3

R

SiMe3

R

X

+

Me3Sn-SnMe3

R

SnMe3

Allylstannane 314 was prepared by the reaction of the allyl ester 313 with the very reactive hetero dimetal compound Bu3 Sn-AlEt2 [115]. OTMS

Pd(PPh3)4

+

DCBO Cl

313

Bu3SnAlEt2

−78 °C ~ rt, 40%

DCB = 2,4-dichlorobenzoyl

OTMS

Bu3Sn Cl 314

As a typical example of umpolung, domino borylation of the allylic acetate 315 with diborane to generate allylborane 316, and intramolecular nucleophilic allylation of ketone afforded the cyclic homoallylic alcohol 317 in 88 % yield [116]. O

O

CO2Me O + OAc

O B

O

B O

Pd(dba)2, AsPh3 toluene, 88%

CO2Me O B

315

O OH

CO2Me 317

316

Reactions with Main Group Organometallic Compounds

473

α-Silyl-β,γ -unsaturated aldehydes (allylsilanes) are prepared by an interesting stereocontrolled Pd-catalyzed rearrangement of silylated vinyloxiranes [117]. As an synthetic application, treatment of the epoxide 318 with Pd(OAc)2 and P(OPh)3 afforded the α-silyl aldehyde 320 by stereocontrolled rearrangement as shown by 319. Addition of a Grignard reagent to 320 afforded the unsaturated lactone 322 with high diastereoselectivity. A pheromone 323 was prepared by desilylation [118].

R3Si

O

Pd(OAc)2, P(OPh)3

O−

TBDMS

O

Pd+ H CO2Me

H

MeO2C

CO2Me SiR3

319

320

318 MeO −O

C11H23MgBr

O O O

C11H23

321

322

O

KF

C11H23

R3Si SiR3 = TBDMS

O

C11H23 SiR3 73%

323

4.3.3 Allylation Involving Umpolung Pd-catalyzed reactions of allyl compounds with carbonyl compounds proceed in the presence of main group organometallic compounds, typically, Et3 B, Et2 Zn, InI, and SnCl2 . In these reactions, nucleophilic allylmetal intermediates are generated by transmetallation of electrophilic π -allylpalladium with these metal compounds and react with carbonyl compounds to afford homoallylic alcohols. As a whole, umpolung of π -allylpalladium intermediates occurs. The umpolung occurring with Et3 B and Et2 Zn can be understood by a simple transmetallation mechanism. On the other hand, reductive transmetallation is involved in the reactions with InI and SnCl2 . Tamaru and co-workers have shown that Et3 B displays two distinctive behaviors in Pd-catalyzed reaction of allylic alcohols [118a]: 1. activation of allyl alcohols for electrophilic allylation (α-allylation of ketones and aldehydes); and 2. promotion of nucleophilic allylation. Activation of allyl alcohols is treated in Chapter 4.1. Concerning nucleophilic allylation, it has been shown that cinnamyl alcohol (324) reacts smoothly with benzaldehyde in the presence of Pd catalyst and Et3 B as a stoichiometric reagent in THF at room temperature to afford homoallylic alcohol 326 [119]. In this reaction, nucleophilic allylboron 325 is generated by transmetallation of π -allylpalladium with Et3 B and reacts with benzaldehyde. When aliphatic aldehydes are used under similar conditions, α-allylation and aldol condensation of aldehydes occur.

474

Pd(0)-Catalyzed Reactions of Allylic Compounds OH OH + Et3B

Ph 324

Pd(0)

PhCHO BEt2

Ph 325

Et-Pd-OH

Pd(OAc)2, PPh3 THF, rt, 64%

Ph Ph 326

CH2=CH2 + H2O + Pd(0)

Nucleophilic allylation of aldehydes with allyl alcohol proceeds smoothly in the presence of Et2 Zn via the formation of nucleophilic allylethylzinc 327 to provide the homoallyl alcohol 328 [120]. CHO

OH + Et2Zn

OH

Pd(0) ZnEt Et2Pd + ZnO

327

Pd(OAc)2, P(n-Bu)3 toluene, rt, 92%

328

Masuyama and co-workers have shown that nucleophilic allyltrichlorostannanes 329 are generated by the reaction of allyl carbonates with SnCl2 and react with aldehydes to give the homoallyl alcohols 330. DMI is a good solvent [121]. Also allyl alcohols can be used for the allylation. Formation of the allyltrichlorostannane 329 from allyl alcohol and SnCl2 was confirmed by NMR studies [122]. α-Methylenelactone 332 was obtained by the reaction of ethyl (α-hydroxyethyl)acrylate 331 with pentanal [123].

OCO2Me + SnCl2

Me

Cl Pd

Pd(0)

Me 329

OH PhCHO

SnCl3

Me

Pd(PPh3)4, DMI, 80% Ph 330

O

CO2Et OH + n-BuCHO 331

Me

SnCl2, PdCl2(PhCN)2

O

DMI, 40% Me

Bu 332

Indium metal or indium iodide as a reducing agent can be used for umpolung of π -allylpalladium. Araki reported that allylic indium(III) reagents 333 are generated in situ by reductive transmetallation of π -allylpalladium with indium(I) salts [124]. Based on this reaction, nucleophilic allylation of benzaldehyde with allylic chlorides, alcohols, and esters occurred at room temperature in the presence

Reactions with Main Group Organometallic Compounds

475

of a stoichiometric amount of In(I) iodide to afford the homoallyl alcohols 334 and 336. It is known that SmI2 shows a similar reactivity [124a].

OH + InI

OH

Pd(0) InX2

PhCHO Pd(PPh3)4

Ph

333

334 OH

Cl + PhCHO

Me

InI, Pd(PPh3)4 THF, rt, 96%

335

Me

Ph 336

Alkenyloxiranes are more versatile and react with both aldehydes and ketones giving mainly 1,5-diols by 1,4-addition in anhydrous DMI. For example, reaction of the epoxide 337 with acetophenone afforded 5-phenyl-2-hexene-1,5-diol (338) [125]. On the other hand, the isoprene monoxide 339 reacted with aldehyde to provide the 1,3-diol 340 regioselectively in aqueous DMI and lavandulol was synthesized [126]. The In-induced umpolung has been applied to the N -acylnitroso cycloadduct 341 as an allylic ether, which reacted with aliphatic aldehydes such as butanal and ketones to give the cis-1,4 adduct 342 predominantly [127]. O

OH

O +

Me

InI, Pd(PPh3)4 Ph

Me

DMI, rt, 78%

337

CHO +

O

HO 338

339

steps OH 340

O N 341

+

lavandulol OH

OH

O

O

OH

OH

InI, Pd(PPh3)4 DMI/H2O, rt, 88%

Ph

InI, Pd(OAc)2, PPh3 H

N

THF, 59% O 342

Domino reaction of the alkyne 343 with allene, and 2-thiophenecarboxaldehyde in the presence of TFP as a ligand and indium powder gave the homoallyl alcohol 347. In this reaction π -allylpalladium 346 was generated by the reaction of 345 with allene. In-induced umpolung of 346 and its nucleophilic allylation of aldehyde provided the homoallyl alcohol 347 [128]. Interestingly, the π -allylpalladium intermediate 349, generated from 2-bromoacetophenone and allene, attacked the ketone to afford the 3-methyl-1-indanol 350 without addition of any organometallic reagent. The uses of the palladacycle 351 as a catalyst and Cs2 CO3 as a base are important [129]. Formation of allylindium by the reaction of allyl halides with In metal has been reported [130]. Also In-InCl3 can be used [131].

476

Pd(0)-Catalyzed Reactions of Allylic Compounds I-Pd I •

+

In powder, Pd(OAc) 2

+

CHO DMF, TFP ( I-3), 51%

S

O

344

343

O

OH S

Pd

X •

345

In, 344

O

O

346

347 O

O Me

Cs2CO3 DMF, 90%

Br

OH

Me

[Pd]

•

+

Me

X Pd

348

350

349

S N Pd OAc 351

4.3.4 Reactions of Amphiphilic Bis-π-Allylpalladium Compounds Although bis-π -allylpalladium complexes were not isolated and identified, their formation is assumed in several reactions. Allylation of aldehydes with allylstannane 348 occurs under acidic conditions in the presence of Lewis acid. Yamamoto and co-workers found that the reaction proceeds smoothly under essentially neutral conditions in the presence of Pd catalyst to give homoallyl alcohol 349 [132]. Allylation of imines to produce amines 350 is more facile. Formation of nucleophilic bis-π -allylpalladium as a key intermediate was assumed in these reactions [133].

PdCl2(PPh3)2

SnBu3 + PhCHO

Ph

rt, 64%

348 SnBu3 348

+ Ph

Ar N

Ar = p-C6H5(CO2Me)

OH 349

PdCl2(PPh3)2 THF, 50 °C, 98%

Ph NHAr 350

Cross-coupling of allyl halides with allylstannane to form 1,5-hexadiene (352) is known [134]. Yamamoto has made an interesting observation that allylation of aldehydes took place to give homoallyl alcohol 353 by the reaction of allyl

Reactions with Main Group Organometallic Compounds

477

halides, allylstannane, and aldehyde without forming 1,5-hexadiene [135]. These reactions are explained by the formation of bis-π -allylpalladium 351 from Pd(0), allyl halides, and allylstannane [136]. R R

SnBu3

Cl +

R

Pd(0) Pd 351 Ph

R

SnBu3

Cl +

H

+

352 Ph

PdCl2(PPh3)2

OH

O

353

Concerning the possibility of allylation and cross-coupling, Yamamoto and coworkers found that PPh3 plays a key role in differentiating these reactions. They carried out the reaction of o-(3-chloro-1-propenyl)benzaldehyde (354) with allylstannane in the presence of Pd2 (dba)3 . In the absence of PPh3 , allylation of aldehyde took place to give 355. On the other hand, cross-coupling took place to afford the biallyls 356 and 357 in the presence of PPh3 (40 mol%) [135]. O

OH H

SnBu3

+ Cl

Pd2(dba)3 , THF, rt, 12 h ( 1.0 equiv)

Cl

88%

354

355 O

O H

Pd2(dba)3 , PPh3, THF, rt, 21 h 73%

356

H

+

96 : 4

357

From these studies, they proposed the formation of bis-π -allylpalladium 359, which is nucleophilic. This is in marked contrast to the well-established fact that the π -allylpalladium complex 358 is electrophilic. Also, they assumed that the bis-π -allylpalladium 360 is amphiphilic and reacts with both nucleophilic and electrophilic carbons. Nu Nu−

El+ Pd

X

Pd

E

Pd

358

359

360

electrophilic

nucleophilic

amphiphilic

478

Pd(0)-Catalyzed Reactions of Allylic Compounds

Intramolecular cross-coupling of allyl acetate and allylstannane in 361 via bis-π allylpalladium was carried out using Pd2 (dba)3 and PPh3 to give the cyclohexane derivative 362 as a single regio- and stereoisomer. The presence of LiCl and H2 O is essential. The cyclized product 362 was converted to epi-elemol [137]. Me

Me SnBu3 PhO2S

Me

LiCl, aq. DMF 80 °C, 91%

OAc

PhO2S

Pd2(dba)3, PPh3

PhO2S PhO2S

Me 361

H

H

HO

Me epi-elemol

Me

362

Reaction of benzylidenemalononitrile (151) with allyl chloride and allylstannane afforded 1,2-diallylated product 364 in high yield, indicating that bis-π allylpalladium 360 is an amphiphilic allylating agent [138]. Instead of allylstannane, (SnMe3 )2 can be used for the coupling of the allyl chloride 365 with 151, and Szabo has shown that nucleophilic allylation occurred at the substituted allyl terminus, and electrophilic allylation took place at the terminal carbon to provide 366 [139]. Ph CN

Ph

151

SnBu3

+

CN

Cl PdCl2(PPh3)2 THF, rt, 99%

+

CN

CN 364

Pd 360

Ph CN

Ph

Cl

+

CN CO2Me

THF, 70% Me2OC

CO2Me

CN 151

+ (SnMe3)2

Pd(PPh3)4

365

CN 366

Heterocyclization of o-(3-chloro-1-propenyl)benzaldehyde (354) occurred with allylstannane to afford the cyclized product 368. The reaction is understandable by assuming the amphiphilic allylation of C=O bond of aldehyde as shown by 367 [140]. Amphiphilic allylation of the C=O bond of aldehyde was observed by the reaction of butadiene with aldehyde [141] (Chapter 5.1). CHO Cl

+

SnBu3

Pd2(dba)3

Cl

DMF, rt, 88% C

354

O

H 367 O

368

allyl

Carbonylation Reactions

479

As a related reaction, Yamamoto reported a novel allylative dearomatization to give 6-allyl-3-methylene-1,4-cyclohexadiene (373) by the reaction of benzyl chloride and allylstannane under mild conditions. In this reaction, the π -benzylpalladium species 370 is generated from benzylpalladium 369. The bis-π -allylpalladium species 371 and 372 are generated by the reaction of π -benzylpalladium 370 with allylstannane. Finally the dearomatization product 373 is formed from 372 by reductive elimination. It is surprising that the dearomatization product 373 is rather stable and no isomerization to a benzene derivative was observed at room temperature [142].

Pd2(dba)3, PPh3 Cl

acetone, rt, 80%

Pd-Cl

Pd-Cl

369

370

SnBu3

Pd

Pd 373

ClSnBu3 371

372

4.4 Carbonylation Reactions β,γ -Unsaturated esters are prepared by the carbonylation of allylic compounds under various conditions depending on the leaving groups. Carbonylation of allylic chlorides proceeds under two-phase (liquid–solid) and mild conditions (room temperature, 1 atm of CO in the presence of K2 CO3 in EtOH) using ligandless Pd catalyst. Ethyl 4-phenyl-3-butenoate was obtained from cinnamyl chloride in 94 % yield [143]. Allylic carbonates are reactive and their carbonylation proceeds under mild neutral conditions [144]. Ph

Ph

Cl

+ CO

O

OMe

+ EtOH + CO

Pd(OAc)2, K2CO3

Ph

CO2Et

Ph

CO2Me

1 atm, rt, 94% Pd(OAc)2, PPh3 5 atm, 50 °C, 94%

O

Less reactive allylic alcohols are carbonylated under harsh conditions. However, carbonylation of allylic alcohols proceeds smoothly in the presence of phenol as a nucleophile. Phenyl 4-phenyl-3-butenoate (374) was obtained in 80 % yield from cinnamyl alcohol under 5 atm of CO at 100 ◦ C. The carbonylation may proceed by the formation of allyl phenyl ether, which is a reactive compound [145]. Allyl alcohol was carbonylated under high pressure of CO2 (50 atm) and CO (50 atm) in dioxane to provide 2-butenoic acid as the main product and 3-butenoic acid as the minor product at 110 ◦ C. Presumably monoallyl carbonate 375 is generated from

480

Pd(0)-Catalyzed Reactions of Allylic Compounds Ph

OH + CO + PhOH

OH

+ CO 50 atm

Pd(OAc)2, PPh3

Ph

CO2Ph

5 atm, 100 °C 80%

374 O

CO2 (50 atm) Pd(PPh3)4, 110 °C dioxane

OH O

375 CO2H

CO2H

+

8%

92%

allyl alcohol and CO2 , and carbonylated to give 3-butenoic acid, which isomerized to 2-butenoic acid [146]. β,γ -Unsaturated δ-hydroxyester 376 was obtained by regioselective carbonylation of the isoprene oxide (20) in EtOH using ligandless Pd catalyst at room temperature under CO pressure (30 atm). Both regioisomers 378 and 379 were also obtained by carbonylation of cyclohexene oxide 377 [147]. Decarboxylationcarbonylation of the vinyl-substituted cyclic carbamate 380 gave the six-membered unsaturated lactam 381 regioselectively in 81 % yield, and D-mannolactam was synthesized from 381 [148]. Me

CO2Et

(p-allyl-PdCl)2, i-Pr2NEt HO + CO + EtOH

30 atm, rt, 86%

O 20

Me 376 OH

OH

O + CO + EtOH

CO2Et

(p-allyl-PdCl)2, i-Pr2NEt

+

50 atm, rt, 65%

377 CO2Et 378

379 9:5

O

O

+ CO

HN

OTBS

PdCl2(PPh3)2 70 °C, 65 atm 81%

O

OTBS

N H

380

381 OH HO

OH

steps O

N H

OH

D-mannolactam

Carbonylation Reactions

481

In the presence of main group organometallic compounds, ketones are obtained. Carbonylation of allylic ester 382 with alkylzinc reagent afforded the ketone 383 in high yield [149]. Carbonylation of allyl chloride 384 in the presence of tin hydride afforded the β,γ -unsaturated aldehyde 385 via hydrogenolysis of acylpalladium intermediate [150].

OCOPh + CO +

Pd(PPh3)4 IZn

CO2Et

rt, 1 atm, PhMe HMPA 87%

382 CO2Et O 383

OMe Cl + CO

EtO2C

+ Bu3SnH

OMe

Pd(Ph3P)4 50 °C, 86%

EtO2C

CHO 385

384

O EtO2C

CHO

Cyclocarbonylation of 3-phenyl-2-methylallyl acetate 386 afforded 1-naphthyl acetate 388 under harsh conditions (160 ◦ C, 70 atm) in the presence of acetic anhydride and Et3 N. This interesting reaction may be explained by electrophilic attack of the acylpalladium group in the intermediate 387 on the benzene ring. Another possibility is the formation of the ketene 389 and its electrocyclization [151].

OAc + CO 386

PdCl2(Ph3P)2, Et3N Ac2O, 160 °C, 70 atm, 76%

X-Pd

O

387

Ac2O

OAc 388

O 387

Ac2O C O 389

H O

OAc 388

482

Pd(0)-Catalyzed Reactions of Allylic Compounds

Vinyl ketene (392) is generated by the carbonylation of the allyl phosphate 390 in the presence of a base as shown by 391. A useful application of the ketene formation is the synthesis of β-lactam skeleton by [2 + 2] cycloaddition of the ketene with imines. Thus, reaction of the imine 393, derived from vicinal dicarbonyl compounds, with the ketene 392 afforded cis-lactam 394 [152]. On the other hand, the trans-lactam 397 was obtained by the carbonylation of the allyl phosphates 395 in the presence of the imine 396 derived from aldehyde [153]. O CO

Pd-X

OPO(OEt)2

b-H elimination

H 390

393

• O

391

392

O OPO(OEt)2

O

+

Ph Pr

+

CO

N

Pd2(dba)3, PPh3 Cy2NMe, THF

H

Ph

rt, 30 atm, 50%

N

393

+

+ CO

O Bn

Pr 394

TBSO

Pd2(dba)3, PPh3 i-Pr2NH, THF

OTBS

OPO(OEt)2

H

O

390

H

H

70 °C, 30 atm, 64%

O

N

N Bn

O

395

394

396

397

Highly unsaturated lactone 403 was obtained by an intramolecular reaction of 2-(propargyl)allyl phosphate 398 with CO (1 atm) catalyzed by ligandless Pd catalyst in the presence of Cy2 NMe. As an explanation, the acylpalladium 400 is converted to the ketene 401, and the palladacycle 402 is generated by oxidative cyclization. Insertion of CO to 402 and reductive elimination provide 403 [154]. (h3-allyl-PdCl)2, Cy2NMe

Cy

THF, 1 atm, 80 °C, 94%

OP(O)(OEt)2

Cy

Cy CO

X

Pd-X

Pd

O

398

400

399 Cy Cy

NR3 •

Pd(0)

CO Pd

O

O

O

H-Pd-X 401

Cy

402

O 403

Intramolecular Reactions with Alkenes and Alkynes

483

4.5 Intramolecular Reactions with Alkenes and Alkynes In contrast to a facile intermolecular insertion of alkenes and alkynes to Pd-aryl and Pd-alkenyl bonds as observed in Heck reaction, curiously intermolecular insertion of alkenes and alkynes to Pd-allyl bond in π -allylpalladium is very rare. On the other hand, intramolecular insertion of alkenes and alkynes to π -allylpalladium occurs smoothly to form five- and six-membered rings. Oppolzer and co-workers have developed a useful synthetic method of cyclic compounds by intramolecular insertions of alkenes and alkynes, and they explained the reaction as Pd-ene reaction as shown by 404. The method has been applied to the syntheses of several natural products and complex cyclic compounds [155,156]. X

X

X

X further transformation

Pd(0) PdX

OR

PdX

PdX 404

Oppolzer and co-workers achieved highly diastereoselective synthesis of (−)erythrodiene via Pd-catalyzed Zn-ene reaction as a key step [157]. In the Pdcatalyzed reaction of the allylic acetate 405 using an excess of Et2 Zn, the allylzinc intermediate 407 was generated by transmetallation of π -allylpalladium 406 with Et2 Zn. The Zn-ene reaction as shown by 407, followed by quenching with iodine, afforded the iodide 408, which was converted to (−)-erythrodiene. The diastereomeric ratio in the cyclization was 95 : 5 by the directing effect of the resident chiral center C-4. Clean and high-yield cyclization occurred by the use of P(n-Bu)3 as a ligand.

OAc

1. Et 2Zn, Pd(OAc)2, P(n-Bu)3 2. I 2

ZnEt PdX

Et2Zn

90%

405

406

I2

407

t-BuOK H I 408

(−)-erythrodiene

Efficient domino cyclization of the allyl acetate bearing an allene moiety 409 under CO in AcOH afforded the tetracyclic diketone 413 [158]. The first step is the attack of the π -allyl group at the central carbon of the allene to form 410 (or insertion of one of the allene double bonds), which is a stable π -allylpalladium 411. Then domino insertion of double bond, CO, double bond, CO, and double

484

Pd(0)-Catalyzed Reactions of Allylic Compounds Pd-OAc •

Pd(Ph3P)4,

+ CO

AcOH, 80 °C 22%

AcO 410

409 Pd-OAc

Pd-OAc

O

CO

Pd-OAc

411 O

O CO

O

O Pd-OAc 412

413

bond occurred to give 412. Finally 413 was obtained by β-H elimination. The overall yield of six C—C bond formations was 22 %. B¨ackvall and co-workers observed that intramolecular reaction of allyl group with allene in 414 (415 to 416) proceeded stereoselectively by an anti attack of allene on π -allylpalladium, generated from cyclic cis-allylic pivalate 414. Overall retention occurred in the cyclization to afford 417. Thus, cyclizations of cis-pivalate 414 and trans-pivalate 418 afforded cis and trans products 417 and 419, respectively [159]. E

E

E

H E

E

E

Pd2(dba)3 toluene, 110 °C 76%

t -BuCOO 414

cis

415 H E

Pd-X

H

XPd

inversion

cis E

E

anti inversion

416 cis

E Pd2(dba)3

H 417 E

418 trans

cis E

H E

H

XPd trans

toluene, 110 °C 40%

t -BuCOO

trans

H E

E

Pd-X

H 419

trans

E

Hydrogenolysis of Allylic Compounds

485

4.6 Hydrogenolysis of Allylic Compounds Alkenes are obtained by Pd-catalyzed hydrogenolysis of allylic compounds via π -allyl complexes with various hydrides. HCO2 H, R3 SiH, HSnBu3 , LiBHEt3 , NaBH4 , and SmI2 are used [160]. Hydrogenolysis would be a useful reaction when it is regio- and stereoselective. Hydrogenolysis of terminal allylic compounds 420 and 421 affords either 1- and 2-alkenes 422 and 423 depending on the nature of the hydrides used. Regioselective formation of 1-alkenes from terminal allylic compounds is a useful reaction and most desirable. HCO2 H is particularly important, because 1-alkenes 422 are formed with high regioselectivity by hydrogenolysis only with formate [161]. A mixture, HCO2 H/Et3 N, which is soluble in organic solvents, is used most conveniently. Other hydrides usually give 2-alkenes 423 as major products. R

X R

H−

420

Pd(0)

R

+

H

R 423

H 422

X 421

4.6.1 Preparation of 1-Alkenes by Hydrogenolysis with Formates Various terminal allylic compounds 420 and 421 are converted to 1-alkene 422 by using HCO2 H/Et3 N. When allylic formates 426 are available from allylic alcohols, they are converted to 1-alkenes 422 by the treatment with Pd catalysts. P(n-Bu)3 is the best ligand to give highest selectivity. Regioselective hydrogenolysis is explained by the formation of π -allylpalladium formate 424 and transfer of hydride to the more substituted side as shown by 425 to give 422. Hydrogenolysis with other hydrides proceeds by transmetallation to generate π -allylpalladium hydride which undergoes reductive elimination to give 423. In this case, transfer of hydride occurs to a terminal carbon to form 2-alkene 423. R

X 420

R

Pd(0)

HCO2− Pd

X

O

O

M-H

421

Pd(0)

H

X

R

R Pd

R

OCHO 426

424

MX R

R

R

R H 423

R Pd

Pd

Pd H

H H O 425

O

H CO2 Pd(0)

422

Many applications of 1-alkene formation have been reported. The allylic acetate 427 was converted to exo methylene 428 by removal of the acetoxy group [162].

486

Pd(0)-Catalyzed Reactions of Allylic Compounds AcO

O H

OTES + HCO2H

O

OTES

H

Et3N, 75 °C, THF, 85%

OAc

H

TESO

O

AcO

Pd2(dba)3, P(n-Bu)3

TESO

O O 427

H

H O

O

O 428

Methylenecyclododecane was prepared by hydrogenolysis of 1-nitromethylcyclododecene (429) by formal anti thermodynamic isomerization of internal double bond to exo position [163]. Treatment of the allylic formate in the hydrindan system 430 with Pd catalyst provided the exo methylene regio- and stereoselectively as shown by 431. In this case, the more stable cis ring junction, rather than the more useful trans junction, was formed [164]. Optically active allylsilane was obtained in 98 % yield with 91 % ee by enantio- and regioselective hydrogenolysis of the silylated allyl carbonate 432 using (R)-MOP-Phen (VI-16) as a chiral ligand [165]. NO2

O CH3NO2

+

base

HCO2H

Pd(acac)2, P(n-Bu)3 NEt3, 89%

429 OTBDMS

OTBDMS

OTBDMS

Pd(acac)2, P(n-Bu)3 H O

benzene, rt, 93%

H

O

Pd O

O 430

CO2 Pd(0)

H

431

Ph

OCO2Me SiMe3

+ HCO2H

Pd2(dba)3, (R)-MOP-Phen (VI-16) Et3N, 98%, 91% ee

Ph Me3Si

H

432

Highly regioselective hydrogenolysis of the aldol product 433 proceeded smoothly in DMF to produce the terminal alkenes 434a and 434b in high yield

Hydrogenolysis of Allylic Compounds

487

in a ratio of 5.7 : 1. High diastereoselectivity was attained under carefully selected conditions (use of DMF and 1 : 2 ratio of P:Pd) [166]. O

OTES OAc

Pd2(dba)3, P(n-Bu)3 + HCO2NH4 DMF, 50 °C, 18 h, 89%

433 O

OTES

OTES

O +

434a

434b

5.7 : 1

Hydrogenolysis of vinyloxirane is regioselective to give homoallylic alcohol 435. Hydrogenolysis of the alkenyloxirane 436 is regio- and stereospecific and proceeds by overall inversion of configuration of the allylic C—O bond to afford the homoallylic alcohol 437 [167]. Sato applied the reaction to the synthesis of an A-ring precursor of vitamin D. The protected homoallylic alcohol 439 was obtained at room temperature from the alkenyloxirane 438 in 90 % yield [168].

O

+ HCO2NH4

Pd2(dba)3, P(n-Bu)3

H O

H

Et3N, dioxane, 85%

OH

CO2Et + HCO2H

436

435 CO2Et Pd2(dba)3, P(n-Bu)3 Et3N, THF, 85%

H

CO2Et OH 437

O

+

HCO2H

TBSO 438 CO2Et

CO2Et Pd2(dba)3, P(n-Bu)3

TBSCl

Et3N, THF, rt, 90% TBSO

TBSO OH

OTBS 439

4.6.2 Hydrogenolysis of Internal and Cyclic Allylic Compounds Regioselectivity in hydrogenolysis of internal allylic systems depends on the bulkiness of substituents. The alkene 441 was obtained regioselectively from tertcarbonate 440. The hydride attacked the congested tert-carbon, but not sec-carbon [169].

488

Pd(0)-Catalyzed Reactions of Allylic Compounds

MOMO OCO2Me (CH2)5OMOM

+

Pd(acac)2, P(n-Bu)3 HCO2H

Et3N, 74%

440

MOMO H (CH2)5OMOM 441

π -Allylpalladium formation proceeds with inversion and hydride transfer from palladium formate proceeds with retention of configuration, and hence stereoselective hydrogenolysis with overall inversion should be possible in rigid systems. Stereocontrolled synthesis of natural and unnatural configurations at C-20 in steroid side chains has been achieved based on the regio- and stereoselective hydrogenolysis of C-20 carbonate [170]. The (E)-β-carbonate 443 was prepared by the reaction of the C-20 keto steroid 442 with (E)-vinyllithium, and converted to α-oriented π -allylpalladium 444 with inversion, which has a stable syn structure. Concerted decarboxylation-hydride transfer as shown by 445 occurred with retention from the α-side to give the unnatural configuration 446.

20

20

OR

O

OCO2Me

OR

1. Li

HCO2H, NEt3

Pd(acac)2, P(n-Bu)3 82%

2. ClCO 2Me R3SiO 442 HCO2 Pd H

443 O Pd

O OR

Me H

OR

H H 20

OR

H

syn form 444

R3Si = t-BuMe2Si

445

CO2 Pd(0)

446

On the other hand, the α-oriented π -allylpalladium 448, formed from the (Z)β-carbonate 447, has an unstable anti structure, which rotates to form the more stable syn structure 450 before decarboxylation. By this rotation, Pd moves from the α-side to β-side as shown by 449, and hydride transfer occurs from β side as shown by 451, and the natural configuration 452 was constructed. Regio- and stereoselective hydrogenolysis of allylic formates in rigid cyclic systems offers a useful method for stereoselective construction of ring junctions. As

Hydrogenolysis of Allylic Compounds

489 OR

OR 442 +

O2CH Pd OCO2Me HCO2H, NEt3 H Pd(acac)2, P(n-Bu)3 92%

Li OR

H

447

448 anti form

OR

O2CH Pd

O2CH Pd

OR H

H

rotation anti syn

OR

H

syn form 450

449 Me

O Pd

O

O2CH Pd

H H

OR

H

OR

H CO2 Pd(0) 451

452

one example, the β-oriented allylic formate 453 was converted to the trans-decalin 455. The hydride attack occurred from the α-side as shown by 454. In addition, the hydride attacked the congested angular carbon regioselectively without forming the regioisomer 456. The cis junction in 459 was constructed from the α-oriented allylic formate 457 by the hydride attack from the β-side as expressed by 458. The reaction has been successfully applied to the construction of either AB cis or trans junction in steroid molecules [171]. OTBDMS

OTBDMS

OTBDMS

Pd(OAc)2 P(n-Bu)3 HCO2

Pd 453

O

H O 454

OTBDMS

H 456

H 455

92%

490

Pd(0)-Catalyzed Reactions of Allylic Compounds OTBDMS

OTBDMS

OTBDMS Pd(OAc)2 P(n-Bu)3

HCO2

Pd

H

H

O

457

459

O

89%

458

The method was applied to a hydrindane system. The trans ring junction 462 was constructed by stereoselective hydrogenolysis of the β-oriented allylic formate 461, derived from 460. No attack by Pd-catalyst to the allyl silyl ether group in 462 occurred. Elimination to provide the 1,3-diene 463 is a side reaction [172]. In the total synthesis of (−)-tuberostemonine, regio-, stereo- and chemoselective hydrogenolysis of 464 to provide 465 was utilized. Only β-oriented angular allylic benzoate was hydrogenolyzed to give the trans junction with overall inversion. No reaction occurred in the allylic alcohol moiety. In this case, tribenzylphosphine [P(Bn)3 ] was used as a ligand [173]. O-t-Bu

O-t-Bu

TBSO

Pd(OAc)2, P(n-Bu)3

TBSO HCO2H

dioxane, 90 °C

N,N-carbonyldiimidazole HO

HCO2 460

461 O-t-Bu

O-t-Bu

TBSO

TBSO +

462

H 4:1 68% from 460

OBz H HO

CO2Me N H Cbz 464

+ HCO2H + Et3N

463 H

Pd2(dba)3, P(Bn)3 THF, 65 °C, 93%

H HO

CO2Me N H Cbz 465

4.7 Allyl Group as a Protecting Group The allyl group is a good protecting group, because facile deprotection based on the formation of π -allylpalladium intermediates is possible. Carboxylic acids are protected as allyl esters, and alcohols and amines are also protected as allyl carbonates and carbamates, respectively. Deprotection can be carried out in two ways. One method is the Pd-catalyzed hydrogenolysis with hydride sources. HCO2 H/Et3 N is the most suitable reagent for hydrogenolysis, which takes place at room temperature under neutral conditions, and the byproducts are propene and CO2 [161]. Also HSnBu3 and HSiR3 are used as hydrides. The second method is allyl transfer to other nucleophiles such as amines, carboxylic acids, and active methylene compounds.

Allyl Group as a Protecting Group

491

Carboxylic acids are protected as allyl esters. In the final step of the total synthesis of reveromycin B, three allyl ester groups in 466 were removed cleanly with HCO2 H/Et3 N to give reveromycin B in 62 % yield [174]. O O

allyl-O2C

O

allyl-O2C

Me

H

Me CO2allyl + HCO2H

O

Me

OH

Me

H Me

466 O O

HO2C Pd2(dba)3, P(n-Bu)3 Et3N, dioxane 50 °C, 62%

O

HO2C

Me

H

Me CO2H

O

Me

H

OH

Me

Me reveromycin B

Deprotection of allyl ester in 467 with HCO2 H/Et3 N was highly chemoselective. In the coexistence of a 2,4-enyne system in 467, at first π -allylpalladium carboxylate 468, formed from the allyl ester, attacked the triple bond to form the butenolide 469 without reacting with formate. Hydrogenolysis with formate took place only at the final step to afford 470 chemoselectively. Also, the alkenyloxirane group, which is allylic epoxide, stayed intact [175].

CO2allyl

OH + HCO2H

O

Pd(PPh3)4

O Pd

O

Et3N, dioxane, rt

OH 467 O

468 O

O

O HCO2H Pd

469

OH O

H

OH 470

Alkyl allyl ethers are difficult to cleave. Therefore alcohols are protected as allyl carbonate. Deprotection of the cyclic carbonate 471 with HCO2 H/Et3 N proceeded regioselectively at room temperature to afford the δ-hydroxy ester 472. The electronic effect is crucial in this case and hydride attacked an electron deficient carbon [176].

492

Pd(0)-Catalyzed Reactions of Allylic Compounds O O

O

EtO2C

+

HCO2H

Me

Pd2(dba)3, PPh3

EtO2C

Et3N, THF 66 °C, 92%

OH

471

472

Phenols are protected as allyl aryl ethers, which can be cleaved smoothly. Deprotection of the allyl aryl ether in 473 to give 474 occurred at room temperature in MeOH in the presence of K2 CO3 using Pd(PPh3 )4 . Allyl benzyl ether was deprotected in refluxing MeOH to provide 475 [177]. The alkyl allyl ether in 476 was cleaved with PMHS in the presence of ZnCl2 as an activator in DMF [178]. Benzenesulfinic acid or Na salt is a good scavenger, and it is claimed that better results are obtained with sulfinic acid even when deprotection of protected acids, amines, and alcohols by other scavengers is not satisfactory. The alkyl allyl ether 477 was deprotected smoothly with toluenesulfinic acid at room temperature [179]. Deprotection of 477 is also possible under neutral conditions by using N ,N -dimethylbarbituric acid (DMBA) as the scavenger [180].

OH

O

OH

Pd(PPh3)4 K2CO3, MeOH

O 473

K2CO3 (3 equiv.), rt, 2 h K2CO3 (6 equiv.), reflux, 12 h

474

85% trace

2. Pd(PPh 3)4 PMHS, ZnCl2 DMF

N

N

O

1. aq. NaOH

O

N

N

5% 90%

Ph OH

N

HN H2N

OH 475

Ph

Cl

H2N

+

O

N

N

476 O O

TolSO2H O O O O 477

Pd(PPh3)4 CH2Cl2, rt 25 min, 99%

DMBA

O O

O OH O

Me

Pd(PPh3)4

THF, 90 °C, 99%

O O

O

N N

O

Me DMBA

Various water-insoluble substrates are deprotected smoothly in water using water-soluble ligand (TPPTS, II-1) in the presence of cyclodextrin [181]. Deprotection of allyl carbonates and carbamates can be carried out in MeCN/H2 O using TPPTS as a ligand and Et2 NH as the scavenger [182]. Chemoselective removal of allyl carbamate in a base-sensitive cephalosporin 478 was achieved with 1 % Pd(0)/TPPTS at room temperature to afford 479, and then the prenyl carboxylate

Allyl Group as a Protecting Group H N

O

S

O

H2N

S

1% Pd(OAc)2, TPPTS

N

Me

O O

493

Et2NH, MeCN/H2O rt, 30 min, 100%

N

Me

O

O

O

O 479

478 H2N

S

5% Pd(OAc)2, TPPTS N

Et2NH, MeCN/H2O rt, 60 min, 100%

O O 480

Me OH

was quantitatively removed using 5 % catalyst to provide 480 [183]. Chemoselective removal of allyl and prenyl groups in aq. MeCN was applied to the synthesis of peptides in solution [184]. Amines are protected as carbamates, which are easily deprotected. Diallylamine can be used as an ammonia equivalent if it is cleaved easily. However, allylamines are difficult to cleave under normal conditions. As an ammonia equivalent, the diallyl groups in 482 were removed in EtOH using Pd/C as a catalyst in the presence of methanesulfonic acid (1 equiv.). Probably diallylamine is activated for Pd-catalyzed cleavage by ammonium salt formation. 4-Aminobiphenyl (483) can be prepared by Pd-catalyzed amination of 4-bromobiphenyl (481) with diallylamine to give 482, followed by deprotection [185]. Also allylamines are deprotected with N ,N -dimethylbarbiturate (DMBA) as the scavenger [186]. N-protection in methyl N ,N ,α-triallylglycinate 484 was removed to form the primary amine 485 using DMBA as the scavenger of allyl groups [187].

Br N

Pd[P(o -Tol)3]2Cl2

+

t-BuONa

N H 481

482 NH2

MsOH, Pd/C EtOH reflux, 84% 483 O N

+ DMBA

Pd(PPh3)4

+

72%

CO2Me

CO2Me 484

Me

NH2

485

O

N N Me

O

494

Pd(0)-Catalyzed Reactions of Allylic Compounds

Pd-catalyzed reaction of the diallyl dicarbamate of hydrazine 486 with Bu3 SnH in the absence of a proton source, produced the tin carbamate, which was converted to free hydrazine 487 by protonation, and to the amide 488 by treatment with acetic anhydride. Transprotection from allyl carbamate 486 to the amide 488 was carried out in this way [188]. O O2C

N

O + Bu3SnH

Pd(PPh3)4

Bu3SnO

N

CH2Cl2

Bu3SnO

N

N

O

O2C O

486 H

H+

N

100%

O

N

H

487 O Ac2O

N

O

N O 488

4.8 1,4-Elimination By the treatment of allylic compounds with Pd(0) catalyst in the absence of nucleophiles, conjugated dienes are formed by 1,4-elimination (dehydropalladation). The elimination provides mainly (E)-dienes, but not completely selectively. P(n-Bu)3 is an effective ligand [189]. H R X

Pd(0)

R

R H Pd

Pd

X

X R

+ Pd(0)

HX

π -Allyl complexes are formed from 4-vinylazetidines or 4-vinyl-2-azetidinones when the amino or amide group is protected with an electron-withdrawing group. N -acetyl-4-vinyl-2-azetidinone 489 was converted to 2,4-pentadienamide as a 1 : 1 mixture of E and Z isomers by 1,4-elimination from π -allylpalladium intermediate 490. No reaction took place with the N -benzyl derivative [89]. Me Pd2(dba)3, P(n-Bu)3 NAc O 489

DMSO, 120 °C 88%

H

Me O Pd +

O

NAc 490

AcHN

Me

1,4-Elimination

495

1,4-Elimination in some cyclic systems proceeds regio- and stereoselectively. The Pd-catalyzed reaction of the racemic carbonate 491 afforded the diene 492 with 86 % ee via desymmetrization of the π -allylpalladium intermediate 493 when (−)-TolBINAP was used as a ligand [190].

(h 3-allyl-PdCl)2 dioxane, 100 °C (−)-p-TolBINAP

H

MeO2CO

(4aS)-(-)-492

racemic 491

66%, 86% ee

H Pd-X 493

Hetero- or homoannular conjugated dienes are prepared in hydronaphthalene derivatives by the Pd-catalyzed regioselective elimination of allylic carbonates under mild conditions. The heteroannular conjugated diene 496 was obtained selectively by the Pd-catalyzed regioselective elimination of the β-oriented allylic carbonate 494 under mild conditions via the stable intermediate 495. The homoanOMOM

OMOM

OMOM Pd(OAc)2, P(n-Bu)3 PhH, rt, 4h, 93% MeOCO2

Pd Pd

OMe

OMe 495

494β

497

OMOM 499

496 OMOM

OMOM

OMOM

Pd(OAc)2, P(n-Bu)3 PhH, rt, 21 h, 95%

MeOCO2 494α

MeOPd Pd

498

OMe 500

OMOM

499

OMOM

100 : 8.5 496

496

Pd(0)-Catalyzed Reactions of Allylic Compounds

nular diene 499 via 497 was not formed because the rate of elimination from the angularly trans tertiary complex 495 is faster than that from the secondary one 497. On the other hand, the homoannular diene 499 was introduced as the main path by elimination of the α-oriented allylic carbonate 494α. In this case, formation of the angularly cis complex 500 is unfavorable due to repulsion, and elimination occurred from the intermediate 498 [191]. Usually preparation of homoannular conjugate dienes is not easy. The Pdcatalyzed method of selective formation of homoannular dienes was applied to introduction of a homoannular diene system in provitamin D. Treatment of the 7α-carbonate 501 with the Pd catalyst at 40 ◦ C afforded the desired homoannular 5,7-diene 503a regioselectively in 89 % yield. No heteroannular diene 503b was detected. In the intermediate complex 502, the 7σ -allylpalladium is β-oriented and suitable for facile syn elimination of 8β-H to afford the 5,7-diene 503a exclusively [191]. The eliminations proceed smoothly with high selectivity when P(n-Bu)3 is used as a ligand.

OSiR3 Pd(OAc)2, P(n-Bu)3

MeO2CO

40 °C, 89% H

8 OCO2Me

MeO2CO 501

7

OSiR3

OSiR3

syn elimination H 8 Pd-OMe 502

MeO2CO

MeO2CO 503a

7

OSiR3 MeO2CO H MeO2CO 503b

It seems likely that β-H elimination occurs syn to Pd. However, Takacs et al. have made an interesting observation. When the cyclohexenyl carbonate 504, which has both syn and anti hydrogens, was subjected to the elimination, the cyclohexadiene 507 was obtained as a sole product, which should be formed by elimination of H anti to Pd in 505. The diene by syn elimination to give 506 was not formed [192].

1,4-Elimination

497 Pd

syn

EtO2CO H

Me

TBDMSO

H

Pd(OAc)2, P(n-Bu)3 inversion

Me

TBDMSO

H

H

anti

504 505

syn-elim. Me TBDMSO

H 506

H

anti-elim. 100%

TBDMSO

Me 507

Mikami and Ohmura reported that isobenzofuran (509) can be generated by the treatment of the benzylic lactol methyl carbonate 508 with phosphine-free Pd catalyst via 1,4-elimination of π -benzylpalladium at 100 ◦ C under neutral conditions. The isobenzofuran 509 was trapped as a cycloadduct 510 in situ with dimethyl acetylenedicarboxylate [193]. OCO2Me O

Pd-OMe

Pd2(dba)3 O

DMSO,100 °C 71%

O

H

508 MeO2C

509

CO2Me

CO2Me

O CO2Me 510

Pd-catalyzed reaction of alkenyloxiranes provides two elimination products, the unsaturated ketones or the dienyl alcohols by elimination of different hydrogens. From cyclopentadiene monoxide (511), the unsaturated ketone 513 was obtained as explained by 512. On the other hand, the dienyl alcohol 516 was obtained from the alkenyloxirane 514 via 515 [194]. O O

_

OH

H

O

Pd(PPh3)4 77% Pd

511 513

512 Pd _ O

Pd(PPh3)4 O

OH

90% H

514

515

516

498

Pd(0)-Catalyzed Reactions of Allylic Compounds

A useful building block 519 for vitamin D synthesis was prepared by reaction of the alkenyloxirane 517 [195]. Under usual conditions of the elimination, both the dienyl alcohol 519 and the unsaturated ketone 520 were formed in equal amounts. Radinov and co-workers discovered an interesting and remarkable effect of the addition of fluorinated alcohols, such as 1,3-bis-(1,1,1,3,3,3-hexafluoro-2hydroxypropyl)benzene or perfluoro-t-butyl alcohol as a proton source, on the chemoselectivity, and the desired 519 was obtained with nearly complete chemoselectivity with these additives [195]. They suggest that rapid protonation of the intermediate alkoxide 518 with these alcohols seems to be important. t-Bu-O2C

t-Bu-O2C Pd+ Pd2(dba)3 (0.5 mol), PPh3 (5 mol%) O

TBSO

H

1,3-C6H4[C(CF3)2OH]2 (2 mol%) toluene, 35 °C,

H+

O

TBSO

H

517

518

t-Bu-O2C

t-Bu-O2C

+ OH

TBSO 519

O

TBSO 520

92 : 1

Tamaru and co-workers reported that benzaldehyde and butadiene are formed from 6-phenyl-4-vinyl-1,3-dioxacyclohexan-2-one (521) at room temperature using ligandless Pd catalyst. Facile C—C bond cleavage (β-carbon elimination or βdecarbopalladation) in the intermediate palladacycle 522 occurs. As an extension, Ph O

O O

H +

MeCN, rt

521

Ph

Ph

Pd2(dba)3

O CO2

O

Pd 522

Pd2(dba)3,MeCN

4

rt, 93% O

3

O

O

Pd

CO2 O

524

523 C-H O only E,E 525

1,4-Elimination

499

they found that a variety of dienals and dienones are formed by Pd-catalyzed ring opening of mono-, di-, and tricyclic 4-vinyl-1,3-dioxacyclohexan-2-ones involving facile β-decarbopalladation. The carbonate 523 was converted to the dienyl aldehyde 525 in high yield, involving cleavage between the C-3 and C-4 bond in 524 [196]. Different products are obtained depending on substituents. Reaction of 526, which has no substituent at C-6, afforded the diene 528 (48 %) and the formate 529 (34 %). In this reaction, formaldehyde is generated and inserts to the intermediate 527 to form 530. The formate 529 was obtained from 530 by β-H elimination to generate 531 and reductive elimination. The diene 528 was obtained in 87 % yield in the presence of t-octylamine as a scavenger of formaldehyde. Also the 1,3-dioxane 532 is formed in the presence of formaldehyde. Thus the reaction of the carbonate 533 with formaldehyde afforded the 1,3-dioxane 535 via 534 in high yield [197]. Me

Me Ph

O

Me

Pd(PPh3)4

Me

Me Ph

MeCN

O

O

528 48%

Pd 527

O

526

in the presence of 87% t-octylamine

H O

Ph + CH2O

Me

insertion

H Me

Me

Me

Me

O

Me

Ph

Ph O

O 532

Ph RE

Pd

H 530

Ph O

O

+

O

O 533

MeCN reflux, 80%

Me

Me

Ph O

H

O

H O 529 34%

531 Ph

Pd(PPh3)4

H H

Pd

O

O H

H

Me

O

Ph

Pd O

O H

H

O 535

534

As a related elimination, allyl alkyl carbonates of primary, secondary, allylic, and benzyl alcohols are converted to ketones and aldehydes in MeCN via facile βH elimination of π -allylpalladium alkoxide 537, formed from allyl alkyl carbonate 536 [198]. The reaction offers a good method of oxidation of alcohols under neutral conditions without using inorganic oxidants.

OH

O

OCO2 Pd2(dba)3

536

MeCN, 80 °C 76%

O

+

Pd

H CO2

Pd(0) 537

H

500

Pd(0)-Catalyzed Reactions of Allylic Compounds

4.9 Reactions via π -Allylpalladium Enolates Allylation of ketone enolates is treated in Chapter 4.2.3. The chemistry of π allylpalladium enolates, which is related, but more versatile than that of simple ketone enolates, is treated in this section. π -Allylpalladium enolates are generated in two ways. One is the transmetallation of silyl and tin enolates with π -allylpalladium alkoxide formed from allyl carbonates. The other is Pd-catalyzed reaction of allyl β-keto esters [199]. 4.9.1 Generation of π-Allylpalladium Enolates from Silyl and Tin Enolates Formation of π -allylpalladium enolates by the reaction of the silyl enolate 539 with allyl carbonate is summarized as follows. The enolate of cyclohexanone is treated as a model compound here. Transmetallation of π -allylpalladium methoxide 538 with the silyl enolate 539 generates either Pd enolates 540 or α-palladaketone 541. Reductive elimination affords allylcyclohexanone 542 in THF [200]. At higher temperature, cyclohexanone 543 is obtained by β-H elimination using ligandless Pd catalyst in MeCN [201]. O O

OMe

Pd(0)

CO2

O Pd

Pd OMe

Me

538 O

allylation Pd2(dba)3, DPPE

O Me

THF, reflux, 90%

SiMe3 540

Me

542

O MeOSiMe3 539

Me

541

Pd

b-H elimination Pd(OAc)2, DPPE

H

MeCN reflux, 87%

O Me

543

Tin enolate 545 is generated by the reaction of enol acetate with MeOSnBu3 . Transmetallation with 538 provides π -allylpalladium intermediates 546 and 547, and at the same time regenerates MeOSnBu3 . Thus, MeOSnBu3 works as a cocatalyst. Then the allyl ketone 548 and the enone 549 are obtained under slightly different conditions. Applications of these reactions have been reported. Wicha and co-workers prepared the allylated ketone 552 in 87 % yield as a synthetic intermediate of vitamin D by the reaction of the silyl enol ether 550 with the cis-allyl carbonate 551 [202].

Reactions via π -Allylpalladium Enolates

501

Pd

O Bu3Sn OAc

O

Pd

MeOSnBu3

538

OMe

546

AcOMe

O MeOSnBu3

545

544

Pd

547 O Pd2(dba)3, DPPE dioxane reflux 93%

548 O

Pd(OAc)2, DPPE MeCN reflux, 97% 549

O H

t-BuS H

+

OCO2Me

Pd2(dba)3, DPPE

OTBDMS

THF, 60 °C, 87%

551 O H

Me3SiO 550

t-BuS H

O OTBDMS 552

The intramolecular version of the allylation has been carried out by Corey. The 11-membered cyclic ketone 554 was obtained from the silyl enol ether 553 in 52 % yield, and short syntheses of humulene and δ-araneosene have been achieved utilizing the reaction as a key step [203].

502

Pd(0)-Catalyzed Reactions of Allylic Compounds OSiMe3

Me

Me

OCO2Me

Me

Me

O

Pd2(dba)3, DPPF

Me

THF, 70 °C, 52%

Me

Me

Me

554

553 Me steps

Me

Me

Me humulene

β-H elimination occurs by the treatment of π -allylpalladium enolates in boiling MeCN to give α,β-unsaturated ketones and aldehydes. Shibasaki and co-workers used the enone formation in the total synthesis of strychnine [204]. The silyl enol ether 555 was treated with diallyl carbonate 556 in MeCN and the cyclohexanone 557 was obtained in high yield.

Me3SiO

OTIPS

+ O

H

555

O

Pd2(dba)3 MeCN

O

90%

O

OTIPS H

OPMB

556

OPMB

557

Esters can be converted to either α-allyl ester 559 or α,β-unsaturated esters 560 by the Pd-catalyzed reaction of ketene silyl acetals such as 558 with allyl carbonate under slightly different conditions [205]. CO2Et

559

OSiMe3 OEt

CO2Et

Pd2(dba)3, DPPE dioxane, 79% O

OEt

+

O

CO2Et

Pd(OAc)2, MeCN 79%

558

560

The cyclohexenyl acetate 561 was converted to the cyclohexanone 562 by the reaction of allyl carbonate using Pd(OAc)2 and Bu3 SnOMe as a bimetallic catalyst [206]. O

OAc O

OEt

+

Pd(OAc)2, DPPE Bu3SnOMe, 85%

O

OAc 561

OAc 562

Reactions via π -Allylpalladium Enolates

503

4.9.2 Reactions of Allyl β-Keto Carboxylates and Related Compounds Allyl β-keto carboxylates 563 undergo facile Pd-catalyzed decarboxylation to form either π -allylpalladium enolates 565 or α-palladaketone 564. Also π -allylpalladium enolates are generated from enol carbonates 566. As summarized below, several transformations to afford 567–573 are possible under different but proper conditions depending on the substituents R [199]. In addition to allyl β-keto carboxylates, other allyl esters such as allyl malonates, cyanoacetates and nitroacetates undergo similar transformations. With these Pd-catalyzed reactions, a new generation of β-keto esters and malonate chemistry has been developed. O R (A) allylation

O

O

567

R

O

(B)

O

dehydrogenation

R +

563 Pd(0)

568 CO2

O

(C) deacetoxylation

+

R = −CH2OAc

O

AcO

Pd

R

570

O

Pd

569

R (D)

O

hydrogenolysis 564

R + CO2 +

HCO2H

565 CO2

571 Pd(0) O

OH

(E)

O

aldol condensation O

O

+

R = −(CH2)3−CHO

R 572 566

O

(F) Michael addition

O

R = −(CH2)3CH=CHCOMe

+

573

504

Pd(0)-Catalyzed Reactions of Allylic Compounds

Each reaction is explained briefly by citing synthetic applications. 4.9.2.1 Decarboxylation–Allylation (A) Formation of allylketones 567 from allyl β-keto esters 563 and allyl enol carbonates 566 is the Pd-catalyzed Carroll rearrangement. As a related reaction, Pd-catalyzed regioselective intramolecular allylation of the allyl enol ether of βketo ester 574 occurred as shown by 575 in DMSO, and afforded a mixture of the endo- and exo-bicyclo[3.2.1]octane frameworks 576 and 577 using DPPE as a ligand. PPh3 is not suitable [207].

CO2R O

CO2R −

O

Pd(dppe)2, DMSO 80 °C, 95%

+ Pd 575

574 O

O CO2R

CO2R +

576

577

1.2 : 1

In order to achieve regio- and stereoselective α-allylation of a cyclohexanone derivative, Paquette and Nicolaou carried out the Pd-catalyzed decarboxylationallylation of the allyl enol carbonate 578 at room temperature to give the allyl ketone 579 in 58 % yield and a regioisomer (24 %) using PPh3 [208]. Me

Me

OMe OMe

OMe Pd(PPh3)4, THF 58%

Me

O OMe

O O

OMe

Me

O H Me

OMe

Me 578

579

Not only allyl β-keto esters, but also the diallyl malonate derivative 580 underwent decaboxylation-allylation to give allyl α-allylcarboxylate 581. The nitro ester 582 is very reactive and the allylation proceeded even at −50 ◦ C to give the αallylnitroalkane 583 [209].

Reactions via π -Allylpalladium Enolates CO2

Pd(OAc)2, PPh3

CO2

120 °C, 65%

CO2 580 O 2N

505

581 NO2 CO2

Pd(OAc)2, PPh3 −50 °C, 59%

582

583

4.9.2.2 Preparation of α,β-Unsaturated Carbonyl Compounds by Decarboxylation–Elimination (B) π -Allylpalladium enolates undergo β-H elimination to afford α,β-unsaturated ketones in MeCN at high temperature. Preparation of the cyclopentenone 585 from allyl α-2-pentynylcyclopentanone carboxylate (584) by β-H elimination is a key step in the commercial production of methyl cis-jasmonate (586) [210]. α,β-Unsaturated nitrile 588 was prepared from the disubstituted allyl cyanoacetate 587 [211]. O

O

O steps

Pd(OAc)2, PPh3 MeCN, 85%

CO2Me

CO2 584

585

586

CN NC

CO2

Pd2(dba)3, PPh3 EtCN, 81%

587

588

4.9.2.3 Synthesis of α-Methylene Compounds by Decarboxylation–Deacetoxylation (C) The acetoxymethyl group is introduced at the α-carbon of cyclopentanonecarboxylate by the reaction of formaldehyde followed by acetylation to give 589, which undergoes facile Pd-catalyzed decarboxylation and deacetoxylation to give α-methylenecyclopentanone 591 [212]. Interestingly, the acetoxy group in 590 is eliminated as allyl acetate more easily than β-H, and the cyclopentenone 592 is not formed. Itaconate 594 was prepared by application to allyl malonate. Treatment of the appropriately substituted ethyl diallyl malonate 593 with Pd catalyst at room temperature provided the allyl ethyl itaconate (594) in 83 % yield.

506

Pd(0)-Catalyzed Reactions of Allylic Compounds O

O

OAc

O

OAc

Pd2(dba)3, PPh3

CO2 589

590 H

O

OAc

+

Pd

MeCN, rt, 93%

591

OAc 592 Pd2(dba)3,PPh3

steps

AcO

CO2

EtO2C

CO2

CH2(CO2allyl)2

MeCN, rt, 83%

593 CO2

+

AcO

CO2Et 594

Allyl α-sulfonyl ester 595 underwent a similar reaction to give the vinylsulfone 596. Pd2(dba)3, PPh3

CO2

AcO

MeCN, rt, 89%

n-Pr

SO2Tol

n-Pr

595

SO2Tol 596

4.9.2.4 Decarboxylation–Hydrogenolysis (D) Hydrolysis of the dialkylated β-keto esters and malonates is not easy, and usually harsh conditions are required. Also decarboxylation occurs only at high temperature. On the other hand, hydrolysis and decarboxylation reactions of substituted allyl β-keto esters and allyl malonates using Et3 N-HCO2 H proceed at room temperature under neutral conditions. THP-protected allyl β-keto ester 597 was converted to 598 at room temperature without deprotection of THP [213]. The free monocarboxylic acid 600 was obtained smoothly from the disubstituted diallyl malonate 599 [214]. O

O CO2 OTHP

+ HCO2H

Pd(OAc)2, PPh3 OTHP

Et3N, THF, rt, 95%

597

598

n-C6H13

CO2

Bn

CO2

599

+ HCO2H

CO2H

Pd(OAc)2, PPh3, Et3N n-C6H13 dioxane reflux, 83%

Bn

H 600

Reactions via π -Allylpalladium Enolates

507

4.9.2.5 Aldol Condensation and Michael Addition (E, F) Typical reactions of metal enolates are aldol condensation and Michael addition. As expected, Pd enolates undergo these two reactions. So far intramolecular reactions proceed efficiently. Intermolecular reactions are competitive with other reactions. Aldol condensation of the keto aldehyde 601 at room temperature provided the aldol product 602 in 82 % yield [215] O

OH

O Pd(OAc)2, PPh3

CO2

MeCN, rt, 82% CHO 601

602

Intramolecular Michael addition occurs under mild conditions [216]. In the Pdcatalyzed reaction of allyl acetoacetate with benzylidenemalononitrile (151), the Michael addition of acetone enolate to benzylidenemalononitrile (151), followed by electrophilic allylation took place to afford 603 [217]. O

O

Pd(PPh3)4, THF

O

O

Ph

Pd

97%

O

NC

151

CN

603

CN

Ph

CN

An interesting strategy for convergent steroid synthesis has been reported by Deslongchamps based on Pd-catalyzed decarboxylation–Michael addition of allyl β-keto ester (bicyclic Nazarov reagent) 605 to cyclohexanone 604. The first intermolecular Michael addition of the Pd-enolate, generated from 605, to 604 afforded 606. Further intramolecular Michael addition constructed the steroid skeleton 607, and the tetracycle 608 was obtained by β-H elimination [218]. OMOM O

O

Pd(PPh3)4, THF

+

E

OMOM E

morpholine. 55%

Pd

OMOM O CO2allyl

OTBDPS

H OTBDPS

605

604 E = CO2Me OMOM O

OMOM O

E

E Pd-allyl

H OTBDPS

H

O

O H OTBDPS

607

608

O 606

508

Pd(0)-Catalyzed Reactions of Allylic Compounds

4.10 Pd(0) and Pd(II)-Catalyzed Allylic Rearrangement [3,3]-Sigmatropic allylic rearrangement of allylic esters is catalyzed by both Pd(II) and Pd(0) by different mechanisms. Pd(II)-catalyzed reaction is explained by formation of cyclic intermediate. N -tosylallylamine 611 was prepared regioselectively from allylic alcohol via the allyl carbamate 609 by the Pd-catalyzed aminopalladation and decarboxylation using Pd(OAc)2 in the presence of LiBr. No reaction occurred in the absence of LiBr. Most probably, Pd(II)-mediated aminopalladation of the double bond as shown by 610 generates the cyclic intermediate 610. Deoxypalladation and decarboxylation give rise to the rearranged product 611 with regeneration of Pd(II) [219]. Me

Me

Pd(OAc)2, LiBr

TsNCO

DMF, 100 °C, 96%

TsHNOCO

HO

609 PdBr

PdBr2 Me

Me

Me NTs

O

O

NHTs 611

NTs CO2

O

O 610

Overman and co-workers carried out extensive studies on Pd(II)-catalyzed asymmetric allylic rearrangement of allylic imidates to form enantioenriched allylic amides. They achieved 97 % ee as the best result by the reaction of the allylic imidate 612 using the cyclopalladated ferrocenyl oxazoline 613 having elements of planar chirality as a catalyst precursor, and discussed the mechanism of the reaction [220].

Ph Ar N

O

[Pd], Ag(O2CCF3)

t-Bu

Ar N

Pd

Fe

I 2

i-Bu (Z)-612 Ar = 4-MeOC6H4

N

O

CH2Cl2, toluene, 90%

i-Bu

SiMe3

O

Ph

97% ee

613

Gais and B¨ohme reported that Pd(0)-catalyzed enantioselective O,S-rearrangement of the racemic O-allylic thiocarbamate 614 using Pd(0) and Trost L-1 as a chiral ligand provided the S-allylic thiocarbamate 615 in 92 % yield with 91 %

Reactions of 2,3-Alkadienyl Derivatives via Methylene

509

ee. Differentiation of allylic termini of the symmetric intermediate took place. Rearrangement of the cyclohexenyl derivative 615a proceeded more efficiently and afforded 616 in 94 % yield with 97 % ee [221]. S OH Me

MeNCS

Me

O

O

Me

NHMe

Pd2(dba)3, Trost L-1

S

CH2Cl2, rt 92%, 91% ee Me

Me

NHMe Me

615

614 S

O

O

NHMe

S

Pd2(dba)3, Trost L-1

NHMe

CH2Cl2, rt 94%, 97% ee 615a

616

4.11 Reactions of 2,3-Alkadienyl Derivatives via Methylene-π -allylpalladiums Reactive methylene-π -allylpalladiums 618 are generated from esters of 2,3-alkadienyl alcohols 617, and react with nucleophiles to afford either 1,2-dienes 619 or 1,3-dienes 620 regioselectively depending on the nature of allyl leaving groups and nucleophiles. A B R • OR′ R 617

A

A

R

R

Pd(0)

R •

619

A or B

B

Pd OR′ 618

R

B R

R 620

The 1,2-dienes (allenes) 622 and 623 were obtained by the reaction of soft carbon nucleophiles such as malonate [222]. On the other hand, reaction of the phosphate 624 with Grignard reagent provided the 1,3-diene 625 [223]. Carbonylation of the carbonate 626 proceeded smoothly under mild conditions (rt, 1 atm) and 3-alkyl-1,3-butadiene-2-carboxylate 627 was obtained in high yield [224]. The 2,3-dienylamine 628 was carbonylated under harsh conditions to provide the αvinylacrylamide 629 in the presence of DPPP and TsOH [225].

510

Pd(0)-Catalyzed Reactions of Allylic Compounds H

CO2Me

+

•

Pd(PPh3)4

CO2Me

OAc 621

H

H •

CO2Me

622

CO2Me

+

•

CO2Me

623

2

CO2Me

26%

47% H

+ C7H15MgBr

•

C7H15

Pd(PPh3)4 80%

OPO(OEt)2 624

625 C6H13

•

CO2Me

Pd(PPh3)4

+ CO + MeOH

rt, 1 atm 91%

OCO2Me

C6H13

626

627

O H •

Et

+ CO

Pd2(dba)3, DPPP, p-TsOH

N

Bn

75 °C, 600 psi, 83%

Bn

628

Et N

629

Murahashi carried out the reaction of the phosphate 630 with the aminomalonate 631 using (R)-MeO-BIPHEP (XIV-6) as a chiral ligand and obtained the allene 632 with 90 % ee, offering a possibility of asymmetric synthesis of substituted allenes [226].

t-Bu

H

• H

CO2Et + HC CO2Et OP(O)(OEt)2 NHAc

630

Pd2(dba)3 (R)-MeOBIPHEP t-Bu (XIV-6) BSA, THF, rt 69%, 90% ee

631

H •

CO2Et

632

NHAc

H

CO2Et

Hayashi found that methylene-π -allylpalladium 635 can be generated from 2bromo-1,3-diene, which is prepared by the Pd-catalyzed cross-coupling of 1,1dibromo-1-alkene 633 with vinylzinc reagent. Thus, the reaction of 1-phenyl-2-

Br Ph 633

+ ClZn

Pd(PPh3)4

Ph

(h3-allyl-PdCl)2, DPBP Br

Br

Ph Na[MeC(CO2Me)2] Ph

H •

H

Pd 635

THF, rt, 91%

634

Br

636

CO2Me Me CO2Me

References

511

bromo-1,3-butadiene (634) with malonate afforded the 1,2-diene 636, presumably via the methylene-π -allylpalladium 635 in 91 % yield by using bisphosphine DPBP (IX-11). Other ligands such as DPPE, DPPP, DPPB, DPPF and PPh3 gave very low yields (<10 %) [227]. Leighton constructed the complex molecule of the CP-263,114 core ring system 641 by elegant application of Pd-catalyzed carbonylation of the 1,3-butadienyl 2-triflate moiety in 637 via the methylene-π -allylpalladium 638 to afford the unsaturated lactone 640. The lactone was subjected to Cope rearrangement to produce 641 as shown by 640 in 56 % overall yield. Formation of the unsaturated lactone 640 by intramolecular acetalization involving the alcohol, ketone, and acylpalladium as shown by 639, is a key reaction [228]. TESO

TESO

TESO O R

+ CO

Pd(PPh3)4, i-Pr2NEt PhCN, 54 atm 65~110 °C, 56%

R

R

TfO

OH

O

O

X Pd

X-Pd

OH

OH

637

638

TESO

O

TESO

TESO

O

CO R

[3,3]

O Pd-X

O

R

O

O R

O

O

OH 639

640

R = (E)-MeCH=CH(CH2)5−

641

O O O

O

Me

O

Me

O O

CO2H

CP-263,114

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Chapter 5 Pd(0)-Catalyzed Reactions of 1,3-Dienes, 1,2-Dienes (Allenes), and Methylenecyclopropanes

5.1 Reactions of Conjugated Dienes Several types of Pd-catalyzed or promoted reactions of conjugated dienes via π -allylpalladium complexes are known. The Pd(II)-promoted oxidative difunctionalization of conjugated dienes with various nucleophiles is treated in Chapter 2.4, and Pd(0)-catalyzed couplings of conjugated dienes with aryl and alkenyl halides are summarized in Chapter 3.2.9.1. Other Pd(0)-catalyzed reactions of conjugated dienes are treated in this section. It is well known that Ni(0) catalyzes the cyclodimerization and cyclotrimerization of butadiene to form COD or CDT. On the other hand no cyclization of butadiene occurs with Pd(0) catalyst. Pd(0)-catalyzed dimerization of butadiene to form 1,3,7-octatriene (1) is the main reaction. All Pd(0)-catalyzed reactions proceed via the formation of π -allylpalladium intermediates, which readily react with various nucleophiles as expected, giving 1 : 1 and 2 : 1 adducts. This is a characteristic feature of Pd(0)-catalyzed reactions of conjugated dienes. The most useful reaction is the dimerization with incorporation of pronucleophiles to give so-called ‘butadiene telomers’ 2 and 3 as shown by the following general scheme. Pd(0)-PPh3 is an active catalyst for the dimerization. No dimerization occurred when PdCl2 was used as a catalyst precursor. The 1 : 1 adducts 4 are obtained depending on the nature of the ligands. No dimerization of substituted dienes and cyclic dienes occurs and only 1 : 1 adducts, such as 5, are formed as described later. Dimerization of butadiene was studied extensively in the 1970s [1]. Since then, few studies have been reported. Beller and co-workers studied the telomerization of butadiene with MeOH, and found that the Pd-carbene (XVI-1) complex was an excellent catalyst and the linear telomer 6 was obtained with 99 % chemoselectivity and 98 % yield at 90 ◦ C. In addition, they claimed that TON = 267 000 was attained with this catalyst. Also they showed that Pd(OAc)2 /3PPh3 is a good catalyst for the telomerization [2]. Telomerization in the presence of water to give 2,7-octadien-1ol (7) proceeded in an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate) at 70 ◦ C. The reaction mixture separated into two phases when it was cooled. After separation of the product, the ionic liquid phase is recycled [3]. Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

520

Pd(0)-Catalyzed Reactions of Dienes Pd(0)

+ NuH

Pd(0)

1 Nu Nu +

Nu

+

2

3

+ NuH

4

Pd(0) Nu 5

Pd/carbene (XVI-1), NaOH

+ MeOH

OMe

90 °C, 98%, selectivity 99% 6 Pd/carbene, NaOH

+ H2O

OH 7

Phenols are reactive substrates and aryl 2,7-octadienyl ethers are obtained in good yield. Beller obtained 1-octadienyl-2-naphthol (9) in high yield, instead of the O-octadienyl ether, when β-naphthol (8) was subjected to telomerization at 90 ◦ C for 16 h using Pd(OAc)2 and PPh3 . Electron-rich phenols, such as 3,4methylenedioxyphenol (10), were converted selectively to 11 without forming the aryl octadienyl ether 12 by using PCy3 as a ligand. Formation of the octadienyl ether 12 is reversible, and irreversible C-octadienylation occurs due to the ambident character of these phenols. Claisen rearrangement of the ether 12 is one possibility, but it is unlikely because a branched 6-octadienylphenol should be formed from 12, and not the linear one 11 [4].

OH +

OH

Pd(OAc)2, PPh3 THF, 90 °C, 84%

8

9

OH

OH Pd(OAc)2, PCy3

+

THF, 90 °C, 46% selectivity 98% O

O O

11 O Claisen rearrangement

10 O

O O

12

Reactions of Conjugated Dienes

521

Octadienylamines 13 and 14 are obtained by the reaction of aqueous ammonia. Under usual conditions, these primary amines react further to give a mixture of di(octadienyl)amine isomers. The primary amines were obtained selectively without producing the secondary amines when the reaction was carried out in two phases (H2 O and toluene) using water-soluble TPPTS (II-1) as a ligand [5]. Nolan found that cationic Pd complexes of carbene XVI-2, coupled with noncoordinating anions such as PF6 or BF4 , are precursors of active catalysts for telomerization of amines such as morpholine with butadiene. The catalyst is inactive when chloride is used. The telomerization proceeded rapidly even at room temperature in THF or toluene with a catalyst loading of 0.2 mol % [5a]. NH2 + NH3

Pd(OAc)2, TPPTS (II-1) H2O/toluene, 80 °C, 55%

13

NH2

14 H N +

carbene (XVI-2)Pd(allyl)Cl, AgBF4

O

THF, 60 °C, 100%

N

O

No dimerization of substituted or cyclic dienes occurs by using Pd-PPh3 as a catalyst under usual conditions, instead the 1 : 1 adducts are formed. For example, dimerization of isoprene using Pd-PPh3 is slow. 1,2-Hydroamination of 1-phenylbutadiene with aniline proceeded to afford the amine 15, and two products 16 and 17 were obtained from isoprene when an exotic Pd complex 18 was used as a catalyst [6]. NHPh + PhNH2

Ph

[Pd] toluene, rt, 92%

Ph 15

+ PhNH2

NHPh

[Pd] toluene, rt, 92%

+

PhHN

88 : 12 16 MeO Ar P [Pd] =

Pd P Ar

MeO 18

Ar = 2,4,6-tri-t-butylphenyl

17

522

Pd(0)-Catalyzed Reactions of Dienes

Hydroamination of prochiral cyclic dienes such as 1,3-cycloheptadiene (19) with aniline gave rise to 3-(N -phenylamino)cycloheptene (20) smoothly using Pd-PPh3 . This reaction suggests the possibility of asymmetric amination. Actually Hartwig carried out successful asymmetric hydroamination of 1,3-cyclohexadiene with 4-aminobenzoate using (R, R)-(XIII-1) as a chiral ligand and obtained N (3-cyclohexenyl)-4-aminobenzoate (21) in 83 % yield with 95 % ee [7]. Pd(PPh3)4, AcOH

+ PhNH2

PhNH

71%

19

20 CO2Et

+

H N

(h3-allyl-PdCl)2, (R,R)-XIII-1 83%, 95% ee

H2N

EtO2C (S)- 21

It is known that 1-silyl-2,7-octadiene is prepared when HSiMe3 is used in the telomerization of butadiene. However, simple hydrosilylation occurs to give 1silyl-2-butene by the reaction with HSiCl3 . Han and Hayashi have shown that the bulky Ar-MOP 25 is an effective ligand for asymmetric hydrosilylation of prochiral cyclic dienes, but the more bulky monodentate phosphine 26 is more effective. Hydrosilylation of cyclopentadiene (22) with HSiCl3 afforded the 3silylcyclopentene 23 at −20 ◦ C in 86 % yield with 90 % ee. Optical purity was determined by converting 23 to 24. 1,3-Decadiene (27) was converted to (R)(Z)-4-(trichlorosilyl)-2-decene (28), which was isolated as a single regioisomer in 91 % yield, and ee % was determined as 68 % ee after converting to 29 [8]. OH + HSiCl3

(h3

SiCl3

-allyl-PdCl)2, 26

PhCHO

Ph

−20 °C, 86%, 90% ee

22

23

24 C8H17

Ph2P

Me

Ph2P

Me

OMe OMe Me

Me

H17C8

25

C6H13

26

+

HSiCl3

SiCl3

(h3-allyl-PdCl)2, 26 20 °C, 91%, 68% ee

PhCHO C6H13

27

28 Ph Ph

Ph MeO2C

OH

OH 29

Reactions of Conjugated Dienes

523

It is well-established that either 3-pentenoate or 3,8-nonadienoate are obtained by the carbonylation of butadiene depending on the nature of the catalysts. So far no successful asymmetric carbonylation of prochiral dienes is known. Alper carried out enantioselective thiocarbonylation of prochiral dienes, such as 2-methyl-1,3pentadiene (30), with thiophenol and obtained the β,γ -unsaturated thioester 31 with 89 % ee in 71 % yield using (R, R)-DIOP as a chiral ligand [9]. O + PhSH + CO

Pd(OAc)2, (R,R)-DIOP CH2Cl2, 27 atm,110 °C

PhS

71%, 89% ee 30

31

Jolly and co-workers carried out mechanistic studies on Pd-catalyzed telomerization and proposed that the bis-π -allyllic palladium 34 is formed at first [10]. It is known that the bis π -allylpalladium 32 is amphiphilic [11]. Similarly, an amphiphilic reaction of 34 is expected as shown by 33. In the telomerization with a pronucleophile, protonation occurs at first, followed by electrophilic attack of the π -allylpalladium moiety as illustrated by 35 to produce the telomers 36 and 37. Thus the reaction of butadiene with malonate gives a mixture of 38 and 39. It should be noted that the protonation takes place at the congested side of the π -allyl system. −

+ E Nu−

Pd

Nu

Pd

− Nu

Pd(0)

2

E+

Nu H

Nu H+

H +

Nu

Pd

+

34

33 −

H

amphiphilic

amphiphilic 32

Nu H

Pd

Nu

36 35

37

COMe CO2Me

2

+

COMe

38

MeOC

CO2Me

CO2Me

39

The amphiphilic nature of the bis-π -allyllic palladium was clearly shown by the reaction of the polarized double bond A=B to give either 42 or 43. In this case, the first nucleophilic attack of one of the π -allylpalladium moieties occurs to generate

524

Pd(0)-Catalyzed Reactions of Dienes

41, from which 42 is formed by reductive elimination, and 43 is obtained by β-H elimination. Actually benzaldehyde reacted with butadiene to give the pyran 46 and unsaturated alcohol 47 via 45 depending on the nature of the Pd catalyst [12]. A similar amphiphilic reaction of phenyl isocyanate afforded divinyl-δ-lactam [13]. B

A

Pd

A

A Pd

B

reductive elimination

42

B b-H elimination

40

AH

41 43

Ph

O

Pd O

Pd Ph

B

46 + 47

H 44

45

2

Ph

Ph

O

O

+ Ph

OH

+

H 46

47

Then Kiji and Tsuji attempted the amphiphilic reaction of excess butadiene with acetoacetate and benzaldehyde in one-pot, expecting the formation of the telomer 48. But the acetoacetate and benzaldehyde behaved separately to yield the telomers 38 and 46, without giving the desired product 48 [14].

+

O

COMe

+ Ph

CO2Me

excess

i-PrOH

H Pd(OAc)2, PPh3

MeOC

COMe

O +

CO2Me 48

Ph

CO2Me

OH 38

Ph

89% 46

54%

Formation of 1 : 1 adducts from substituted dienes 49 can be understood by the following mechanism. In this case, generation of bis-π -allylic palladium is not possible for steric reasons. Instead, insertion of a diene to H-Pd bond of H-Pd-Nu occurs to afford the π -allylpalladium complex 50, and nucleophilic attack at the allylic terminus gives 51.

Reactions of Allenes Nu-H + Pd(0)

525

Nu-Pd-H

Nu

H R

bis-p-allylpalladium

Pd

R

Nu 50

R

51

49

5.2 Reactions of Allenes 5.2.1 Introduction Allenes (1,2-dienes) are more reactive than alkenes, and Pd-catalyzed reactions of allenes with carbon and heteroatom nucleophiles proceed mostly via the formation of π -allylpalladium intermediates, and offer useful methods for making carbon–carbon and carbon–heteroatom bonds. The first report on Pd-catalyzed reaction of allenes with amines and malonate was given by Coulson in 1973 [15]. A comprehensive review on Pd-catalyzed reactions of allenes is available [16]. Pd-catalyzed and promoted reactions of allenes can be classified into three groups. The first one is promoted by Pd(II). For example, aminopalladation of hexa-1,2-dienyl-6-amine with Pd(II) generates the alkenylpalladium intermediate 52, which is converted to functionalized alkene 53 with generation of Pd(0). In order to make the reaction catalytic, Pd(0) has to be oxidized to Pd(II) with some oxidants. This type of reaction is treated in Chapter 2.5. • NHR

AH

+ Pd(II)X2

+ Pd(0)

−HX

N R

N R

PdX oxidation Pd(0)

A

52

Pd(II)X2

53

In the Pd(0)-catalyzed reaction of allene 54 with aryl halide, carbopalladation of allene with Ar-Pd-X takes place to give the π -allylpalladium intermediate 55, which is attacked by a pronucleophile to give 56. For example, reaction of 1,2-hexadiene (57) with iodobenzene and pyrrolidine afforded the allylic amine 58 [17]. The catalytic reactions of this type have been extensively studied. They are surveyed in Chapter 3.2.9.2. Ar-X + Pd(0)

Ar-Pd-X

Ar

Ar-Pd-X

Ar

R1

Ar

Nu-H

Nu

R1 •

R1

R1

Pd

Pd-X

X 54

•

55

57

Ph

Pd(OAc)2, DPPE

+ Ph-I + N H

n-Bu

56

82%

N

n-Bu 58

526

Pd(0)-Catalyzed Reactions of Dienes

Facile Pd(0)-catalyzed reactions of 2,3-alkadienyl derivatives 59 with nucleophiles occur via the formation of methylene-π -allylpalladium intermediates 60, from which 1,2- and 1,3-dienes 61 and 62 are formed depending on the nature of the pronucleophiles. These reactions are treated in Chapter 4.11. R2

R1 R2

R1

R1

Pd(0)

•

•

R2

Nu

Nu-H

OR

61

Nu

Pd

59

60

OR

R1

R2 62

In this section, Pd(0)-catalyzed reactions of allenes with nucleophiles are treated, which are clearly different mechanistically from the reactions explained in the above. Attack of nucleophiles may occur at C-1, C-2, and C-3 carbons of the allenes 63. Among them, attack at C-3 to give 64 is predominant. Most importantly, reactions of allenes with pronucleophiles start by the oxidative addition of pronucleophiles to Pd(0) to generate H-Pd-Nu 65. The formation of 64 by hydrocarbonation can be explained in two ways in the case where Nu-H is the carbon pronucleophile. As one possibility, hydropalladation of one of the two double bonds occurs to afford the terminal palladium intermediate 66, which is stabilized by the formation of π -allyl complex 67, and reductive elimination provides the C-3 adduct 68. Another possibility is carbopalladation to generate 69, and subsequent reductive elimination provides 68. Of these two possibilities, the hydropalladation mechanism is preferable. EWG H-Nu = pronucleophile

H

C

CN H

EWG

Y R1 1

2 •

3

+

EWG

R2

R1

H-OAc

H-NR2

Y = alkyl, aryl

Y

Pd(0)

H-Nu

C

H Nu

R2 63

64

H-Nu + Pd(0)

H-Pd-Nu 65 H

H-Pd-Nu R1

hydropalladation

•

R1

R1

H

R1

R2

R2

H Nu

R2

R2 Pd Nu

Pd-Nu 67

66

68

H-Pd-Nu R1 R2

•

carbopalladation

R1

Pd-H Nu

R2 69

R1

H Nu

R2 68

Reactions of Allenes

527

Various reactions of pronucleophiles with allenes has been reviewed by Yamamoto and Radhakrishnan [18]. Regioselectivity in these reactions is controlled by steric and electronic effects. The attack at C-3 is a main path, but several exceptional cases have been reported. Due to electronic bias, the hydrocarbonation of alkoxy- or phenoxyallenes 70 gives allylic ethers as the C-1 adduct 72 either exclusively or predominantly via π -allylpalladium 71 [19]. Trost expanded the regioselective formation of allylic ether to an asymmetric reaction. Addition of the Meldrum’s acid 74 to the allenyl ether 73 catalyzed by palladium trifluoroacetate and (S, S)-XIII-1 as a chiral ligand in the presence of trifluoroacetic acid afforded the the allylic ether 75 with 99 % ee in 75 % yield [20]. −

RO

Nu

Nu

RO

+ H-Nu

H 71 Pd

70

OR

+

72

O

Ph O

Ph

+ Me

H 73

O

O

Pd(CF3CO2)2, (S,S)-XIII-1

O O H

O

CF3CO2H, CH2Cl2 75%, 99% ee

Me

74

O O

O

75

The reaction of the phenylallenes substituted by EWG at para-position provides C-2 adducts exclusively or predominantly. A mixture of the C-2 adducts 79 and 80 was obtained regioselectively from p-trifluoromethylphenylallene (76). The reaction of phenylallene possessing electron-donating groups, such as methoxy, provides the C-3 adduct, and a mixture of the C-2 and C-1 adducts is formed from arylallenes bearing other substituents [21]. F3C + H

Me

CN

H

CN

Pd2(dba)3, DPPB

Me

F3C

CN CN

77

76

Pd

78

F3C

H

F3C +

Me CN 79

47%

Me

CN

CN 80

20%

Me

CN

5.2.2 Reactions with Pronucleophiles 5.2.2.1 Reactions with Carbon Pronucleophiles Gore et al. carried out the reaction of malonate and acetoacetate with deca-1,2diene (81) under basic conditions using DPPE as a ligand and obtained a mixture

528

Pd(0)-Catalyzed Reactions of Dienes

of C-3 adducts 82 and 84 as major products and C-1 adduct 83 as a minor product [22]. Yamamoto et al. found methylmalononitrile (77) is more reactive. The CN group seems to be more effective to activate pronucleophiles than carbonyl groups, and it is known that malononitrile is more reactive than malonate in some reactions. It should be noted that the addition of 77 to 3-phenyl-1,2-butadiene (85) proceeded in the absence of a base to give the C-3 adducts 86 and 87 using DPPB as a ligand. It is remarkable that carbon–carbon bond formation involving pronucleophiles occurs under neutral conditions [23]. H15C7

COMe

Pd2(dba)3, DPPE

CO2Me

EtONa, EtOH, 50%

+ 81

+

+

H15C7

CO2Me 82

Ph

MeOC

50%

+

83

Pd2(dba)3, DPPB

H

CN

THF, 75%

84

CO2Me

25%

77 H

CN CN

Me

2

10%

CN

85

H15C7

CO2Me

Me

Me

Ph

COMe

H15C7

COMe

CN

+

CN

Ph

Me Me

Me 86

H 87

As an intramolecular version, the vinylcyclopentane 89 was obtained from methyl 4,5-hexadienylcyanoacetate (88) by C-1 attack in 57 % yield using DPPF in the absence of a base [24]. In the intermolecular reaction of 2,3-butadienylmalononitrile (90) with the activated alkene 91, at first Michael-type addition of malononitrile to the alkene occurred to give 93, which underwent cyclization to give the cyclopentane 92 via the formation of hydridopalladium 94 [25]. Trost carried out the addition of bis(benzenesulfonyl)methane (96) to the allene 95 in the presence of t-BuOK using DMPPP [di(2-methoxyphenyl)phosphinopropane, IX-6] as a ligand to yield 97 [26]. Preparation of medium and large rings has been carried out by intramolecular reaction of various pronucleophiles with 1,2-dienes. The 12-membered ring 99 was obtained from the allene 98 in 55 % yield in the presence of AcOH as an acid and DMAP as a base [27].

CN

CN

(h3-allyl-PdCl)2 , DPPF THF, 70 °C, 57%

CO2Me

CO2Me 88

89

Reactions of Allenes CN

529

CN (h3-allyl-PdCl)2, DPPF

+ CN

Ph

90

CN

NC

91 CN

Michael addition

CN

THF, 100 °C, 71%

CN

Ph

NC 92

Ph

CN 91

Pd-H CN

Pd(0)

CN CN

NC

Ph

NC

CN

NC

Ph

NC 94

93

OH

OEt OEt

+

95

SO2Ph

(h3-allyl-PdCl)2, DMPPP

SO2Ph

t-BuOK, THF, 71%

96 OH

PhO2S

OEt OEt

SO2Ph 97

CN SO2Ph

CN

(h3-allyl-PdCl)2, DPPP

SO2Ph

AcOH, DMAP, 55% 99

98

5.2.2.2 Hydroamination Hydroamination of alkylallene was carried out using PPh3 as a ligand to give the corresponding allylic amines such as 100 [28]. Similarly, arylallene 101 was aminated at terminus to give the allylic amine 102 in high yield using DPPF as a ligand in the presence of AcOH [29]. Under similar conditions, 2,5-disubstituted pyrrolidine 104 was obtained from the hexa-4,5-dienylamine 103 in 80 % yield [30]. It should be pointed out that some Pd-catalyzed reactions of allenes with nucleophiles proceed by a different mechanism. The mechanistically interesting intramolecular reaction of allenylcarbamate 105 with acrolein afforded the oxazolinone 106 in the presence of Pd(OAc)2 and LiBr. This reaction is promoted by Pd(II), not by Pd(0) [31]. Unlike the Pd(0)-catalyzed reactions surveyed in the above section,

530

Pd(0)-Catalyzed Reactions of Dienes

H15C7

Pd2(dba)3, PPh3

+ Et2NH

H15C7

NEt2

Et3NI, THF, 70%

100

Me Me Pd2(dba)3, DPPF

+ HN(Bn)2

AcOH, THF, 80 °C, 99%

H

N(Bn)2 102

101 (h3-allyl-PdCl)2, DPPF Ph

AcOH, THF, 70 °C, 80%

NH

Ph

N Tf

Tf

104

103

intramolecular aminopalladation as shown by 107 generates alkenylpalladium intermediate 108, which undergoes insertion of acrolein to give the alkylpalladium 109. The last step is protonolysis of 109 to provide the saturated aldehyde 106 and regenerates Pd(II), and hence the whole reaction proceeds catalytically with Pd(II). A similar catalytic reaction via oxypalladation using Pd(II) was reported [32] (see Chapter 2.5). • O

NHTs

CHO

Pd(OAc)2,LiBr

+

CHO

THF, rt, 74%

O

O

N-Ts 106

O

105

Pd(II) H+ Pd(II)

•

Pd(II) Pd(II)

O

NHTs

O

N-Ts

107

O

N-Ts O

O

O

CHO

CHO

108

109

5.2.2.3 Reactions of Oxygen Nucleophiles Allylic acetate 110 was obtained by regioselective hydroacetoxylation of phenylallene at the terminal double bond. DPPF is the most effective ligand. The reaction is explained by hydropalladation of allene with H-Pd-OAc to form π -allylpalladium acetate 111 and reductive elimination [33]. Addition of secondary alcohol 112 to 1-methoxyallene (113) occurred selectively at the C-1 position as expected to form the acetal 114 using Pd(OAc)2 and DPPP [34]. The reaction of the alcohol 115 with benzyloxyallene was applied to the synthesis of highly functionalized acetal 116 [35].

Reactions of Allenes Ph •

+ AcOH

Pd2(dba)3, DPPF

531 Ph

OAc

THF, 83% 110

H-Pd-OAc

Ph

Pd OAc 111

+ MeO

Pd(OAc)2, DPPP

•

Et3N, MeCN, 98%

OMe

O

MeO2C

OH

MeO2C 112

113

114

O + BnO

O

O

O

O

O

O

O Pd(OAc)2, DPPP •

Et3N, MeCN, 99%

O

OH OBn

116

115

5.2.3 Carbonylation Few studies on Pd-catalyzed carbonylation of allenes have been reported. Grigg carried out the carbonylation of allene in the presence of phenol under 1 atm at 100 ◦ C and obtained phenyl methacrylate (117) by the attack of the central carbon [36]. Carbonylation in the presence of secondary amine and AcOH occurred at the C-2 position to give α,β-unsaturated amides such as 118 [36]. Me

Pd(PPh3)4,LiBr + CO + PhOH

•

1 atm, 100 °C

CO2Ph 117

n-Oct n-Oct

Me

Pd(PPh3)4, AcOH •

+ CO +

N H

THF, 110 °C, 64%

N O 118

532

Pd(0)-Catalyzed Reactions of Dienes

On the other hand, thiocarbonylation of simple allenes such as 119 with benzenethiol afforded the β,γ -unsaturated thioester 120 in good yield. Attack of CO at the terminal carbon occurred. Somewhat unexpectedly, thiocarbonylation of methoxyallene 113 also took place at the C-3 carbon to give the thioester 121 [37].

•

+ CO + PhSH

Pd(OAc)2, PPh3 CO2SPh

THF, 100 °C 25 atm, 94%

119

120

MeO •

+ CO + PhSH

Pd(OAc)2, PPh3

MeO CO2SPh

THF, 100 °C 25 atm, 83%

113

121

5.2.4 Hydrometallation and Dimetallation Facile metallation of allenes offers convenient synthetic methods of functionalized alkenes. Pd-catalyzed cis hydrostannation of allenes proceeds smoothly via either hydropalladation or stannylpalladation of 1,2-dienes with H-Pd-SnBu3 to produce allylstannanes 122 or vinylstannane 123 [38]. H-SnBu3 R

R

SnBu3

• R •

+ HSnBu3

122

SnBu3-H R

R

SnBu3

• HSnBu3 + Pd(0)

H-Pd-SnBu3

CH3 123

Hydrostannation of arylallenes such as 124 proceeded regio- and stereoselectively to provide allylstannane 125 [39]. Reaction of allenyl silyl ethers such as 126 also proceeded regioselectively to produce allylstannanes. A mixture of the stereoisomers 127 and 128 was obtained, but in this case the Z isomer 128 was obtained predominantly. As shown above, allylstannanes are obtained by metallation at the terminal carbon [40]. However, Lautens et al. reported that the vinylstannane 130 was obtained from alkylallene 129 when ligandless heterogeneous Pd(OH)2 on carbon was used as a catalyst. It was confirmed that the allylstannane 131 was obtained when Pd(PPh3 )4 was used. The catalysts changed the selectivity [41]. As a synthetic application, Grigg applied the regioselective hydrostannation of alkoxyallene to the hydrostannation–cyclization sequence, and obtained the benzodihydrofuran 134 from the allenyl ether 132 via the allylstannane 133 in one pot [42].

Reactions of Allenes

533

MeO

MeO •

+ HSnBu3

Pd(PPh3)4 75%

SnBu3

124

125

E : Z = 95 : 5 TBDMSO

Pd(PPh3)4

+ HSnBu3

•

72%

126 SnBu3 TBDMSO

SnBu3

+ TBDMSO

23 : 87 127

128 OH

SnBu3

Pd(OH)2/C OH

THF, rt, 58% •

Ph

Ph 130

+ HSnBu3

OH Pd(PPh3)4

129

SnBu3

THF, rt, 55%

Ph 131

SnBu3 I + HSnBu3 O 132

Pd(PPh3)4

I

THF

Pd(0), Et4NCl O

133

O

MeCN, 134 85%

Stereoselective allylation of aldehydes via Pd-catalyzed in situ hydrostannation of allenes using SnCl2 was carried out by Chang. In this reaction, the π allylpalladium 137 is generated by hydropalladation of the alkylallene 135 with H-Pd-Cl, and umpolung of 137 with SnCl2 occurs to give the allylstannane 138. Then the homoallyl alcohol 136 is formed by the reaction of 138 with aldehyde [43]. Pd-catalyzed dimetallation of allenes with dimetallic reagents has been studied extensively. For example, regioselective 1,2-disilylation of alkylallene gave 139 [44]. Regio- and stereoselectivities in Pd-catalyzed silylstannation (silastannation) of allenes are not always satisfactory. They are markedly improved by the use of phosphine-free Pd catalyst, particularly Pd2 (dba)3 . The allylstannane 141 was

534

Pd(0)-Catalyzed Reactions of Dienes OH Me •

+ SnCl2 + PhCHO

Me

PdCl2(PPh3)2

Ph

HCl, DMF, rt, 95%

Me

Me

135

136

H-Pd-Cl PhCHO

SnCl3

SnCl2 Pd Cl 137

138

SiMe3 Me +

•

Pd(PPh3)4 Me3SiSiMe3

Me SiMe3 139

obtained regio- and stereoselectively in high yield by the silylstannation of 1,2heptadiene with Me3 Si-SnBu3 (140). Silylpalladation to form π -allylpalladium 142 is the first step, and reductive elimination gives rise to the 1-stannyl-2-silyl-2heptene 141 [45]. This regioselective silylstannation is a useful reaction, because selective transformations of the silyl and stannyl groups in 141 to other functional groups are possible. n-Bu •

+

Me3Si-SnBu3

Pd2(dba)3 toluene, rt, 90%

140

SiMe3

H

n-Bu

SnBu3 141

Me3Si-Pd-SnBu3

SiMe3

•

n-Bu

n-Bu Pd SnBu3 142

Inter- and intramolecular versions of regioselective silylstannation of allenes with 140 have been utilized for the preparation of functionalized cyclic compounds. Silylstannation–cyclization of 5-aza-nona-1,2,7,8-tetraene (143) with 140 using Pd(PPh3 )4 gave trans-1,2-(1-silylvinyl)(1-stannylvinyl)cyclopentane

Reactions of Allenes

535

144 [46]. Silylstannation–cyclization of octa-1,2-dien-7-yne (145) with 140 proceeded cleanly via π -allylpalladium intermediate 146 to give the cyclized product 147 by using P(C6 F5 )3 as a ligand. It is claimed that P(C6 F5 )3 is a better ligand than PPh3 [47]. SiMe3 +

TsN

Me3Si-SnBu3

Pd(PPh3)4, dioxane TsN

THF reflux, 78%

140

SnBu3 143

144

E

+ Me3Si-SnBu3

E

Pd2(dba)3, P(C6F5)3

E

71%

E

140

SiMe3 Pd

SiMe3 SnBu3

E = CO2Et

145

E SnBu3

E 147

146

Silylstannation of the allenyl aldehyde 148 with 140 in THF at room temperature generated the allylstannane 149, which attacked intramolecularly the formyl group to yield the cyclic homoallylic alcohol 150. Phosphine-free π -allylpalladium chloride was the most effective catalyst [48].

SiMe3

TsN CHO

+

Me3Si-SnBu3 140

(h3-allyl-PdCl)2 THF, rt, 71%

SnBu3 TsN CHO

148

149 H

SiMe3

TsN OH H 150

Borylsilylation (borasilylation) of alkylallene 151 with the silylborane 152 provided the 2-boryl-3-silyl-1-alkene 153 regioselectively in 99 % yield. Hindered 2,6-xylyl isocyanide (154) was the effective ligand for the reaction [49]. A similarly good result was obtained by using Pd2 (dba)3 in combination with cyclic phosphite (III-2) as a catalyst [50]. A mixture of the allylphosphonate 156 and alkenylphosphonates 157 and 158 was obtained by the Pd-catalyzed hydrophosphorylation of 1,2-heptadiene with 4,4,5,5-tetramethyl-1,3,2-dioxaphospholane-2-oxide (155) using Pd(PPh3 )4 as a catalyst. When PdMe2 (dppf) was used, the allylphosphonate 156 was obtained regioselectively in 87 % yield [51]. The allylphosphonium salts such as 159 were

536

Pd(0)-Catalyzed Reactions of Dienes

Ph +

PhMe2Si

O

Pd(acac)2, Ar-NC

O

octane, 120 °C 99%

B

151

O

O B Ph

152

SiMe2Ph 153

Ar-NC =

NC

154

prepared by Pd-catalyzed addition of PPh3 to allenes in the presence of methanesulfonic acid. Various 1,3-dienes were prepared by a Wittig-type reaction of the salts such as 159 with aldehydes [52]. n-Bu

O

Pd(PPh3)4, dioxane

O

90%

+ H(O)P 155

n-Bu

P O

n-Bu

O O

P

+

O

O O

n-Bu P O

+

O O

158

156

157 66 : 32 : 2

with PdMe2(dppf)

Bn

+ PPh3

156 = 87% 1. Pd(PPh 3)4, THF, MeSO3H −10 °C, 82%

PPh3+

Bn 159

2. NaClO 4, EtOH 82%

ClO4−

5.2.5 Miscellaneous Reactions Dimerization of alkylallene 160 proceeded regioselectively at each C-2 carbon, and the cross-conjugated triene 161 was obtained in high yield using P(o-Tol)3 as a ligand and p-nitrophenol as an additive [53]. In the presence of formic acid, reductive dimerization at C-2 carbons occurred to give the conjugated dienes 164 and 165. The dimerization is explained by the formation of the palladacycle 163, formed by oxidative cyclization, as an intermediate [54]. Pd2(dba)3, P(o-Tol) 3

p-NO2C6H4OH THF, 96%

C7H15 160

Me

C7H15 + HCO2H

HO C7H15 161

162

Reactions of Methylenecyclopropanes

537

HO HO

OH

OH

Pd(PPh3)4, DMF

HCO2H

164 +

30 °C, 42% Pd 163

1:1

HO

OH 165

5.3 Reactions of Methylenecyclopropanes 5.3.1 Introduction Methylenecyclopropanes (MCPs) 166 show unique reactivity mainly due to high strain, and are attracting the attention of synthetic chemists. Many studies have been carried out on their transition metal-catalyzed reactions, particularly cycloadditions with unsaturated polar bonds. A comprehensive review on recent advances in metal-catalyzed reactions of MCPs by Nakamura and Yamamoto is available [55]. In this section, typical Pd-catalyzed addition reactions are mainly surveyed. Although MCPs are rather simple compounds, they undergo a variety of Pd-catalyzed reactions. Different reactions take place depending on the structures of the MCPs, reacting substrates, and catalysts, and some of the reactions are mechanistically complicated and not easily understood. Formally Pd-catalyzed reactions of MCPs may be explained by two palladacycles 167 and 168, formed by oxidative addition of MCP with cleavage of the distal and proximal bonds. These intermediates are not enough to explain all reactions. In addition, two types of addition patterns of Pd complexes to the exomethylene to provide 169 and 170 should be considered as intermediates. Pd(0)

distal

Pd

R-Pd-A R

167 166 Pd

Pd(0)

proximal

168

Pd-A 169

R-Pd-A A-Pd

R 170

5.3.2 Hydrostannation and Dimetallation Hydrometallation proceeds by proximal bond cleavage. Addition of HSnBu3 affords the homoallylstannane 172 [56]. The addition may be understood formally by the formation of the palladacycle 171, but explanation by the formation of the cyclopropylcarbinylpalladium 173 is more appropriate. The intermediate 173 undergoes β-carbon elimination to generate the homoallylpalladium 174, which then gives rise to 172 by reductive elimination. Addition of HSnBu3 to a substituted MCP 175 to yield 176 can be understood by this mechanism.

538

Pd(0)-Catalyzed Reactions of Dienes SnBu3

Pd(0)

+ HSnBu3

Pd H

166

SnBu3

H

172

171

Pd(0)

Pd-SnBu3 + H-Pd-SnBu3

Bu3SnPd

H 173

H Pd(PPh3)4 Me

HO

90%

174

H Me

SnBu3

SnBu3 Cy

Me

HO

Cy 175

Cy

H

176

OH

Dimetallation may be understood by participation of both palladacycles 167 and 168. In general, addition of dimetallic reagents occurs via the palladacycles 177 with cleavage of the proximal bond to provide 178. For example, borylsilylation of the MCP 179 with 180 gave 181 using a combination of Pd(OAc)2 with t-octyl isocyanide (XVII-6). On the other hand, addition via the distal bond cleavage was observed in the reaction of the same reagent 180 with the MCP 182, and the product 183 was obtained via 184 [57]. Pd(0)

MR

RM-MR Pd

Pd

RM

168

MR

MR

178

177 Ph Ph

SiMe2Ph

O

+

Pd(OAc)2 SiMe2Ph

B O 180

179

+

B

t-Oct-NC O

O 181

O

SiMe2Ph O

Pd2(dba)3, P(OEt)3 B

SiMe2Ph

O

73%

B O

182

183

180 Pd

SiR3 Pd B(OR)2

184

5.3.3 Hydrocarbonation and Hydroamination Two products 186 and 187 are obtained by the addition of carbon pronucleophiles (Nu-H) by the cleavage of both distal and proximal bonds in 185. These reactions look somewhat complicated and their mechanisms are not easily understood.

Reactions of Methylenecyclopropanes

539 H

R Nu + R

H

+ H-Nu

Me

R

185

Nu 186

187

Reaction of MCP 179 with deuterated methylmalononitrile (188) catalyzed by Pd(PPh3 )4 gave rise to the proximal bond cleavage product 189 in 86 % yield, which is deuterated at C-2 exclusively. This product corresponds to 187 [58]. The reaction of 179 with 188 starts by the addition of Nu-Pd-D to the methylene bond to generate the cyclopropylcarbinylpalladium 190, which is converted to 191 by β-carbon elimination. Then the rather unusual rearrangement of 191 to the π -allylpalladium intermediate 192 takes place. The rearrangement can be understood by elimination of H-Pd-Nu from 191 and readdition. Then reductive elimination provides 189. Me

D Me

Ph + D

CN

Ph

1

Mechanism Ph

Me 189

188

Nu-D

CN

2

3

THF, 86%

CN 179

CN

Pd(PPh3)4

179 D

Ph

Ph Nu-Pd

Pd-Nu

D

Ph

Me

Ph

Nu

D

D

Pd

191

190

189

Nu

Me

192

On the other hand, addition of methylmalononitrile (188) to the MCP 193 gave the distal bond cleavage product 194 in 82 % yield, which is deuterated at the C-3 position. Obviously, the product 194 corresponds to 186. The reaction starts from the addition product 195, which is converted to the allylpalladium 196 by β-carbon elimination, and then to the π -allylpalladium intermediate 197. The final product 194 is obtained from 197. Me

Me

R

+ D

CN

Pd(PPh3)4

CN

R 3

THF, 82%

1

R = Ph(CH2)3−

188

D

188

194

193

R

R

R

CN

2

CN

193

Mechanism R

R Pd

D

Pd-Nu 195

Pd-Nu D

D 196

Nu 197

Nu

D 194

Ketones are allylated with MCPs using Pd(PPh3 )4 as a catalyst under neutral conditions [59]. Reaction of acetophenone (199) with MCP 198 afforded the allylated acetophenone 200 in 79 % yield. The reaction is understood by the generation of H-Pd-CH2 COPh under neutral conditions, and the addition to form 201. The

540

Pd(0)-Catalyzed Reactions of Dienes

rearrangement of 201 via β-carbon elimination to the π -allylpalladium enolate 202 and reductive elimination provide 200.

Pd(PPh3)4

+ Ph

n-Bu 198

n-Bu

O

O

n-Bu

Me

n-Bu

Ph

79%

200

199

n-Bu

n-Bu

n-Bu O

O

Pd H

n-Bu

Pd

Ph

Ph 201

202

Interesting hydrofurylation of MCP 198 with furans occurs by activation of the CH bond in furans, involving distal bond cleavage [60]. Reaction of the furan 203 with the MCP 198 afforded the 2-allylated furan 204 by using Pd(PPh3 )4 . Interestingly the addition of tributylphosphine oxide is important for the smooth reaction. The reaction starts by the oxidative addition of the C-H bond of furan to Pd(0) to form 205, and the addition to 198 generates 206. Subsequent rearrangement of 206 to the π -allylpalladium 207 and reductive elimination provide the allylated furan 204. n-Bu + H

n-Bu 198

H-Pd

O 205

Me

O 203

Me

Pd(PPh3)4

n-Bu

P(O)Bu3, 70%

n-Bu

O 204

n-Bu

n-Bu Pd

n-Bu

Me

H

n-Bu

H Pd 206

Fu

Fu

H

Fu = 5-methyl-2furyl

207

The distal bond cleavage occurs in hydroamination. Reaction of MCP 208 with dibenzylamine afforded the allylic amine 209 by using the combination of π allylpalladium chloride with DPPP as a catalyst [61]. Similarly sulfonamide 211 was allylated with MCP 210 to produce the diallylated amide 212 using a complex mixture of Pd(0), Pd(II), and PPh3 as a catalyst [62]. The use of Pd(0)-PPh3 in an appropriate ratio seems to be effective. Ph + NHBn2 208

(h3-allyl-PdCl)2 DPPP, DME, 91%

NBn2 Ph 209

References n-Hep + NH2Ts Me

Pd(PPh3)4, Pd(OAc)2

541

NTs

n-Hep

PPh3, toluene, 100%

211

Me

210

2

212

References 1. J. Tsuji, Adv. Organomet. Chem., 17, 141 (1979); Acc. Chem. Res., 6, 8 (1973). 2. R. Jackstell, M. G. Andreu, A. Frisch, K. Selvakumar, A. Zapf, H. Klein, A. Spannenberg, D. R¨ottiger, O. Breil, P. Karch, and M. Beller, Angew. Chem. Int. Ed., 41, 986 (2002); F. Vollm¨uller, W. M¨agerlein, S. Klein, J. Krause, and M. Beller, Adv. Synth. Catal., 343, 29 (2002). 3. J. E. L. Lullius, P. A. Z. Suarez, S. Eninloft, R. F. de Souza, J. Dupont, J. Fischer, and A. D. Cian, Organometallics, 17, 815 (1998). 4. A. Krotz, F. Vollm¨uller, G. Stark, and M. Beller, Chem. Commun., 195 (2001). 5. T. Prinz and B. Driessen-H¨olscher, Chem. Eur. J., 5, 2069 (1999); T. Prinz, W. Keim, and B. Driessen-H¨olscher, Angew. Chem. Int. Ed. Engl., 35, 1708 (1996). 5a. M. S. Viciu, F. K. Zinn, E. D. Stevens, and S. P. Nolan, Organometallics, 22, 3175 (2003). 6. T. Minami, H. Okamoto, S. Ikeda, R. Tanaka, F. Ozawa, and M. Yoshifuji, Angew. Chem. Int. Ed., 40, 4501 (2001). 7. O. L¨ober, M. Kawatsura, and J. F. Hartwig, J. Am. Chem. Soc., 123, 4366 (2001). 8. J. W. Han and T. Hayashi, Chem. Lett., 976 (2001); Tetrahedron: Asymmetry, 13, 325 (2002). 9. W. J. Xiao and H. Alper, J. Org. Chem., 66, 6229 (2001). 10. R. Benn, P. W. Jolly, R. Mynott, B. Raspel, S. Schenker, K. P. Schick, and G. Schroth, Organometallics, 4, 1945 (1985); P. W. Jolly, R. Mynott, B. Raspel, and K. P. Schick, Organometallics, 5, 473 (1986). 11. H. Nakamura, K. Aoyagi, J. G. Shim, and Y. Yamamoto, J. Am. Chem. Soc., 123, 372 (2001). 12. K. Ohno, T. Mitsuyasu, and J. Tsuji, Tetrahedron Lett., 67 (1971); Tetrahedron, 28, 3705 (1972); P. Haynes, Tetrahedron Lett., 3687 (1970); P. M. Manyik, W. E. Walker, K. E. Atkins, and E. S. Hammack, Tetrahedron Lett., 3813 (1970). 13. K. Ohno and J. Tsuji, J. Chem. Soc., Chem. Commun., 247 (1971). 14. J. Kiji, T. Okano, T. Nomura, K. Saiki, T. Sai, and J. Tsuji, Bull. Chem. Soc. Jpn., 74, 1939 (2001). 15. D. R. Coulson, J. Org. Chem., 38, 1473 (1973). 16. R. Zimmer, C. U. Dinesh, E. Nandana, and F. A. Khan, Chem. Rev., 100, 3067 (2000). 17. I. Shimizu and J. Tsuji, Chem. Lett., 233 (1984). 18. Y. Yamamoto and U. Radhakrishnan, Chem. Soc. Rev., 28, 199 (1999). 19. Y. Yamamoto and M. Ali-Masum, Synlett, 969 (1995). 20. B. M. Trost, C. J¨akel, and B. Pietker, J. Am. Chem. Soc., 125, 4438 (2003). 21. Y. Yamamoto, M. Ali-Masum, N. Fujiwara, and M. Asao, Tetrahedron Lett., 36, 2811 (1995). 22. L. Besson, J. Gore, and B. Cazes, Tetrahedron Lett., 36, 3853 (1995). 23. Y. Yamamoto, M. Ali-Masum, and M. Asao, J. Am. Chem. Soc., 116, 6019 (1994). 24. M. Meguro, S. Kamijo, and Y. Yamamoto, Tetrahedron Lett., 37, 7453 (1996). 25. M. Meguro and Y. Yamamoto, J. Org. Chem., 64, 694 (1999). 26. B. M. Trost and V. J. Gerusz, J. Am. Chem. Soc., 117, 5156 (1995). 27. B. M. Trost, P. Y. Michellys, and V. J. Gerusz, Angew. Chem. Int. Ed. Engl., 36, 1750 (1997). 28. L. Besson, J. Gore, and B. Cazes, Tetrahedron Lett., 36, 3857 (1995). 29. M. Ali-Masum, M. Meguro, and Y. Yamamoto, Tetrahedron Lett., 38, 6071 (1997). 30. M. Meguro and Y. Yamamoto, Tetrahedron Lett., 39, 5421 (1998).

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Pd(0)-Catalyzed Reactions of Dienes G. Liu and X. Lu, Org. Lett., 3, 3879 (2001). G. Liu and X. Lu, Tetrahedron Lett., 44, 127 (2003). M. Al-Masum and Y. Yamamoto, J. Am. Chem. Soc., 120, 3809 (1998). F. P. J. T. Rutjes, T. M. Kooistra, H. Hiemstra, and H. E. Schoemaker, Synlett, 192 (1998). H. Ovaa, M. A. Leewenburgh, H. S. Overkleeft, G. A. van der Marcel, and J. H. van Boom, Tetrahedron Lett., 39, 3025 (1998). R. Grigg, M. Monteith, V. Sridharan, and C. Terrier, Tetrahedron, 54, 3885 (1998). W. J. Piao, G. Vasapollo, and H. Alper, J. Org. Chem., 63, 2609 (1998). N. D. Smith, J. Mancuso, and M. Lautens, Chem. Rev., 100, 3257 (2000). V. Gevorgyan, J. X. Liu, and Y. Yamamoto, J. Org. Chem., 62, 2963 (1997). K. Koerber, J. Gore, and J. M. Vatele, Tetrahedron Lett., 32, 1187 (1991). M. Lautens, D. Ostrovsky, and B. Tao, Tetrahedron Lett., 38, 6343 (1997). R. Grigg and J. M. Sansano, Tetrahedron, 52, 13441 (1996). H. M. Chang and C. H. Cheng, Org. Lett., 2, 3439 (2000). H. Watanabe, M. Saito, N. Sutou, K. Kishimoto, J. Inose, and Y. Nagai, J. Organomet. Chem., 225, 343 (1982). M. Jeganmohan, M. Shanmugasundaram, K. J. Chang, and C. H. Cheng, Chem. Commun., 2552 (2002). S. K. Kang, T. G. Baik, A. N. Kulak, Y. H. Ha, Y. Lim, and J. Park, J. Am. Chem. Soc., 122, 11529 (2000). S. Shin and T. V. RajanBabu, J. Am. Chem. Soc., 123, 8416 (2001). S. K. Kanf, Y. H. Ha, B. S. Ko, Y. Lim, and J. Jung, Angew. Chem. Int. Ed. 41, 343 (2002). M. Suginome, Y. Ohmori, and Y. Ito, Synlett, 1567 (1999). S. Onozawa, Y. Hatanaka, and M. Tanaka, Chem. Commun., 1863 (1999). C. Q. Zhao, L. B. Han, and M. Tanaka, Organometallics, 19, 4196 (2000). M. Arisawa and M. Yamaguchi, Adv. Synth. Catal., 343, 27 (2001). M. Arisawa, T. Sugihara, and M. Yamaguchi, Chem. Commun., 2615 (1998). C. H. Oh, H. S. Yoo, and S. H. Jung, Chem. Lett., 1288 (2001). I. Nakamura and Y. Yamamoto, Adv. Synth. Catal., 344, 111 (2002). M. Lautens, C. Meyer, and A. Lorenz, J. Am. Chem. Soc., 118, 10676 (1996). M. Suginome, T. Matsuda, and Y. Ito, J. Am. Chem. Soc., 122, 11015 (2000). N. Tsukada, A. Shibuya, I. Nakamura, and Y. Yamamoto, J. Am. Chem. Soc., 119, 8123 (1997). D. H. Camacho, I. Nakamura, B. H. Oh, S. Saito, and Y. Yamamoto, Tetrahedron Lett., 43, 2903 (2002). I. Nakamura, A. I. Siriwardana, S. Saito, and Y. Yamamoto, J. Org. Chem., 67, 3445 (2002). I. Nakamura, H. Itagaki, and Y. Yamamoto, J. Org. Chem., 63, 6458 (1998). M. Shi, Y. Chen, and B. Xu, Org. Lett., 5, 1225 (2003).

Chapter 6 Pd(0)-Catalyzed Reactions of Propargyl Compounds

6.1 Introduction and Classification of Reactions Pd(0)-catalyzed reactions of various propargyl compounds proceed by the formation of either the σ -allenylpalladiums 1 or the propargylpalladiums (or σ -prop-2ynylpalladiums) 2 as intermediates. R1 R3

R2

R1

Pd(0)

+

• R3

X

R1

R2 R3

Pd 1

R2 Pd-X 2

X

The Pd(0)-catalyzed reactions of propargyl compounds so far discovered can be classified into several types from a mechanistic viewpoint [1]. The σ -allenylpalladium complexes 1 as intermediates undergo three types of transformations depending on reactants. The first one is insertion of unsaturated bonds to the σ -bond. The insertions of alkenes, alkynes, and CO generate the alkylpalladium 3, 1,3,4-trienylpalladium 4, and acylpalladium compounds 5, respectively. These intermediates undergo further transformations. R5 R1

R4

•

R6

R4

R3

4

X

CO

Pd-X R2

R7

•

R7

Pd 1

3

R1

R2

R3

R5

• R3

Insertion R1

R2

R6

R1

R2 •

R3

Pd-X

O

5 Pd-X

Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

544

Pd(0)-Catalyzed Reactions of Propargyl Compounds

The second type of reactions proceed by transmetallation of the complexes 1. MR (M = main group metals) and metal hydrides MH undergo the transmetallation with 1 to generate 6. Subsequent reductive elimination gives the allene derivative 7. Also reactions of 1 with 1-alkynes in the presence of CuI to afford allenylalkynes belong to this type. Transmetallation R1

R2 •

R3

R1

M-R

X

R1

• Pd 6

MX

R2 •

R3

Pd 1

R2

R 7

R

M = Mg, Zn, B, Si, Cu

+ Pd(0)

R3

R = aryl, alkenyl, alkynyl, H

The third type of reactions occur by attack of a nucleophile at the central sp carbon of the allenyl system in 1. Reactions of soft carbon nucleophiles, as well as oxygen and nitrogen nucleophiles belong to this type. The attack of the nucleophile generates the intermediates 8, which are regarded as palladium–carbene complexes 9. The intermediates 8 pick up a proton from the substrate to form the π -allylpalladium complexes 10, which undergo further reactions with a nucleophile as expected; hence two nucleophiles are introduced to give the alkenes 11. Nucleophilic attack R1 •

Nu

R2 NuH

Nu R2

R2 _

H

-X

R1

X-Pd

1

R2 Pd

8 Nu

R1

HX

Nu

R1

• X-Pd

H

X-Pd

R1

_

Nu R2

Nu

R1

R2

H

Pd

X-Pd

9

NuH

R1

Nu R2

HX

X

11

10

Two reactions via the propargylpalladiums 2 (12), namely, hydrogenolysis to form alkynes 13 and β-H elimination to give enynes 14, are known. Reaction of propargylpalladium R

R MeO2CO

R

+ Pd(0)

X-Pd

R 12

hydrogenolysis

R H

β-H elimination

R 13

R R 14

Reactions via Insertion of Alkenes and Alkynes

545

Several propargyl derivatives can be used for the Pd-catalyzed reactions, but they have different reactivities. Although propargyl alcohols are most easily available, they are less reactive substrates. Their esters such as acetates, carbonates, and phosphates are reactive, however. Propargyl carbonates 15 undergo various Pd-catalyzed reactions smoothly, especially under neutral conditions, because the σ -allenyl(methoxy)palladiums 16 are generated, which pick up a proton from pronucleophiles. Also 2-(1-alkynyl)oxiranes 17 undergo facile reactions under neutral conditions by forming the alkoxyallenylpalladium complexes 18 as an intermediate. Pd(0)

1

R

R

3

+ Pd(0)

1

R2 •

3

R

R

OCO2Me

OCO2Me

15

R1

R2

R2

MeO

Pd

R3

16

CO2 Pd(0)

R2

R1

R3

R1

+

O

R2 •

Pd

O

17

_

R3

18

6.2 Reactions via Insertion of Alkenes and Alkynes Smooth insertion of alkene 19 into the σ -allenylpalladium bond generates 20, and subsequent β-H elimination affords 1,2,4-trienes 21. Intramolecular domino reactions proceed smoothly to afford cyclic compounds [2]. Domino 5-exo cyclization of the carbonate 22 generated the allenyl intermediate 23, and 3-exo cyclization of 23 gave the cyclopropane 24, which was converted to a dimeric product 25 [3]. R1 R2

R3

1 Pd(0) R

+ 19

OCO2Me 15

Y

R3 •

R1 Pd OMe

R2 H

Y

20

R2 Pd(0) MeOH PdOMe

E OCO2Me

E

Pd(OAc)2, PPh3

E

MeCN, 85 °C

E

E = CO2Me

22

23

E E

E E

E

MeOPd 24

25

E 36%

R3 • 21

Y

546

Pd(0)-Catalyzed Reactions of Propargyl Compounds

The allenylpalladium 27, formed from the carbonate 26, undergoes 5-exo cyclization to give 28 and its 3-exo cyclization, without β-H elimination, generates the bicyclo[3.1.0]hexane system 29, which has no β-hydrogen to be eliminated. Thus transmetallation of 29 with the tin reagent 30, followed by reductive elimination affords the azabicyclo[3.1.0]hexane 31 diastereoselectively [4]. The synthesis of (−)-α-thujone was achieved by diastereoselective domino cyclization of the chiral carbonate 32, and trapping with dimethylzinc to give 33 as a key reaction [5]. OCO2Me Et

Et •

X-Pd •

Pd-X

Pd-X

Et

Et

Pd(OAc)2 PPh3, THF 85%

N

N

N

SO2Ph

SO2Ph

SO2Ph

SO2Ph

26

27

28

29

N

S H

SnBu3

S

Et

30

H

N 31

PhO2S

PhO2S

SO2Ph Me (R)

SO2Ph

PhO2S

SO2Ph Me

Pd2(dba)3

Me2Zn

X-Pd

SO2Ph Me

(R) Me

H

H 33

OCO2Me O

32

steps

Me

(R) (S)

(R) H

(-)-a-thujone

Insertion of triple bonds generates the 1,3,4-trienylpalladium intermediates 4, which undergo further transformations. Domino cyclizations of the propargyl carbonate 34 with two more triple bonds provided 38 smoothly in surprisingly high yield (82 %). The reaction is understood by 6-exo-dig and 5-exo-dig cyclizations of 35 to generate 36, followed by 6-exo-trig cyclization to give 37. The β-H elimination gave rise to 38 [6].

Reactions via Insertion of Alkenes and Alkynes

547

OCO2Me CO2Me

Pd(PPh3)4

CO2Me

MeCN, 2 h 82%

CO2Me

PdOMe

CO2Me N

N Ts

Ts

34

35

XPd 6-exo-dig

6-exo-trig

CO2Me

5-exo-dig

CO2Me N Ts

36

Pd-X CO2Me

CO2Me

CO2Me

CO2Me

N

N 37

Ts

Ts

38

The Pd-catalyzed reaction of o-alkynylphenol 39 with tertiaryl propargyl carbonate 40 gave the 2-substituted 3-allenylbenzo[b]furan 43 under neutral conditions. Attack of phenoxide anion to the triple bond from the opposite side of σ -allenylpalladium intermediate as shown by 41 generates allenyl(benzofuryl)palladium intermediate 42, and the coupling product 43 is formed by reductive elimination [7].

C5H11

OCO2Me +

Me Me 40

OH 39

H

Me

X-Pd

Me C5H11

Pd(PPh3)4 MeCN, 2 h 77% OH

Me H

Me

Me

Pd

O 42

Me C5H11

C5H11

O 43

41

548

Pd(0)-Catalyzed Reactions of Propargyl Compounds

Similarly 2-substituted 3-allenylbenzo[b]furan 45 was prepared by the Pd-catalyzed reaction of the propargyl o-(alkynyl)phenyl ether 44. The isomer 46 was a minor product [8]. Ph

Pd(PPh3)4, K2CO3 DME, 90%

O 44 Me

Me

+

O

Me

O

Ph

45

Ph 46

73 : 27

Propargyl ethyl carbonate 47 substituted with bulky TBDMS group underwent an interesting reductive coupling via propargylpalladium intermediate to give the allenylalkyne 50 as a major product and the 1,5-diyne 51 as a minor product. The reaction is explained by insertion of the triple bond of 47 to propargylpalladium 48 to generate 49, followed by β-carbonate elimination to afford 50 [9].

Pd(PPh3)4

R3Si OCO2Et 47

R3Si

R3Si

OCO2Et

Pd

toluene reflux 75%

EtO2CO 48 R3Si

OCO2Et

R3Si R3Si 49

Pd

R3Si

•

R3Si = TBDMS

+

R3Si

OCO2Et 50

91 : 9

R3Si 51

6.3 Carbonylations Propargyl compounds undergo facile mono- and dicarbonylations depending on reaction conditions [10]. Monocarbonylation proceeds under mild conditions using propargyl carbonates [11]. Firstly CO insertion into the allenylpalladium intermediate generates the acylpalladium 52, which reacts with alcohol to give the 2,3alkadienoate 53. Under certain conditions, isomerization of 53 to the 2,4-dienoate 54 occurs. Carbonylation of propargyl carbonates under mild conditions stops at this stage. Under a high pressure of CO, or in the presence of an activating group (for example, R3 = CO2 R), further attack of CO at the central sp carbon of the allenyl system in 53 takes place to give the diester 55.

Carbonylations

549 R1

R1 + CO

R3 R2

R3 •

Pd(0)

O

R2

OCO2Me

Pd OMe

52 R1

R1

R3 •

R3

R2

R2

CO2Me

CO2Me 53

R1

54 R1

R3 + CO + R

• R2

4OH

CO2R4

Pd(0) R3

R2

CO2R4 53

55

CO2R4

The carbonylation of the propargylamine 56 in the presence of TsOH gave 2,3-alkadienamides 57 by insertion of CO with cleavage of propargylic C—N bond [12].

+ CO

Ph NBn

O

Pd2(dba)3, DPPP, THF CH2Cl2, 40 atm, 100 °C, 82%

Et

Et

56

•

BnN Ph

57

Cross-coupling of the propargyl carbonate 58 with the indolylborate 59 gave the allenyl ketone 60, which, without isolation, underwent 1,4-addition to the allenyl ketone in 60 to afford the cyclopenta[b]indole derivative 61 [13]. OCO2Me (CH2)3-Cl

PdCl2(PPh3)2, THF

+ CO + N Me

58

BEt3Li

60 °C, 10 atm. 20 h 60%

59

(CH2)3-Cl (CH2)3-Cl N Me

O 60

N Me

O 61

The allenic acid 63, obtained by the carbonylation of the chiral propargyl mesylate 62, was converted stereospecifically to the butenolide 64 by treatment with AgNO3 as a catalyst. Racemization occurred by the carbonylation of the

550

Pd(0)-Catalyzed Reactions of Propargyl Compounds

corresponding propargyl carbonate [14]. Carbonylation of the cyclic propargylic trifluoroacetate 65 gave the dienoic acid 66 with net inversion of configuration, which was converted to the butenolide 67 [15]. MsO

Pd(PPh3)4 Me

+ CO + H2O

Me H

THF

H

C7H15

AgNO3

CO2H 63

C7H15

62

95% ee

C7H15

•

Me

O

O 64

62%, 90% ee

CO2t-Bu

Me

CO2t -Bu

+ CO

O

Pd(PPh3)4 2,6-lutidine, TFAA THF, H 2O

Me

O

• TFAO

CO2t-Bu

65

CO2H 66

O

AgNO3 58%

H

Me

O O

67

Propargyl alcohols are less reactive than their esters. Carbonylation of the tertiary propargyl alcohol 68 at 95 ◦ C under pressure of CO and H2 and neutral conditions using DPPB provided the 2(5H )-furanone 69. It was claimed that H2 was required for this reaction [16]. O OH + CO (40 atm) + H2 (14 atm)

68

Pd(dba)2, DPPB, CH2Cl2

O

95 °C, 92%

69

Carbonylation of propargyl alcohol 70 in the presence of thiophenol unexpectedly gave rise to 3-(phenylthio)-2-buten-4-olide 71 in high yield [17]. Similarly, 3-(phenyseleno)-2-buten-4-olide 73 was obtained from propargyl alcohol (72) in the presence of diphenyl diselenide [18]. By introduction of an ester group to an acetylenic terminus of propargyl carbonates, facile dicarbonylation becomes a main path. The monocarbonylation product

Carbonylations Me OH

+ CO + PhSH

551 SPh

Pd(PPh3)4 DME, 100 °C, 40 atm, 88% O

70

O

Me

71 SePh Pd(PPh3)4 OH

+ CO + (PhSe)2 PhH, 100 °C, 60 atm, 53% O

72

O 73

75 of the cyclododecyl derivative 74 was isolated when the reaction was stopped in 1 h. Further carbonylation of the diester 75 for 40 h gave the triester 76. Bidentate ligands DPPP and DPPF are the most effective for the dicarbonylation [19]. CO2Me 2h

CO2Me

•

75% OCO2Me

+ CO + MeOH

Pd(OAc)2 , DPPF

75

1 atm, 25 °C

CO2Me

CO2Me

CO2Me

40 h

74

78%

CO2Me 76

Butyne-1,4-diol derivatives undergo dicarbonylation of different types. A simple synthetic method of bis(methylene)succinate 78 is the carbonylation of the dicarbonate of but-2-yne-1,4-diol (77) at 50 ◦ C [20]. OCO2Et + 2 CO

EtO2CO 77

Pd(OAc)2 , PPh3

CO2Et

EtO2C

EtOH, 50 °C 10 atm, 70%

78

Fulgide (isopropylidenesuccinic anhydride derivative) 80 was obtained from 79 in benzene [21]. The fulgide formation was improved by using Pd(OAc)2 as a catalyst in the presence of iodine. When PdCl2 (PPh3 )2 was used as the catalyst, the furanone 81 was obtained in 61 % yield [22]. O OH + 2 CO

HO 79

Pd(OAc)2, I2 O

PhH, 70 atm, 90 °C 86%

O OH PdCl2 (PPh3)2, PhH 70 atm, 90 °C, 61%

O 81

O

80

552

Pd(0)-Catalyzed Reactions of Propargyl Compounds

6.4 Reactions of Main Group Metal Compounds Reactions of propargyl halides, carbonates, acetates, mesylates, and phosphates with hard carbon nucleophiles MR (M = Mg, Zn, B, Si) give allenyl derivatives [23]. Propargyl acetates react with phenylzinc chloride smoothly. The reaction of the chiral propargyl mesylate 82, bearing 1-trifluoromethyl group, with PhZnCl proceeded with high anti selectivity to give 83 [24]. MsO

C6H13 + PhZnCl

F3C

Pd(PPh3)4, THF

F3C

rt, 83%

C6H13

H

82

Ph 83

The functionalized enamine 85 was prepared by coupling of propargyl bromide with the α-stannyl enamide 84 using AsPh3 as a ligand and CuCl as an additive [25]. Ts Br + Bu3Sn

•

Pd2(dba)3, AsPh3

N Bn

CuCl, THF, 50 °C, 53%

Ts

84

N Bn

85

The cyanoallene 88 was prepared by the reaction of the carbonate 86 with trimethylsilyl cyanide (87). In the presence of excess 87, the dicyanated product 89 was obtained in high yield [26]. Treatment of the chiral (R)-disilanyl ether 90 with the Pd catalyst coordinated by hindered isonitrile 93 (XVII-6) yielded the allenylsilane 91, which was trapped with cyclohexanecarboxaldehyde to give syn-homopropargylic alcohol 92 with 93.3 % ee with high diastereoselectivity [27]. Me C6H13

OCO2Me + Me SiCN 3 Me

Me

NC

Me

THF, 91%

88

CN + Me3SiCN

Pd(PPh3)4 THF, 89%

C6H13

87

Me NC

88 Ph2Si

Me

NC

87

86 C6H13

C6H13

Pd(PPh3)4

Me 89

SiMe2Ph 1. Pd(acac) 2, 93 toluene reflux

O C6H13

2. n-BuLi, THF 86%

Me 90

TiCl4

SiMe2Ph C6H13

Me 91

OH

CyCHO 76%, 93.2% ee

H

Cy

NC

C6H13 Me

93 (XVII-6) 92

Me

Reactions of Main Group Metal Compounds

553

No cross-coupling of propargyl compound 94 with an excess of Et2 Zn occurred. Instead, a nucleophilic propargyl species is generated by ‘umpolung’ and reacts with benzaldehyde to give 95 [28]. Me + PhCHO + Et2Zn

Me

Pd(PPh3)4

Ph

72%

OCO2Me 94

95

OH

Further studies on the reaction of propargyl compounds with Et2 Zn have been carried out using chiral propargyl mesylates [29]. Treatment of allenylpalladiums 96 with Et2 Zn generates the allenylzinc reagents 97, which are nucleophilic and attack the carbonyl group to give homopropargyl alcohols 99 with high stereoselectivity as shown by 98. R2

R1

R1

Pd(0)

H

MsOPd

OMs

R1

Et2Zn

•

H •

R2

MsOZn

R2

96 R1

97

H

R2

•

RCHO

MsOZn

R

R2 R O

R1

H

98

OH 99

Under carefully controlled conditions, the reaction proceeds with excellent stereocontrol. Addition of the allenylzinc reagent derived from the (R)-mesylate 101 to (R)-aldehyde 100 proceeded at −20 ◦ C to give the anti–anti triad 102 in 70 % yield with a small amount of the anti–syn isomer [30]. As an intramolecular version, the propargyl benzoate 103 attacked the methyl ketone to afford the cyclopentanol 104 using Et2 Zn and an Lewis acid with high stereocontrol. The most effective Lewis acid was Yb(OTf)3 . A good catalyst was Pd(OAc)2 -P(n-Bu)3 [31]. Me

Me Me H

TBSO

+

Me

Et2Zn, Pd(OAc)2

H

PPh3, THF, 70%

TBSO

OMs

OH

O (R) 100

(R) 101

102

anti-anti : anti-syn = 93 : 7

Me

O

OBz

Me

Et2Zn, Pd(OAc)2

OBn

BnO

(CH2)2-OBn

(CH2)2-OBn

BnO 103

P(n-Bu)3, Yb(OTf) 73%

HO BnO

OBn BnO

104

554

Pd(0)-Catalyzed Reactions of Propargyl Compounds

Allenylindiums are prepared by transmetallation of allenylpalladiums with indium iodide and used for the reaction with aldehydes to afford homopropargyl alcohols. Addition of an transient allenylindium reagent derived from the chiral mesylate 105 to cyclohexanecarboxaldehyde produced the anti form 106 with high selectivity using Pd(dppf)Cl2 as a catalyst [32], but Pd(OAc)2 -PPh3 was found to be a superior catalyst in the reaction of the mesylate 108 with cyclohexanecarboxaldehyde to give the anti form 109 with higher selectivity [33]. An allenylindium reagent bearing a protected amino group was obtained from 3-alkyl-2-ethynylaziridine 110 in high yields, and stereoselective addition of the allenylindium to acetaldehyde afforded the 2-ethynyl-1,3-amino alcohol 111 bearing three chiral centers in good yields [34]. OMs Me H

CHO

Me

Me

InI, Pd(dppf)Cl2

+

+

THF, HMPA 76%, 95% ee H

H 105

HO 106

TMS MsO

anti : syn = 95 : 5

InI, Pd(OAc)2, PPh3 THF, HMPA, 75%

Me

Me 109

108

H

anti : syn = 99 : 1

InI, Pd(PPh3)4

+ MeCHO

H2O, THF, HMPA 70%, > 99 : 1

H

N

107 TMS

OH

CHO

+

Bn

HO

H

Bn

Me NH

OH

Mtr

Mtr

111

110

6.5 Reactions of Terminal Alkynes; Formation of 1,2-Alkadien-4-ynes 1,2-Dien-4-ynes (allenylacetylenes) 114 can be prepared in good yields by Pdcatalyzed coupling of terminal alkynes 113 with propargyl compounds 112 such as carbonates, acetates, and halides in the presence of a catalytic amount of CuI as a cocatalyst. The Pd/Cu-catalyzed coupling of propargyl carbonates proceeds rapidly at room temperature [35]. R1 R2

R3 X

+

112

X = OCO2Me, OAc, Cl, Mes

R4 113

Pd(0) CuI

R1

R3 •

R2

114 R4

5-Butyldodeca-3,4-dien-6-yne (116) was obtained in 91 % yield by the reaction of 3-chloro-4-nonyne (115) with 1-heptyne in diisopropylamine. Coupling of the

Reactions of Nucleophiles on Central sp Carbon

555

propargylic acetate 117 with 1-heptyne is possible in the presence of 3 equivalents of zinc chloride with or without using CuI to give the 1,2-alkadien-4-yne 118 [36]. Cl +

Bu 115

Bu

Pd(PPh3)4, CuI C5H11

Et

Et •

(i -Pr)2NH, 91%

116 C5H11 Bu

Bu

OAc

+

C5H11

117

Pd(PPh3)4, CuI

•

THF, ZnCl 2, 65 °C 74%

118 C5H11

6.6 Reactions of Nucleophiles on Central sp Carbon of Allenylpalladium Intermediates In contrast to facile Pd(0)-catalyzed reactions of allyl esters with soft carbon nucleophiles via π -allylpalladium intermediate, propargyl esters such as acetate are less reactive toward soft carbon nucleophiles. However, β-keto esters and malonates react under neutral conditions with propargyl carbonates using DPPE as a ligand [37]. Acetoacetate reacts with methyl propargyl carbonate (119) in THF at room temperature to afford 4-(methoxycarbonyl)-5-methyl-3-methylene2,3-dihydrofuran (120) in 88 % yield. The furan 121 was obtained by isomerization of the methylenefuran 120 under slightly acidic conditions. CO2Me

CO2Me COMe + 119

OCO2Me

H+

Pd2(dba)3

CO2Me DPPE, 25 °C, 88%

O O 121

120

The furan 123 was obtained by intramolecular reaction of the propargyl benzoate with an enolate of the β-keto ester in 122 using DPPF as a ligand, and the reaction was applied to the synthesis of the C(1)-C(18) segment of lophotoxin [38]. CO2Me

CO2Me Pd(OAc)2 , DPPF, K 2CO3

O BzO TMS 122

MeCN, 84 °C, 72% OPMB

O TMS

OPMB

123

Propargyl carbonate 124 which has a hydroxy group at C-5 undergoes cyclization by attack of the hydroxy group at the central carbon of the allenyl system 125. The intermediary σ -allylpalladium complex 126 undergoes β-H elimination to give the diene 127, which is converted to the more stable furan 128 in 80 %

556

Pd(0)-Catalyzed Reactions of Propargyl Compounds

yield using DPPP and DBU [1a, p. 2608]. Similarly, the unsaturated dihydropyran 131 was obtained from 1-phenyl-6-hydroxy-2-hexynyl carbonate (129) via the π -allylpalladium intermediate 130 [39]. R

HO

OH C8H17

R

OCO2Me

124 R = C10H21

C8H17

•

DBU, 90 °C dioxane, 80%

Pd-OMe 125

O

R

Pd(OAc)2, DPPP

R

C8H17

O

O

R

C9H19

C8H17

Pd

128

127

OMe

126

Ph OH Ph

O

Pd2(dba)3, DPPB

OCO2Me THF, 50 °C, 40%

129

Pd-OMe 130

Ph O

131

The asymmetric three-component reaction of the carbonate 132 with omethoxyphenol under CO2 atmosphere afforded the cyclic carbonate 135 in 83 % yield with 91 % ee using (S)-BINAP as a chiral ligand. In this reaction, the π -allylpalladium intermediate 133, formed by the attack of phenol to the allenylpalladium intermediate, reacts with CO2 to generate the carbonate 134. Then intramolecular attack of the carbonate anion to the π -allylpalladium terminus provides the cyclic carbonate 135 [40]. HO

X-Pd

OCO2Me + ArOH + CO2

Cy

Cy

Pd2(dba)3, (S)-BINAP

OAr

Cy 132

Cy

O

O

Pd

O

Cy

OH

O

ArOH = OAr

Cy

Cy

133

O

O CO2

HO

dioxane, 83%, 91% ee

ArO 134

Cy 135

OMe

Reactions of Nucleophiles on Central sp Carbon

557

2,3-Dihydro-1,4-benzodioxines 139 and 140 are prepared by the reaction of propargyl carbonates 136 with catechol (137) by attacking either terminus of the π -allylpalladium intermediate 138. OH

OCO2Me 1

R

L2Pd

PdLn

2

R

R1

3

•

OH

R2

137

R3

R 136

R2 O

O

R3

a

a O

R1

O

b

139

1

R2

R

R1

b O

H Pd R3 138

R2

O

3

R

140

The reaction of propargyl carbonate (141) with catechol (137) using DPPB gave 2-methylenebenzodioxin 142. The reaction of methyl-substituted alkynyl carbonate 143 with 137 afforded 3-methylbenzodioxin 144, and a mixture of 146 and 147 was obtained from 145 in a ratio of 22 : 78 [41]. OCO2Me H

H

Pd2(dba)3, DPPB

+

H 141

OH

Et3N, THF, rt 81%

137

OCO2Me Me

O

OH

OH +

H H

OH

143

O 142 O

Pd2(dba)3, DPPB Et3N, THF, rt 93%

O

Me

144

137

C5H11 O OCO2Me C5H11

Ph

OH +

H 145

OH

Pd2(dba)3, DPPB Et3N, THF, rt 98%

O 146

Ph Ph

O

137 C5H11 O 22 : 78 147

558

Pd(0)-Catalyzed Reactions of Propargyl Compounds

The reaction of propargylic mesylate 148 with aniline proceeded without a catalyst to afford the propargylamine 150 with inversion of configuration. On the other hand, the Pd-catalyzed reaction of 148 gave 149 with retention of configuration [42]. NHPh Me

Pd(PPh3)4 OMs

C7H15

THF, 78%

149

Me + PhNH2

NHPh

C7H15

MeCN

148

Me

63%

C7H15

150

In some intramolecular reactions, the amino group attacks either the sp2 or sp carbon of σ -allenylpalladium intermediates depending on the monodentate or bidentate ligand being used. Carbapenam skeletons are prepared by intramolecular attack of 6-aminopropargyl compounds. Treatment of the propargyl phosphate 151 having a β-lactam moiety with Pd2 (dba)3 and bidentate ligand (DPPF) afforded the carbapenam skeletons 154 and 155. In this reaction, the lactam nitrogen attacked the central sp carbon of the σ -allenylpalladium 152 as expected and the π -allylpalladium intermediate 153 was generated. R3SiO H

R3SiO

H

H

H

PdX

Pd2(dba)3, DPPF PhCO2Na, THF

NH

NH

O

O OPO(OEt)2

151

152 R3SiO

R3SiO H

H

H

O

Pd 153

H

H

+

N

N

R3SiO

H

OCOPh N

O

O 154

22%

155

44%

R3SiO = TBDMSO

In the reaction of the propargyl benzoate 156, attack of the lactam nitrogen occurred in two ways as shown by 157 depending on the ligands used. The carbapenam 159 was formed by attack of the amino nitrogen to Pd-X to form the palladacycle 158, followed by reductive elimination by using monodentate ligand P(o-Tol)3 and Cs2 CO3 . On the other hand, the carbacepham 161 was obtained via the formation of π -allylpalladium 160 when DPPF was used [43]. Treatment of the propargyl benzoate 162 with Pd2 (dba)3 and DPPF in the presence of N -alkyltosylamide generated the allenylpalladium 163, and the π allylpalladium intermediate 164 was generated by the attack of the amino group.

Reactions of Nucleophiles on Central sp Carbon

559

R3SiO H

H

R3SiO H

H a

Pd(0)

NH O

Pd-X

NH O

b

OCOPh 156

157 R3SiO

R3SiO H

Pd2(dba)3 P(o-Tol) 3

a

Cs2CO3 toluene, 57%

H

H

N

N

O

Pd

O

159

158 b

R3SiO

R3SiO Pd2(dba)3 DPPF

H

Cs2CO3 toluene, 56%

H

H

H

H

N

N O

O Pd-X 160

161

PdX

R

R Pd(0)

R

R

OCOPh NHTs

NHTs 162

R = CH2OBn

163 R

R

R

R Pd2(dba)3, DPPF

Cl

Cs2CO3, toluene, TsNHMe (2 equiv.) 95%

Pd

TsNHMe N

N Ts 164 R

R

NTs

165

Me

R

R

Pd2(dba)3, P(o-Tol) 3

Ts

+

Cs2CO3, toluene N

N

Ts

Ts

166

41%

167

19%

Finally the azepine derivative 165 was obtained in 95 % yield by the attack of N -alkyltosylamide to the π -allylpalladium intermediate 164. On the other hand, the 2-allenyl- and 2-vinylpiperidines 166 and 167 were obtained from 162 when P(o-Tol)3 was used [44].

560

Pd(0)-Catalyzed Reactions of Propargyl Compounds

6.7 Hydrogenolysis and Elimination of Propargyl Compounds Allenes 169 and alkynes 170 are prepared by hydrogenolysis of propargyl compounds with several hydrides. Triethylammonium formate is used most conveniently under mild conditions [45]. Chromium tricarbonyl-complexed phenylallene 172 was prepared from the carbonate 171 [46]. The alkyne 174 was obtained selectively from the propargyl formate 173 having an amino group [47]. R1 R2

+

Pd(0) HCO2H

Et3N

X

R1

R2 +

R1 R2

H

H

168

H

169 OCO2Me

170

Pd(acac)2, P(n-Bu)3

+ HCO2NH4

THF, 79%

Cr(CO)3

Cr(CO)3

171

172 OCHO Pd(acac)2, P(n-Bu)3 THF, 25 °C, 93%

HN

HN

C6H13

Boc

173

C6H13

Boc 174

acetylene / allene = 97 / 3

Reaction of propargyl formate 175 affords two products 179 and 181 depending on the kind of intermediates being subjected to hydrogenolysis with formate. When 5-exo cyclization of 176 and 3-exo cyclization of 177 to give the cyclopropane 178 occurred before the hydrogenolysis, the bicyclo[3.1.0]hexane 179 was obtained. On the other hand, the cyclopentane 181 was formed by hydrogenolysis of 176, and the cyclopentane 181 was obtained by Pd-catalyzed cyclization of 180 [3].

E OCHO

E

Pd(OAc)2, PPh3

E

MeCN, 85 °C

E

175

Pd-H

176 Pd-H

E E

E

E

E

E

54% 177

178

E

E

E

E

180

HPd

179

179 : 181 1:3 181

Hydrogenolysis and Elimination of Propargyl Compounds

561

Pd-catalyzed reduction of propargyl compounds with SmI2 is possible in the presence of proton sources [48]. Yoshida and Mikami reported a dramatic change of chemoselectivity in the reduction of propargyl phosphates with SmI2 and various proton sources [49]. The alkyne 183 was a main product from the primary propargyl phosphate 182 using t-BuOH as a proton source. The allene 184 was a minor product. The propargyl phosphate 185 bearing an ester group gave the allene 186 exclusively. The chemoselectivity of the reduction of secondary phosphate 187 depends on the proton sources. The allene 188 was obtained by the use of t-BuOH, and the alkyne 189 was a major product when dimethyl L-tartrate was used. + SmI2

C8H17

Pd(PPh3)4, t-BuOH THF, rt, 50%

OPO(OEt)2

182

C8H17 183

C8H17 Me + H 184

94 : 6 MeO2C

Pd(PPh3)4, t-BuOH

+ SmI2

OPO(OEt)2

MeO2C

THF, rt, 83%

H

185

186 Et

Ph OPO(OEt)2

187

Pd(PPh3)4, THF

+ SmI2

Et

Ph

proton source, rt

t-BuOH, 80% dimethyl L-tartrate, 81%

> 99% Et

+ Ph

188

189

> 99

<1

15

85

Furthermore Mikami and Yoshida have studied regio- and enantioselective synthesis of allenic esters by Sm(II)-mediated reduction of propargyl compounds. Attempted chirality transfer by SmI2 reduction of the optically active propargylic phosphate 190 (91 % ee) provided the racemic compound 191. Then they carried out dynamic kinetic resolution based on asymmetric protonation using racemic propargyl phosphate 192. Among several chiral proton sources, (R)-pantolactone 193 gave the optically active allenic ester 194 with the highest % ee (95 % ee). Interestingly the yield of 194 was 68 %, which is higher than the maximum yield (50 %) obtained by ordinary kinetic resolution. The efficient asymmetric protonation is attained due to the chelation of the chiral alcohol 193 with Sm (III) intermediate species possessing high Lewis acidity and oxophilicity [50]. OPO(OEt)2 +

Pd(PPh3)4, t-BuOH SmI 2

THF, 10 min, 53%

CO2Me

CO2Me 190

191

91% ee

racemic

O OPO(OEt)2 + 192

CO2Me

SmI 2

O OH Pd(PPh3)4, (R)-193 CO2Me

68%, 95% ee (R)-194

562

Pd(0)-Catalyzed Reactions of Propargyl Compounds

When propargyl carbonates 195 are treated with a Pd catalyst in the absence of other reactants, β-H elimination from the propargylpalladium intermediates 196 occurs to give conjugated enynes 197. Formation of cumulative 1,2,3-alkatrienes 199 from the allenylpalladiums 198 does not take place. Preparation of the conjugated ene–yne–ene system 201 in high yield from the propargyl carbonate 200 is an example [51]. MeOPd R1

R1

R2

PdOMe

H

H

•

195

R2

Pd(OAc)2, PPh3

•

R1

R2 199

198 OCO2Me

H •

R1

C6H13

R2 197

196

Pd(0)

MeO2CO

R1

R2

C6H13

THF, reflux, 96% 200

201

C6H13

C6H13

E/Z = 57/43

References 1. Reviews: (a) J. Tsuji, Angew. Chem. Int. Ed. Engl., 34, 2589 (1995); (b) J. Tsuji and T. Mandai, in Metal-Catalyzed Cross-Coupling Reactions, Eds. F. Diedrich and P. J. Stang, Wiley-VCH, New York, 1998, p. 455. 2. R. Grigg, R. Rasul, J. Redpath, and D. Wilson, Tetrahedron Lett., 37, 4609 (1996). 3. A. G. Steinig and A. de Meijere, Eur. J. Org. Chem., 1333 (1999). 4. J. Bohmer, R. Grigg, and J. D. Marchbank, Chem. Commun., 768 (2002). 5. W. Oppolzer, A. Pimm, B. Stammen, and W. E. Hume, Helv. Chim. Acta, 80, 623 (1997). 6. R. Grigg, R. Rasul, and V. Savic, Tetrahedron Lett., 38, 1825 (1997). 7. N. Monteiro, A. Arnold, and G. Balme, Synlett, 1111 (1998). 8. S. Cacchi, G. Fabrizi, and L. Moro, Tetrahedron Lett., 39, 5101 (1998). 9. S. Ogoshi, S. Nishiguchi, K. Tsutsumi, and H. Kurosawa, J. Org. Chem., 60, 4650 (1995). 10. Review, J. Tsuji, and T. Mandai, J. Organomet. Chem., 451, 15 (1993). 11. J. Tsuji, T. Sugiura, and I. Minami, Tetrahedron Lett., 27, 731 (1986). 12. Y. Imada and A. Alper, J. Org. Chem., 61, 6766 (1996). 13. M. Ishikura, H. Uchiyama, and N. Matsuzaki, Heterocycles, 55, 1063 (2001). 14. J. A. Marshall, M. A. Wolf, and E. M. Wallace, J. Org. Chem., 62, 367 (1997). 15. G. S. Bartley, and E. M. Wallace, J. Org. Chem., 61, 5729 (1996); J. Org. Chem., 60, 796 (1995); J. A. Marshall and E. A. Van Devender, J. Org. Chem., 66, 8037 (2001). 16. W. Y. Yu and H. Alper, J. Org. Chem., 62, 5684 (1997). 17. W. J. Xiao and H. Alper, J. Org. Chem., 62, 3422 (1997). 18. A. Ogawa, H. Kuniyasu, N. Sonoda, and T. Hirao, J. Org. Chem., 62, 8361 (1997). 19. T. Mandai, Y. Tsujiguchi, S. Matsuoka, J. Tsuji, and S. Saito, Tetrahedron Lett., 35, 5697 (1994). 20. J. Kiji, T. Okano, E. Fujii, and J. Tsuji, Synthesis, 869 (1997). 21. (a) J. Tsuji and T. Nogi, Tetrahedron Lett., 1801 (1966); (b) T. Nogi and J. Tsuji, Tetrahedron, 25, 4099 (1969). 22. J. Kiji, T. Okano, H. Kitamura, Y. Yokoyama, S. Kubota, and Y. Kurita, Bull. Chem. Soc. Jpn., 68, 616 (1995). 23. S. Ma and A. Zhang, J. Org. Chem., 67, 2287 (2002).

References

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24. T. Konno, M. Tanikawa, T. Ishihara, and H. Yamanaka, Chem. Lett., 1360 (2000). 25. S. Miniere and J. C. Cintrat, J. Org. Chem., 66, 7385 (2001). 26. Y. Tsuji, M. Taniguchi, T. Yasuda, T. Kawamura, and Y. Obora, Org. Lett., 2, 2635 (2000). 27. M. Suginome, A. Matsumoto, and Y. Ito, J. Org. Chem., 61, 4884 (1996). 28. Y. Tamaru, S. Goto, A. Tanaka, M. Shimizu, and M. Kimura, Angew. Chem. Int. Ed. Engl., 35, 878 (1996). 29. Review: J. A. Marshall, Chem. Rev., 100, 3174 (2000). 30. (a) J. A. Marshall and N. D. Adams, J. Org. Chem. 67, 733 (2002); (b) J. A. Marshall and G. M. Schaaf, J. Org. Chem., 66, 7825 (2001). 31. J. M. Aurrecoechea, M. Arrate, and B. Lopez, Synlett, 872 (2001). 32. J. A. Marshall and C. M. Grant, J. Org. Chem., 64, 696 (1999). 33. J. A. Marshall, H. R. Chobanian, and M. M. Yanik, Org. Lett., 3, 3369 (2001). 34. H. Ohno, H. Hamaguchi, and T. Tanaka, Org. Lett., 2, 2161 (2000). 35. T. Mandai, T. Nakata, H. Murayama, H. Yamaoki, M. Ogawa, M. Kawada, and J. Tsuji, Tetrahedron Lett., 31, 7179 (1990). 36. S. Condon-Gueugnot and G. Linstrumelle, Tetrahedron Lett. 34, 3853 (1993); Tetrahedron, 56, 1851 (2000). 37. J. Tsuji, H. Watanabe, I. Minami, and I. Shimizu, J. Am. Chem. Soc., 107, 2196 (1985). 38. P. Wipf and M. J. Soth, Org. Lett., 4, 1787 (2002). 39. C. Foumier-Nguefack, P. Lhoste, and D. Sinou, Synlett, 553 (1996). 40. M. Yoshida, M. Fujita, T. Ishii, and M. Ihara, J. Am. Chem. Soc., 125, 4874 (2003). 41. (a) J. R. Labrosse, P. Lhoste, and D. Sinou, Org. Lett., 2, 527 (2000); (b) J. R. Labrosse, P. Lhoste, and D. Sinou, J. Org. Chem., 66, 6634 (2001). 42. J. A. Marshall and M. A. Wolf, J. Org. Chem., 61, 3238 (1996). 43. Y. Kozawa and M. Mori, Tetrahedron Lett., 42, 4869 (2001). 44. Y. Kozawa and M. Mori, Tetrahedron Lett., 43, 1499 (2002). 45. Review, J. Tsuji, T. Sugiura, and I. Minami, Synthesis, 1 (1996). 46. M. Ansorge, K. Polborn, and T. J. J. M¨uller, J. Organomet. Chem., 630, 198 (2001). 47. T. Mandai, T. Matsumoto, M. Kawada, and J. Tsuji, Tetrahedron Lett., 34, 2161 (1993). 48. J. Inanaga, Y. Sugimoto, and T. Hanamoto, Tetrahedron Lett., 33, 7035 (1992). 49. A. Yoshida and K. Mikami, Synlett, 1375 (1997). 50. K. Mikami and A. Yoshida, Angew. Chem. Int. Ed. Engl., 36, 858 (1997); Tetrahedron, 57, 889 (2001). 51. T. Mandai, Y. Tsujiguchi, S. Matsuoka, and J. Tsuji, Tetrahedron Lett., 34, 7615 (1993).

Chapter 7 Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

7.1 Reactions of Alkynes Alkynes undergo a variety of reactions using either Pd(II) or Pd(0), and each topic appears in separate chapters. Oxidative reactions of alkynes with Pd(II) are surveyed in Chapter 2.6, and Pd(0)-catalyzed reaction of alkynes with organic halides are summarized in Chapter 3.4, and other typical reactions of alkynes are treated in this chapter. Since benzynes are regarded as reactive alkynes, they are surveyed in this chapter. 7.1.1 Carbonylation Hydroesterification of alkynes proceeds smoothly using PdCl2 (PPh3 )2 as a standard catalyst, offering a convenient synthetic method of α, β-unsaturated esters 1. Carbonylation of 1-alkynes and asymmetric alkynes yields a mixture of regioisomers. R

R

R + CO + ROH

R

CO2R 1

In contrast to facile hydroformylation of alkenes, only a few successful examples of hydroformylation of alkynes have been reported. Hidai and co-workers have found that PdCl2 (PCy3 )2 is an effective catalyst for hydroformylation of alkynes. Furthermore, a bimetallic catalyst of PdCl2 (PCy3 )2 and Co2 (CO)8 showed remarkably high catalytic activity. Reaction of 4-octyne under CO and H2 pressure (35 atm each) at 150 ◦ C in the presence of Et3 N produced the 2-n-propyl-2-hexenal (2) in 95 % yield [1]. Co2 (CO)8 alone is inactive. Also no hydroformylation of alkenes occurred with this bimetallic catalyst.

n-C3H7

n-C3H7

+

CO + H2

35 atm

35 atm

PdCl2(PCy3)2-Co2(CO)8 Et3N, benzene, 150 °C 95%

Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

n-C3H7

n-C3H7 2

CHO

566

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Carbonylation proceeds in the presence of chalcogen compounds without poisoning Pd catalysts. Pd-catalyzed stereo- and regioselective carbonylative double thiolation of 1-octyne with diphenyl disulfide (3) afforded the (Z)-β-(phenylthio)α,β-unsaturated thioester 4 [2]. The thioester 4 can be converted to 3-(phenylthio)2-alkenal 5 by Pd-catalyzed reduction with HSnBu3 under mild conditions [3]. When propargyl alcohol was subjected to the carbonylation in the presence of either diphenyl diselenide (6) or disulfide 3, 3-phenylselenobutenolide 7 or 3-phenylthiobutenolide was obtained. The transformation involves isomerization of the acylpalladium intermediate 8 to 9 [4]. Pd(PPh3)4, benzene

+ CO + (PhS)2 3

n-Hex

n-Hex

SPh

60 atm, rt, 91%

SPh

O

4

n-Hex

SPh SPh

n-Hex

Pd(PPh3)4

+ HSnBu3

H + PhSSnBu3

benzene, rt 91%

O

SPh

4

5

O

Z = 98% SePh

HO

Pd(PPh3)4

+ CO + (PhSe)2 100 °C, 60 atm 6 43%

O

O 7

HO

PhSe

PhSe

O

isomerization

HO O

PhSePd 8

9

PhSePd

As a related reaction, hydrocarbometallation of alkynes takes place by Pdcatalyzed reaction of 1-alkyne with trifurylgermane (10) and CO under mild conditions in the presence of a catalytic amount of quinoline to give the acylgermane 11 using tri(2,4-di-t-butylphenyl) phosphite III-4 as a ligand. The reaction is explained by hydropalladation of alkyne to generate 12, and the acylpalladium 13 is formed by CO insertion. The 2-nonenamide 14 was prepared by DMAP-catalyzed reaction of 11 with N ,N -dibenzylamine [5].

+

n-C6H13

+ CO O 10

GeH

3

(h3-allyl-PdCl)2 phosphite III-4

n-C6H13 Ge

toluene, quinoline rt, 1 atm, 78%

11

H-Pd-GeR3

O

3

Bn2NH DMAP

n-C6H13

n-C6H13

O

CO H

H

PdGeR3 12

R3GePd 13

n-C6H13

O R = 2-furyl

O 14

NBn2

Reactions of Alkynes

567

7.1.2 Hydroarylation Pd-catalyzed hydroarylation of alkynes via aromatic C—H bond activation has been reported by Fujiwara. The reaction offers a good synthetic method of arylalkenes, which are usually prepared by Heck reaction of alkenes. Electronrich arenes bearing more than one OH, OMe, and alkyl groups react with electron-deficient alkynes [6]. The reaction proceeds with a catalytic amount of Pd(OAc)2 in trifluoroacetic acid (TFA) at room temperature. Hydroarylation of ethyl propiolate (15) with p-dimethoxybenzene yielded ethyl (Z)-3-(2,5dimethoxyphenyl)-2-propenoate (16). Mesitylene (17) is an active arene and the reaction of 17 with 3-butyn-2-one (18) afforded the unsaturated ketone 19 which has E-form [7]. OMe

OMe H +

CO2Et 15

Pd(OAc)2, TFA

CO2Et

CH2Cl2, rt, 78%

OMe Me

Me H +

Me 17

16

OMe

COMe 18

Me

COMe

Pd(OAc)2, TFA CH2Cl2, rt, 78% Me

Me 19

Electron-rich heterocycles such as furans and pyrroles undergo facile reactions. The furan 20 is an active compound and the reaction with ethyl phenylpropiolate (21) proceeded at room temperature in dichloromethane in the presence of AcOH, instead of TFA, to give rise to (Z)-2-alkenylfuran 22 exclusively [8]. The 3-alkenylpyrrole 24 was obtained by the reaction of the trisubstituted pyrrole 23 with 21 [9]. Pd(OAc)2, AcOH

+ Ph Me

O

CO2Et 21

CH2Cl2, rt, 72%

CO2Et Me

O 22

20

Ph Ph

Me

Me Pd(OAc)2, AcOH

+ Ph EtO2C

N H 23

Me

CO2Et 21

CH2Cl2, rt, 66%

CO2Et EtO2C

N H 24

Me

In 1996, Trost and Toste reported a new synthetic method of coumarins by the Pd-catalyzed reaction of electron-rich phenol with propiolate 15 at room temperature using Pd2 (dba)3 in formic acid. 2,5-Dimethoxycoumarin (26) was obtained from 3,5-dimethoxyphenol (25) [10]. On the other hand, Fujiwara carried out the

568

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

preparation of the coumarin 29 from 25 and ethyl methylpropiolate (28) using Pd(OAc)2 in trifluoroacetic acid [11]. The hydroarylation of ethyl propiolate (15) with the chroman derivative 30 proceeded in HCO2 H using Pd2 (dba)3 and AcONa, and a mixture of 31 and 32 was obtained in a ratio of 1.0 : 2.8 [12]. Two groups, the groups of Fujiwara and Trost, used Pd(II) and Pd(0) catalysts, respectively, and the mechanism of their reactions should be different. OMe

OMe Pd2(dba)3, AcONa

+

CO2Et

HCO2H, rt, 77%

15

OH

MeO

MeO

O

25

O

26

OMe

OMe + Me

CO2Et 28

OH

MeO

Me

Pd(OAc)2, TFA rt, 97% MeO

O

25

O

29 OH +

CO2Et 15

O

1. Pd 2(dba)3, AcONa, HCO2H 2. MeI, K 2CO3, acetone

OH

68%

30 OMe OMe + O

O O

O 31

O 1.0 : 2.8

32

O

The Pd(II)-catalyzed hydroarylation of alkynes reported by Fujiwara can be explained by the following mechanism [6]. Fujiwara reported previously the oxidative coupling of benzene with alkenes using Pd(OAc)2 and some oxidants in AcOH. In this reaction, phenylpalladium acetate 33 is formed at first, and insertion of alkene to 33 generates the alkylpalladium intermediate 34. The reaction is terminated by β-H elimination to give 35 with generation of Pd(0). In order to make the reaction catalytic, Pd(0) is oxidized to Pd(II) by oxidants. This Pd(II)-promoted reaction is treated in Chapter 2.2.8. The Pd(II)-catalyzed reaction of arenes with alkynes proceeds by insertion of alkyne to form the alkenylpalladium intermediate 36, which has no possibility of β-H elimination, and the reaction can be terminated only by protonolysis, giving 37. At the same time, Pd(II) is regenerated, and hence the reaction proceeds catalytically without addition of oxidants and other reagents. Trost and Toste explain their Pd(0)-catalyzed reaction by the following mechanism. First, reaction of Pd(0) and HCO2 H generates hydridopalladium 38, and the vinylpalladium intermediate 39 is formed by insertion of alkyne, and either the

Reactions of Alkynes H

569

PdOAc

R

R

+

R A

A

A

Pd(OAc)2

Pd(0)

35

34

PdOAc H+

R

A

A

33

+

R

A

PdOAc

36

Pd(II)

R H

37

C-bound or O-bound vinylpalladium (40 or 41) is formed by the exchange reaction of 39 with phenol. Finally reductive elimination yields the hydroarylation product 42 and then coumarin 43 [12]. The hydroarylation reaction has been carried out with phenolic substrates, and it is interesting to know whether the Pd(0)-catalyzed reaction can be applied to non-phenolic substrates such as mesitylene or not, but so far no example has been given. On the other hand, Pd(II)-catalyzed hydroarylation with mesitylene proceeds smoothly. OH

HCO2H + Pd(0)

E

H-Pd-OCOH

HCO2

H

Pd

39

38

E HCO2H

O

O

OH

O

Pd

O

Pd 40

E

41

E

Pd(0)

E

42

43

E = CO2Et

7.1.3 Hydroamination, Hydrocarbonation, and Related Reactions Addition of C, N, and O-pronucleophiles to alkynes is catalyzed by Pd complexes. Pd-catalyzed hydroamination of alkynes is rare. Intramolecular hydroamination of 6-amino-1-hexyne (44) was catalyzed by a Pd(II) compound and 2-methyl-1,2dehydropiperidine (46) was obtained as a final product via 2-methylenepiperidine 45 [13].

Pd(MeCN)2(BF4)2 NH2

H2C

H N

H3C

N

83%

44 45

46

570

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Intermolecular hydroamination of internal alkynes with o-aminophenol proceeded smoothly using ligandless Pd(NO3 )2 as a catalyst in dioxane to give the enamine 47 as a product, which was isolated after hydrolysis to the ketone 48 in good yield. The amine 49 was obtained after reduction. Satisfactory hydroamination is possible only with o-aminophenol [14]. Hydroamination of the diyne 50 with o-aminophenol afforded the 2-substituted benzoxazole 53 and the ketone 54. The reaction involves carbon–carbon bond cleavage. The intermediate 51 formed by bis-hydroamination undergoes ring formation and bond cleavage as demonstrated by 52, and 2-butylbenzoxazole (53) and the ketone 54 were obtained in high yields [15]. n-C5H11 NH2 Pd(NO ) dioxane 3 2,

n-C5H11 +

n-C5H11

n-C5H11 NH

100 °C OH

H2O

OH

n-C5H11

47

n-C5H11

76% O 48

n-C5H11

ZnCl2, NaBH3CN 62%

n-C5H11 NH

OH

49

NH2

n-Bu +

n-Bu

Pd(NO3)2, n-BuOH 97%

50

N

H

N

HO n-Bu

OH

OH

n-Bu

51 HO H N

N N

+ O

O

O

n-Bu 52

n-Bu

n-Bu

n-Bu 53

54

1-Phenyl-1-propyne (55) underwent facile formal intermolecular hydroamination, affording the allylic amine 56 in high yield at 0 ◦ C in the presence of AcOH or benzoic acid. In this reaction, at first, Pd-catalyzed isomerization of 55 to phenylallene (57) occurs by addition–elimination of H-Pd-OAc to internal alkyne 55, and then the allene 57 is converted to π -allylpalladium intermediate 58 by hydropalladation. The final step is a well-known amination to produce the allylic amine 56. As an intramolecular version, 2-(2-phenylpropenyl)pyrrole (60) was obtained from 1-phenyl-7-amino-1-hexyne 59 [16,16a]. Similarly Pd/benzoic acid-catalyzed hydroalkoxylation of 55 with (−)-menthol (61) afforded the allylic ether 62 [17].

Reactions of Alkynes Pd(PPh3)4 AcOH, dioxane Ph 0 °C, 98%

Me + NHBn2

Ph

571

55 H-Pd-OAc

NBn2

56

NHBn2

H-Pd-OAc Pd-OAc H-Pd-OAc

• 57

Ph

Ph 58

Ph

NHBn Ph

70%

N 60

59

Bn

Pd(PPh3)4

55 +

PhCO2H, dioxane Ph 82%

HO

O

62

61

Also hydrocarbonation of 55 with methylmalononitrile (63) took place to give 64 [18]. On the other hand, efficient intramolecular hydrocarbonation of the 5alkynylmalononitrile 65 gave the cyclopentane 67 in 89 % yield using Pd(OAc)2 and COD in ethanol. The use of COD or 1-octene as an additive is important. Formation of the Z isomer suggests that the reaction does not proceed through π -allylpalladium intermediate, but involves the coordination of H-Pd+ to the triple bond and subsequent trans carbopalladation as shown by 66. No reaction occurred with the corresponding malonate and cyanoacetate, and Pd(PPh3 )4 and Pd2 (dba)3 are ineffective. Cyclization of the malononitrile derivative 68 afforded the diand monocyclization products 69 and 70 suggesting that the reaction proceeds by carbopalladation of alkyne with H-Pd species [19]. Me 55 + HC

CN

Pd(PPh3)4

Me Ph

CN

AcOH, dioxane

CN

CN 63

64

Pd(OAc)2 , COD

n-Bu

EtOH, rt, 89%

H NC

H-Pd+

n-Bu

CN

NC

65

66

H-Pd

n-Bu

NC

CN

n-Bu

NC 67

CN

CN

572

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes n-Bu

n-Bu n-Bu Pd(OAc)2 , COD

+

EtOH, rt, 73% NC NC

CN

CN 69

CN

NC

6:4

68

70

Conjugated enynes are very reactive and show interesting reactivity in the presence of Pd catalysts. Hydroamination of the conjugated enyne 71 in the presence of AcOH afforded 1,4-diamino-2-butene 72. In this reaction, Pd-catalyzed isomerization of the enyne to allene, followed by generation of the methyleneπ -allylpalladium 73 occurs, and amination yields the allenylamine 74. Further Pd-catalyzed amination of 74 affords the diamine 72. The reaction took place in the presence of AcOH using DPPF as a ligand [20]. A similar reaction occurred with carbon pronucleophiles [21]. Me

+ NHBn2

Me

(h3-allyl-PdCl)2, DPPF

NBn2

AcOH, THF, 80 °C, 70%

Bn2N

71

72

H-Pd-NBn2 Me Me

H-Pd-NBn2

• 74

Pd

NBn2

NBn2 73

7.1.4 Hydrometallation and Hydro-Heteroatom Addition Hydrometallations of alkynes with HSiR3 , HSnBu3 and HBR2 are useful reactions, because introduced metal groups MR in 75 are reactive and can be displaced with other functional groups to give the functionalized alkenes 76. Also hydroheteroatom addition occurs using substrates containing H-S, H-Se, and H-P bonds.

R + H

R

MR

Pd(0)

R

R H

E+

MR 75

H

R

R H

E 76

MR = H-SiR3, HSnBu3, H-BR2 , H-hetero atoms

Compared with hydrosilylation of alkenes, less extensive studies have been carried out on hydrosilylation of alkynes. Mono- and dihydrosilylation occur depending on conditions. Yamamoto found concomitant dimerization–hydrosilylation of 1-heptyne catalyzed by Pd-PPh3 catalyst to give a mixture of products 77, 78, and 79. Their ratios depend on the hydrosilanes used. The head–tail dimer 78 was the main product when HSiCl3 was used. The expected monohydrosilylation

Reactions of Alkynes

573

took place to give 77 with HSiMe2 Cl. A small amount of tail–tail dimer 79 was obtained with HSiCl3 and HSiMeCl2 [22]. Oshima found that hydrosilylation with less reactive triorganosilanes can be carried out by using electron-rich phosphines. Hydrosilylation of terminal alkyne 80 with HSiPh3 was carried out using PCy3 as a ligand at room temperature to provide 81 regioselectively in high yield [23].

+ HSiX3

n-C5H11

(h3-allyl-PdCl)2, PPh3 CH2Cl2, 50 °C

n-C5H11 n-C5H11

+ SiX3

n-C5H11 +

n-C5H11 SiX3

77

78

9

76

15

HSiMeCl2

38

46

16 15

HSiMe2Cl

97

3

HSiCl3

+

t-Bu

HSiPh3

n-C5H11

79

SiX3

t-Bu

Pd2(dba)3-PCy3 rt, 95%

80

81

SiPh3

Preparation of chiral benzylic alcohols has been achieved by asymmetric dihydrosilylation of terminal arylalkynes, followed by oxidation [24]. The chiral diol 85 with 95 % ee was obtained by direct Pd-catalyzed asymmetric dihydrosilylation of phenylacetylene (82) with HSiCl3 using MOP [(R)-VI-18], followed by oxidation of 1,2-disilylated product 84, but the yield of 84 was 33 % (the main product was 1-trichlorosilyl-2,4-diphenyl-1,3-butadiene). Better results were obtained by hydrosilylation using two catalysts. The first Pt-catalyzed monosilylation to give 83 was followed by the second hydrosilylation catalyzed by the chiral Pd catalyst. The diol 85 with 95 % ee was obtained in 87 % overall yield by this method.

+ HSiCl3

Ph

[PtCl2(C2H4)]2

Ph

82

(h3-allyl-PdCl)2-(R)-VI-18 83

SiCl3

HSiCl3 (h3-allyl-PdCl)2-(R)-VI-18 33% Ph

Ph SiCl3 SiCl3 84

OH OH 85

87% from alkyne 95% ee

Hydrostannation of alkynes proceeds smoothly to give alkenylstannanes, which are used for further transformations. The reaction is induced by transition metal catalysts and free-radical sources, giving different regioisomers 86 and 87 [25].

574

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Pd complexes are effective catalysts for cis addition. Usually a mixture of the regioisomers 86 and 87 is obtained, and the ratio depends on the substituents of the alkynes and ligands. Hydrostannation of 82 afforded equal amounts of the regioisomers 88 and 89. + HSnBu3

R

SnBu3

Pd(0)

+

SnBu3

R

R 86 + Bu3SnH

Ph

87 Ph

Ph

Pd(Ph3P)4

+ Bu3Sn

82

SnBu3

88, 48%

89, 48%

Several reports on regioselective hydrostannation have been published. In hydrostannation of asymmetric diarylacetylene 90, stannation occurred regioselectively at the carbon close to the ortho-substituted benzene to give 91 [26]. Hydrostannation of the serine-derived ynoate 92 at −10 ◦ C afforded the α-stannyl ester 93 with high regioselectivity (16 : 1), and the reaction was applied to the total synthesis of asperazine [27].

+ HSnBu3

PdCl2(PPh3)2 THF, 94% MeO

OMe

Bu3Sn

90

O

+ HSnBu3

NBoc

Pd(PPh3)4 CH2Cl2, −10 °C 88%

O

CH2OMe

92

H

NBoc CO2Me H

H

91

SnBu3 93

Usually, hydrostannation of propargyl alcohols is not regioselective. However, the β-stannyl alcohol 95 was obtained with complete regioselectivity by hydrostannation of the propargyl alcohol 94 using P(o-Tol)3 as a ligand, and the reaction was applied to the total synthesis of zoanthamine [28]. While Pd-catalyzed hydrostannation of the conjugated enyne 96 afforded the alkadienylstannane 97 regioselectively, a radical-initiated reaction provided the terminal adduct 98 [29]. MOMO MOMO

OH + HSnBu3

OH

PdCl2[P(o-Tol) 3]2

OTBDMS

THF, rt, 84% SnBu3

94

OTBDMS

95

Reactions of Alkynes

575

PdCl2(PPh3)2 O

O

85%

O O

OMe

OMe

+ Bu3SnH

SnBu3

97 AIBN

O

90 °C, 55%

96

OMe SnBu3 98

Cyclization of the 1,6-enyne 99 with HSnBu3 provided the cyclopentane 102 at room temperature. Ligandless Pd(OAc)2 was used. In this reaction, regioselective hydropalladation of the alkyne generates 100 at first, and subsequent alkene insertion yields 101. Finally reductive elimination gives rise to the cyclized product 102 [30]. O + HSnBu3

O

Pd(OAc)2, THF

O

Bu3Sn

rt, 61%

Pd O

H 99 Bu3Sn

100 O

Pd

O

Bu3Sn

H

H

O 101

O 102

Hydrogermylation of 1-octyne with tri(2-furyl)germane 10 at room temperature in water provided the 1,3-dienylgermane 104 in high yield [31].

+ R3GeH

C6H13

C6H13

(η3-allyl-PdCl)2, III-4

10

H2O, 91%

GeR3 C6H13

104

R3GeH = (2-furyl)3GeH

Hydrophosphinylation of 1-octyne with diphenylphosphine oxide (105) afforded the alkenylphosphine oxide 106 by internal attack with high regioselectivity. However, addition of a small amount of Ph2 P(O)OH changed the regioselectivity to provide the product 107 by terminal attack [32].

+ Ph2P(O)H

C6H13

105

[PdMe2(PPhMe2)2] 70 °C, 92%

C6H13 106

O PPh2

C6H13 107

PPh2 O

576

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

The alkenylphosphonium salt 108 was prepared by the addition of PPh3 at the internal carbon of 1-alkyne in the presence of methanesulfonic acid. After anion exchange with LiPF6 , the conjugated diene 109 was obtained by the reaction of 108 with an aldehyde [33]. + PPh3 Ph

1. Pd(PPh 3)4, MeSO3H

Ph

2. LiPF 6, EtOH, 91%

PF6− PPh3 108

1. (TMS) 2NNa 2. n-C7H15CHO 78%

C7H15

Ph 109

Hydrothiolation of 1-alkynes with thiols gives vinyl sulfides with high regio- and stereoselectivities. Reaction of 1-octyne with benzenethiol catalyzed by Pd(OAc)2 gave the Markonikov-type product 110. Isomerization of the double bond occurred and the isomer 111 was obtained when PdCl2 (PhCN)2 was used [34]. R

Pd(OAc)2 85%

SPh 110

+ PhS-H

PdCl2(PhCN)2

R

R

66%

R = n-C5H11

111

SPh

7.1.5 Dimetallation and Related Reactions Functionalized alkenes are prepared by the syn addition of dimetallic reagents and related compounds. α,β-Dimetallated compounds 112, easily prepared by the Pd-catalyzed addition of dimetallic reagents (Rn M-MRn
) of main group metals to alkynes, are reactive, and can be converted to functionalized alkenes 113. Also addition of dichalcogen compounds produces the functionalized alkenes 114. Many examples are known, and some recent examples are cited.

R

R + M-M′′

R

R

M

M′

M, M′ = main group metals

R

R + C-D

R

R

A

B 113

R

R

D

C A, B = hetero atoms

112

A+, B+

114

The first step of the Pd-catalyzed silylstannation–cyclization of the 1,6-enyne 115 is silylpalladation of the triple bond to generate alkenylpalladium 117, and the cyclopentane bearing silylvinyl group 116 was obtained via 118. The carbene–Pd complex 119 was the most effective catalyst [35].

Reactions of Alkynes EtO2C

+ Me3SiSnBu3

EtO2C

[Pd], toluene 45 °C, 81%

577

EtO2C

SiMe3

EtO2C

SnBu3

115

116 Me3SiSnBu3 SiMe3

EtO2C

Pd+

EtO2C

EtO2C

SiMe3

EtO2C

Pd+

N [Pd] =

N

C

C

N

Pd Br2

Me 117

N

118

Me

119

Borylsilylation of 1-octyne with 120 provided the alkenylboronate 121 in high yield using Pd(OAc)2 and bulky isocyanide (1,1,3,3-tetramethylbutyl isocyanide, XVII-6) as a ligand. The product 121 was subjected to Suzuki coupling catalyzed by PdCl2 (dppf) [36]. Under similar conditions, no intermolecular bis-silylation of internal alkynes took place. However, intramolecular bis-silylation of disilanyl ether of homopropargylic alcohol proceeded smoothly with 5-exo-dig cyclization [36a]. HOCH2CH2

O + HOCH2CH2

B

PhMe2Si

Pd(OAc)2, (XVII-6) toluene, 77%

O

O

121 O

120

O

B

PhMe2Si

Me2 Si SiMe3

Pd(OAc)2, (XVII-6) Me

O

toluene, 93%

Me2 Si

SiMe3 Me

122

Although mechanistically different, functionalized alkenylsilanes are prepared stereoselectively by the reaction of 1-alkynes with iodotrimethylsilane (123) and diethylzinc. At first oxidative addition of 123 to Pd(0) generates 125. Then insertion of 1-octyne to 125 affords the alkenylpalladium 126. Transmetallation with Et2 Zn gives 127 and reductive elimination provides the alkenylsilane 124. The reaction can be regarded as a Heck-type reaction of alkyne with Me3 Si-I, followed by Negishi coupling [37].

n-Hex

+ Me3Si-I + Et2Zn 123

Me3Si-I + Pd(0)

n-Hex

125

Pd(PPh3)4 dioxane, 68%

n-Hex Et 124

SiMe3

Pd(0) Me3Si-Pd-I 125

n-Hex

Et2Zn

I-Pd

SiMe3 126

n-Hex Et-Pd 127

SiMe3

578

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Some examples of carbometallation are known. Although intermolecular cyanoboration of alkynes is rather difficult, intramolecular cyanoboration of 128 proceeds smoothly using Pd2 (dba)3 as a catalyst to provide the cyclic alkenylborane 129, which undergoes Suzuki coupling [38]. Carbostannation of 1-alkyne 82 with alkynylstannane catalyzed by iminophosphine I-16 gave the enyne 130 as the main product with high regio- and stereoselectivities [39]. CN O

NPr2

BNPr2

O

B

Pd2(dba)2

CN

80 °C, 98% 128

129 + Bu

Ph

(h3-allyl-PdCl)2

SnBu3

Ph

82 PPh2 Bu

I-16

Bu SnBu3 Ph

SnBu3

+

H 130

H

Ph

92 : 8

Various 1,2-bifunctionalized alkenes containing heteroatoms are prepared by addition to alkynes. Thiophosphorylation of 1-octyne with phosphorothiolate 131 provided (Z)-1-(diphenoxyphosphinyl)-2-(phenylthio)-1-octene in good yield [40]. A useful synthetic method for (Z)-3-phenylthioacrylate derivative is the Pdcatalyzed thioesterification of 1-alkynes with O-methyl S-phenyl thiocarbonate (132). Addition of 132 to 1-octyne using Pd(PCy3 )2 as a catalyst afforded methyl (Z)-3-phenylthio-2-nonenoate in 86 % yield [41]. (Z)-1,2-Bis(phenylthio)alkene was prepared in good yield by stereoselective Pd-catalyzed addition of (PhS)2 (3) to 1-alkyne [2].

C6H13

+

(PhO)2P(O)SPh 131

C6H13

Pd(PPh3)4 100 °C, 92%

PhS

P(OPh)2 O

C6H13

+ PhS-CO2Me 132

C6H13

+ PhS-SPh 3

Pd(PCy3)2 110 °C, 86%

C6H13 PhS

Pd(PPh3)4 benzene, 80 °C, 91%

CO2Me C6H13 PhS

SPh

7.1.6 Cyclization of 1,6-Enynes and 1,7-Diynes Facile Pd-catalyzed cyclizations of 1,6-enyne 133 and diynes is a useful synthetic method for substituted cyclopentanes, and called cycloisomerization. The reactions

Reactions of Alkynes

579

have been studied extensively by Trost [42]. One mechanistic explanation of the reactions is shown by the following scheme (palladacycle mechanism). At first oxidative cyclization of 1,6-enyne 133 generates the palladacycle 134. Then β-H elimination generates either the alkenylpalladium 135 or 137 depending on which H is eliminated. Finally the diene 136 or 138 is obtained by reductive elimination. The diene 136 is the same product obtained by the thermal Alder-ene reaction of 133 at higher temperature. The conjugated diene 138 can not be obtained by the thermal reaction, but is produced only by the Pd-catalyzed reaction. Another path is reductive elimination of 134 to generate the strained cyclobutene 139, which undergoes electroisomerization to afford the diene 140. This path is called enyne metathesis [43]. I. Palladacycle mechanism oxidative PdLn cyclization

PdLn H

133

134

H

PdLn

H

H

PdLn 134

136

135

b-H elimination

Cycloisomerization (Alder-ene reaction)

H

H H

PdLn

reductive elimination

H 137

138 Cycloisomerization

139

thermal H Alder-ene reaction 140 Enyne metathesis

H

133 136

A number of interesting applications of cycloisomerization to natural product syntheses have been carried out by Trost. As an example, total synthesis of picrotoxinin has been achieved based on cycloisomerization (Alder-ene reaction) of the 1,6-enyne system 141 as a key reaction. No satisfactory cyclization of 141 occurred when phosphine ligands such as P(o-Tol)3 , DPPB, and triisopropyl phosphite were used. However, smooth cyclization took place to give the Alder-ene product in a quantitative yield at 50 ◦ C when N ,N
-bis(benzylidene)ethylenediamine (BBEDA) was used as a ligand, and the triol 142 was obtained in 75 % yield after

580

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

deprotection, and the asymmetric synthesis of picrotoxinin has been carried out. The effect of the BBEDA ligand is remarkable [44]. 1. Pd(OAc) 2, BBEDA CH2Cl2, 50 °C

HO

2. TBSF

TBDMSO TMSO

HO OMOM

OH

141 Ph

N

N

142

75%

Ph

BBEDA

The cycloisomerization of 1,6-enynes proceeds smoothly in the presence of AcOH or HCO2 H and the reaction is explained by the following mechanism (hydridopalladium acetate mechanism) [45]. Most importantly, oxidative addition of AcOH to Pd(0) generates H-Pd-OAc 143, and the cyclization of 1,6-enynes starts by insertion of the triple bond to 143 to afford the alkenylpalladium 144. Subsequent intramolecular insertion of the double bond gives the alkylpalladium 145. The termination step is β-H elimination and either the diene 136 or 138 is formed with regeneration of H-Pd-OAc. It should be noted that the alkenylpalladium 144 is a similar species formed in a Heck reaction by oxidative addition of alkenyl halide to Pd(0). Based on this reaction, alkyne is a useful starter in domino cyclization of polyenynes. II. Hydridopalladium acetate mechanism AcOH + Pd(0)

oxidative addition

HPdOAc 143 H

H

HPdOAc

Pd OAc

PdLn OAc 144

133 b-H elimination

+ HPdOAc

Ene reaction

carbopalladation (insertion)

136

Pd OAc 145

b-H elimination + HPdOAc

Cycloisomerization 138

By way of an example, the formation of 147 from 146 in the presence of AcOH is explained by this mechanism [45]. Cycloisomerization of 1,7-enynes is more difficult than that of 1,6-enynes. Seemingly difficult cyclization of 1,7-enyne 148

Reactions of Alkynes

581

bearing a hindered double bond was achieved in the presence of HCO2 H, an acid stronger than AcOH, and in the absence of ligand. The six-membered ring compound 149 was obtained in 83 % yield under the conditions. This reaction is a key step in the total synthesis of cassiol [46]. E

E

Ts

E

N

Pd2(dba)3, PPh3

H

H

Ts N

E

AcOH, PhH, 80 °C, 40% H H 146

147

Ene reaction O

O

TMS

TMS Pd2(dba)3 OSiR3 R3SiO 148

OSiR3

HCO2H, rt R3SiO 83%

OSiR3

149

OSiR3

Mikami developed an efficient Pd-catalyzed asymmetric ene reaction of 1,6and 1,7-enynes. The 1,6-enyne 150 was converted to the tetrahydrofuran (S)151 with 99 % ee in 99 % yield using Pd(OCOCF3 )2 and (R)-SEGPHOS XIV-3 in C6 D6 [47]. Similarly the asymmetric ene reaction of 1,6-enyne 152 afforded the (S)-spiro compound 153 using a cationic Pd(II) complex in DMSO in the presence of HCO2 H. As a chiral ligand, (aS)-binaphthyldiphenylphosphine bearing an ‘achiral’ gem-dimethyl oxazoline unit (VI-19) was used [48]. CO2Me CO2Me

Pd(OCOCF3)2, (R)-XIV-3 C6D6, 100 °C, 99%, 99% ee O

O 150 O

(S)-151 CO2Me

O [(MeCN)4Pd](BF4)2 (aS)-VI-19

N Ts 152

HCO2H, DMSO, 100 °C 99%, 93% ee

CO2Me O N Ts

N PPh2

(S)-153

L = (aS)-VI-19

Highly enantioselective synthesis of the quinoline 155 was achieved via ene cyclization of the 1,7-enyne 154 using a cationic Pd(II) complex and (S)-BINAP in DMSO in the presence of HCO2 H with very high % ee (98 % ee) and in high

582

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

yield (99 %). Also the spiro quinoline bearing a macrocycle 157 with 86 % ee was obtained from the 1,7-enyne 156 [49]. O

[(MeCN)4Pd](BF4)2 (S)-BINAP HCO2H, DMSO, 100 °C 99%, 98% ee O

N Ts

N Ts 155

154

[(MeCN)4Pd](BF4)2 (S)-BINAP N Ts

HCO2H, DMSO, 100 °C, 53%, 86% ee

N Ts

156

157

Ene-type cyclization of the 1,6-enyne 158 to provide a five-membered ring is not possible. Instead, the cyclohexenes 159 and 160 were obtained using cationic Pd(II) and (R)-BINAP. The reaction can be understood by two reaction paths. The rather unusual 6-endo cyclization of 161 to generate 162 is one possibility. The formation of the neopentyl-type palladium intermediate 163 by 5-exo cyclization is another possibility. Then the olefin insertion affords the cyclopropane 164, and subsequent β-carbon elimination provides 165, from which 159 and 160 are formed by β-H elimination [50]. CO2Me Me

CO2Me

[(MeCN)4Pd](BF4)2 (R )-BINAP

Me D

DMSO, D 2O, 100 °C O 158

CO2Me +

Me D

O 159

O 160

XPd

H Me Pd

6-endo

CO2Me

Me

b-H elimination

159 + 160

O 162

CO2Me 5-exo

Pd-X

O Me

161

CO2Me

CO2Me

Me

X-Pd O 164

O 163 b-carbon elimination

CO2Me XPd

H

Me O 165

159 + 160

Reactions of Alkynes

583

For all these asymmetric ene cyclizations, Mikami proposed a reaction mechanism, in which he claimed that Pd(II) is a real catalytic species, rather than generally accepted Pd(0) species, and stresses the importance of the use of weakly coordinating anions such as BF4 , which stabilize the cationic Pd(II) complex. The cyclization of the enediyne 166 (1,6-diyne system) in the presence of HCO2 H involved cyclopropanation via 168 and the neopentylpalladium 169, which provides the cyclopropane 170. Since β-H elimination hardly takes place, the cyclized product 167 was formed by reduction of alkylpalladium 170 with HCO2 H and Pd(0) is regenerated [51]. H

(h3-allyl-PdCl)2, PPh3 EtO2C HCO2H, DMF, 70 °C, EtO C 2 71%

EtO2C EtO2C

O

166

167

O

HCO2-Pd-H

Pd(0) HCO2H

EtO2C

PdX

Pd-X

EtO2C

EtO2C EtO2C

O 168

169

Pd-X

EtO2C EtO2C

O

170

O

The cycloisomerization of 1,6-diyne 171 in the presence of AcOH is terminated by reduction of the alkenylpalladium 172 with hydride such as H-SiEt3 to afford the conjugated diene 173. III. Hydropalladation and reductive cyclization hydride (Et3SiH)

AcO-Pd-H

+ Pd(0) H

Pd-OAc 171

172

AcOSiEt3

173

In the total synthesis of siccanin, cyclization of the 1,7-diyne 174 was carried out in the presence of HCO2 H and HSiEt3 using TFP (I-3) as a ligand to provide the alkenylpalladium 175. The reaction can be terminated only by reduction of 175 with hydrosilane to give the 1,3-diene 176 in 79 % yield [52]. Genet et al. reported an interesting cyclization of 1,6-enynes in an aqueous solution. Treatment of the 1,6-enyne 177 with PdCl2 in aqueous dioxane afforded the methylenetetrahydrofuran 178 in 85 % yield. The reaction is explained by involvement of H-Pd-OH species, namely, formation of 179 by insertion of the alkyne to H-Pd-OH, followed by cyclization, and reductive elimination [53]. 7.1.7 Benzannulation Cyclotrimerization of substituted alkynes catalyzed by various transition metal complexes to produce benzene derivatives is a well-known reaction. As a recent example,

584

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes Me

Me

MeO

Pd2(dba)3, TFP (I-3) OMe

TBDMSO

Et3SiH, HCO2H, PhMe, 80 °C, 79%

OMe MeO TBDMSO

Pd-X

H

H

174

175 Me HO

Me

H OMe MeO TBDMSO

Et3SiH

O steps O H

Et3SiX

Me

H siccanin

H 176

PdCl2, TPPTS(II-1) O Ph

dioxane, H 2O, 85%

O

Ph H

177

OH

178

H-Pd-OH Pd(0) Pd-OH

O

O

Ph

Ph 179

H

Pd-OH

Yokota et al. reported quantitative cyclotrimerization of symmetric internal alkynes using a complicated catalyst system of Pd(II)/chlorohydroquinone/NPMoV under oxygen [54]. In addition, regiocontrol to produce a single isomer is one problem inherent in cyclotrimerization of substituted alkynes, and many attempts to achieve regioselective cyclization have been carried out with partial success. Perez and co-workers reported a novel Pd-catalyzed cyclotrimerization of cycloalkynes. They generated highly strained cyclohexyne (181) by the treatment of 2-trimethylsilylcyclohexenyl triflate (180) with CsF in the presence of Pd(PPh3 )4 . Cyclotrimerization of cyclohexyne (181) occurred rapidly as soon as it was generated, and they obtained dodecahydrotriphenylene (182) in 62 % yield [55].

Reactions of Alkynes R

585

R R

R

R

R

R

R

catalyst

R R

R

SiMe3

R

Pd(PPh3)4, CsF MeCN, rt, 64%

OTf 180

181

182

Yamamoto et al. have developed novel methods of regioselective syntheses of polysubstituted benzenes based on [4 + 2] addition of an enyne with an alkyne, offering useful synthetic methods of substituted benzenes in short steps [56]. Two types of [4 + 2] addition have been reported. One of them is the homobenzannulation of conjugated enynes 183 catalyzed by Pd(PPh3 )4 . The reaction proceeds with remarkably high regioselectivity to give 1,4-disubstituted benzenes 185 as a single isomer via the path as shown by 184. The isomers 187 via 186 are not formed [57]. R

R H

H

H

H

R

R 185 R

184 R R

183

R 186

R 187 not formed

The reaction has many synthetic applications. 4-Substituted anisole 189 was obtained from 2-methoxyenyne 188 using Pd(PPh3 )4 and additional P(o-Tol)3 , and the product was converted to 4-methoxyacetophenone 190 [58]. The intramolecular reaction is useful for the synthesis of various phane derivatives. Several oxaparacyclophanes 192 have been prepared from 191 using Pd(PPh3 )4 and additional ligands in DMSO in good yields [59]. The presence of an EWG in the enynes accelerates the reaction. The conjugated cyclic enynone 193 underwent smooth homobenzannulation to give the diketone 194 at 50 ◦ C [60]. Benzannulation of the highly reactive enyne 195, possessing an EWG, was carried out in a fluorous biphasic system of perfluorodacalin, toluene, and hexane using perfluoro-tagged triarylphosphine 197, and the disubstituted

586

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes OMe

OMe H

H

OMe

H+

Pd(PPh3)4, P(o-Tol) 3

H

H

THF, 100 °C, 52% 188 OMe

O

189

190

(OCH2CH2)n (OCH2CH2)n

Pd(PPh3)4, DMSO CH2

(CH2)3

100 °C, high dilution

191

(CH2)3

n

yield

additional ligand

1 2 3 4

34 100 95 50

+ PPh3 + PPh3 + P(o-Tol) 3 + P(o-Tol) 3

CH2

192

benzene 196 was obtained as a single product. The reaction can be carried out several times without loss of catalytic activity [61]. Reactivity-controlled crossbenzannulation of 195 with the enyne 198 was carried out by slow addition of the more reactive enyne 195 (1 equiv.) to a solution of the enyne 198 (1.5 equiv.). In this way, the cross-coupled benzene 199 was obtained in 75 % yield. The isomers 200 and 201 were minor products [62].

Pd(PPh3)4, toluene O

O

50 °C, 72%

193

O 194 CO2Et Pd2(dba)3, L 195

CO2Et hexafluorodecalin, 78% EtO2C 196 L=

n-C6F13

P 3

197

n-Hex

195 CO2Et CO2Et

Pd(PPh3)4

CO2Et +

+

toluene, 30 °C

EtO2C 198

n-Hex

n-Hex

n-Hex 199 75%

200 5%

201 10%

Reactions of Alkynes

587

In the second type [4 + 2] addition, the conjugated diynes 202 are used as the partner of the enynes 183, and the arylalkynes 204 are obtained by the path as shown by 203. The other expected isomers 206 via 205 are not formed [63]. R

R H

H

H

H R

R′

R′

R′

183

203

+

R′

204

R′ R R R′

202 R′ R′

R′ R′ 205

206

not formed

The aniline derivative 208 was obtained by cross-benzannulation of the aminoenyne 207 with dodeca-5,7-diyne (50) [64]. Cross-benzannulation of the 1,4disubstituted enyne 209 with the diyne 50 afforded the 1,2,3,4-tetrasubstituted benzene 210 [63]. Pentasubstituted benzene 212 can be synthesized by the coupling of the trisubstituted 1-buten-3-yne 211 with the diyne 50 [63]. NH2

NH-Boc

n-Bu

NH-Boc +

n-Bu

n-Bu

n-Bu

207

H

H

H

H

50

n-Bu

n-Bu 208 Me

n-Bu Ph

Me

+

77% Ph

n-Bu

n-Bu 50

209

210

n-Bu

Me CO2Me

Me

n-Bu Pd(PPh3)4, Pd(OAc)2

+ Ph 211

CO2Me n-Bu

TDMPP, 72%

Ph

n-Bu

50

n-Bu

212

588

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Intermolecular enyne-diyne cross-benzannulation offers a convenient synthetic method for cyclophanes. The cyclic enyne 213 reacted smoothly with 12-carbontethered cyclic diyne 214, and the meta-cyclophane having both 15- and 16membered rings 215 was prepared in high yield (72 %) [65]. The phthalide 217 was prepared by intramolecular reaction of the highly unsaturated ester 216 using Pd(PPh3 )4 in the presence of DPPF. Similarly 3,4dihydroisocoumarins were synthesized [66].

Pd(PPh3)4, THF

+

100 °C, 72%

213

214

16 15

215

O

O

O

O Pd(PPh3)4, DPPF toluene, 80 °C, 52%

Ph

Ph

216

217

The most desirable aim in benzannulation is selective cyclization of three different alkynes to give a single isomer; Yamamoto offered a solution. Reaction of phenylacetylene (82) with 5-dodecadiyne (50) using Pd(PPh3 )4 and additional P(o-Tol)3 as a catalyst, afforded the tetrasubstituted benzene 218 as a single product in 89 % yield. In this case, dimerization of phenylacetylene to 1,3-diphenylbut-1yn-3-ene (219) took place. +

2 Ph

n-Bu

n-Bu

82

50

Pd2(dba)3, P(o-Tol) 3 TDMPP, toluene, 89% Ph

Ph

n-Bu

n-Bu 50

219

Ph

Ph

218 218

n-Bu

n-Bu

Reactions of Alkynes

589

Then selective cyclization of three different alkynes, that is, 1-decyne, an acceptor alkyne 220, and diyne 50 proceeded selectively to give pentasubstituted benzene 222 as a single product in 60 % yield using Pd(PPh3 )4 , Pd(OAc)2 and electron-rich TDMPP [tri(2,6-dimethoxyphenyl)phosphine] (I-9). In this case, at first TDMPP accelerates the selective coupling of 1-decyne with the reactive alkyne 220 to give 221, and the coupling product 221 reacted with diyne 50 to produce the pentasubstituted benzene 222 [67]. Pd(PPh3)4, Pd(OAc)2

+ Me

n-Oct

CO2Et

TDMPP, toluene, 60%

220

Me

n-Bu

Me

n-Bu

EtO2C

n-Oct

50 EtO2C

n-Oct

n-Bu

n-Bu 222

221

The 1,3,5-unsymmetrically substituted benzene 224 was prepared in 64 % yield by intermolecular cyclotrimerization of 1,3-decadiyne (223). The reaction was surprisingly regioselective to give 224 as a single product [68]. n-Hex Pd2(dba)3, PPh3 THF, 64%

n-Hex

n-Hex

223

224

n-Hex

Benzannulation occurred by the reaction of allyl tosylate (225) and internal alkynes such as 3-hexyne to give the pentasubstituted benzene 227 in 93 % yield using Pd2 (dba)3 and PPh3 . The reaction is explained by repeated insertion of the triple bond to the π -allylpalladium bond (228) to give 229 and 230. Subsequent intramolecular insertion affords 231. β-H elimination provides the pentasubstituted benzene 227 via 232. No reaction occurred when allyl bromide or acetate were used. The trisubstituted benzene 233 was obtained by the reaction of 1-alkyne with allyl tosylate 225 when P(OPh)3 was used as a ligand [69]. Me TsO

Pd2(dba)3, PPh3

225 Et

Et

CH2Cl2, 80 °C, 93%

Et

Et Et

Et

Et

226

227

Et

7.1.8 Homo- and Cross-Coupling of Alkynes Homo-dimerization of terminal alkynes is catalyzed by Pd complexes. Usually control of regio- and stereoselectivities is difficult and a mixture of isomers 234, 235

590

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes Et

Et Pd-OTs

Et

Et

Et Et

Et

Pd-X

228

Et

Et Pd-X

Et

229

230 Me

Et

Et

Et

Et

Et

Et

Et Pd-X

Et

Et

Et Et

231

Et 227

232

Me +

t-Bu

t-Bu

Pd2(dba)3, P(OPh)3 TsO

47% 225

t-Bu 233 R

R

+

R R

R +

R 234

R

235

236

Ph (h3-allyl-PdCl)2

Ph 82

TDMPP, Et 2NH 70% Ph

237

and 236 is obtained. The reaction is selective only under carefully controlled conditions. Head to head dimer 237 of phenylacetylene (82) was obtained selectively when (η3 -allyl-PdCl)2 and TDMPP (I-9)were used in the presence of Et2 NH [70]. Yang and Nolan carried out dimerization of 1-alkynes using Pd(OAc)2 combined with carbene ligand (XV-1). As shown by the examples, use of Cs2 CO3 and K2 CO3 changed the ratios of the head-to-head and head-to-tail dimers (238, 239 and 240), showing that the control of regio- and stereoselectivities is a very delicate problem [71]. R

R R + R

R R = n-C5H11

R Pd(OAc)2, XVI-1, Cs2CO3, DMF, 94% Pd(OAc)2, XVI-1, K2CO3, DMA, 92%

238

+ 239

90 : 3 : 7

11 : 1 : 88

R

240

Reactions of Alkynes

591

Control of selectivities in cross-dimerization of two alkynes is more difficult. Trost et al. carried out selective dimerization of 1-alkynes with acceptor alkynes, possessing an EWG, using TDMPP [72]. Furthermore, Trost and McIntosh succeeded in the selective cross-coupling of 1-alkyne 241 with unactivated alkyne 242, obtaining the coupled product 243 in 62 % yield [73]. O

O

Pd(OAc)2,

+

TDMPP, 62%

OH

HO

OH

HO

241

242

243

Yamamoto et al. reported a new and more complicated dimerization of diynes. Pd(PPh3 )4 -catalyzed reaction of dodecadiyne (50) in the presence of AcOH afforded (E)-1,2-dialkenyl-1,2-dialkynylethylene 244 in 65 % yield [74]. n-Bu n-Bu

n-Bu 50

Pd(PPh3)4, AcOH n-Pr THF, 40 °C 3 days, 65%

n-Pr n-Bu

244

7.1.9 Miscellaneous Reactions Intramolecular cyclization of alkynes with imines offers a new synthetic method for indoles [75]. Reaction of 2-(1-alkynyl)-N -alkylideneaniline 245 catalyzed by Pd(OAc)2 and P(n-Bu)3 afforded 2-alkyl-3-(1-alkenyl)indole 246. The reaction starts by insertion of triple bond to H-Pd-OAc to generate 247, followed by insertion of C=N bond to afford 248. Finally, β-H elimination provides the indole Et

Et

Pd(OAc)2, P(n-Bu)3 THF, 100 °C, 52%

N

N H 246

245 H-Pd-OAc

H

Et

Et

PdOAc H N

N Pd-X

247

248

592

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

246. As another synthetic method for indoles, N -(propoxycarbonyl)indole 250 was obtained by the treatment of 2-(alkynyl)phenylisocyanate 249 with Na2 PdCl4 in 1-propanol [76]. Pr + n-PrOH

Na2PdCl4 CH2Cl2, 70%

Pr N

N=C=O 249

250

CO2Pr

7.2 Reactions of Benzynes 7.2.1 Cyclotrimerization and Cocyclization Benzyne (252), generated by the treatment of 2-trimethylsilylphenyl triflate (251) with CsF [77], can be regarded as a very reactive alkyne. Therefore, similar to alkynes, Pd-catalyzed cyclotrimerization and cocyclization of arynes with other unsaturated bonds are expected. Transition metal-catalyzed reactions of benzyne is a newly developing field of research. Benzyne (252) is generated by the treatment of 251 with both CsF and Pd(0) complexes in the presence of other reactants and undergoes further reactions as soon as it is generated. Although there is no evidence, the Pd(0) catalyst may accelerate the generation of benzyne from 2trimethylsilylphenyl triflate (251). SiMe3 + CsF OTf 251

252

Recently, the Yamamoto group and the Guitian group as pioneers in this field have developed efficient Pd-catalyzed reactions of arynes, particularly cyclotrimerization and cocyclization with alkynes, offering useful synthetic methods for polycyclic aromatic compounds [78]. The Spanish group reported that the cyclotrimerization of benzyne, generated from 251, occurred in situ at room temperature in the presence of Pd(PPh3 )4 in MeCN, and obtained triphenylene (253) in 83 % yield [79].

SiMe3 + CsF OTf 251

Pd(PPh3)4 83% 252 253

Reactions of Benzynes

593

The cyclization of methoxybenzyne (255), generated from 254, proceeded to give trimethoxytriphenylene 257 with high regioselectivity and 258 as a minor product in 81 % total yield. The high regioselectivity of the cyclotrimerization to form 257 is explained by the formation of the palladacycle 256 as an intermediate, which is generated by oxidative cyclization of two benzynes. OMe OMe

OMe SiMe3

Pd(PPh3)4, CsF Pd(PPh3)2

MeCN, rt, 81% OTf 254

255 OMe 256 MeO MeO

OMe

255 +

MeO

OMe

MeO

257

93 : 7

258

The cyclization of arynes can be applied to the synthesis of various polycyclic aromatics. Hexabenzo[a,c,g,I,m,o]triphenylene (260) was obtained as a single product in 39 % yield from 9,10-didehydrophenanthrene generated from 259 [80]. Cyclization of 3,4-didehydrophenanthrene 261 gave rise to the polycyclic compound 262, which has a double helicene structure, in 26 % yield [81].

SiMe3 Pd2(dba)3, CsF MeCN, 39% OTf

259

260

SiMe3

OTf

261

Pd2(dba)3, CsF rt, 26%

262

594

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

Pd-catalyzed cocyclization of arynes with alkynes also proceeds smoothly. Yamamoto obtained phenanthrene derivatives exclusively in good yield, regardless of the electronic nature of the alkynes using Pd(OAc)2 and P(o-Tol)3 . The reaction of 251 with 4-octyne gave rise to the phenanthrene 263 [82]. Similarly, Perez carried out the reaction of benzyne with electron-deficient alkynes such as dimethyl acetylenedicarboxylate (DMAD) (264), and obtained the phenanthrene 265 as the main product using Pd(PPh3 )4 . On the other hand, when Pd2 (dba)3 was used, the naphthalene derivative 266 was the main product [83]. n-Pr SiMe3

n-Pr

Pd(OAc)2, CsF

+ n-Pr

n-Pr

P(o -Tol) 3, 63%

OTf 263

251 SiMe3 + MeO2C

CO2Me

CsF

264

OTf

CO2Me

251

CO2Me

CO2Me +

CO2Me

CO2Me 265

266

CO2Me

Pd(PPh3)4

84%

7%

Pd2(dba)3

10%

83%

The polycyclic arynes derived from phenanthrenes 267, 269, and 271 underwent cocyclization with two molecules of DMAD, giving the tetraesters 268, 270, and 272, respectively, in good yield [84,85]. SiMe3

CO2Me

TfO

CO2Me

Pd2(dba)3

+ MeO2C

CO2Me 264

CO2Me

CsF, 74%

CO2Me 267

268 CO2Me

SiMe3 + MeO2C OTf

CO2Me 264

Pd2(dba)3

CO2Me

CsF, 96% CO2Me CO2Me

269 270

Reactions of Benzynes

595 CO2Me CO2Me

MeO2C

SiMe3 OTf

Pd2(dba)3

+ MeO2C

CO2Me 264

CO2Me

CsF, 91%

271

272

Yamamoto et al. found that benzyne and methallyl chloride 273 underwent an interesting 2 : 1 cycloaddition to afford the phenanthrenes 274 and 275 using phosphinefree Pd2 (dba)3 [86]. This novel reaction is explained by the following mechanism. First, insertion of benzyne to π -allylpalladium generates 276, which undergoes the insertion of benzyne again to give 277. Subsequent intramolecular alkene insertion, and β-H elimination provide 278, and then 279. Me

Me SiMe3 + Me

Cl 273

OTf

Pd2(dba)3

Me

+

CsF, 70%

251

274

7:3

275

Pd Cl

Pd-Cl

insertion

Pd-Cl 152

277

276 Pd-Cl

Me b-H elimination

278

279

Furthermore, the 1 : 1 : 1 cycloaddition of benzyne generated from 251, allyl chloride, and alkyne 280 afforded the naphthalene 281 [86]. Me

SiMe3 + OTf

Cl + n-Pr

n-Pr 280

251

Pd2(dba)3, DPPF CsF, MeCN, 47%

n-Pr 281 n-Pr

7.2.2 Addition Reactions of Arynes 1,2-Diallylbenzene (283) was obtained by the reaction of benzyne (252) with allyl chloride and allylstannane 282. Yamamoto et al. reported that Pd-catalyzed

596

Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes

reaction of allyl chloride and allylstannane generates bis-π -allylpalladium (284), and insertion of benzyne to 284 affords 285, and subsequent reductive elimination yields diallylbenzene (283) [87]. SiMe3 +

Pd2(dba)3, CsF

Cl +

SnBu3

OTf

76%

282

251

283

+

Pd

Pd(0)

Pd 284

252

285

Carbostannation of arynes with alkynylstannanes such as 286 as well as alkenylstannanes is catalyzed by Pd-iminophosphine (I-16) complex to give rise to 2alkynylphenylstannane 287, which is convertible to a variety of 1,2-functionalized arenes such as 288 [88]. Ph SiMe3 + Ph

SnBu3 286

OTf 251

(h3-allyl-PdCl)2,

PhCOCl

I-16, CsF, 54%

Pd(0), 50% SnBu3 287 Ph

COPh 288

Bis-silylation of benzyne with the disilane 289, catalyzed by the Pd complex of t-octyl isocyanide (XVII-6) gave the 1,2-disilylbenzene derivative 290 [89].

SiMe3

Me3Si

SiMe3 Pd(OAc)2, KF, t-Oct-NC ( XVII-6)

+

18-crown-6, THF, 20 °C, 66%

OTf 251

SiMe3

Me3Si

289

290

Benzyne can be carbonylated in the presence of allyl acetate to give 2methyleneindanone 291 under atmospheric pressure of CO using DPPE as a ligand [90]. In this reaction, at first the 2-allylphenylpalladium 292 is generated.

References

597

CO insertion affords the acylpalladium 293, and the following intramolecular insertion of alkene to the acylpalladium bond in 293 provides 294, which is converted to 291 by β-H elimination. O SiMe3 OAc + CO

+ 251

OTf

(h3-allyl-PdCl)2, CsF DPPE, MeCN, 1 atm, 80 °C, 80%

291 O

Pd-OAc + Pd

Pd-OAc

CO

OAc 292

293

O Pd-OAc

291

294

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61. S. Saito, Y. Chounan, T. Nogami, O. Ohmori, and Y. Yamomoto, Chem. Lett., 444 (2001). 62. S. Saito, O. Ohmori, and Y. Yamomoto, Org. Lett., 2, 3853 (2000). 63. V. Gevorgyan, A. Takeda, M. Homma, N. Sadayori, U. Radhakrishnan, and Y. Yamomoto, J. Am. Chem. Soc., 121, 6391 (1999); V. Gevorgyan, A. Takeda, and Y. Yamomoto, J. Am. Chem. Soc., 119, 11313 (1997). 64. S. Saito, N. Uchiyama, V. Gevorgyan, and Y. Yamomoto, J. Org. Chem., 65, 4338 (2000). 65. V. Gevorgyan, N. Tauboya, and Y. Yamomoto, J. Org. Chem., 66, 2743 (2001). 66. T. Kawasaki, S. Saito, and Y. Yamamoto, J. Org. Chem., 67, 2653 (2002); T. Kawasaki and Y. Yamamoto, J. Org. Chem., 67, 5138 (2002). 67. V. Gevorgyan, U. Radhakrishnan, A. Takeda, M. Rubina, M. Rubin, and Y. Yamomoto, J. Org. Chem., 66, 2835 (2001). 68. A. Takeda, A. Ohno, I. Kadota, V. Gevorgyan, and Y. Yamomoto, J. Am. Chem. Soc., 119, 4547 (1997). 69. N. Tsukada, S. Sugiwara, and Y. Inoue, Org. Lett., 2, 655 (2000). 70. M. Rubina and V. Gevorgyan, J. Am. Chem. Soc., 123, 11107 (2001). 71. C. Yang and S. P. Nolan, J. Org. Chem., 67, 591 (2002). 72. B. M. Trost, M. T. Sorum, C. Chan, A. E. Harms, and G. R¨uhter, J. Am. Chem. Soc., 119, 698 (1997). 73. B. M. Trost and M. C. McIntosh, Tetrahedron Lett., 38, 3207 (1997). 74. D. H. Camacho, S. Saito, and Y. Yamomoto, J. Am. Chem. Soc., 124, 924 (2002). 75. A. Takeda, S. Kamijo, and Y. Yamomoto, J. Am. Chem. Soc., 122, 5662 (2000). 76. S. Kamijo and Y. Yamomoto, J. Org. Chem., 68, 4764 (2003). 77. Y. Himeshima, T. Sonoda, and H. Kobayashi, Chem. Lett., 1211 (1983). 78. Review, H. Pellissier and M. Santelli, Tetrahedron, 59, 701 (2003). 79. D. Pena, S. Escudero, D. Perez, E. Guitian, and L. Castedo, Angew. Chem. Int. Ed., 37, 2659 (1998). 80. D. Pena, D. Perez, E. Guitian, and L. Castedo, Org. Lett., 1, 1555 (1999). 81. D. Pena, D. Perez, E. Guitian, and L. Castedo, Org. Lett., 5, 1863 (2003). 82. K. V. Radhakrishnan, E. Yoshikawa, and Y. Yamamoto, Tetrahedron Lett., 40, 7533 (1999). 83. D. Pena, D. Perez, E. Guitian, and L. Castedo, J. Am. Chem. Soc., 121, 5827 (1999). 84. D. Pena, D. Perez, E. Guitian, and L. Castedo, J. Org. Chem., 65, 6944 (2000). 85. D. Pena, D. Perez, E. Guitian, and L. Castedo, Synlett, 1061 (2000). 86. E. Yoshikawa and Y. Yamamoto, Angew. Chem. Int. Ed., 39, 173 (2000); E. Yoshikawa, K. V. Radhakrishnan, and Y. Yamamoto, J. Am. Chem. Soc., 122, 7280 (2000). 87. E. Yoshikawa, K. V. Radhakrishnan, and Y. Yamamoto, Tetrahedron Lett., 41, 729 (2000). 88. H. Yoshida, Y. Honda, E. Shirakawa, and T. Hiyama, Chem. Commun., 1880 (2001). 89. H. Yoshida, J. Ikadai, M. Shudo, J. Ohshita, and A. Kunai, J. Am. Chem. Soc., 125, 6638 (2003). 90. N. Chatani, A. Kamitani, M. Oshita, Y. Fukumoto, and S. Murai, J. Am. Chem. Soc., 123, 12686 (2001).

Chapter 8 Pd(0)-Catalyzed Reactions of Alkenes

Various reactions of alkenes are surveyed separately in several chapters. Pd(II)promoted oxidative reactions of alkenes are treated in Chapter 2.2 and Pd(0)catalyzed reactions of alkenes with organic halides are discussed in Chapter 3.2. Other Pd(0)-catalyzed reactions of alkenes are discussed in this chapter.

8.1 Carbonylation The oxidative carbonylation of alkenes, which is promoted by Pd(II), is described in Chapter 2.2.7. The Pd(0)-catalyzed carbonylation reactions, which are mechanistically different from the oxidative carbonylation, are treated in this section. Preparation of carboxylic acids and esters by the reaction of alkenes, CO, and water or alcohols can be carried out under mild conditions. The reaction is called hydrocarboxylation or hydroesterification of alkenes, and PdCl2 (PPh3 )2 as a standard catalyst precursor is used in the presence of acids such as HCl as a proton source [1]. Usually a mixture of linear and branched esters 1 and 2 are obtained. Their ratios depend on the structure of the alkenes and catalytic species, and control of the regioselectivity is an important problem. Carbonylation of 1-alkenes proceeds under mild conditions (room temperature, 1 atm) to give branched esters 2 with high selectivity using PdCl2 in the presence of CuCl2 , HCl, and O2 (Alper recipe) [2]. Interestingly, although the Alper’s carbonylation is carried out in the presence of CuCl2 and O2 , no oxidative carbonylation occurs. R1 + CO + ROH

PdCl2(PPh3)2 HCl

CO2R

R1 1

R1 + CO + ROH

PdCl2, CuCl2

R1

+

R1

CO2R 2

CO2R

O2, HCl, rt, 1 atm 2

Several Pd complexes have been claimed to be highly active catalysts. The linear ester 4 was obtained as the main product along with the branched ester 3 as the minor product by the carbonylation of 1-octene using [Pd(MeCN)2 (PPh3 )2 ](BF4 )2 Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

602

Pd(0)-Catalyzed Reactions of Alkenes

C6H13 + CO + MeOH

+ CO + MeOH

[Pd(MeCN)2(PPh3)2] C6H13 (BF4)2 100 °C, 5 atm, 61%

CO2Me

3

[Pd(MeCN)2(PPh3)2] (BF4)2

CO2Me

+ C6H13 24 : 76

4

CO2Me

100 °C, 5 atm, 69% 5

[3]. Also cyclohexene was carbonylated smoothly to afford methyl cyclohexanecarboxyl are (5) with this catalyst. Pd(OAc)2 immobilized on montmorillonite is an active catalyst for carbonylation in MeOH in the presence of PPh3 to give branched esters [3a]. The branched ester 6 was obtained from styrene in 96 % yield with 94 % selectivity using Pd(OAc)2 -(S)-MeO-MOP (VI-12) in the presence of p-TsOH, although % ee was negligible [3]. The commercially important branched ester 8 was obtained in 89 % yield with 97.5 % selectivity from 2-vinyl-6-methoxynaphthalene (7) using PdCl2 (PPh3 )2 and p-TsOH and LiCl as effective promoters [4]. The Pd complex of pyridine-2-carboxylic acid is an active catalyst for carbonylation of alkenes with alcohols [5]. Carboxylic acids are prepared by the carbonylation in water by the use of water-soluble phosphines such as II-8 in the presence of p-TsOH [5a].

+ CO + MeOH

Pd(OAc)2-(S)-MOP TsOH, rt, 20 atm 96%

CO2Me 6

+ CO + H2O MeO 7

CO2Me +

94 : 6

PdCl2(PPh3)2, TsOH, LiCl MEK, 115 °C, 54 atm, 89%

CO2H MeO 8

The formation of branched esters suggests the potential for asymmetric carbonylation. Only a few successful asymmetric carbonylations are known. Zhou and co-workers reported the highly successful asymmetric carbonylation of styrene. They obtained the branched ester 6 with 99.3 % ee and high regioselectivity of the branched ester using the Alper catalyst, PdCl2 -CuCl2 in the presence of the chiral monophosphine DDPPI 9 in methyl ethyl ketone [6]. Cyclocarbonylation of substituted allylic alcohols to give rise to γ -lactones proceeds regio- and stereoselectively using DPPB as a ligand under pressure of CO and H2 in dichloromethane. It is claimed that the presence of H2 is essential

Carbonylation

+ CO + MeOH

603

PdCl2, CuCl2, L

CO2Me

MEK, 80 °C, 50 atm 100% conversion

92.8%, 99.3% ee

6

OTs

H

+

O

CO2Me

L= O Ph2P

H

7.2%

9

for the lactone formation. Carbonylation of (E)-allylic alcohol 10 afforded the trans-disubstituted lactone 11. The 2-alkylidenecyclohexanol 12 was converted to a mixture of stereoisomers, which is known as an insect repellent 13 [7]. Carbonylation of 2-allylphenol in dichloromethane using DPPB gave the seven-membered lactone as a main product (52 %) and six-membered lactone in 21 % yield [8]. As an application, carbonylation of 2,4-diallyl-1,3-dihydroxy-5-alkylbenzene 14 under CO and H2 pressure using DPPB in toluene afforded the seven-membered lactone 15 regioselectively in 90 % yield [9]. Me

Me Me

+ CO/H2

OH

Pd(OAc)2, DPPB, CH2Cl2 110 °C, 5.5 atm, 68%

O Me

10

O

11 H

OH

+ CO/H2

O

Pd(OAc)2, DPPB, CH2Cl2

O

110 °C, 55 atm, 85%

Me H 13

12

Me O

HO O + CO/H2 OH

C15H31

Pd(OAc)2, DPPB, toluene 120 °C, 48 atm, 90% C15H31

O O

14

15

Under similar conditions, 2-allyl-4-toluidine (16) was converted to the sevenmembered lactam 17 as the main product and the six-membered lactam 18 as the minor product under CO and H2 pressure in 95 % total yield [8]. Carbonylation of some alkenes catalyzed by a cationic Pd complex yields polyketones, which are alternating copolymers. The polyketone 19 of ethylene or propylene named ‘carilon’ is produced commercially by Shell [10]. A Chain-transfer mechanism for the alternating copolymerization of CO and ethylene was proposed

604

Pd(0)-Catalyzed Reactions of Alkenes Me +

CO/H2

NH2

Pd(OAc)2, DPPB, CH2Cl2 100 °C, 48 atm, 95%

16 Me

Me

Me

+ N H 17

N H

O

O

18

78 : 21

O

O H2C

CH2

+ CO

[L2Pd]+ O

n 19

[Pd(II), III-6]

+ CO 3 atm

CH2Cl2, 20 °C

2 atm

O 20

[Pd((R,S)-binaphos)-(Me)(MeCN)][BAr4] Ar = 3,5-bis(trifluoromethyl)phenyl

[11]. Nozaki and co-workers prepared the completely isotactic chiral polyketone 20 having (S) form and high molecular weight cleanly by copolymerization of CO and propylene at room temperature with very high enantioselectivity by using a cationic Pd complex coordinated by the asymmetric chiral phosphine–phosphite ligand [(R,S)-BINAPHOS](III-6). They showed that the enantioselectivity for the propylene insertion was at least 95 % ee [12]. The high enantioselectivity is explained by the assumption that CO always coordinates at the position trans to the phosphine ligand, and propylene coordinates trans to the phosphite ligand. As a related reaction, hydrosulfination of propylene with SO2 and H2 gives alkane sufinic acid 21, which is unstable and trapped in situ by Michael addition to α,β-unsaturated ketones such as mesityl oxide (22), and the γ -oxo sulfone 23 is isolated in high yields. The hydrosulfination proceeds in CH2 Cl2 using DPPP as a ligand [13]. O Me +

SO2

O

+

H2

(dppp)PdCl2(MeCN)2

SO2H

80 °C, CH2Cl2 21

S O2 23

22

Hydroamination

605

8.2 Hydroamination Preparation of aliphatic amines by direct hydroamination of alkenes with amines is a highly desirable reaction. However, except for the well-established hydroamination of 1,3-dienes via π -allylpalladiums, no smooth hydroamination of simple alkenes is known. As a breakthrough, Kawatsura and Hartwig reported that the hydroamination of styrene derivatives with aniline is catalyzed by Pd(TFA)2 and DPPF in the presence of trifluoroacetic acid (TFA) or triflic acid as a cocatalyst to afford the branched amine 24 regioselectively in 99 % yield. Formation of the branched amine 24 offers an opportunity of asymmetric amination. They obtained the (S)-amine 25 in 80 % yield with 81 % ee using (R)-BINAP as a chiral ligand [14]. The reaction is explained by insertion of styrene to the H-Pd bond and nucleophilic attack of amine on an η3 -benzylpalladium complex [15]. Hii and coworkers obtained the amine 24 with 70 % ee in 75 % yield using the dicationic Pd complex, [Pd(MeCN)(H2 O)(R-BINAP)](OTf)2 [16]. NHPh

+ PhNH2

Pd(TFA) 2, DPPF

Me

CF3CO2H, 100 °C, 99%

24 NHPh

+ PhNH2 F3C

Pd(OTf) 2[(R)-binap]

Me

25 °C, 80%, 81% ee F3C (S)-25

In addition, they carried out enantioselective Michael-type hydroamination of the alkenoyl-N -oxazolidinone 26 with aniline and obtained the chiral amine 27 with 93 % ee. Furthermore, they reported hydroamination of dihydrofuran (28) and 2,3dihydropyran (30). Reaction of dihydrofuran (28) with morpholine proceeded at room temperature to give 2-aminotetrahydrofuran 29 regioselectively in high yield. Hydroamination of 2,3-dihydropyran (30) with morpholine proceeded at 80 ◦ C to give 2-morpholinotetrahydropyran (31). For this hydroamination, phosphine-free O

O

O + PhNH2

N

Me

[Pd(MeCN)(H2O)binap](OTf) 2 25 °C, 93%, 93% ee

Me

26 K2Pd(SCN)4

+ O

rt, 91%

N

O

N H

28

O 29

O K2Pd(SCN)4

+ O 30

N

* 27

O

N H

80 °C, 98%

O

N O

31

O

O

PhNH

O

606

Pd(0)-Catalyzed Reactions of Alkenes

K2 Pd(SCN)4 was used as an active catalyst. The hydroamination did not appear to be acid-catalyzed since sulfuric and p-toluenesulfonic acids failed to induce any reaction even after heating at 60 ◦ C for 24 h [17].

8.3 Hydrometallation Mainly hydrosilylation has been studied as the hydrometallation of alkenes. Hydrosilylation of 1-alkenes is often carried out using reactive HSiCl3 . Triorganosilanes are less reactive. Hydrosilylation of 1-alkenes with HSiCl3 produces terminal silanes as expected when PPh3 is used. However, Hayashi and co-workers found that regioselectivity changes drastically when bulky ligands are used. The attack of the trichlorosilyl group at an internal carbon of the terminal double bond occurs and offers the possibility of asymmetric hydrosilylation. This is synthetically useful because chiral alcohols can be prepared by the Tamao method, that is, oxidative conversion of silyl groups to alcohols. Successful studies on asymmetric hydrosilylation of simple 1-alkenes, norbornene, and styrene have already been carried out extensively by Hayashi’s group mainly by using MeO-MOP (VI-12) as a chiral ligand [18,19]. They found that H-MOP (VI-1) is more effective than VI-12 for the hydrosilylation of styrene, and obtained the chiral 1-trichlorosilyl-1-phenylethane (32) with 93 % ee, which was converted oxidatively to the chiral alcohol 33. Further modification of H-MOP ligand improved the efficiency. For example, the highest % ee (98 % yield) was obtained for hydrosilylation of styrene when HMOP(m,m-2CF3 ), which has 3,5-ditrifluoromethylphenyl groups instead of phenyl, was used. While the silane with 97 % ee was obtained by hydrosilylation of 4methoxystyrene using H-MOP(m,m-2CF3 ), it was only 61 % ee when H-MOP was used [20]. SiCl3 + HSiCl3

(h3-allyl-PdCl)2-(R)-VI-1

OH

Me

Me

0 °C, 100%, 93% ee 32

33

Johannsen and co-workers found that the phosphoramidite of axially chiral BINOL (III-9) is an effective chiral ligand, and they obtained 32 with 99 % ee in 87 % yield from styrene. Also they prepared 1-trichlorosilyl-1-phenylpropane (35) with 98 % ee in 91 % yield by the hydrosilylation of β-methylstyrene (34) with this ligand, and chiral 1-phenyl-1-propanol was prepared from 35 [21]. Furthermore, they claimed that arylmonophosphinoferrocene was an efficient ligand. In particular, the p-MeO-Ph-MOPF (VIII-8) they synthesized was the most effective ligand for asymmetric hydrosilylation of styrene, and ultrafast asymmetric hydrosilylation occurred with TOF exceeding 180 000 h−1 [22]. As an extension of hydrosilylation of alkenes, cyclization-hydrosilylation of 1,6-dienes occurs by the reaction with HSiR3 [23]. The cationic complex 37, generated in situ from (phen)Pd(Me)Cl and NaBAr4 , is an active catalyst, catalyzing the reaction of dimethyl diallylmalonate (36) with HSiCl3 to give the disubstituted cyclopentane 38 with 98 % trans selectivity in 92 % yield [24]. A mechanism different from that of usual hydrosilylation, which postulates formation of H-Pd-SiR3 and hydropalladation of alkene, was proposed by Widenhoefer

Hydrometallation

607 OH

SiCl3 Me + HSiCl3

(h3-allyl-PdCl)2-(SA, RC, RC)-III-9

Et

Et

20 °C, 91%, 98% ee (R)-35

34

F3C H

O P

P

N

O F3C

2

H-MOP (m,m-2CF3)

III-9 OMe

Fe

PPh2 (S)-VIII-8

for the cyclization–hydrosilylation. At first, generation of silylpalladium 39 is assumed. Insertion of 36 to the Pd-Si bond in 39 (silylpalladation) provides alkylpalladium 40. Cyclization of 40 gives 41, which reacts with HSiEt3 to produce the product 38 and regenerates the catalytic species 39. The polycyclic compound 44 was obtained efficiently in 74 % yield by domino cyclization–hydrosilylation of the triene 43 catalyzed by 37 with high diastereoselectivity (20 : 1) [26]. An asymmetric version has been carried out using a chiral catalyst precursor generated from (N ,N )Pd(Me)Cl(R)-4-isopropyl-2-(2-pyridyl)2-oxazoline (42) and NaBAr4 . Reaction of 36 with HSiEt3 using 42 afforded the (S,S)-cyclopentane 45 in 82 % yield with 87 % ee [25,27]. The triethylsilyl group in 45, obtained by hydrosilylation with HSiEt3 , can not be oxidized to the corresponding alcohol due to low reactivity. Therefore the cyclization–hydrosilylation of the 1,6-diene 46 was carried out using pentamethyldisiloxane (47), and the cyclized product 48 was oxidized smoothly to the alcohol 49 with 76 % ee in 82 % overall yield [27]. Cyclization–hydrosilylation of 1-cyclopropyl-1,6-diene 50 with a siloxane proceeded smoothly using 37 as a catalyst, and the cyclopentane 51 was obtained in 93 % yield [28]. i-Pr CF3 N

N

37

+ Me Ar = Pd BAr4 OEt2

O

N Me Pd N

CF3 (R)-42

Cl

608

Pd(0)-Catalyzed Reactions of Alkenes E

E

SiEt3

37

+ HSiEt3

CH2Cl2, 0 °C

E

E

36

Me 92%

38

N

+ Me Pd N

N

N

HSiEt3

SiEt3 Pd

C Ar

N

N

CH4

C

39

Ar

37a 36 E

Et3Si

E

Me 38

HSiEt3 SiEt3

E

Et3Si

N

E

E N

Pd N

C

Pd

Ar

E

N

N 41

40 SiEt3

Me

+ E

E

37

HSiEt3

74%

E

E E

E

E

E 44

43 E +

HSiEt3

E

[Pd] 42 / NaBAr4

E

82%, 87% ee

E

SiEt3 Me (S,S)-45

36 E + E

HSiMe2OSiMe3

Bu

E

[Pd] 42 / NaBAr4

SiMe2OSiMe3

E

47

Bu

46 KF, AcOOH

48 E

OH

E

Bu

(S,S)-49

82%, 76% ee

E + HSiMe2OSiPh2(t-Bu) E 50

37

E

93%

E

SiR3

51

Miscellaneous Reactions

609

Hydrophosphorylation of alkenes has been regarded as a rather difficult reaction. Tanaka discovered that efficient hydrophosphorylation of simple alkenes and cyclic alkenes is possible by using the five-membered cyclic phosphonate 52. The reaction of 1-octene with 52 proceeded at 100 ◦ C to afford the linear phosphonate 53 in 89 % yield. Regioselectivity depends on the nature of the alkenes, and the branched phosphonate 54 was formed by the reaction of styrene. DPPB was found to be a suitable ligand [29]. Hydrophosphination of styrene with diphenylphosphine (55) proceeded regioselectively by using phosphine-free Pd catalyst to afford 2-phenylethyl(diphenyl)phosphine (56) [30]. C6H13

O +

H(O)P O

O

PdMe2(dppb)2

P

100 °C, 89%

C6H13 53

52 Ph

O +

H(O)P O

O

PdMe2(dppb)2

Ph

100 °C, 100%

Ph2PH 55

P

O O

Me

52

+

O O

54 PPh2

PdCl2(MeCN)2 90 °C, 75% 56

8.4 Miscellaneous Reactions In the presence of a proton source, 1,6-heptadiene (57) undergoes cycloisomerization to afford 1,2-disubstituted cyclopentenes. Insertion of one of the double bonds of 57 to H-Pd-X generates 58. Further insertion of the double bond in 58 gives 59, and β-H elimination affords 60, 61, and 62 depending on the reaction conditions [23]. Pd (0)+ H-X

H-Pd-X Pd-X Pd-X Me 58

59

H

57 Me

Me +

60

Me

Me 61

62

Me

Lewis acids as cocatalysts are effective for Pd-catalyzed cycloisomerization. The reaction of diallylmalonate 36 in the presence of AgOTf afforded 63 with high selectivity [31]. Asymmetric cyclization of 1,6-diene 36 was carried out using PdCl2 (MeCN)2 -AgBF4 in the presence of a chiral ligand [32]. Cycloisomerization

610

Pd(0)-Catalyzed Reactions of Alkenes

of 36 was catalyzed by 37 to afford 64 in 71 % yield [33]. Furthermore, reaction of the 1,6-diene 36 with an equivalent amount of HSiEt3 gave unexpectedly the cycloisomerization product 65 as the major product when π -allylpalladium-PCy3 and NaBAr4 were used without giving the expected cyclization–hydrosilylation product 45 [34]. E

PdCl2(MeCN)2, AgOTf

E

rt

E +

E

Me

E

E

rt, 71%

Me 4%

93%

63

37, NaBAr4

E

Me

36

E

Me

E

E Me

36

64

E

(η3-allyl-PdCl)2, PCy3, AgBF4

E

E

HSiEt3, CH2Cl2, 89%

E

36

Me

Me 65

The Pd(OAc)2 -catalyzed cyclopropanation of alkenes with diazomethane is a good synthetic method for cyclopropanes and has been used extensively. As a recent example, reaction of alkenylboronate 66 with diazomethane afforded two isomeric cyclopropanes 67 and 68 in 79 % yield with a diastereomeric ratio of 86 : 14, and they were converted to cyclopropyl alcohols 69 and 70 [35]. Ph O

O

Me

OMe

B

N Boc

Me

Ph

Ph

Ph

Ph O Me

Ph

O

Me

Ph O

OMe

+

B

N Boc

Ph

Me Me

OMe

O 67

Et2O, 0 °C, 79%

OMe

O 66

Pd(OAc)2

+ CH2N2

68 86 : 14

O Me

N Boc 69

OH

+ Me Me

O OH

N Boc 70

OMe

O

OMe

B

N Boc

Ph

Me

Ph

O

Ph

Ph

References

611

References 1. J. Tsuji, M. Morikawa, J. Kiji, Tetrahedron Lett., 1437 (1963); K. Bittler, N. V. Kutepow, K. Neubauer, and H. Reis, Angew. Chem., 80, 352 (1968). 2. H. Alper, J. B. Woell, B. Despeyroux, and D. J. H. Smith, J. Chem. Soc., Chem. Commun., 1270 (1983); H. Alper and N. J. Hamel, J. Am. Chem. Soc., 112, 2803 (1990); J. Chem. Soc., Chem. Commun., 135 (1990); H. S. Yun, K. H. Lee, and J. S. Lee, J. Mol. Catal. A, Chem., 95, 11 (1995). 3. S. Oi, M. Nomura, T. Aiko, and Y. Inoue, J. Mol. Catal. A, Chem., 115, 289 (1997). 3a. C. W. Lee and H. Alper, J. Org. Chem., 60, 250 (1995). 4. A. Seayad, S. Jayasree, and R. V. Chaudhari, Org. Lett., 1, 459 (1999). 5. S. Jayasree, A. Seayad, and R. V. Chaudhari, Org. Lett., 2, 203 (2000). 5a. M. S. Goedheijt, J. N. H. Reek, P. C. J. Kamer, and P. W. N. M. van Leeuwen, Chem. Commun., 2431 (1998). 6. H. Zhou, J. Hou, J. Cheng, S. Lu, H. Fu, and H. Wang, J. Organomet. Chem., 543, 227 (1997). 7. M. Brunner and H. Alper, J. Org. Chem., 62, 7565 (1997). 8. B. E. Ali, K. Okuro, G. Vasapollo, and H. Alper, J. Am. Chem. Soc., 118, 4264 (1996). 9. R. Amorati, O. A. Attanasi, B. E. Ali, P. Filippone, G. Mele, J. Spadavecchia, and G. Vasapollo, Synthesis, 2749 (2002). 10. E. Drent and P. H. M. Budzelaar, Chem. Rev., 96, 663 (1996). 11. M. A. Zuideveld, P. C. J. Kamer, P. W. N. M. van Leeuwen, P. A. A. Klusener, H. A. Stil, and C. F. Roobeek, J. Am. Chem. Soc., 120, 7977 (1998). 12. Review: K. Nozaki and T. Hiyama, J. Organomet. Chem., 576, 248 (1999); K. Nozaki, N. Sato, and H. Takaya, J. Am. Chem. Soc., 117, 9911 (1995); K. Nozaki, N. Sato, Y. Tonomura, M. Yasutomi, H. Takaya, T. Hiyama, T. Matsubara, and N. Koga, J. Am. Chem. Soc., 119, 12779 (1997). 13. W. Keim, H. Herwig, and G. Pelzer, J. Org. Chem., 62, 422 (1997). 14. M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 122, 9546 (2000). 15. U. Nettekoven and J. F. Hartwig, J. Am. Chem. Soc., 124, 1166 (2002). 16. K. Li and K. K. Hii, Chem. Commun., 1132 (2003). 17. X. Cheng and K. K. Hii, Tetrahedron, 57, 5445 (2001). 18. Y. Uozumi, K. Kitayama, T. Hayashi, K Yanagi, and E. Fukuyo, Bull. Chem. Soc. Jpn., 68, 713 (1995). 19. Y. Uozumi, K. Kitayama, and T. Hayashi, Tetrahedron: Asymmetry, 4, 2419 (1993). 20. T. Hayashi, S. Hirate, K. Kitayama, H. Tsuji, A. Torii, and Y. Uozumi, Chem. Lett., 1272 (2000). 21. J. E. Fensen, B. Y. Svendsen, T. V. la Cour, H. L. Pedersen, and M. Johannsen, J. Am. Chem. Soc., 124, 4558 (2002). 22. H. L. Pedersen and M. Johannsen, J. Org. Chem., 67, 7982 (2002). 23. R. A. Widenhoefer, Acc. Chem. Res., 35, 905 (2002). 24. R. A. Widenhoefer and M. A. DeCarli, J. Am. Chem. Soc., 120, 3805 (1998). 25. N. S. Perch and R. A. Widenhoefer, J. Am. Chem. Soc., 121, 6960 (1999). 26. X. Wang, H. Chakrapani, C. N. Stengone, and R. A. Widenhoefer, J. Org. Chem., 66, 1755 (2001). 27. T. Pei and R. A. Widenhoefer, Org. Lett., 2, 1469 (2000); T. Pei and R. A. Widenhoefer, J. Org. Chem., 66, 7639 (2001). 28. X. Wang, S. Z. Stankovich, and R. A. Widenhoefer, Organometallics, 21, 901 (2002). 29. L. B. Han, F. Mirzael, C. Q. Zhao, and M. Tanaka, J. Am. Chem. Soc., 122, 5407 (2000). 30. M. O. Shulyupin, M. A. Kazankova, and I. P. Beletskaya, Org. Lett., 4, 761 (2002). 31. C. H. Oh, J. D. Kim, and J. W. Han, Chem. Lett., 1290 (2001). 32. A. Heumann and M. Moukhliss, Synlett, 1211 (1998). 33. P. Kisanga, L. A. Goj, and R. A. Widenhoefer, J. Org. Chem., 66, 635 (2001). 34. R. A. Widenhoefer and N. S. Perch, Org. Lett., 1, 1103 (1999); P. Kisanga and R. A. Widenhoefer, J. Am. Chem. Soc., 122, 10017 (2000). 35. J. Pietruszka and A. Witt, Synlett, 91 (2002).

Chapter 9 Pd(0)-Catalyzed Miscellaneous Reactions of Carbon Monoxide

Several Pd(0)-catalyzed reactions which are not covered in Chapters 2–8 are treated in this chapter. A useful preparative method of N -acylamino acids by the reaction of amides, aldehydes, and CO is known as amidocarbonylation, and cobalt carbonyl is an active catalyst [1]. Beller et al. found that the reaction can be also catalyzed by Pd complexes. Reaction of acetamide, cyclohexanecarboxaldehyde, and CO (60 atm) at 120 ◦ C using ligandless Pd/C as a catalyst in NMP in the presence of LiBr and H2 SO4 afforded the acylamino acid 1 in 98 % yield [2]. In this reaction, N -α-hydroxyalkylamide 2 is formed from amide and aldehyde, and converted to the alkylpalladium complex 3. Acylamino acid 1 is formed by CO insertion.

Me

+

+

H N

Me

CHO

NH2

CO2H

Pd/C, LiBr, H 2SO4 CO

O

NMP, 120 °C, 60 atm 15 h, 98%

O 1 CO

H N

Me

OH

Pd(0), HX

O

H N

Me

Pd-X

H2O

O H2O

2

3

Imidazolidine-2,4-diones, generally called hydantoins, are prepared when urea and N-substituted ureas are used instead of amides in the amidocarbonylation. Carbonylation of cyclohexanecarboxaldehyde, and N ,N -dimethylurea (4) in NMP using PdBr2 and PPh3 in the presence of LiBr and H2 SO2 afforded the hydantoin 5 in 80 % yield [3]. Dghaym et al. reported that α-amino acid derived imidazoline 7 can be synthesized by Pd-catalyzed reaction of the imine 6, CO, and benzoyl chloride using Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

614

Pd(0)-Catalyzed Miscellaneous Reactions of Carbon Monoxide O Me

CHO

NHMe +

MeHN

+ CO

O

N

PdBr2, PPh3, LiBr H2SO4, NMP, 80 °C 60 atm, 80%

N Me

4

O 5

Ph

p-Tol

O +

+

N Me

Ph

Pd2(dba)3, bipy, CO

MeCN, 1 atm, 55 °C 4 days, 92%

Cl

Me + N

N

Me − CO2

p-Tol

6

P-Tol 7

Pd2 (dba)3 and 2,2
-bipyridine as a ligand under atmospheric pressure of CO at 55 ◦ C for 4 days in 92 % yield [4]. It is known that nitrene can be generated by Pd-catalyzed deoxygenation of organic nitro compounds with CO. Based on the nitrene formation, carbonylation of the enamine 8, derived from 2-nitroaniline and α-substituted aldehyde, was carried out using Pd(dba)2 and DPPP and a mixture of 1,2-dihydroquinoxaline 9 (71 % yield) and 3,4-dihydroquinoxalinone 10 (11 % yield) was obtained [5].

NO2

N +

CO

Pd(0)

+

CO2

nitrene H N

H N

N + CO

Pd2(dba)3, DPPP

+

4 atm, 70 °C

N H

NO2 8

O

9

N H 10

References 1. Review: M. Beller and M. Eckert, Angew. Chem. Int. Ed., 39, 1010 (2000). 2. M. Beller, M. Eckert, F. Vollm¨uller, S. Bogdanovic, and H. Geissler, Angew. Chem. Int. Ed., 36, 1494 (1997); M. Beller, W. A. Moradi, M. Eckert, and H. Neumann, Tetrahedron Lett., 40, 4523 (1999). 3. M. Beller, M. Eckert, W. A. Moradi, and H. Neumann, Angew. Chem. Int. Ed., 38, 1454 (1999). 4. R. D. Dghaym, R. Dhawan, and B. A. Arndtsen, Angew. Chem. Int. Ed., 40, 3228 (2001). 5. B. C. G. S¨oderberg, J. M. Wallace, and J. Tamariz, Org. Lett., 4, 1339 (2002).

Chapter 10 Miscellaneous Reactions Catalyzed by Chiral and Achiral Pd(II) Complexes

Some Pd(II) compounds are known to behave as moderate, but very efficient Lewis acids, and to catalyze several reactions, which are known to be catalyzed by common Lewis acids under milder conditions. Pd(II) compounds activate substrates by forming complexes with lone pairs of C=Y (Y = O, N) and facilitate nucleophilic attack to electronically positive carbons. As an example, formation of cyclic alkenyl ethers 2 and 3 from acetylenic aldehyde 1 is catalyzed by Pd(OAc)2. . Also, 2-alkynylbenzaldehyde 7 was converted to the cyclic alkenyl ether 8 in high yield in the presence of Pd(OAc)2 (5 mol%) in MeOH. In these reactions, Pd(OAc)2 as a Lewis acid, coordinates to the carbonyl group to facilitate the formation of the hemiacetals as shown by 5. Then either 5-exo or 6-endo cyclization (oxypalladation of triple bond) occurs to give 6 or 6a. Finally, protonolysis of 6 and 6a affords the cyclized products 2 and 3 with regeneration of Pd(OAc)2. . In this reaction, Pd(OAc)2 exhibits dual roles [1]. OMe

OMe CHO Pd(OAc)2

O

+

O

MeOH

Ph Ph

Ph 1

MeOH

2

3

9%

66%

OMe

H

OMe

OH

O

+

O

Pd(OAc)2

OMe O Ph

4

Ph

Ph Pd(OAc)2 5

Ph AcOPd

AcOPd

Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

6

6a

616

Miscellaneous Reactions Catalyzed by Pd(II) Complexes OMe CHO Pd(OAc)2

O

MeOH, 90% Ph Ph

7

8

Pd(OAc)2 , combined with DPPE, catalyzes aldol condensation of aldehydes or ketones with ketene silyl acetal (Mukaiyama reaction) under neutral conditions. The ketene silyl acetal of methyl isobutyrate (10) reacted smoothly with methyl pyruvate (9) or benzaldehyde (12) in THF or MeCN using 0.1 % of the catalyst. In this reaction the Pd enolate 14 is generated by transmetallation of the ketene silyl acetal with Pd(OAc)2 , and the Pd moiety as a Lewis acid activates the carbonyl group to facilitate the attack by the enolate to provide 11 and 13 [2]. OSiMe3

O +

Me

OMe

CO2Me

+

MeCN, 94%

OPdOAc

OH

Pd(OAc)2, DPPE

OMe

CO2Me Me

Ph

Me

Me

Me 10

12

Me

11

Me

H

CO2Me Me

OSiMe3

O

OH

Me

THF, 95%

Me 10

9

Ph

MeO2C

Pd(OAc)2, DPPE

Me

OMe Me 14

13

Sodeoka found that Pd(II) hydroxide complexes of BINAP derivatives 18 are excellent catalysts for asymmetric synthesis. Pd enolates are generated from silyl enol ethers by transmetallation. The asymmetric Mannich-type reaction of silyl enol ether of acetophenone (15) with the imine 16 proceeded smoothly using Pd complex of Tol-BINAP, and the ester of amino acid 17 with 90 % ee was obtained in 95 % yield [3]. MeO

OMe

OSiMe3

[PdL2]-2BF4, DMF +

Ph

28 °C, 95%, 90% ee

N 15

16 CO2i-Pr

PAr 2

H O

O Ph

Ar2 P

Ar2 P P Ar2

O P PAr 2 H Ar2 2 TfO − 18

CO2i-Pr 17

Pd+

Pd+

HN

Ar = C6H5-4-Me

Pd2+

OH2 OH2

2 TfO − 19

= PdL2, X2

Miscellaneous Reactions Catalyzed by Pd(II) Complexes

617

The Pd diaquo complex of BINAP 19 efficiently catalyzed the diastereoselective and enantioselective Michael addition of the β-keto ester 20 to 3-penten-2-one (21), and the Michael adduct 22 was obtained in 89 % yield (diastereomeric ratio = 8/1) and the ee of the major isomer was 99 %. Thus, congested vicinal tertiary and quaternary carbon centers were constructed. It is interesting to know that the Pd aquo complex 19 allows the successive supply of a Br¨onsted base and a Br¨onsted acid. The former activates the carbonyl compound to give the chiral palladium enolate and the latter cooperatively activates the enone [4]. O O

O CO2t-Bu +

CO2t-Bu

[PdL2]-2 OTf, THF

Me

Me 21

20

0 °C, 89%, 99% ee dr = 8 : 1 Ar = Ph

O

Me Me 22

Lectka has shown that (R)-BINAP-Pd(ClO4 )2 , is effective for enantioselective reaction of imines with silyl enol ethers such as 15. While Sodeoka used the aquo complexes, Lectka carried out the reaction under anhydrous conditions [5]. Efficient enantioselective fluorination of the β-keto ester 23 with (PhSO2 )2 NF was achieved by using the (R)-DM-BINAP-Pd(II) complex in EtOH to give 24 with 91 % ee in 96 % yield, which was converted to a pharmaceutically important α-fluoro-β-amino acid ester 25 [6]. O

O CO2Me + [(PhSO2)2NF]

Me 23

CO2Me

[PdL2]-2 OTf, EtOH 20 °C, 96%, 91% ee Ar = C6H3-3,5-Me

Me

NHBoc

F

24

CO2Me

steps

F

Me 25

Furthermore, Pd(II) complexes catalyze asymmetric ene and Diels-Alder reactions. Mikami and co-workers reported enantioselective synthesis of α-hydroxy esters by the ene reaction of glyoxylate 27 using a chiral Pd catalyst. They obtained the (R)-hydroxy ester 28 with 88 % ee in 97 % yield by the reaction of methylenecyclohexane (26) with ethyl glyoxylate (27) at 60 ◦ C using the cationic Pd(II) complex of (S)-Tol-BINAP [7]. O

[Pd(II)L2]X2

+ H 26

CO2Et

OH

CH2ClCH2Cl, toluene 60 °C, 97%, 88% ee

27 [Pd(II)L2]X2 = [Pd(MeCN)2(S)-Tol-BINAP](SbF 6)2

CO2Et (R)-28

618

Miscellaneous Reactions Catalyzed by Pd(II) Complexes

Ene reaction of 26 with ethyl trifluoropyruvate (29) proceeded with high enantioselectivity using the dicationic Pd catalyst prepared by the reaction of SEGPHOS (XIV-3)-PdCl2 with AgSbF6 to give 30 with 96 % ee quantitatively [8]. O

[Pd(II)L2]X2

+ F3C 26

CO2Et

HO

CF3

CH2Cl2, rt, 15 min 100%, 96% ee

CO2Et

29

30

[Pd(II)L2]X2 = (S)-SEGPHOS-PdCl2 + AgSbF6

Ghosh found that the cationic (R)-BINAP-Pd(II) complex efficiently catalyzed the asymmetric Diels-Alder reaction of cyclopentadiene with acryloyl-N oxazolidinone (31) at −78 ◦ C, and obtained the endo-(2S)-cycloadduct 32 with 99 % ee in 75 % yield [9].

O

O N

O

(R)-BINAP-Pd(ClO4)2

+

O

CH2Cl2, −78 °C 75%, 99% ee

O

31

N

O

(2S)-32

Mikami carried out the asymmetric hetero Diels-Alder reaction of ethyl glyoxylate (27) with 1,3-cyclohexadiene and obtained the cycloadduct 33 with 94 % ee in 62 % yield [10].

O H

+ CO2Et

27

[Pd] 39 , CH2Cl2

O H

rt, 62%, 94% ee 33

CO2Et

For this efficient asymmetric reaction, Mikami developed a very interesting chiral catalyst. He reasoned that the reaction of Pd(II) complex 35, formed from BIPHEP 34, which is tropos [11], with a chiral activator should give one of the diastereomers 36 selectively. Actually his group carried out the reaction of BIPHEP complex 37 with 1.0 equivalent of (R)-diaminobinaphthyl (DABN) 38, and obtained (R)-BIPHEP-Pd/(R)-DABN 39 as a single diastereomer as expected, and this complex was used as the efficient chiral catalyst. By this unique strategy, ‘asymmetric activation’ of a racemic Pd catalyst bearing the tropos BIPHEP ligand was achieved without enantiomeric resolution or asymmetric synthesis. As further elaboration, Mikami has shown that TETRAPHOS-Pd/DABN 40 gives better results than 39 in the ene reaction of 26 with 27 [12].

Miscellaneous Reactions Catalyzed by Pd(II) Complexes

PPh2 PPh2

Pd(II)

X

PPh2

Pd2+

Ph2P

619

X

∗

Pd2+

X

PPh2

X

PPh2 ∗ activator

34 BIPHEP

35

tropos

racemic

NCMe

PPh2

H2N +

Pd2+ NCMe

PPh2

36

H2N

[SbF6]2 37

38 (R)-DABN 1.0 equiv.

N

PPh2

PPh2

Pd2+ PPh2

∗

Pd2+

H2 N

PPh2

N H2

PPh2

[SbF6]2

Ph2P

Pd2+

39

N

[SbF6]4 N

N (R)/(R) only

40

∗

Gagne et al. group obtained high enantiomeric excesses (99 % ee) in the DielsAlder reactions of 31 with cyclopentadiene, and the ene reaction of 26 with 27 using Pd complex of (S)-MeO-BIPHEP, coordinated by 3,5-di(trifluoromethyl)benzonitrile 41 [13].

MeO

PPh2

MeO

PPh2

NCAr Pd2+ NCAr

Ar = 3,5-(CF3)2C6H3

[SbF6]2 41

A Friedel-Craft type reaction of N -methylindole with glyoxylate 27 is catalyzed by the Lewis acidity of Pd(II) complexes [14]. While the α-hydroxyindolylacetate 42 was obtained in 96 % yield when PdCl2 (MeCN)2 was used, the diindolylacetate 43 was the main product when BIPHEP complex was used.

620

Miscellaneous Reactions Catalyzed by Pd(II) Complexes O + N Me

Pd(II), rt H 27

CO2Et HO

CO2Et

CO2Et + N Me 42 PdCl2(MeCN)2

N Me

N Me 43

96%

[Pd(MeCN)2(BIPHEP)](SbF6]2

95%

It is known that Claisen rearrangement of allyl vinyl ethers is catalyzed by Pd(II), and the reaction proceeds at room temperature [15]. Various vinyl ethers are prepared by the Pd(II)-catalyzed exchange reaction of easily available ethyl vinyl ether with alcohols. The phenanthroline–Pd(OAc)2 complex is an active catalyst [16].

ROH

1,10-phenanthroline-Pd(OAc)2

+ OEt

+

EtOH

OR

Sugiura and Nakai carried out Pd(II)-catalyzed regiocontrolled Claisen rearrangement of allyl vinyl ethers prepared by in situ enol ether exchange [17]. Treatment of a mixture of the regioisomers of 1-cyclohexenyl methyl ether 44a and 44b and 2-buten-1-ol in the presence of PdCl2 (PhCN)2 and TFA (trifluoroacetic acid, 10 mol%) at room temperature afforded the cyclohexanones 46 and 47 in a ratio of 96 : 4 via in situ formation of the allyl enol ethers 45a and 45b. On the other hand, thermal rearrangement at 100 ◦ C exhibited opposite regioselectivity, producing a mixture of 46 and 47 in a ratio of 7 : 93. Clearly Pd-catalyzed reaction provides the cyclohexanone 46 arising from the less-substituted enol ether 45b. The enol ethers 45a and 45b are interconvertible under the conditions, and the regioselectivity seems to be determined by the difference in rate of rearrangement between the regioisomeric enol ethers 45a and 45b. Miyaura and co-workers found that conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds can be carried out by using cationic Pd(II) complexes such as [Pd(dppe)(PhCN)2 ]X2 as catalysts. Neutral Pd complexes such as PdCl2 (dppe) are not active. As anions, X− = ClO4 − , OTf− , BF4 − , PF6 − , and SbF6 − are effective. Coordination of DPPE and PhCN is important. The reaction proceeds at room temperature in THF or dioxane, and requires the presence of water. The addition of boronic acid 48 to cyclohexenone took place to give 49 in 95 % yield [18]. Also 3-phenylcyclohexanone (50) is prepared by the conjugate addition of PhSi(OEt)3 to cyclohexenone [19].

References

621 O

OMe

OMe 45b

OH + 44a

PdCl2

19 : 81

O

44b

45a PdCl2(PhCN)2, TFA (10 mol%), rt, 54% TFA (10 mol%), toluene, 100 °C, 77% O

46 O

47 46 : 47 96 : 4 7 : 93

O

O B(OH)2 + OMe

[Pd(dppe)(PhCN)2](SbF6)2

OMe

THF, H 2O, 20 °C, 95% 49

48 O

O +

PhSi(OEt)3

Pd(OAc)2, SbCl3 AcOH, TBSF-3H 2O MeCN, 60 °C, 73%

Ph 50

References 1. N. Asao, T. Nogami, K. Takahashi, and Y. Yamamoto, J. Am. Chem. Soc., 124, 764 (2002). 2. H. Doucet, J. L. Parrain, and M. Santelli, Synlett, 871 (2000).

622

Miscellaneous Reactions Catalyzed by Pd(II) Complexes

3. E. Hagiwara, A. Fujii, and M. Sodeoka, J. Am. Chem. Soc., 120, 2474 (1998). 4. Y. Hamashima, D. Hotta, and M. Sodeoka, J. Am. Chem. Soc., 124, 11240 (2002). 5. D. Ferraris, B. Young, T. Dudding, and T. Lectka, J. Am. Chem. Soc., 120, 4548 (1998). 6. Y. Hamashima, K. Yagi, H. Takano, L. Tamas, and M. Sodeoka, J. Am. Chem. Soc., 124, 14530 (2002). 7. J. Hao, M. Hatano, and K. Mikami, Org. Lett., 2, 4059 (2000). 8. K. Aikawa, S. Kainuma, M. Hatano, and K. Mikami, Tetrahedron Lett., 45, 183 (2004). 9. A. K. Ghosh and H. Matsuda, Org. Lett., 1, 2157 (1999). 10. K. Mikami, K. Aikawa, and Y. Yusa, Org. Lett., 4, 95 (2002). 11. For the meaning of tropos and review on tropos ligands: K. Mikami, K. Aikawa, Y. Yusa, J. J. Jodry, and M. Yamanaka, Synlett, 1561 (2002). 12. K. Aikawa and K. Mikami, Angew. Chem. Int. Ed., 42, 5457 (2003). 13. J. J. Becker, L. J. Van Orden, P. S. White, and M. R. Gagne, Org. Lett., 4, 727 (2002). 14. J. Hao, S. Taktak, K. Aiwa, Y. Yusa, M. Hatano, and K. Mikami, Synlett, 1443 (2001). 15. J. L. van der Baan and F. Bickelhaupt, Tetrahedron Lett., 27, 6267 (1986); K. Mikami, T. Takahashi, and T. Nakai, Tetrahedron Lett., 28, 5879 (1987); K. Mikami, K. Takahashi, T. Nakai, and T. Uchimaru, J. Am. Chem. Soc., 116, 10948 (1994). 16. P. M. Weinrtraub and C. H. R. King, J. Org. Chem., 62, 1560 (1997); M. Bosch and M. Schlaf, J. Org. Chem., 68, 5225 (2003). 17. M. Sugiura and T. Nakai, Tetrahedron Lett., 37, 7991 (1996). 18. T. Nishikata, Y. Yamamoto, and N. Miyaura, Angew. Chem. Int. Ed., 42, 2768 (2003). 19. S. E. Denmark and N. Amishiro, J. Org. Chem., 68, 6997 (2003); T. Nishikata, Y. Yamamoto, and N. Miyaura, Chem. Lett., 32, 752 (2003).

Table 1.1 Monophosphines. Me P

P

P

P 3

O

3

I-1

P

I-4

I-5 MeO

Me

P

P 3

3 3

Me

Me

Me

3

TFP I-3

I-2

P

Me Me

Me

Me

MeO

3

3

I-6

P

I-8

I-7

3

TDMPP I-9

MeO P P

OMe

MeP 2

MeO

3

3

I-11

TTMPP I-10

I-12 Ph

NMe2

PPh2

Ph

N

N

PPh2

PPh2

N PPh2 I-13

I-14

I-16

I-15

O N O N P

PCy2

N

I-17 Tetrahedron Lett ., 40, 1237 (1999)

PF6− Bu

Me PPh2 I-19

Synlett, 1613 (2000) I-18 Angew. Chem. Int. Ed ., 41, 1521 (2002)

n-Bu P t-Bu P t-Bu I-20

+ N

N

I-21

624 Table 1.2 Water-soluble phosphines.

P

Ph2P SO3H

Ph2P SO3H

3

TSPP or TPPTS

DPSPP or TPPMS

II-1

II-2 HO

CO2H Ph2P

CO2H

4-DPPBA II-3

CO2H

Ph2P

PPh2 SO3H

CO2H

PPh2

CO2H

II-5

II-4

CO2H

CO2H

II-6

II-7

J. Organomet. Chem ., 645, 14 (2002) Me PPh2

PPh2 O

HO3S

P

SO3H

P

SO3H

2

SO3H Me

Me

Me

sulfoxantphos

2

(R)-TolBINAP, sulfonated II-9

II-8 SO3H

SO3H

NMe3Cl

Ph2P II-11

HO3S

P

P

NMe3Cl

t-Bu2P

SO3H

II-12 Ph2PCH2CO2Na II-10

t-Bu2P

II-13

II-14

NMe2Cl

Cy2P

NMe2Cl

Org. Lett ., 3, 2757 (2001) NH

OH H

II-15

OH OH CH2OH

O Ph2P

H

OH H

GLCA II-16 Synlett, 856 (2000)

H

625 Table 1.3 Phosphites. O P

P O O

O 3

P

MeO

t-Bu

O

3

t-Bu

TMPP III-2

III-1

P

O

III-3

III-4

3

OMe PPh2

t-Bu O

O

t-Bu P

O

O

O

O

P

P

O

O

O

BIPHEPHOS

(R,S)-BINAPHOS

III-5

III-6

(R)-phosphoramidites

O

O P

O P

NMe2

NiPr2

P

O

O

O

III-9

III-8 J. Am. Chem. Soc., 124, 4558 (2002)

III-7

O P O

III-10

O

O

Ph O

O

N

O

O

t-Bu

Ph

Ph

P

NMe2

Ph

III-11 J. Am. Chem. Soc., 124, 184 (2002)

N

626 Table 1.4 Biphenyl-based monophosphines.

Me

IV-2

IV-1

i-Pr

IV-3

Me

IV-4

PCy2

IV-5

Me

Me2N PPh2

Me2N

O

P(t-Bu)2

P(i-Pr)2

IV-14

IV-13

i-Pr

i-Pr

PCy2

IV-16

P(t-Bu)2

IV-15

i-Pr

O

PCy2

IV-12

IV-11

IV-10

Me2N

IV-8

Me2N

P(t-Bu)2

IV-9

PCy2

IV-7

Me

PCy2

Me

PCy2

IV-6 Me

Me

Me

Me

i-Pr

P(t-Bu)2

Me

P(t-Bu)2

P(l-Ad)2

PCy2

P(t-Bu)2

PCy2

IV-17

627 Table 1.5 Polyphenyl-based monophosphines.

P(t-Bu)2

PCy2

Me P(t-Bu)2

PPh2

V-1

V-2

V-3

V-4

P(t-Bu)2

PCy2

V-6

V-5

PPh2

V-7

Table 1.6 Binaphthyl-based monophosphines (chiral and racemic).

PPh2

H-MOP VI-1

PCy2

P(t-Bu)2

VI-3

VI-2

H

P(t-Bu)2

Me

Bu

PCy2

PCy2

H

VI-4

VI-5

VI-6

(continued overleaf )

628 Table 1.6 (continued )

NMe2

NMe2

NMe2

PPh2

PCy2

P(t-Bu)2

(MAP)

VI-8

VI-9

VI-7 H NMe2

NMe2

P(t-Bu)2

P

H

OMe PPh2

t-Bu Ph

VI-10

(R)-MeO-MOP VI-12

VI-11

OH

SiMe3

PPh2

PCy2

(R)-VI-13

VI-14

MeO AsPh2

O P(i-Pr)2

PPh2

(R)-MOP-Phen VI-16

VI-15

(R)-VI-17

O

CF3

N PPh2

P CF3 (R) VI-18

PPh2

2

(aS)-VI-19

629 Table 1.7 Chiral monophosphines. PHOX (Phosphinooxazoline) ligands

MeO PPh2 N

O

N

i-Pr

N

O

VII-4

t-Bu

Ph VII-2

VII-1

P

PPh2

PPh2 O

Me

VII-3

Me Me

N

Me

Me

PhCH2

N

Me

P P O

N

Ph

P

Ph

Ph

(S)-ALAPHOS VII-6

Ph

(S)-PHEPHOS VII-7

VII-5

Ph O

NHSO2Me

t-Bu

P Me

N Me

PPh2

Ph

P

Me Ph

VII-9

Ms-VALPHOS VII-8

VII-10

Ph P i-Pr

PPh2

i-Pr VII-11

NMDPP VII-12

Ph

630 Table 1.8 Ferrocenyl monophosphines (chiral and racemic). PPh2

P(t-Bu)2

Fe

Fe

Fe

FcPPh2

FcP(t-Bu)2

VIII-1

VIII-2

Fe

Me

Me VIII-4 P(t-Bu)2

PPh2 Me

Me Me

SiMe3

Fe

VIII-3

PPh2 Me

PPh2

NMe2 P(t-Bu)2

Fe

SiMe3 Me Me

Me

Fe

Ph

Ph Ph

Ph

Me

Me

Ph

VIII-5

VIII-6

Ph5FcP(t-Bu)2 VIII-7 J. Org. Chem., 67, 5553 (2002) Me

OMe NMe2 Fe

PPh2

PPh2

Fe

(S)-VIII-8 (R,S)-PPFA VIII-9 Me

Me Me N

OMe Ad

Fe

PPh2

Fe

PPh2

Ad = adamantyl

(R,S)-PPFOMe

VIII-10

VIII-11

631 Table 1.9 Diphosphines. PPh2

PPh2 PPh2

PPh2

PPh2

PPh2

PPh2 DPPE IX-2

IX-1

PPh2

DPPP IX-3

DPPB IX-4

MeO P

P

P 2

P

P

P MeO

2

DiPPP

PPh2

Ph2P

DiPPB

DMPPP IX-6

IX-5 Ph2P

IX-8

IX-7 PPh2

Ph2P

O

O

DPEphos

Me Me Xantphos IX-10

IX-9 Ph2P

PPh2

PPh2 PPh2

PPh2 DPBP

DPPBz

IX-11

IX-12

Table 1.10 Polydentate phosphines. PPh2

Ph2P PPh2 Ph2P

PPh2

N PPh2 n

n = 4~64 Tedicyp X-1

= dendrimers X-2

632 Table 1.11 Ferrocenyl diphosphines (chiral and achiral). P(o-Tol) 2

PPh2 Fe

Fe

Fe

P(t-Bu)2

PCy2 DtBPF XI-4

XI-3

XI-2

Et

PPh2

P Et

Fe

P(o-Tol) 2

PPh2 DPPF XI-1

P(t-Bu)2

PCy2

PAr 2

Me

Fe Et

Fe

(S,S)-Et-FerroTANE

XI-6

Me

PPh2

Fe

PPh2

P Et

Ar = 3,5-Xyl (R,S)-Josiphos

XI-5

XI-7

PCy2

PCy2

Me

Me

PPh2

Fe

Fe

(R,S)-Cy-Josiphos

P(t-Bu)2

PPh2 Me

PCy2

PCy2

Fe

XI-9

Me PPh2

Fe

XI-10

XI-11

XI-8 PEt2 Me

Me

Me

Me Me

NMe2 Fe

PPh2

OH Fe

PPh2

PPh2

Fe

OAc Fe

PPh2

PPh2

PEt2 Fe

PPh2

(rac)-BPPFA

(R,S)-BPPFOH

(R,S)-BPPFOAc

(R,R)(S,S)-EtTRAP

XI-12

XI-13

XI-14

XI-15

633 Table 1.12 Chiral diphosphines. R

OMe

H

Me

P

Me

OMe

P

P

O

PPh2

R

P

PPh2

O

Bis-P

H (R,R)-DIOP

R = t-Bu XII-2 R = adamantyl XII-3

XII-4

(R,R)-DIPAMP XII-1 Cy2P

Ph2P

Cy2P

H

PPh2

PPh2

H

PPh2

PPh2

N

N

N

CO2t-Bu

CONHMe

CO2t-Bu

H PPh2 H

(S,S)-BPPM

(2S,4S)-MCCPM

(S,S)-BCPM

BICP

XII-5

XII-6

XII-7

XII-8

Ph2P

PPh2 O O H

Me

Me

Et

Et

P

P

P

P

Me

Me

Et

Et

(R)-spirOP

R = Me; ( S,S)-Me-DuPHOS

(S,S)-Et-DuPHOS

XII-9

XII-10

XII-11

i-Pr

i-Pr

P

P

Me Me

i-Pr

P

P

i-Pr

Me

Me

P

P Me

i-Pr

i-Pr

Me

XII-12

(R,S,R,S)-Me-PennPHOS

(R,R)-i-Pr-BPE

XII-13

XII-14

(continued overleaf )

634 Table 1.12 (continued ) Me Me

Me

Me

H

H P

P Me

t-Bu t-Bu

(R,R)-Me-BPE

TangPhos

Me

XII-15

Me

P

P

P

P

Me Me Me

XII-16

Me-UCAP-DM XII-17 PPh2

Me

PPh2

PPh2

Ph

PPh2

(S,S)-CHIRAPHOS

(S)-PROPHOS

XII-18

PPh2

PPh2

PPh2

PPh2

(S)-PHENPHOS

(R,R)-NORPHOS

XII-20

XII-21

XII-19

PPh2

H PPh2 R

PPh2

O

N PPh2

PPh2

O Ph2P

H

(S,S)-PYRPHOS (Degphos)

(S)-(2,2)-PHANEPHOS

DDPPI

XII-22

XII-23

XII-24

635 Table 1.13 DPPBA and DPPA-based diphosphine derivatives.

O

O NH PPh2

O

O

HN

NH

Ph2P

PPh2

(S,S)-XIII-1

HN Ph2P

(S,S)-XIII-2

O

O NH PPh2

HN Ph2P

(S,S)-XIII-3

O

O NH PPh2

HN Ph2P

(S,S)-XIII-4 PPh2

Ph2P

HN

NH

O O

O

O NH

HN

PPh2

XIII-5

(S,S)-XIII-6

N

636 Table 1.14 Chiral biphenyl-based diphosphines. O

O

PPh2

PCy2

O

PPh2

O

PAr 2

PPh2

PCy2

O

PPh2

O

PAr 2

O

O

(R)-BIPHEMP

(R)-BICHEP

(R)-SEGPHOS,

XIV-1

XIV-2

XIV-3

(R)-SEGPHOS, Ar = 3,5-xyl XIV-4

t-Bu OMe

O O

P

t-Bu

P

O

t-Bu

O

MeO

PAr 2

MeO

PAr 2

2

t-Bu Ar =

t-Bu

OMe

t-Bu

(R)-MeO-BIPHEP

2

XIV-6

(R)-DTBM-SEGPHOS, XIV-5

t-Bu

MeO

P

t-Bu

MeO

P

t-Bu

t-Bu XIV-7

O 2

PPh2

(CH2)n

PPh2

O

2

Cn TunaPhos XIV-8

J. Org. Chem. , 65, 6223 (2000)

637 Table 1.15 Chiral binaphthyl-based diphosphines and diphosphites.

PPh2

P(o-Tol) 2

PPh2

PPh2

P(o-Tol) 2

PPh2

(R)-BINAP

(R)-TolBINAP

(R)-H8-BINAP

XV-1

XV-2

XV-3 Ph

OPPh2

OPAr 2

OPPh2

OPAr 2

Ph (R)-BINAPO XV-4

(R)-o-substituted BINAPO XV-5 S

NHPPh2

PPh2

NHPPh2 PPh2 S H8-BDPAB

(R)-BITIANP

XV-6

XV-7

638 Table 1.16 Heterocyclic carbene ligands.

N

i-Pr

i-Pr

Me

Me

N

N

••

••

Me Me

Me

N C

C

Me

XVI-2

Cy

Cy N

i-Pr

i-Pr

XVI-1

Me

N

N C ••

N C

••

Me ••

Cy

Ar

Ar

C

Cy Me

N

N

XVI-3 XVI-4 Me

i-Pr

Me N

N

i-Pr N

N

C

C

••

••

Me Me

Me

Me

i-Pr

i-Pr

XVI-5

XVI-6

Cy

Cy N

Me

Me

N C

N

••

N C

••

Cy

Cy

Me

Me Me

XVI-8

N

N

XVI-9

N

N

C

C

XVI-10

XVI-11

••

••

Me

639 Table 1.16 (continued ) Me N

N

N C

••

O

Me N

N

N

Me

C ••

Me

XVI-12

N C ••

Me

Me XVI-13

Me N

N

PPh2

C ••

Me

S

NMe C

Me

••

XVI-14

XVI-15 Tet.Lett ., 42, 4701 (2001)

Table 1.17 Miscellaneous ligands. SO2Ar N N N ArO2S

N

N SO2Ar XVII-1

XVII-2

O

O

N H

HN

N

N

N

N

XVII-4 XVII-3 O Ph

NC

Ph dba XVII-5

AsPh3 XVII-7

XVII-6

Me

640 Table 1.18 Stable palladacycles and Pd complexes used as catalyst precursors. Me

Tol-o

O

O

O

O

Pd

Pd P

o-Tol

Tol-o

P(i-Pr)2

o-Tol P

Pd TFA P(i-Pr)2

Me

XVIII-2

XVIII-1

JACS , 119, 11687 (1997)

t-Bu

t-Bu

OH P

t-Bu

t-Bu

P(t-Bu)2

O P H

Pd TFA Cl

t-Bu

P(t-Bu)2

HO P Pd P OH t-Bu t-Bu Cl

XVIII-3

POPd

t-Bu

t-Bu H

O

P

O P t-Bu

Pd

SPh Pd Cl

XVIII-7

Cl

t-Bu

POPd 1

SPh

t-Bu Cl

t-Bu

OH

t-Bu

t-Bu P

XVIII-4

t-Bu

O

P

H

Pd P

t-Bu

Pd

O

Cl

Cl Cl

t-Bu

Cl Pd P HO

POPd 2

XVIII-5

P(i-Pr)2 Pd P(i-Pr)2 XVIII-8

t-Bu t-Bu

XVIII-6

P(t-Bu)2 TFA

Pd P(t-Bu)2 XVIII-9

TFA

641 Table 1.18 (continued ) OMe

OMe

I

O P MeO

O P

Pd

O

O

OMe

XVIII-10

Tetrahedron Lett ., 40, 7379 (1999) t-Bu

t-Bu

t-Bu O P

O

t-Bu

t-Bu

Pd Cl

2

t-Bu XVIII-11

2

Me

Me

P S-t-Bu

NMe2 Cl XVIII-12

O Pd

Pd

Pd 2

Cl XVIII-13

Me

O

2

XVIII-14

Me

J. Org. Chem ., 67, 5588 (2002)

(continued overleaf )

642 Table 1.18 (continued ) Cl

OH

Fe N N

OH

N

Pd Cl

Pd

OH

Pd

Cl

Cl

Cl

XVIII-15

XVIII-16

XVIII-17

N

t-Bu

N

N C • •

O

O

PdX2

P(OAr)2

N

Pd

t-Bu Cl

PCy3

Ar = C6H3-2,4-t-Bu2

Me P(t-Bu)2 Pd OAc

N Me XVIII-20

XVIII-18

XVIII-19

Angew. Chem. Int. Ed 41, 4120 (2002)

Org. Lett ., 4, 1411 (2002)

Org. Lett ., 5, 2413 (2003)

Index

aceanthrylene 253 acetanilide 84 acetic anhydride 279 acetophenone 90, 275 acetoxybenzene 79 acetoxylation 77 acetylene surrogates 216–19 achiral Pd(II) complexes 615–22 acid anhydride, oxidative addition to Pd(0) 284 aconitate 71 acylamino acids 613 acyl chlorides 265–88 acyl halides carbonylation 282–86 Heck reaction 123 2-(acylmethylene)propanediol diacetate 468 acylpalladium 279 adamantyl(di-t-butyl)phosphine 300 adol condensation 507 aflatoxin B1 459–60 Ag2 O, silanol promoter 346 ailanthoidol 211 alaphos 220 alcohols alkenes 30, 35–8 allylation 456–58 arylation 394–96 aryl halides with β-carbon elimination 416–27 oxidation 90–4 oxidative carbonylation 86–9 protection as allyl carbonate 491 aldehydes allylation 455, 476–77 arylation 359–62 carbonylation 275–82 2,3-alkadienyl derivative reactions, methylene-π-allylpalladiums 509–11

1,2-alkadien-4-ynes 554–55 alkenes alcohols 30, 35–8 amines 41–4 aromatic compounds 50–2 1,2-bifunctionalized 578 carbon nucleophiles 44–5 carbonylation 601–4 carboxylic acids 30, 39–41 cyclic oxidation 35 cycloisomerization 609 cyclopropanation 610 enantio-differentiation 448–49 Heck reaction 125–32 hydroamination 605–6 hydrocarboxylation 601 hydroesterification 601 hydrometallation 606–9 hydrophosphorylation 609 hydrosilylation 606 intramolecular reactions 483–84 ketones from 32–3 organometallic compound coupling 52–3 oxidative carbonylation 45–9 oxidative reactions with Pd(II) compounds 29–53 palladation 29 phenols 35–8 propargyl compounds 545–48 water 30, 32–5 1-alkenes, hydrogenolysis with formates 485–87 alkenylalkynes, terminal alkyne reactions 201–31 alkenyl–alkynyl coupling 208–10 alkenylation, carbon nucleophiles 351–69 alkenylborane coupling 304–6 alkenyl chlorides Heck reactions 122

Palladium Reagents and Catalysts—New Perspectives for the 21st Century J. Tsuji  2004 John Wiley & Sons, Ltd ISBNs: 0-470-85032-9 (HB); 0-470-85033-7 (PB)

644 alkenyl chlorides (continued ) Sonogashira coupling 208 alkenyl halides 108 alkylborane coupling 306–9 alkynes 231–65 carbonylation 267 oxidative addition 8 alkenyl iodides 267, 268 alkenyloxiranes 434, 475 alkenylsilanes coupling 341–44 preparation 339, 577 alkenylsilanol coupling 344–45 alkenylstannanes 573 coupling 320–26 alkenyl triflates alkynylsilane coupling 225–26 carbonylation 267 Heck reactions 122 alkenyltrifluoroborates 292 alkenylzinc reagent coupling 329–32 preparation 329 alkoxysilane coupling 344–45 alkylbenzene derivative 338 alkylborane coupling 306–10 alkyl carbonate 88–9 alkyl halides alkylborane coupling 309–10 alkylmetal coupling 289 arylborane coupling 303 γ -alkylidenebutenolide 215 9-alkylidene-9H-fluorene 254 alkyl nitrites 28 alkyl phosphines 3 alkylstannane coupling 326–27 alkylzinc reagents coupling 332–35 preparation 328–29 alkynes 565–92 alkenylalkynes 201–31 alkenyl halides 231–65 arylalkynes 201–31 aryl halides 231–65 benzannulation 583–89 borylsilylation 577 carbometallation 578 carbonylation 565–66 carbopalladation, living process 232 cross-coupling 589–91 cyanoboration 578 cyclization of 1,6-enynes and 1,7-diynes 578–83 cyclotrimerization 583–84 dimetallation 576–78 homocoupling 228, 589–91 hydroamination 569–72

Index hydroarylation 567–69 hydrocarbometallation 566 hydrocarbonation 569–72 hydroesterification 565 hydroformylation 565 hydrogermylation 575 hydro-heteroatom addition 572–76 hydrometallation 572–76 hydrophosphinylation 575 hydrosilylation 572–73 hydrostannation 573–74 hydrothiolation 576 intermolecular reactions 233–35 intramolecular cyclization with imines 591 intramolecular reactions 483–84 oxidative carbonylation 66–7, 70–1 oxidative dicarbonylation 67 oxidative reactions with Pd(II) compounds 61–77 Pd(0) catalyzed reaction 201–65, 565–92 Pd(II) catalyzed reaction 565–92 propargyl compounds 545–48, 554–55 regioselective hydration 62 alkynyl borones 224 alkynylsilanes, coupling with aryl and alkenyl triflates 225–26 alkynylzinc coupling 221–22 allenes (1,2-dienes) asymmetric synthesis 510 borylsilylation 535 carbon pronucleophiles 527–29 carbonylation 531–32 dimerization 536–37 dimetallation 532–36 Heck reaction 159–69 hydroamination 529–30 hydrometallation 532–36 hydrostannation 532–33 oxidative reactions with Pd(II) compounds 58–61 oxygen nucleophiles 530–31 Pd(0)-catalyzed reactions 525–41 pronucleophiles 527–31 relay switch 251 silylstannation 533–35 allenylindiums 554 allyl acetate 39, 40 allyl alcohols 437 allylation 474 allylamines 437 allylation alcohols 456–58 aldehydes 455, 476–77 allyl alcohols 474

Index amines 460–61 ammonia 462 ammonia surrogates 462–63 asymmetric 443–50 bis-allylic compounds 466–69 carbon nucleophiles 451–56 cross-coupling 477 cycloadditions 466–69 electron-withdrawing groups 451 esters 455 ketones 454 malonates 443–44 nitroalkanes 456 nitrogen nucleophiles 460–66 oxygen nucleophiles 456–60 Pd(0)-catalyzed reactions 438–69 phenols 459 regiochemistry 438–43 stereochemistry 438–43 umpolung 473–76 π-allyl complexes, stoichiometric reactions 54–6 allyl cyanamide 464 allyl groups, protecting groups 490–94 alcohols 491 amines 493 carboxylic acids 491 phenols 492 allyl halides, oxidative addition 10–11 allylic acetates 433 allylic alcohols 436–37 alkene component of Heck reactions 128 carbonylation 479–80 allylic carbonates 434 allylic chlorides, carbonylation 479 allylic compounds, hydrogenolysis 485–90 allylic ethers, aryl halides 128 allylic geminal dicarboxylates 469 allylic metal compounds 471–73 allylic phosphates 433 allylic rearrangement 508–9 allylic termini, enantio-differentiation 445–47 allylindium 475 allyl β-keto carboxylates 503–7 allyl ketones 471 π-allylnickel complexes 431, 433 allyl nitro compounds 437 π-allylpalladium complexes 10–11, 431 π-allylpalladium enolates 500–7 allyl β-keto carboxylates 503–7 enol carbonates 503 silyl enolates 500–2 tin enolates 500–2

645 allylphosphonium salts 535–36 allylsilanes 473, 486 allylstannanes 472, 532 2-allyltetrazoles 463 allyl vinyl ethers, Claisen rearrangement 620 amides acyl chloride carbonylation 266–75 arylation 362–66, 384–86 CO-free methods 274 amines alkenes 41–4 allylation 460–61 arylation 381–83 oxidative carbonylation 86–9 protection as carbamates 493 amino acids arylation 364 asymmetric synthesis 449 2- or 4-amino alken-1-ols 161 amino Heck reaction 169–71 ammonia, allylation 462 ammonia surrogates allylation 462–63 arylation 386–87 ammonium formate, hydrogenolysis 427 amphidinolide 283, 321, 457 anatoxin-a 465 aniline 386, 605 anion capture, termination 134–35 anti attack 438 antibiotics 208 δ-araneosene 501 aromatic compounds alkenes 50–2 homocoupling and oxidative substitution 77–9 aromatic rings cyclization 252–56 regiospecific functionalization 80 aromatics 176–99 α-aryl acetic acid 363 arylalkynes, terminal alkyne reactions 201–31 aryl–alkynyl coupling 203–8 arylamines 373–75 arylarsines 408 arylation active methylene compounds 352–54 alcohols 394–96 aldehydes 359–62 amides 362–66, 384–86 amines 381–83 amino acids 364 ammonia surrogates 386–87

646 arylation (continued ) aromatics 190–99 azoles 181, 384–86 benzene derivatives 192 1H-benzimidazole 183–84 benzofuran 177–79 benzo[b]oxazole 183 benzo[b]thiazole 182–83 benzothiophene 179–80 carbamates 384–86 carbon nucleophiles 351–69 carboxylic acids 363 N,N -dialkylamides 365 diethyl malonate 353 esters 362–66 furan 177–79 heterocycles 177–84, 389–90 imidazole 183–84 imines 387–88 indole 180–82, 387–88 ketones 189–90, 354–59 nitriles 362–66 nitro alkanes 366–67 nitrogen nucleophiles 373–90 oxazole 183 phenols 184–88, 392–93 phosphinates 405–8 phosphine oxides 399–405 phosphines 399–405 phosphonates 405–8 pyrrole 180–82 sulfonamides 384 thiazole 182–83 thiols 397–98 thiophene 179–80 α,β-unsaturated carbonyl compounds 359–62 arylborane coupling 297–303 alkyl halides 303 aryl bromides and iodides 297 aryl chlorides and triflates 298–303 arylboronates, new synthetic methods 290–92 arylboronic acid added to α,β-unsaturated carbonyl compounds 620 aryl bromides arylamine synthesis 374 arylborane coupling 297 Heck reactions 121 aryl chlorides 105–6 arylation 381 arylborane coupling 298–303 facile coupling 289 Heck reactions 121 oxidative step 3

Index Pd(t-Bu3 P)2 2 Sonogashira coupling 203 arylchlorosiletanes 341 aryl cyanides 334 aryldicyclohexylphosphine 300 aryl fluorides 7, 289 aryl halides 108 alcohols with β-carbon elimination 416–27 alkylborane coupling 306–9 alkynes 231–65 allylic ethers 128 arylamine synthesis 374–75 intramolecular attack on carbonyl groups 369–71 potassium alkynyltrifluoroborate coupling 225 Sonogashira coupling 203–4 Sonogashira-type carbonylation 281 unsaturated alcohols 128 aryl iodides arylamine synthesis 374 arylborane coupling 297 ethylene 127 σ -arylpalladium bonds 79, 80 arylphosphines 3 arylpiperazines 373 arylpropiolates 228 arylsilanes coupling 340–41 preparation 339 arylsilanol coupling 344–45 arylstannanes preparation 313–14 coupling 317–19 aryl sulfides 397 aryltriethoxysilanes 339 aryl triflates alkynylsilane coupling 225–26 arylation 381 arylborane coupling 298–303 Heck reactions 122 potassium alkynyltrifluoroborate coupling 225 aryltrifluoroborate salts 292 arylzinc reagent coupling 329–32 arynes addition reactions 595–97 carbostannation 596 cocyclization and cyclotrimerization 592–95 asperlicin 385 AsPh3 114 aurone 281 azaazulene 170 azepine derivatives 559 azetidines 164

Index azide, ammonia surrogate 463 azoles arylation 181, 384–86 vinylation 386 baccatin II 147 benzaldehyde 90 benzannulation, alkynes 583–89 benzene Catellani reaction 411 meta dialkylation 414 benzene derivatives alkynes 583–89 intramolecular arylation 192 1H-benzimidazole, arylation 183–84 benzofuran 177–79, 211, 237 benzonitrile 269 benzo[b]oxazole, arylation 183 benzo[c]phenanthridine alkaloids 193 benzophenone imine, ammonia surrogate 387 benzo[b]thiazole, arylation 182–83 benzothiophene, arylation 179–80 benzyl chlorides, Heck reaction 122 benzylic alcohols 270 benzynes 592–97 addition reactions 595–97 carbonylation 596 cocyclization 592–95 cyclotrimerization 592–95 β-carbon elimination 18–19 alcohols with aryl halides 416–27 β-H elimination 15–17 β-heteroatom elimination 17–18 biarylacetylenes, symmetric and asymmetric 218 biaryls arylboranes with aryl bromides and iodides 297 aryl halides/triflates with aromatic rings 192 oxidative coupling, organometallic compounds 77–8 bicyclopropylidene, Heck reaction 132 bidentate ligands 148, 289 bidentate phosphines 4, 289 BINAP, asymmetric Heck reactions 148 biphenyly(dicyclohexyl)phosphine derivatives, aryl chloride coupling 300 bis-allylic compounds, allylation 466–69 bis-π-allylpalladium compounds 476–79 bis-annulation 33

647 BMim, Sonogashira coupling 206 boronic acids 292, 620 borrelidin 327 borylsilylation alkynes 577 allenes 535 brefeldin A 468 bromodienyne, cyclization 258 3-bromofuran 225 p-bromotoluene, carbonylation 273–74 Br¨onsted acid/base 617 BU3 In 275 bulky Cp ligands 368 bulky monophosphines 289 bulky phosphines 375–81 butadiene cyclization 10 telomerization 519–24 1,4-butanediol 57 butenolides 163, 211 butyl benzoate 267 butyl chloroformate 285 t-butyl group 84 n-butyl nitrite 87 n-butyl oxalate 87 2,6-di-t-butylphenol 187 butyl phenylpropiolate 286 butyl picolinate 267 butyne-1,4-diol derivatives, dicarbonylation 551 Cadiot–Chodkiewicz reaction 226 calicheamicinone 228 calichemicin 208 callipeltodise 324, 459 callystatin A 307 calyculin 332 camptothecin 140, 251–52, 271 capnellene 134, 152 carbamates, arylation 384–86 carbapenems 300, 326, 558 carbazoles 77 multisubstituted 382 carbene ligands 5, 289, 379–80 carbometallation, alkynes 578 carbon–carbon bond formation 1, 288 carbon monoxide 613–14 insertion 13 carbon nucleophiles 20 alkenes 44–5 allylation 451–56 arylation and alkenylation 351–69 carbon pronucleophiles, allenes 527–29 carbonylation 265–88, 479–82 acyl halides 282–86

648 carbonylation (continued ) aldehydes 275–82 alkenes 601–4 alkenyl halides 267 alkenyl iodide 267 alkenyl triflates 267 alkynes 565–66 allenes 531–32 allylic alcohols 479–80 allylic chlorides 479 benzynes 596 p-bromotoluene 273–74 1-iodo-1,4-, 1,5- and 1,6-dienes 277 double 272 esters 286 α-halo ketones 286 halomethyl ketones 286 iodobenzene 273 iodoferrocene 273 2-iodophenol 279 2-iodostyrene 277 ketones 89, 275–82, 481 propargyl compounds 548–51 carbonyl groups intramolecular attack by aryl halides 369–71 tolerance 1 carbopalladation 11, 12 carbostannation, arynes 596 carboxylic acids acyl chloride carbonylation 266–75 alcohol oxidation 90 alkenes 30, 39–41 anhydrides and aldehydes, Heck reactions 123–25 arylation 363 carbonylation 602 protection as allyl esters 491 carilon 603 cascade reactions 13 cassiol 581 Castro reaction 201 catalytic cycle 21–3 catechol, propargyl carbonate 557 Catellani reactions 409–16 cephalotoxine 145 chain-transfer mechanism 603 charcoal 6 chelation, regioselective reactions 79–86 chiral Pd(II) complexes 615–22 chloroanisole 275 chlorobenzene, carbonylation 267 4-chlorobenzofuran 394 chloroformates, 1-alkyne coupling 228 chlorohydrins 35

Index chlorothricolide 305 chuangxinmycin 397 ciguatoxins 270, 309 cinnamaldehydes 127 Claisen rearrangement, allyl vinyl ethers 620 cocyclization, benzynes 592–95 coenzyme Q10 334 1,4-conjugated addition 130–31 conjugated dienes cyclization 10 heteroannular 495–96 homoannular 495–96 Pd(0)-catalyzed reactions 519–25 Pd(II) compounds 56–8 coordinatively saturated complexes 7 Cope rearrangement 269 corticosteroids 72 coumarins 567–69 CP-263,114 70, 511 cross-coupling alkynes 589–91 allylation 477 1-haloalkynes 226–28 main group organometallic compounds 288–351, 469–71 Cs2 CO3 352 cyanoboration, alkynes 578 cyclization aromatic rings 252–56 bromodienye 258 1,6-enynes and 1,7-diynes 578–83 exo, endo 136–37 oxidative 9–10 reductive 10 Sonagashira coupling 211–16 type 1 236–44 type 2 244–48 type 3 249–52 cycloadditions, allylation 466–69 cycloalkenylation 96–7 cyclobutanes 139 cyclobutanols ring-opening 420 tert-cyclobutanols, oxidative rearrangement 91–2 cycloisomerization alkenes 609 alkynes 578–83 cyclopentanone formation 421–23 cyclopentenes 609 cyclophanes 588 cyclopropanation, alkenes 610 cyclopropanes 138, 258, 610 cyclopropyl alcohols, ring-opening 426 cyclopropyl iodide 303

Index cyclotrimerization alkynes 583–84 benzynes 592–95 cystothiazole E 304, 331 decarboxylation–allylation 504–5 decarboxylation–deacetoxylation 505–6 decarboxylation–elimination 505 decarboxylation–hydrogenolysis 506 dehydropalladation 15–17 deprotection 490 diadamantyl-n-butylphosphine 300 N ,N -dialkylamides, arylation 365 dialkyl oxalate 86–7 diarylmethanes 347 diazonamide A 146–47 diazonium salt 119–20, 293 dibenzo[a, g]corannulene 194 1,2-dibromobenzene 361 di(t-butyl)phosphine oxide 300 dicarbonylation, butyne-1,4-diol derivatives 551 Diels-Alder reaction 617–19 dienes carbonylation 277 cyclization–hydrosilylation 606–7 Heck reaction 155–59 see also conjugated dienes diethyl p-anisylphosphonate 405 diethyl malonate, arylation 353 dihydro-2-methylcinnamaldehyde 128 19-nor-1α,25-dihydroxylvitamin D3 305 α-diketones 72 dimerization, allenes 536–37 dimetallation alkynes 576–78 allenes 532–36 methylenecyclopropanes 537–38 1-iodo-2,3-dimethoxybenzene 196 3,3-dimethoxypropionitrile 35–6 N ,N -dimethylbenzamide 274 dimethyl carbonate 86, 88 dimethylglyoxime complex 6 dimethyl pimelate 89 diphenyl carbonate 88 9,10-diphenylphenanthrene 254 2-(diphenylphosphinoethyl)trimethyl ammonium halide 4 1,7-diynes, cyclization 578–83 DMF 274 domino cyclization 147–48, 193, 256 domino reactions 13, 195–96 DPEphos 384 DPPA 436

649 DPPB 4, 267 DPPBA 436 DPPE 4 DPPF 4, 267, 290 DPPP 4 dyenemicin 227 18-electron rule 7 electron-rich phosphines 375–81 electron-withdrawing groups (EWGs) 125–26, 451 electrophilic attack, organopalladium species 19–21 1,4-elimination 494–99 enantiotopic leaving groups 449–50 endo cyclization 136–37 enediyne structures, Sonogashira coupling 208–9 ene reactions 617–19 enol carbonates, π-allylpalladium enolates 503 enone formation, ketones 95–6 enterolactone 427 enyne metathesis 579 enynes cycloisomerization 578–83 haloalkyne coupling 227–28 epothilone 308, 463 eptazocine 152 erythrodiene 483 espermicin 208 esters acyl chloride carbonylation 266–75 allylation 455 arylation 362–66 carbonylation 286 CO-free methods 274 estrone, enantiopure synthesis 140 Et2 B propargyl compounds 553 umpolung 473 1-ethoxybutadienylboronate 304 ethylene, aryl iodide reaction 127 ethyl phenylcarbamate 88 Et3 N 130, 131 Et2 Zn 473, 553 exo cyclization 136–37 ferrocenylphosphine 299 Fischer indole synthesis 387–88 flavones 281, 282 fluoren-9-ones 280 fluoride-free procedures 345–48 fluorination, β-keto esters 617 fluviricin B1 452 Friedel–Craft type reaction 619

650 frondosin 178 fulgide 551 fulvenes 234–35 furans 177–79, 211, 540, 555 furaquinocin 441 galanthamine 459 gambierol 309, 321 GB 13 95 gelsemine 141–42 gibberellin 96 gilvocarcin 193 Glaser coupling 203, 228 glyoxylate 619 Grignard reactions 21–2 Grignard reagents 6 Grignard-type reaction 21, 369–71 guanacastepene 471 gymnocin A 309 halenaquinol 249 halenaquinone 249 halichondrin 458 halides Heck reaction 119–25 homocoupling 428–30 1-haloalkynes, homo-and cross-couplings 226–28 halo dienynes, tricycles 256–60 halo enediynes, tricycles 260–61 α-halo ketones, carbonylation 286 halomethyl ketones carbonylation 286 η2 complexes 9 Heck reaction 23, 109–71 acyl halides 123 additives 114–19 alkenes 125–32 alkenyl chlorides 122 alkenyl triflates 122 allylic alcohols 128 amino 169–71 aryl bromides 121 aryl chlorides 121 aryl triflates 122 asymmetric 148–55 bases 114–19 benzyl chlorides 122 carboxylic acid anhydrides and aldehydes 123–25 catalysts 113–14 diazonium salts 119–20 1,2-dienes 159–69 1,3- and 1,4-dienes 155–59 elemental reactions 111 halides 119–25 heteroaryl 176

Index intermolecular asymmetric 149–50 intramolecular 135–48 intramolecular asymmetric 150–55 ligands 113–14 neopentylpalladium 133–35 nonaflates 123 oximes, amino reactions 169–71 Pd nanoparticles 3 pseudohalides 119–25 quaternary carbon centers 148, 152–55 reaction conditions 114–19 solvents 114–19 tertiary carbon centers 148, 150–52 triflates 122–23 α,β-unsaturated ketones 130–31 variable factors 113 1,6-heptadiene, cycloisomerization 609 Herrmann complex 3, 113 heteroannular conjugated dienes 495–96 heteroaromatics 176–99, 302 heteroaryl Heck reactions 176 heteroarylstannanes, coupling 317–19 heteroatoms, regioselective reactions 79–86 heterocycles arylation 177–84, 389–90 synthetic methods 211 heterocyclic carbenes 289 Hiyama coupling 338–48 advantages and drawbacks 340 alkenylsilanes 341–44 alkenylsilanols 344–45 alkoxysilanes 344–45 arylsilanes 340–41 arylsilanols 344–45 fluoride-free procedures 345–48 homoannular conjugated dienes 495–96 homocoupling alkynes 228, 589–91 aromatic compounds 77–9 1-haloalkynes 226–28 organic halides 428–30 Sonogashira reaction 203, 226–28 homopropargyl alcohols 554 humulene 501 huperzine 466 hydantoins 613 hydrides 8 hydrogenolysis 427–28 hydridopalladium acetate mechanism 580 hydrindane system 490 hydroamination alkenes 605–6

Index alkynes 569–72 allenes 529–30 methylenecyclopropanes 538–41 hydroarylation, alkynes 567–69 hydroboration-coupling protocol 306 hydrocarbometallation, alkynes 566 hydrocarbonation alkynes 569–72 methylenecyclopropanes 538–41 hydrocarboxylation, alkenes 601 hydroesterification alkenes 601 alkynes 565 hydroformylation, alkynes 565 hydrogenolysis 1-alkenes with formates 485–87 allylic compounds 485–90 decarboxylation 506 hydrides 427–28 propargyl compounds 560–62 vinyloxirane 487 hydrogermylation, alkynes 575 hydro-heteroatom addition, alkynes 572–76 hydrometallation alkenes 606–9 alkynes 572–76 allenes 532–36 hydropalladation 11 hydrophosphinylation, alkynes 575 hydrophosphorylation, alkenes 609 hydrosilylation alkenes 606 alkynes 572–73 hydrostannation alkynes 573–74 allenes 532–33 methylenecyclopropanes 537–38 hydrothiolation, alkynes 576 4-hydroxybiphenyl 187 hydroxy groups, tolerance 1 hypericin analog 252 hypoxyxylerone 95 ibuprofen 351, 363 imidazole, arylation 183–84 imidazolidine-2,4-diones 613 imidazoline 613–14 imidazolium salts 5, 383 imidazol-2-ylidenes 5 imines arylation 387–88 intramolecular cyclization with alkynes 591 silyl enol ethers 617 indanone 127

651 indium metal/iodide 474–75 indoles alkaloids 153, 358 arylation 180–82, 387–88 intramolecular cyclization of alkynes with amines 591–92 o-iodoaniline with internal alkynes 238 Sonagashira coupling 211 indolo[2.3-a]carbazole 245 innocent ligands 5 insect repellent 603 insertion 11–13 2-iodoanisole, domino reactions 195–96 iodobenzene, carbonylation 273 iodoferrocene, carbonylation 273 2-iodophenols carbonylation 279 furans 211 o-iodophenols, benzofurans 237 2-iodostyrene, carbonylation 277 isobenzofuran 497 3-isochromanone 270 isocoumarin 238 isocynometrine 76 isoindolo[2.1-a]indole 239 isopropyl methylvinylphosphinate 405 isoquinoline 170 itaconate 505 jasmonoids 446 Jeffery’s ligandless conditions 116–19 ketenes 481–82 β-keto esters carbonylation 286 fluorination 617 ketones acyl halides 283–85 alkenes 32–3 allylation 454 arylation 189–90, 354–59 carbonylation 89, 275–82, 481 enone formation 95–6 methylenecyclopropanes 539 α-β unsaturated, Heck reactions 130–31 Kosugi–Migita–Stille coupling 202, 313–27 alkenylstannanes 320–26 alkylstannanes 326–27 arylstannanes 317–19 heteroarylstannanes 317–19 mechanistic studies 316

652 γ -lactams 76, 157 lactones 40–1, 74–6, 278, 279 Lewis acids 436 ligands 1–6 LiN(TMS)2 386–87 lophotoxin 555 macrolactin A 323 main group metal compounds, propargyl compounds 552–54 main group organometallic compounds cross-coupling 288–351, 469–71 Pd(0)-catalyzed reactions 469–79 maitotoxin 323 malonates, allylation 443–44 malyngolide 448 mannolactam 480 MeCN 238 medermycin 323 Merrifield resin 5 mesembrane 447 meso compounds, enantio-discrimination 444 metal acetylide coupling 219–26 metallocenes, perarylation 368 metal–metal bonds, oxidative addition 8 o-methylbenzaldehyde 80 methyl benzoate 274 methyl benzylacetate 286 methyl 6-chlorohexanoate 89 methylene-π-allylpalladiums, 2,3-alkadienyl derivative reactions 509–11 methylene compounds, arylation 352–54 α-methylene compounds, decarboxylation–deacetoxylation 505–6 methylenecyclododecane 486 methylenecyclopropanes (MCPs) 537–41 dimetallation 537–38 hydroamination 538–41 hydrocarbonation 538–41 hydrostannation 537–38 N-methylindole 619 methyl ketones alkene oxidation 32 CO-free synthesis 279–80 methylmalononitrile 539 methyl nitrite 36 methyl phenylcarbamate 89 methyl phosphinate 405, 407 methyl thioethers 302 Mg acetylides, coupling 220

Index Michael addition 507 migratory insertion 13 Mizoroki–Heck reaction see Heck reaction MKC-242 396 muconate 56 Mukaiyama reaction 616 naphthofuran-2(3H )-one 271 1-naphthol 188 naphthylisoquinoline alkaloid 193 naproxen 270, 351, 363 Negishi coupling 327–35 alkenylzinc reagents 329–32 alkylzinc reagents 332–35 arylzinc reagents 329–32 neopentylpalladium, Heck reaction 133–35 nitrene 614 nitriles, arylation 362–66 nitro alkanes allylation 456 arylation 366–67 nitrogen nucleophiles allylation 460–66 arylation 373–90 nonaflates, Heck reaction 123 norbornene alkyne reaction 251, 255–56 Catellani reactions 409–16 hydrosilylation 606 nostoclide 334 nucleophiles 19–21 alkenylation and arylation 351–400 enantio-differentiation 449 propargyl compounds 544, 555–59 okaramine N 50 oligoenynes 219 organic halides, homocoupling 428–30 organoboron compounds 289–310 alkenylborane coupling 304–6 alkylborane coupling 306–10 arylborane coupling 297–303 preparative methods 289–93 organomagnesium compounds 335–38 organometallic compounds acyl halide coupling 283–84 alkene coupling 52–3 biaryls 77–8 cross-coupling 288–351, 469–71 organosilicon compounds 338–48 alkenylsilanes 341–44 alkenylsilanols 344–45 alkoxysilanes 344–45 arylsilanes 340–41

Index arylsilanols 344–45 fluoride-free procedures 345–48 preparation 338–40 organostannanes 313–27 alkenylstannanes 320–26 alkylstannanes 326–27 arylstannanes 317–19 heteroarylstannanes 317–19 preparation 313–17 organotrifluoroborate salts 292 organozinc compounds 327–35 alkenylzinc coupling 329–32 alkylzinc reagents 332–35 arylzinc reagent coupling 329–32 preparation 327–29 ortho–ortho diarylation 189, 190 ortho-palladation 8 oxaparacyclophanes 585 oxazole arylation 183 2-oxazolidinone 88 oxidation 1 alcohols 90–4 oxidative addition 3, 6–11 oxidative carbonylation alcohols and amines 86–9 alkenes 45–9 alkynes 66–7, 70–1 oxidative cyclization 9–10 oxidative dicarbonylation, alkynes 67 oxidative homocoupling 77 oxidative substitution, aromatic compounds 77–9 oxime derivatives, oxidative addition 9 oximes, amino Heck reactions 169–71 oxygen nucleophiles allenes 530–31 allylation 456–60 P(n-Bu)3 3, 4, 6, 379 P(o-Tol)3 379 P(t-Bu)3 2, 3–4, 299, 376–77, 379 palladacycle mechanism 579 palladacycles 3 palladium on carbon 3, 294 compounds, complexes and ligands 1–6 fundamental reactions 6–24 nanoparticles 3, 294 polymer-based 5 price 1 ratio to ligands 5 recovery and reuse 5–6 toxicity 1 palladium-catalyzed/promoted reactions characteristic features 1 termination 21–3

653 palladium enolates from silyl enol ethers 616 palladium hydrides 8 pallescensin 95 PAMAM 267 pancratistatin 463 parviflorin 268 PCy3 4, 298, 377, 379 Pd(0) complexes 1, 2 reactions 23–4 Pd(II) 1–2 in situ regeneration 27–9 reactions 23–4 Pd(II) hydride 7 Pd(dba)2 2 Pd2 (dba)3 2–3 Pd2 (dba)3 -CHCl3 2 Pd(OAc)2 2, 3, 615–16 Pd(PPh3 )4 2 Pd(t-Bu3 P)2 2 Pd charcoal 266 PdCl2 2 PdCl2 (PPh3 )2 6 PD-imino bond 9 PEG 5, 114–15 PEG-PS 5, 266, 446, 451 pentaarylcyclopentadienes 368 4-pentenyl iodide 286 PEP 266, 446, 451 PET tracers 319 phane derivatives 585 9, 10-disubstituted phenanthrenes 252 phenols alkenes 35–8 allylation 459 arylation 184–88, 392–93 from benzene 79 protection as allyl aryl ethers 492 thiophenols from 398 phenylacetylene 203 phenyl benzoate 266 phenylboronic acid 292 4-phenylfurfural 77 phenylpalladium halides 107 o-phenylphenol 185 2-phenylpyridine 170 2-phenylpyrrole 181 phenyl seleno benzoate 283 (Z)-3-phenylthioacrylate derivative 578 phenyl triflate 275 pheromones 435, 473 phomoiderides 269 phosphinates, arylation 405–8 phosphine mimics 5 phosphine oxides 4 arylation 399–405

654 phosphines 3–4 arylation 399–405 bidentate 4, 289 bulky and electron rich 375–81 innocent/spectator ligands 5 tri(o-tolyl)phosphine 3 phosphine sulfide 46 phosphinooxazolines, asymmetric Heck reactions 148 phosphinous acids 4 phosphites 4 phosphonates, arylation 405–8 picrotoxinin 579–80 pinacol arylboronate 290–92 pinene 54 piperidine 468 polyamines 6 polycyclic compounds 261–63 cyclization of arynes 592–93 domino cyclization 147–48, 256 sequential insertions 13 polyenynes polycyclic compound synthesis 256 termination step in domino cylization 193 polyethylene 5 poly(ethylene glycol) 5, 114–15 polyketones 603–4 polymer-anchored phosphines 6 polymer-base Pd 5 polyoxalate 87 POPd/d1/d2 4 potassium alkynyltrifluoroborate, coupling with aryl halides and triflates 225 potassium organotrifluoroborates 292 PPFA 379 PPF-OMe 379 PPh3 3, 4, 379 preussin 460 prochiral carbonyl surrogates 449–50 pronucleophiles, allenes 527–31 propargyl alcohols 545 acetylene surrogates 218 carbonylation 71, 550 propargyl benzoate 558 propargyl bromide 552 propargyl carbonates 545 carbonylation 548 catechol 557 nucleophiles 555–57 trimethyl silyl cyanide 552 propargyl compounds 543–63 1,2-alkadien-4-ynes 554–55 alkene insertion 545–48 alkynes 545–48, 554–55 carbonylation 548–51

Index classification of reactions 543–45 derivatives 545 elimination 560–62 hydrogenolysis 560–62 main group metal compounds 552–54 nucleophiles 544, 555–59 Sm(II)-mediated reduction 561 SmI2 reduction 561 transmetallation 544 unsaturated bonds to σ -bond 543 propargyl esters 555 propargyl mesylate 552, 553, 558 propiolate coupling 222 propionic acid 363 prosopinine 42 prostaglandin derivative 82 provitamin D 496 pseudoconhydrine 468 pseudohalides 107 Heck reaction 119–25 psilocin 238 psycholeine 153 pumiliotoxin 60, 333 pyrazolo[1,5-f ]phenanthridine 192 pyridines 170 4-pyridylglyoxamide 272 3-pyridylmagnesium chloride 337 2-(3-pyridyl)pyridine 337 pyrimido[4,5-b]indole 192 pyrroles amino Heck reactions 169 arylation 180–82 pyrrolidine 167 quadrigemine C 153 quaternary carbon centers, Heck reaction 148, 152–55 quinolines 170, 239, 581–82 reductive cyclization 10 reductive elimination (coupling) 14–15, 428–30 resorcinol 188 reveromycin B 491 rhopaloic acid 60 roseophilin 452 salicylihalamide A 308 saponaceolide 128 Schiff base 272 scopadulcic acid 145 siccanin 583 silica gel 6 α-silyl aldehyde 473

Index silyl enolates, π-allylpalladium enolates 500–2 silyl enol ethers imines 617 Pd enolates 616 silylstannation, allenes 533–35 Sn acetylides, coupling 223–24 sodium tetralkynylaluminates 225 Sonogashira coupling 201–31 acetylene surrogates 216–19 alkenyl–alkynyl 208–10 alkyne homocoupling 228 aryl–alkynyl 203–8 BMim 206 catalysts 203–8 chloroformates 228 cross-coupling 226–28 cyclization 211–16 homocoupling 203, 226–28 metal acetylides 219–26 reaction conditions 203–8 on resin 206 temperature 204, 205 THF 204 water 205–6 sparteine 91 spectator ligands 5 sphingofungin 332, 450 sphingosine 463 staurosporine aglycone 77 stemodane diterpenes 145 steroid 258, 261, 488, 489, 507 strychnine 131, 142–45, 275, 306, 502 styrene 117, 602, 605, 606, 609 sufinic acid 604 sulfonamides, arylation 384 Suzuki–Miyaura coupling 289–310 advantages 290 alkenylboranes 304–6 alkylboranes 306–10 arylboranes 297–303 bases 295 catalysts 293–96 ligands 295 Pd nanoparticles 3 reaction conditions 293–96 solvents 295 water 295–96 tabersonine 158 tamoxifen 355 tandem reactions 13 TDAE 429 TDMPP 3 Tedicyp 4, 451 teleocidin B4 core 82–3 telomerization 519–24

655 terpenoids with1,5-diene units 334 terphenyls 413 tertiary carbon centers, Heck reaction 148, 150–52 tetracyanoquinodimethane 352 2-acyl-1,4,5,6-tetrahydropyridine 304 tetrahydropyridines 164 tetraponaine 461 tetronomycin 48 THF 57, 204 thiazole, arylation 182–83 thioethers 397 thiols, arylation 397–98 thiophene, arylation 179–80 thiophene dendrimers 318 thiophenols, from phenols 398 thujone 546 tin enolates, π-allylpalladium enolates 500–2 TMC-95A 111, 297 TMPP 4 TMS-acetylene 216, 225 tosyl 300 TPPMS 4 TPPTS 4 transmetallation 13–14, 288–312, 544 triarylphosphine oxides 402 tricholomenyn 210, 224 tricycles halo dienynes 256–60 halo enediynes 260–61 tricyclohexylphosphine 3 triethylammonium formate 560 triflates, Heck reaction 122–23 triisopropylphosphite 4 trimethylsilylacetylene 216, 225 2-(trimethylsilylmethyl)allyl acetate 467 triphenylamine 376 triphenylphosphite 4 TTMPP 3 tuberostemonine 490 tubifoline 447 Ullmann reaction 288, 428–30 umpolung 169, 471–72, 473–76 α,β-unsaturated carbonyl compounds arylation 359–62 arylboronic acid addition 620 decarboxylation–elimination 505 α,β-unsaturated esters 268 α,β-unsaturated ketones, Heck reaction 130–31 uvaricin 458 valienamine 444 vellosimine 360

656 vernolepin 151 Vilsmeier reagent 274 vinyl acetate 30, 39 vinylboronic acid 293, 304 vinylcyclobutanol 91–2, 93 vinyl ethers, Claisen rearrangement 620 vinyl ketene 482 vinyloxirane, hydrogenolysis 487 vinyltin reagent 249, 250 vitamin D 487, 498, 500 Wacker process 5, 19, 27–8 Wadsworth–Emmons reagents 120

Index water alkenes 30, 32–5 Sonagashira coupling 205–6 Suzuki–Miyaura coupling 295–96 xantphos 380, 384 xestocyclamine A 308 xestoquinone 136 zearalenone 320 Zn acetylides, coupling ZnCl2 328 zoanthenol 131

With kind thanks to Christine Boylan for creation of this index.

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